WO2006073365A1 - Non-anilinic derivatives of isothiazol-3(2h)-thione 1,1-dioxides as liver x receptor modulators - Google Patents

Non-anilinic derivatives of isothiazol-3(2h)-thione 1,1-dioxides as liver x receptor modulators Download PDF

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WO2006073365A1
WO2006073365A1 PCT/SE2006/000028 SE2006000028W WO2006073365A1 WO 2006073365 A1 WO2006073365 A1 WO 2006073365A1 SE 2006000028 W SE2006000028 W SE 2006000028W WO 2006073365 A1 WO2006073365 A1 WO 2006073365A1
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het
sir
independently selected
optionally substituted
following independently
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PCT/SE2006/000028
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French (fr)
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Lanna Li
Marianne Swanson
Kay Brickmann
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Astrazeneca Ab
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Priority to EP06700066A priority Critical patent/EP1838684A1/en
Priority to JP2007550338A priority patent/JP2008526843A/en
Priority to US11/813,458 priority patent/US20080319017A2/en
Publication of WO2006073365A1 publication Critical patent/WO2006073365A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to certain novel substituted 4-(amino)isothiazol-3(2H)-thione 1,1-dioxides, to processes for preparing such compounds, to their the utility in modulation of nuclear hormone receptors Liver X Receptor (LXR) ⁇ (NR1 ⁇ 3) and/or ⁇ (NR1H2) and in treating and/or preventing clinical conditions including cardiovascular diseases such as atherosclerosis; inflammatory diseases, Alzheimer's disease, lipid disorders (dyslipidemias) whether or not associated with insulin resistance, type 2 diabetes and other manifestations of the metabolic syndrome, to methods for their therapeutic use and to pharmaceutical compositions containing them.
  • LXR ⁇ and ⁇ use oxysterols as natural ligands. They appear to act as cholesterol sensors with target genes that are required for cholesterol efflux from macrophages, like ATP binding cassette transporter Al (ABCAl) and apoE, as well as gene products, like cholesterol ester transferase protein (CETP) and phospholipid transport protein (PLTP), that are required for the function of high density lipoprotein (HDL) in the reverse cholesterol transport.
  • ABCAl ATP binding cassette transporter Al
  • CETP cholesterol ester transferase protein
  • PLTP phospholipid transport protein
  • HDL high density lipoprotein
  • LXR ligands seem to stimulate the hepatobiliary secretion of cholesterol, a pathway controlled by the ABCG5 and ABCG8.
  • the s-ame cholesterol transporters appear to reduce cholesterol absorption in enterocytes, therefore influencing total body cholesterol balance.
  • LXR ligands GW3965 (Glaxo) and T-0901317 (Tularik) were reported to increase glucose tolerance in fat fed obese mouse, which was interpreted to result from reduced hepatic gluconeogenesis and increased glucose uptake in adipocytes Lafitte BA et al. (Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5419-24). Activation of LXR' s improves glucose tolerance through coordinated regulation of glucose metabolism in liver and adipose tissue.
  • JP2001163786A discloses the synthesis of certain novel 2-(substituted alkyl)-4-(substituent)- 5 ⁇ (sub3tit.uent)isothiazol"3(2H)-one 1,1-dioxides wherein the 4- or 5-posititins are substituted by e.g. ⁇ , lower alky! or carboxyl.
  • MMP matrixmetalloproteirjase
  • MMP-13 matrixmetalloprotemase-13
  • aggrecanase inhibitory activity are useful in the prevention or treatment of arthritis (especially osteoarthritis) and for inhibiting metastasis, infiltration or proliferation of cancer (especially breast cancer).
  • EP1069110A1 discloses the synthesis of certain novel 2-(substituted alkyl)-4-(substituenl)-5 ⁇ (substituent)isothiazol-3(2H)-one 1,1-dioxides wherein the 4- or 5-positions are substituted by e.g. ⁇ , lower alkyl or carboxyl. These compounds are reported to have matrixmetalloproteinase-13 (MMP-13) inhibitory activity and aglycanase inhibitory activity, and are useful for treating arthritic disorders such as reumatoid arthritis.
  • MMP-13 matrixmetalloproteinase-13
  • WO9708143A1 discloses the synthesis of 2-(substituted alkyl)-4-(substituent)-5-
  • WO05/035551 discloses certain novel 2-(substituent)-4-(substituent.)-5- (substituent)isothiazol-3(2H)-one 1,1 dioxide,?. These compounds are reported to modulate the activity of a target protein such as a phosphatase.
  • LXR modulator refers to the ability of a compound to modulate the biological activity of LXR ⁇ and/or LXR ⁇ via increase or decrease of the function and/or expression of LXR ⁇ and/or LXR ⁇ , where LXR ⁇ and/or LXR ⁇ function may include transcription regulatory activity and/or protein-binding. Modulation may occur in vitro or in vivo. Modulation, as described herein, includes antagonism, agonism, partial antagonism and/or partial agonism of a function or characteristic associated with LXR ⁇ and/or LXR ⁇ , either directly or indirectly, and/or the upregulation or downregulation of LXR ⁇ and/or LXR ⁇ expression, either directly or indirectly.
  • LXR modulator either enhances or inhibits the biological activities of LXR via the function and/or expression of LXR. If such a modulator partially or completely enhances the biological activities of LXR via the function and/or expression of LXR, it is a partial or full LXR agonist, respectively. It is the object of the present invention to provide LXR modulators. Another object of this invention is to provide LXR modulator compounds being LXR agonists.
  • the LXR modulator compound must bind to the ligand binding domain of the LXR and recruit either the specific peptide derived from the co-activator protein, SRCl, to the modulator compound-bound LXR complex in the described Co-activator recruitment assay, or one or more of the nuclear hormone receptor co-factors present in the U2OS cell-based method described herein.
  • the compounds of this invention that form an LXR-modulator compound- complex may recruit at least one or more of the other >80 known different nuclear hormone receptor cofactors in any other cell-based method prepared and assayed according to known procedures.
  • LXR modulator compound-complex may also displace co-repressors, such as NcOR, with simultaneous recruitment of a co-activator or may only displace a co-repressor without co-activator recruitment, leading to partial activation of certain LXR regulated genes.
  • Recruiter peptides derived from any of these other nuclear hormone receptor cofactors may be similarly prepared and assayed according to known procedures!.
  • X which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , OR b , SR b , S(O)R b , SO 2 R b , C(O)R b , C(0)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , NR a C(0)NR a R a , or d-C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , OR b , SR b , S(O)R b , SO 2 R b , C(O)R b or NR a C(
  • X which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(0)R b , NR a C(0)R b , C(0)NR a R a , OC(O)R b , C(O)OR a , S0 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , NR a C(O)NR a R a , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , OR b , SR b , S(O)R b , SO 2 R b , C(O)R b or NR a
  • M and Her 3 each optionally is substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NR a R a , OR b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR a R a , OC(O)R b , C(O)OR 3 , SO 2 NR a R a , NR a SO 2 R b , OC(O)NR a R a , NR a C(O)OR b , NR a C(O)NR a R a , Q, QT, Het 1 , HeI 1 T, R, RT, Het 2 , Het 2 T, or C r C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R
  • halogen Cl, F, Br, I
  • OH CN
  • NR a R a OR b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , OC(O)NR a R a , NR a C(O)OE b , NR a C(O)NR a R a , OSO 2 R b , SO 2 NR a C(O)R b , Q, QT, Het 1 , He ⁇ T, R, RT, Het 2 , Het 2 T, or Ci-C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN
  • NR a C(O)OR b OSO 2 R b , SO 2 NR a C(O)R b , NR a C(O)NR a R a , Q, QT, Het 1 , HBt 1 T, R, RT, Het 2 , Het 2 T, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN 1 NR a R a , OR b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a or NR a
  • X denotes a straight or branched, saturated or unsaturated alkyl group having 1 to 6 carbon atoms wherein said alkyl group may optionally be interrupted by O, S, SiR b R b , S(O), SO 2 , C(O), NR a , OC(O), C(O)O, NH a C(0), C(0)NR a , S0 2 NR a or NR a S0 2 . It shall be understood that when X is present more than once in the same compound then the value may be the same or different.
  • Examples of said "X" include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, tert-bntyl, isobutyl, pentyl, hexyl, vinyl, isopropenyl, allyl, but-2- enyl, ethynyl, 2-propynyl, 2-methoxyethyl, 3-methylpropyl, methylthiomethyl, 3- hydroxypropyl, 2-(2-methoxyethoxy)ethyl, 3-(2-methoxyethoxy)propyl, 2,2-dimethylpropyl, 2-hydroxy ethyl, 2,2,2-trifluoroethy ⁇ , 2,3-dihydroxypropyl, 2-cyanoethyl and methyl ethanoylglycinate.
  • Y denotes a straight or branched, saturated or unsaturated alkylene group having 1 to 3 carbon atoms wherein said alkylene group binds to nitrogen in 2-position in the isothiazol-3(2H)-thione 1,1-dioxide and may optionally be interrupted or ended by one of the following: O, S, SiR b R b , S(O), SO 2 , C(O), OC(O), C(O)O, NR C C(O), C(O)NR C , NR C and/or Y is optionally substituted by one or more of the following independently selected from: OH, F, CN, NR a R a , C r C 4 alkyl, 0R b , SR b , SiR b R b R b , S(O)R b or SO 2 R b .
  • Y the term “ended by O, S, SiR b R b , S(O), SO 2 , C(O), OC(O), C(O)O, NR 0 C(O), C(O)NR 0 , NR C " means that the alkylene group has as the last position O, S, SiR b R b , S(O), SO 2 , C(O), OC(O), C(O)O, NR 0 C(O), C(O)NR 0 or NR 0 before it binds further to phenyl, heteroaryl, cycloalkyl or heterocyclyl.
  • Y examples include, but are not limited to, methylene, ethylene, propylene, 2-methylethylene, and 1-methylethylene.
  • Z denotes a straight or branched, saturated or unsaturated alkylene group having 1 to 6 carbon atoms wherein said alkylene group binds to E or Het 4 and one of the following: Q, Het 1 , R or Het 2 , and may optionally be interrupted or ended by one of the following: O, S, SiR b R b , S(O), SO 2 , C(O), OC(O), C(O)O, C(0)CR a , NR 3 C(O), C(0)NR a , NR a , SO 2 NR a , NR a SO 2 , or is one of the following: O, S, SiR b R b , S(O), SO 2 , C(O), OC(O), C(O)O, NR a C(0), C(0)NR a , NR
  • Examples of said "Z" include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, O, S, S(O), SO 2 , C(O), OC(O), C(O)O, C(O)CH 2 , CH 2 C(O), C(O)(C r C 4 alkyl), NHC(O), C(O)NH, NH, SO 2 NH, NHSO 2 , N(C 1 -QaIkVl)C(O), C(O)N(C 1 - C 4 alkyl), N(C 1 -QaIkVl) , SO 2 N(C 1 -QaIkVl), N(C 1 -C 4 alkyl)SO 2 , 1-methylpropylene, 2- methylpropylene and 3-methylpropylene.
  • Z it is to be understood that specific values bind in the order written, i.e. from left to right. For example, when Z is C(O)CH 2 then C(O) in said C(O)CH 2 binds to E or Het 4 and CH 2 in said C(O)CH 2 binds to Q, Het 1 , R or Het 2 .
  • M denotes a saturated or unsaturated non-aromatic monocarbocyclic ring composed of 3, 4, 5, 6, 7 or 8 carbon atoms or a saturated or unsaturated non-aromatic or partly aromatic bicyclic ring system composed of 8, 9 or 10 carbon atoms.
  • M examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctanyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl, cyclooctadienyl, decaline, hydrindane, indane, indene, and bicyclo[4.2.0]octa-l,3,5-triene.
  • E denotes a saturated or unsaturated non-aromatic monocarbocyclic ring composed of 3, 4, 5, 6, 7 or 8 carbon atoms or a saturated or unsaturated non-aromatic or partly aromatic bicyclic ring system composed of 8, 9 or 10 carbon atoms.
  • the ring binds, unless otherwise specified, through its non-aromatic part to nitrogen in 4-position on the isothiazol-3(2H)-thione 1,1-dioxide.
  • E examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctanyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl, cyclooctadienyl, decaline, hydrindane, indane, indene andbicyclo[4.2.0]octa-l,3,5-triene.
  • A denotes an aromatic monocyclic ring composed of 6 carbon atoms or an aromatic bicyclic ring system composed of 10 carbon atoms.
  • Examples of said “A” include, but are not limited to, phenyl, naphtalene and azulene.
  • P denotes a straight or branched, saturated or unsaturated alkylene group having 1 to 6 carbon atoms wherein the alkylene group binds to nitrogen in 4-position on the isothiazol-3(2H)-thione 1,1-dioxide and is optionally interrupted or ended by one of the following: O, NR a , S, SiR b R b , S(O), SO 2 , C(O), OC(O), C(O)O, NR a C(0), C(0)NR a , S0 2 NR a , NR a SO 2 and/or P is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , C(O)R C , 0R b , SR b , SiR 13 RV, S(O)R b , SO 2 R 15 , phenyl, phenylQ-Csalkyl, or CrQalkyl
  • the term "ended by O, NR a , S, SiRV, S(O), SO 2 , C(O), OC(O), C(O)O, NR a C(0), C(0)NR a , S0 2 NR a , NR a SO 2 " means that the alkylene group has as the last position O, NR a , S, SiRV, S(O), SO 2 , C(O), OC(O), C(O)O, NR 2 C(O), C(0)NR a , SO 2 NR 3 or NR a S0 2 " before it binds further to M, Het 3 , A or Het 5 .
  • Examples of said "P” include, but are not limited to, methylene, ethylene, propylene, butylene, ethyleneoxy, propyleneoxy, butyleneoxy, ethyleneamino, ethylenethio, propylenethio, CH 2 C(O)NHCH 2 , CH 2 C(O)O, CH 2 CH 2 C(O)O-CH 2 CH 2 CH 2 C(O)O, CH 2 C(O)OCH 2 , CH 2 C(O)OCH 2 CH 2 , CH 2 CH 2 OCOCH 2 , CH 2 C(O)OCH(CH 3 )CH 2 , 1-methylpropylene, 2-methylpropylene and 3- methylpropylene.
  • Q denotes a saturated or unsaturated non-aromatic monocyclic ring composed of 3, 4, 5, 6, 7 or 8 carbon atoms, which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , phenylQalkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , NR a C(O)NR a R a , or C r C 4 alkyl which is optionally substituted
  • Examples of said "Q" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctanyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl and cyclooctadienyl.
  • R denotes a phenyl group which is optionally substituted by one or more of the following independently selected from: halogen (Cl, F, I, Br), OH, CN, NO 2 , NR a R a , 0R b , SR b , SiR 13 RV, S(O)R b , SO 2 R b , C(O)R b , phenylCialkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR 3 , OC(O)R b , SO 2 NR a R a , NR a S0 2 R b , NR a C(0)0R b , OC(O)NR a R a , OSO 2 R b , NR 3 C(O)NR 3 R 3 , S0 2 NHC(0)R b , or Q-Qalkyl which is optionally substituted by one
  • T denotes methylene or is one of the following: O, NR a , S, SiR b R b , S(O), SO 2 , C(O), OC(O), C(O)O, NR a C(0), C(0)NR a , S0 2 NR a or NR a S0 2 .
  • T binds to M, Her 3 , A or Het 5 and one of the following: Q, Het 1 , R or Het 2 .
  • T examples include; but are not limited to, methylene, O, NR a , S, SiRV, S(O), SO 2 , C(O), OC(O), C(O)O, NR 3 C(O), C(O)NR 3 , SO 2 NR 3 and NR 3 SO 2 .
  • Qalkyl denotes an alkyl group having 1 carbon atom.
  • An example of said alkyl includes, but is not limited to, methyl.
  • Q-Csalkyl denotes a straight or branched, saturated or unsaturated alkyl group having 1 to 3 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, vinyl, isopropenyl, allyl, ethynyl, and 2-pro ⁇ ynyl.
  • CrQalkyl denotes a straight or branched, saturated or unsaturated alkyl group having 1 to 4 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, tert-butyl, vinyl, isopropenyl, allyl, but-2-enyl, ethynyl, 2-propynyl, and but-2-ynyl.
  • halogen denotes fluoro, chloro, bromo and iodo groups.
  • cycloalkyl denotes a saturated or unsaturated non-aromatic monocyclic ring composed of 3, 4, 5, 6, 7 or 8 carbon atoms.
  • examples of said "cycloalkyl” include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctanyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl and cyclooctadienyl.
  • heterocyclyl denotes a saturaced or unsaturated non-aromatic 3, 4, 5, 6, 7 or 8 membered monocyclic ring in which one or more of the atoms in the ring is an element other than carbon independently selected from one or more of for example nitrogen, oxygen or sulfur.
  • sulfur shall be understood to include sulphoxide (S(O)) and sulphone (SO 2 ).
  • nitrogen shall be understood to include nitrogen oxide (NO).
  • heterocyclyl examples include, but are not limited to, aziridine, azetidine, 2- pyrroline, 3- pyrroline, pyrrolidine, imidazoline, piperidine, piperazine, 2-pyrazoline, oxirane, oxetane, tetrahydrofuran, tetrahydropyian, 1,4-dioxaiie, 1,3-dioxolane, 1,2-oxathiolane, morpholine, 3- pyrazoline, pyrazolidine, 2H-pyrane, 4H-pyrane, 1,4-dithiane, 1,4-oxathiane and thiomorpholine.
  • heteroaryl denotes an aromatic 5 or 6 membered monocyclic ring in which one or more of the atoms in the ring is an element other than carbon independently selected from one or more of for example nitrogen, oxygen and sulfur.
  • sulfur shall be understood to include sulphoxide (S(O)) and sulphone (SO 2 ).
  • nitrogen shall be understood to include nitrogen oxide (NO).
  • heteroaryl examples include, but are not limited to, furan, pyrrole, pyrazine, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, pyridine-1-oxide, isoxazole, oxazole, isothiazole, thiazole, thiophene, 1,2,4-triazole, furazane, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,5-thiadiazole, 1,2,4-thiadiazole and 1,2,3-thiadiazole.
  • Het 1 denotes a saturated or unsaturated non-aromatic 3, 4, 5, 6, 7, 8, 9, or 10 membered monocyclic ring in which one or more of the atoms in the ring is an element other than carbon independently selected from one or more of for example nitrogen, oxygen or sulfur, and wherein the ring optionally is substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , phenyldalkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR 3 , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR b ,
  • sulfur shall be understood to include sulphoxide (S(O)) and sulphone (SO 2 ).
  • nitrogen shall be understood to include nitrogen oxide (NO).
  • Et 1 include, but are not limited to aziridine, azetidine, 2- pyrroline, 3-pyrroline, pyrrolidine, imidazoline, piperidine, piperazine, 2-pyrazoline, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, 1,4- dioxane, 1,3-dioxolane, 1,2-oxathiolane, morpholine, 3-pyrazoline, pyrazolidine, 2H-pyrane, 4H-pyrane, 1,4-dithiane, 1,4-oxathiane and thiomorpholine.
  • Het 2 denotes an aromatic 5 or 6 membered monocyclic ring in which one or more of the atoms in the ring is an element other than carbon independently selected from one or more of for example nitrogen, oxygen and sulfur, and which is substituted by one or more of the following independently selected from: halogen (Cl, F, I, Br), OH, CN, NO 2 , NR a R ⁇ 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , phenylCialkyl, C(O)NR 3 R 3 , NR a C(0)R b , C(O)OR 3 , OC(O)R b , SO 2 NR 3 R a , NR a S0 2 R b , NR a C(O)OR b , OC(O)NR 3 R 3 , OSO 2 R b
  • Het 2 examples include, but are not limited to, furan, pyrrole, pyrazine, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, pyridine- 1 -oxide, isoxazole, oxazole, isothiazole, thiazole, thiophene, 1,2,4-triazole, furazane, 1,2,3-oxadiazole, 1,2,4- oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,5-thiadiazole, 1,2,4-thiadiazole and 1,2,3- thiadiazole.
  • Het 3 denotes a saturated or unsaturated non-aromatic 3, 4, 5, 6, 7, 8, 9 or 10 membered monocyclic ring or a saturated or unsaturated non-aromatic or partly aromatic 9 or 10 membered bicyclic ring system in which one or more of the atoms in the monocyclic ring or bicyclic ring system is an element other than carbon independently selected from one or more of for example nitrogen, oxygen or sulfur.
  • sulfur shall be understood to include sulphoxide (S(O)) and sulphone (SO 2 ).
  • nitrogen shall be understood to include nitrogen oxide (NO).
  • Het 3 examples include, but are not limited to aziridine, azetidine, 2- pyrroline, 3-pyrroline, pyrrolidine, imidazoline, piperidine, piperazine, 2- pyrazoline, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, 1,3-dioxolane, 1,2-oxathiolane, morpholine, 3-pyrazoline, pyrazolidine, 2H-pyrane, 4H-pyrane, 1,4-dithiane, 1,4-oxathiane, thiom ⁇ tpholi ⁇ e, indoiine, l,3-dihydro-2-benzofuran, 2,3-dihydro-l- benzofuran, 1,3-benzodioxole, 2;3-dihydro-l,4-benzodioxine, chroman and isochroman
  • Het 4 denotes a saturated or unsaturated non-aromatic 3, 4, 5, 6, 7, 8, 9 or 10 membered monocyclic ring or a saturated or unsaturated non-aromatic or partly aromatic 9 or 10 membered bicyclic ring system in which one or more of the atoms in the monocyclic ring or bicyclic ring system is an element other than carbon independently selected from one or more of for example nitrogen, oxygen or sulfur.
  • sulfur shall be understood to include sulphoxide (S(O)) and sulphone (SO 2 ).
  • nitrogen shall be understood to include nitrogen oxide (NO).
  • the ring binds, unless otherwise specified, through its non- aromatic part to nitrogen in 4-position on the isothiazol-3(2H)-thione 1,1-dioxide.
  • ⁇ et 4 include, but are not limited to, aziridine, azetidine, 2- pyrroline, 3-pyrroline, pyrrolidine, imidazoline, piperidine, piperazine, 2-pyrazoline, oxirane, oxetane, tetrahydrofuran, furan, tetrahydropyran, 1,4-dioxane 1,3-dioxolane, 1,2-oxathiolane, morpholine, 3-pyrazoline, pyrazolidine, isoxazole, 2 ⁇ -pyrane, 4H-pyrane, 1,4-dithiane, 1,4- oxathiane, thiomorpholine, indoiine, l,3-dihydro-2-benzofuran, 2,3-di
  • Het 5 denotes an aromatic 5 or 6 membered monocyclic ring or an aromatic 9 or 10 membered bicyclic ring in which one or more of the atoms in the monocyclic ring or bicyclic ring system is an element other than carbon independently selected from one or more of for example nitrogen, oxygen or sulfur.
  • sulfur shall be understood to include sulphoxide (S(O)) and sulphone (SO 2 ).
  • nitrogen shall be understood to include nitrogen oxide (NO).
  • Het 5 examples include, but are not limited to, furan, pyrrole, pyrazine, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, pyridine-1-oxide, isoxazole, oxazole, isothiazole, thiazole, thiophene, 1,2,4-triazole, furazane, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,5-thiadiazole, 1,2,4-thiadiazole 1,2,3-thiadiazole, benzofuran, isobenzofuran, indole, isoindole, benzothiophene, benzo[c]thiophene, benzimidazole, purine, indazole, benzoxazole, benzisoxazole, bnezthiazole,
  • R a independently represents H or a straight or branched, saturated or unsaturated Q ⁇ alkyl chain optionally substituted by one or more F.
  • R b independently represents a straight or branched, saturated or unsaturated Q-C ⁇ alkyl chain optionally substituted by one or more F.
  • R c independently represents H or a straight or branched, saturated or unsaturated Q-Csalkyl chain optionally substituted by one or more F. . .
  • R a R ⁇ or R c when a substitutent bears more than one of R a , R ⁇ or R c then each of these may be the same or different.
  • NR a R a includes amino, alkylamino and dialkylamino.
  • R b or R c when different substituents in the same compound bear more than one of R a , R b or R c then each of these may be the same or different.
  • R 1 represents
  • X which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , OR b , SR b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , NR a C(O)NR a R a , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , OR b , SR b , S(O)R b , SO 2 R b , C(O)R b or
  • halogen Cl, F, I, Br
  • OH C(O)R b
  • SO 2 R b C(0)R b , C(O)NR 3 R 3 , NR 3 C(O)R", C(O)OR 3 , OC(O)R b , SO 2 NR 3 R 3 , NR a SO 2 R b , NR 3 C(O)OR", OC(O)NR 3 R 3 , OSO 2 R", NR 3 C(O)NR 3 R 3 , SO 2 NHC(O)R", or C r C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR 3 R 3 , 0R b , SR b , 5 S(O)R b , SO 2 R", C(O)R", C(O)NR 3 R 3 R 3 , or C r C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN,
  • NR 3 C(O)NR 3 R 3 SO 2 NHC(O)R b , or CrQalkyl which is optionally substituted by one or more of the following: F, OH, CN, NR 3 R 3 , 0R b , SR b , S(O)R b , SO 2 R 5 , C(O)R b , C(O)NR 3 R 3 , NR a C(O)R b , C(O)OR 3 , 0C(0)R b , NR a SO 2 R b , SO 2 NR a R a , NR a C(O)OR b , OC(O)NR a R a or NR a C(O)NR a R a ; R 3 represents
  • X which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , NR 3 C(O)OR", OC(O)NR a R a , NR a C(O)NR a R a , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , OR b , SR b , S(O)R b , SO 2 R b , C(O)R b or NR
  • R.. RT Het 2 , Het 2 !', or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a or NR a C(0)NR a R ⁇ • and wherein M or Het 3 each optionally is substituted on the aromatic ring by one or more of the following: halogen (Cl, F, Br, I), OH, CN, NR a R a ,
  • R, RT, Het 2 , Het 2 T, or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, , CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , NR a C(0)0R b , OC(O)NR a R a or NR a C(O)NR a R a ; AP or Het 5 P wherein A and Het 5 each optionally is substituted by one or more of the following: halogen (F, Cl, Br, I), OH, CN, NO 2 , NR X
  • NR a C(O)OR b NR a C(0)NR a R a , OSO 2 R b , SO 2 NR a C(O)R b , Q, QZ, Het 1 , HtSt 1 Z, R, RZ, Het 2 ,
  • Het 2 Z, or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH,
  • R 1 represents
  • X which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , or Ci-C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , OR b , SR b , S(O)R b , SO 2 R b or C(O)R b ; cycloalkyl or heterocyclyl each optionally substituted by one or more of the following: F, OH,
  • CN NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , or C r C 4 alkyl which is optionally substituted , by one or more of the following: F, OH, CN, NR a R a , OR b , SR b , S(O)R b , SO 2 R b or C(O)R b ; phenyl or heteroaryl each optionally substituted by one or more of the following: halogen (Cl,
  • cycloalkylY or heterocyclylY wherein cycloalkyl or heterocyclyl each optionally is substituted by one or more of the following: F, OH, CN, NR a R a , OR b , SR b , S(O)R b , SO 2 R b ,
  • C(O)R b or C ⁇ -C 4 alkyl which is optionally substituted by one or more of the following: F, OH,
  • CN NR a R ⁇ 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b ; phenylY or heteroarylY wherein phenyl or heteroaryl each optionally is substituted by one or more of the following: halogen (Cl, F, I, Br), OH, CN, NO 2 , NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(0)R b , or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b ;
  • R 2 represents phenyl which is optionally substituted by one or more of the following: halogen (Cl, F, I, Br), OH, CN, NO 2 , NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , or C r C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , R 3 is the same as in the first group of compounds of formula I.
  • R 1 represents
  • X which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(0)R b , C(O)OR a , OC(O)R b , S0 2 NR a R a ,
  • NR a SO 2 R b NR a C(O)OR b , OC(O)NR a R a , NR a C(O)NR a R a , or d-C 4 alkyl which is optionally substituted by one or more of the following: F, OH 7 CK NR a R ⁇ 0R b , SR b , S(O)R b , SO 2 R b ,
  • R 2 is the same as in the second group of compounds of formula L
  • R 3 is the same as in the first group of compounds of formula I.
  • R 1 represents
  • R 1 is the same as in the first group of compounds of formula I,
  • R 2 is the same as in the first group of compounds of formula I, and
  • R 3 represents
  • X which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(0)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a ,
  • NR a S0 2 R b NR a C(O)OR b , OC(O)NR a R a , NR a C(0)NR a R a , or Ci-C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b ,
  • R is the same as in the first group of compounds of formula I, R is the same as in the first group of compounds of formula I, and R 3 represents
  • M and Het 3 P wherein M and Het 3 each optionally is substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NR a R a , OR b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(0)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , OC(O)NR a R a , NR a C(O)OR b , NR a C(O)NR a R a , Q, QT, Het 1 , Het lr T, R, RT, Het 2 , HeI 2 T, or C r C 4 alkyl which is optionally substituted by one or more of the following: F, OH
  • R 1 is the same as in the first group of compounds of formula I
  • R is the same as in the first group of compounds of formula I
  • R 3 represents
  • E or Het 4 each optionally substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(0)NR a R a , OC(O)R b , C(O)OR 2 , SO 2 NR a R a , NR a SO 2 R b , OC(O)NR a R a , NR a C(O)OR b , NR a C(O)NR a R a , Q, QZ, Het 1 , Hd 1 Z, R, RZ, Het 2 , Het 2 Z, or CrC 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a
  • R 1 is the same as in the second group of compounds of formula I,
  • R 2 is the same as in the second group of compounds of formula I, and
  • R 3 represents .
  • X which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b ,
  • SR b S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(0)NR a R a , OC(O)R b , C(O)OR 3 , SO 2 NR 3 R 3 , NR a S0 2 R b , NR 3 C(0)0R b , 0C(0)NR a R 3 , NR 3 C(O)NR 3 R 3 , or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NR 3 R a , 0R b , SR b , S(O)R b , SO 2 R b ,
  • R 1 is the same as in the second group of compounds of formula I,
  • R 2 is the same as in the second group of compounds of formula I, and
  • R 3 represents
  • M and Het 3 P wherein M and Het 3 each optionally is substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NR 3 R 3 , 0R b , SR b , S(O)R b , SO 2 R b , C(0)R b , NR a C(0)R b , C(O)NR 3 R 3 , OC(O)R b , C(O)OR 3 , SO 2 NR 3 R 3 , NR a SO 2 R b , OC(O)NR 3 R 3 ,
  • NR 3 C(0)0R b , NR 3 C(O)NR 3 R 3 , Q, QT, Het 1 , HeI 1 T, R, RT, Het 2 , Het 2 T, or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NR 3 R 3 , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a or NR a C(O)NR a R a , and wherein M or Het 3 each optionally is substituted on the aromatic ring
  • -C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a or NR a C(O)NR a R a ; AP or Het 5 P wherein A and Het 5 each optionally is substituted by one or more of the following: halogen (F, Cl, Br, I), OH, CN, NO 2 , NR a R a , OR b , SR b , S
  • R 1 is the same as in the second group of compounds of formula I
  • R 2 is the same as in the second group of compounds of formula I
  • R 3 represents
  • E or Het 4 each optionally substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NR a R a , OR b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(0)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , S0 2 NR a R a , NR a SO 2 R b , OC(O)NR a R a , NR a C(O)OR b , NR a C(0)NR a R a , Q, QZ, Het 1 , HeI 1 Z, R, RZ, Het 2 , Het 2 Z, or Q ⁇ alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0
  • R 1 is the same as in the third group of compounds of formula I
  • R 2 is the same as in the third group of compounds of formula I
  • R 3 represents
  • X which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , NR a C(O)NR a R a , or C r C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R
  • R 1 is the same as in the third group of compounds of formula I
  • R 2 is the same as in the third group of compounds of formula I
  • R 3 represents
  • M and Het 3 each optionally is substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(0)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , OC(O)NR a R a , NR a C(O)OR b , NR a C(O)NR a R a , Q, QT, Het 1 , HeI 1 T, R, RT, Het 2 , Het 2 T, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR
  • R 1 is the same as in the third group of compounds of formula I,
  • R 2 is the same as in the third group of compounds of formula I, and R 3 represents
  • E or Het 4 each optionally substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NR a R a , OR b , SR b , S(O)R b , SO 2 R b , C(O)F b , NR a C(O)R b , 0(0)NR a R a ,
  • NR a C(O)OR b NR a C(0)NR a R a , OSO 2 R b , SO 2 NR a C(O)R b , Q, QZ, Het 1 , Het'Z, R, RZ, Het 2 , Het 2 Z, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(0)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a or NR a C(0)NR
  • R 1 is the same as in the fourth group of compounds of formula I
  • R 2 is the same as in the fourth group of compounds of formula I
  • R 3 represents X which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(0)R b , C(O)NR a R a , OC(O)R b , C(O)OR 3 , SO 2 NR a R a , NR a SO 2 R b , NR a C(0)0R b , 0C(0)NR a R 3 , NR a C(O)NR a R a , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R
  • R 1 is the same as in the fourth group of compounds of formula I
  • R 2 is the same as in the fourth group of compounds of formula I
  • R 3 represents
  • M and Het 3 P wherein M and Het 3 each optionally is substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NR a R a , OR b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(0)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , OC(O)NR a R a , NR a C(O)OR b , NR a C(0)NR a R a , Q, QT, Het 1 , HeI 1 T, R, RT, Het 2 , Het 2 T, or C r C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN,
  • R 1 is the same as in the fourth group of compounds of formula I
  • R 2 is the same as in the fourth group of compounds of formula I
  • R 3 represents E or Het 4 each optionally substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NR a R a , OR b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , OC(O)NR a R a , NR a C(O)OR b , NR a C(O)NR a R a , Q, QZ, Het 1 , HCt 1 Z, R, RZ, Het 2 , Het 2
  • NR a C(O)OR b NR a C(0)NR a R a , OSO 2 R b , SO 2 NR a C(O)R b , Q, QZ, Het 1 , HeI 1 Z, R, RZ, Het 2 , Het 2 Z, or CrC 4 alkyl which is optionally substituted by one or more ofthe following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(0)NR a R a , OC(O)R b / C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a or NR a C(O)NR a
  • R 1 represents X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , NR a C(O)NR a R a , or C r C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R ⁇ 0R b , SR b , SiR b
  • R 1 is phenyl or hetercaryl each optionally substituted by one or more of the following independently selected from: halogen (Cl, F, I, Br), OH, CN, NO 2 , NR a R a , 0R b , SR b 5 SiR 13 R 13 R", S(O)R b , SO 2 R b , C(0)R b , C(O)NR a R a , NR a C(0)R b , C(O)OR a , OC(O)R b , S0 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b ,
  • OC(O)NR a R a OSO 2 R b , NR a C(0)NR a R a , SO 2 NHC(O)R b , or C 1 -C 4 ⁇ yI optionally substituted by one or more of the following independently selected from: F, OH, CN, OT ⁇ a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(0)NR a R a , NR a C(O)R b , C(0)0R a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(0)0R b , OC(O)NR a R a or NR a C(O)NR a R a ; or R 1 is cycloalkylY or hetero
  • R 2 represents phenyl which is optionally substituted by one or more of the following independently selected from: halogen (Cl, F, I, Br), OH, CN, NO 2 , NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(0)R b , C(O)NR a R a , NR a C(O)R b ,
  • R 3 represents
  • X which is optionally substituted by one or more of ihe following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR a R a , OC(O)R b , C(O)OR 3 , SO 2 NR a R a ,
  • NR a SO 2 R b NR a C(O)OR b , OC(O)NR a R a , NR a C(0)NR a R a , or C 1 -C 4 aikyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR 13 RV 5 S(O)R", SO 2 R b , C(O)R b or NR a C(O)NR a R a ; or R 3 is MP or Het 3 P wherein M and Het 3 each optionally is substituted on the non- aromatic ring by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)
  • QT, Het 1 , Het lr T, R, RT, Het 2 , Het 2 T, or Q-Qalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a or NR a C(O)NR a R a ; or R 3 is AP or Het 5 P wherein A and Het 5 each optionally is substituted by one
  • R, RT, Het 2 , Het 2 T, or C 1 -C -I aIlCyI which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , NR a C(0)R b , C(O)NR a R a , OC(O)R b , C(0)0R a , ⁇ SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , 0C(0)NR a R a or NR a C(O)NR a R a ; or R 3 is E or Het 4 each optionally substituted on the non-aromatic ring by one or more of the following independently selected from:
  • R 1 represents X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR B , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , NR a C(O)NR a R a , or Q-Qalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R ⁇ 0R b , SR b , SiR b R b R
  • R 1 is cycloalkyl or heterocyclyl each optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a ,
  • NR a C(0)NR a R a or Q-Qalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(0)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a S0 2 R b , NR a C(O)OR b , OC(O)NR a R a or NR a C(0)NR a R a ; or R 1 is phenyl or heteroaryl each optionally substituted by one or more of the following independently selected from: halogen (Cl, F, I, Br), OH, CN
  • R 1 is cycloalkylY or heterocyclylY wherein cycloalkyl or heterocyclyl each optionally is substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a ,
  • NR a SO 2 R b NR a C(O)OR b , OC(O)NR a R a , NR a C(O)NR a R a , or d-C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(0)0R b , OC(O)NR a R a or NR a C(0)NR a R a ; or R 1 is pheny
  • SO 2 NHC(O)R b or C ! -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R 3 , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR 3 R 3 , NR c C(0)R b , C(O)OR 3 , OC(O)R b , SO 2 NR 3 R 3 , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR 3 R 3 or NR 3 C(O)NR 3 R 3 ;
  • R 2 represents phenyl which is optionally substituted by one or more of the following independently selected from: halogen (Cl, F, I, Br), OH, CN, NO 2 , NR a R 3 , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR 3 R 3 , NR a C(0)R b , C(O)OR 3 , OC(O)R 5 , SO 2 NR 3 R 3 , NR a SO 2 R b , NR a C(0)0R b , OC(O)NR 3 R 3 ,
  • X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b ,
  • C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , NR a C(0)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a orNR a C(O)NR a R a , and wherein M or Het 3 each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen (Cl, F, Br, I), OH, CN, NR a R a , 0R
  • R 3 is E or Het 4 each optionally substituted on the non-aromatic ring by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR 1 SO 2 R", OC(O)NR a R a , NR a C(O)OR b ,
  • NR a C(0)NR a R a , Q, QZ, Het 1 , HeI 1 Z, R, RZ, Het 2 , Het 2 Z, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b ,
  • R, RZ, Het 2 , Het 2 Z, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b ,S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a or NR a C(0)NR a R a .
  • R 1 represents X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , or d-C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R ⁇ 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b or C(O)R b ; or R 1 is cycloalkyl or heterocyclyl each optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O
  • C(O)R b or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(0)R b ; or R 1 is phenylY or heteroarylY wherein phenyl or heteroaryl each optionally is substituted by one or more of the following independently selected from: halogen (Cl, F, I, Br), OH, CN, NO 2 , NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(0)R b , or Q-Qalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR
  • R 1 represents
  • X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR 13 RV, S(O)R b ,
  • NR a SO 2 R b NR a C(O)OR b , OC(O)NR a R a , NR a C(O)NR a R a , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b or NR a C(O)NR a R a ,
  • R 2 is the same as for the second embodiment .
  • R J ⁇ s the same as for the first embodiment.
  • R 1 represents X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b ,
  • R 2 is the same as for the second embodiment
  • R 3 is the same as for the first embodiment.
  • R 1 is the same for the first embodiment
  • R 2 is the same as for the first embodiment
  • R 3 represents X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , NR a C(0)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , NR a C(O)NR a R a , or C 1 -QaIkVl which is optionally substituted by one or more of the following independently selected from: F, OH, CN,
  • R 1 is the same as for the first embodiment
  • R 2 is the same as for the first embodiment
  • R 3 represents MP or Het 3 P wherein M and Het 3 each optionally is substituted on the non- aromatic ring by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b ; SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR a R a , OC(O)R b , C(O)OR 3 , SO 2 NR a R a , NR a SO 2 R b , OC(O)NR a R a , NR a C(O)OR b , NR a C(O)NR a R a , Q 5 QT, Het 1 , HCt 1 T,
  • R 3 is AP or Het 5 P wherein A and Het 5 each optionally is substituted by one or more of the following independently selected from: halogen (F, Cl, Br, I), OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , NR a C(0)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , S0 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a or NR a C(O)NR a R a ; or R 3 is AP or Het 5 P wherein A and Het 5 each optionally is substituted by one or more of the following independently selected from: hal
  • NR a C(O)OR b OSO 2 R b , SO 2 NR a C(O)R b , NR a C(0)NR a R a , Q, QT, Het 1 , HeI 1 T, R, RT, Het 2 , Het 2 T, or Ci-C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR 3 R 8 , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a
  • R 1 is the same as for the first embodiment
  • R 2 is the same as for the first embodiment
  • R 3 represents
  • E or Het 4 each optionally substituted on the non-aromatic ring by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b ,
  • NR a C(O)NR a R a Q, QZ, Het 1 , HfJt 1 Z, R, RZ, Het 2 , Het 2 Z, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R h ,
  • R, RZ, Het 2 , Het 2 Z, or C 1 -QaIkVl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(0)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR 3 R 3 , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR 3 R 3 or NR 3 C(O)NR 3 R 3 .
  • R 2 is the same as for the second embodiment, and
  • R 3 represents
  • X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b ,
  • NR a SO 2 R b NR a C(O)OR b , OC(O)NR a R a , NR a C(O)NR a R a , or Q-C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b or NR a C(O)NR a R a .
  • R 1 is the same as for the second -embodiment
  • - R 2 is the same as for the second embodiment
  • R 3 represents
  • M and Het" each optionally is substituted on the non- aromatic ring by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(0)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , OC(O)NR a R a ,
  • NR a C(O)OR b NR a C(O)NR a R ⁇ Q, QT, Het 1 , Het lr T, R, RT, Het 2 , Het 2 T, or C 1 - C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a or NR a C(0)NR a R a
  • R, RT, Het 2 , HeI 2 T, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R ⁇ 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR a R a , OC(O)R b ,
  • R 1 is the same as for the second embodiment
  • R 2 is the same as for the second embodiment, and - ⁇ ⁇ -
  • R 3 represents
  • E or Het 4 each optionally substituted on the non-aromatic ring by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b ,
  • NR a C(0)NR a R a , Q, QZ, Het 1 , HeI 1 Z, R, RZ, Het 2 , Het 2 Z, or C r C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b ,
  • NR a SO 2 R b , NR a C(O)OR b , 0C(0)NR a R a or NR a C(O)NR a R a , and E or Het 4 each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen (F, Cl, Br, I), OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b ,
  • R, RZ, Het 2 , Het 2 Z, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiRVR 13 , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR a R a , OC(O)R b , C(O)OR 3 , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a or NR a C(O)NR a R a .
  • R 1 is the same as for the third embodiment
  • R 2 is the same as for the third embodiment, and R 3 represents
  • X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , NR a C(0)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b 5 NR a C(O)OR b , OC(O)NR a R a , NR a C(O)NR a R a , or Q-Qalkyl which is optionally substituted ' by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R
  • R 1 is the same as for the third embodiment
  • R 2 is the same as for the third embodiment
  • R 3 represents
  • M and Het 3 P wherein M and Het 3 each optionally is substituted on the non- aromatic ring by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , NR a C(0)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , OC(O)NR a R a , NR a C(O)OR b , NR a C(O)NR a R a , Q, QT, Het 1 , Het lr T, R, RT, Het 2 , Het 2 T, or C 1 - C 4 alkyl which is
  • QT, Het 1 , Het lr T, R, RT, Het 2 , Het 2 T, or Q-Qalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a or NR a C(O)NR a R a ; or R 3 is AP or Het 5 P wherein A and Het 5 each optionally is substituted by one
  • R, RT, Het 2 , Het 2 T, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, GN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(0)NR a R ⁇ OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a S0 2 R b , NR a C(O)OR b , 0C(0)NR a R a or NR a C(O)NR a R a .
  • R 1 is the same as for the third embodiment
  • R 2 is the same as for the third embodiment
  • R 3 represents
  • E or Het 4 each optionally substituted on the non-aromatic ring by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(0)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , OC(O)NR a R a , NR a C(O)OR b ,
  • NR a C(O)NR a R a Q, QZ, Het 1 , HeI 1 Z, R, RZ, Het 2 , Het 2 Z, or Q-Qalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR a R a , OC(O)R b , C(O)OR 3 , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a or NR a C(O)NR a R a , and E or Het 4 each optionally is substituted
  • R 1 is the same as for the fourth embodiment
  • R is the same as for the fourth embodiment
  • R 3 represents
  • X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b ,
  • R 1 is the same as for the fourth embodiment
  • R 2 is the same as for the fourth embodiment
  • R 3 represents
  • M and Het 3 P wherein M and Het 3 each optionally is substituted on the non- aromatic ring by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , OC(O)NR a R a , NR a C(O)OR b , NR a C(O)NR a R a , Q, QT, Het 1 , HeI 1 T, R, RT, Het 2 , Het 2 T, or C 1 - C 4 alkyl which is optionally
  • R 3 is AP or Het 5 P wherein A and Het 5 each optionally is substituted by one or more of the following independently selected from: halogen (F, Ci, Br, I), OH, CN, NO 2 , NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , NR a C(0)R b ,
  • R 1 is the same as for the fourth embodiment
  • R is the same as for the fourth embodiment
  • R 3 represents E or Het 4 each optionally substituted on the non-aromatic ring by one or more of the following independently selected from: F, OH, CN, NR a R a , 0R b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR a R a , OC(O)R b , C(O)OR 3 , SO 2 NR a R a , NR a SO 2 R b , OC(O)NR a R a , NR a C(O)OR b , NR a C(O)NR a R a , Q, QZ, Het 1 , HeI 1 Z, R, RZ, Het 2
  • the compounds of formula I have activity as medicaments.
  • the compounds of formula (I) are LXR agonists.
  • Specific compounds of the invention are 4-( ⁇ l-[3-chloro-5-(trifluoromethyl)pyridin-2- yl]piperidin-4-yl ⁇ amino)-2-isopropyl-5-phenylisothiazole-3(2H)-thione 1,1-dioxide and 2- isopropyl-5-phenyl-4-[(4-phenylbutyl)amino]isothiazole-3(2H)-thione 1,1-dioxide or a pharmaceutically acceptable salt thereof.
  • a compound according to formula (V) in which R isopropyl and R is phenyl in which R isopropyl and R is phenyl.
  • Certain compounds of the present invention may exist as tautomers or stereoisomers (e.g. racemate, enantiomer, diastereomer or E- or Z-isomer). It is to be understood that the present invention encompasses all such tautomers or stereoisomers.
  • Certain compounds of the present invention may exist as solvates or hydrates. It is to be understood that the present invention encompasses all such solvates or hydrates.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention. :
  • a suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, nitric, methansulphonic, sulphuric, phosphoric, trifluoroacetic, p ⁇ ra-toluene sulphonic, 2-mesitylen sulphonic, citric, acetic, tartaric, fumaric, lactic, succinic, malic, malonic, maleic, 1,2-ethanedisulphonic, adipic, aspartic, benzenesulphonic, benzoic, ethanesulphonic or nicotinic acid.
  • an inorganic or organic acid for example hydrochloric, hydrobromic, nitric, methansulphonic, sulphuric, phosphoric, trifluoroacetic, p ⁇
  • a suitable pharmaceutically acceptable salt of a compound of the invention is, for example, a base-addition salt of a compound of the invention which is sufficiently acidic, for example, a metal salt, for example, sodium, potassium, calcium, magnesium, zinc or aluminum, an ammonium salt, a salt with an organic base which affords a physiologically acceptable cation, which includes quartenery ammonium hydroxides, for example methylamine, ethylamine, diethylamine, trimethyl amine, tert- butylamine, triethylamine, dibenzylamine, N,N-dibenzylethylamine, cyclohexylethylamine, tris-(2-hydroxyethyl)amine, hydroxyethyl diethylamine, (IR, 2S)-2-hydroxyinden-l-amine, morpholine, N-methylpiperidine, N-ethylpiperidine, piperazine, methylpiperazine, adamantyl
  • the compound of the formula (I), or other compounds disclosed herein, may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the formula (I).
  • pro-drugs include in vivo hydrolysable esters and in vivo hydrolysable amides of a compound of the formula (I).
  • the compounds of the invention may be prepared as outlined in the Schemes below. However, the invention is not limited to these methods.
  • the compounds may also be prepared as described for structurally related compounds in the prior art.
  • the reactions can be carried out according to Standard procedures or as described in the experimental section.
  • reagent means a reagent that can transform the hydroxy group in the compound of formula (V) into a leaving group L.
  • leaving groups are for instance Cl, Br, I, methanesulfonate (OMs) or trifluoromethanesulfonate (OTf).
  • inert organic solvent refers to a solvent which does not react with the starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
  • solvents are for instance dimethylformamide, methylene chloride and acetonitrile.
  • the individual reactions steps in Scheme I may be performed while heating either using conventional means such as heating the reaction mixture on an oil bath, or heating the reaction mixture in a microwave oven.
  • R 1 group in a compound of formula (I) can be replaced by another R 1 group, e.g. cyclopentyl.
  • R 1 when R 1 is tert-bnty ⁇ it can be removed by deprotection with trifluoroacetic acid, and the resulting compound can subsequently be reacted with an alkylating agent containing the new R 1 group.
  • protecting group for functionalities such as for example hydroxyl groups, amino groups, and carboxyl groups.
  • Further representative protecting groups can be found in T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., Wiley and Sons, Inc., New York (1999), which is incorporated hereby by reference in its entirety.
  • R 1 or R 3 represent nitrogen oxides in compounds of formula I these are prepared from the corresponding amines and an oxidizing agent such as metachloropeibenzoic acid (MCPBA) optionally in the presence of an inert organic solvent 5 such as dichloromethane.
  • MCPBA metachloropeibenzoic acid
  • the compounds of the invention will normally be administered via the oral, parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable salt or solvate 0 thereof, or a solvate of such a salt, in a pharmaceutically acceptable dosage form.
  • the compositions may be administered at varying doses. Suitable daily doses of the compounds of the invention in therapeutical treatment of humans are about 0.0001-100 mg/kg body weight, preferably 0.01-10 mg/kg body weight.
  • Oral formulations are preferred particularly tablets or capsules which may be formulated by methods known to those skilled in the art to provide doses of the active compound in the range of 0.007 mg to 700 mg for example 1 mg, 3 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg and 250 mg.
  • a pharmaceutical formulation including any of the compounds of the invention, or pharmaceutically acceptable derivatives thereof, in admixture with pharmaceutically acceptable excipients, oils which may be glycerides, diluents and/or carriers.
  • the compounds of formula (I) are useful for normalization of cholesterol homeostasis, decreasing intestinal cholesterol absorption, improving reverse cholesterol transport, improving HDL functionality, increasing HDL-cholesterbl levels, decreasing LDL-cholesterol levels, decreasing cholesterol content of apoB -containing lipoproteins, stimulating cholesterol efflux from vascular cells and/or decreasing the inflammatory response of vascular cells. As a consequence of these properties the compounds of formula (I) are expected to have anti- atherosclerotic effects.
  • the compounds of formula (I) are useful in the prevention or treatment of cardiovascular disease in a mammal, particularly a human.
  • the compounds of formula (I) are useful in the prevention or treatment of atherosclerosis in a mammal, particularly a human.
  • Cardiovascular disease includes but is not limited to conditions associated with atherosclerosis, arteriosclerosis, hypercholesterolemia, and other kinds of dyslipidemia that increase the risk for cardiovascular disease.
  • the compounds of formula (I) are useful in the treatment or prevention of cardiovascular disease, especially those involving atherosclerosis, hypercholesterolemia and dyslipidemia.
  • the compounds of formula (I) also serve to prevent lipid accumulation in, or remove lipids from, tissue deposits such as atherosclerotic plaques or xanthomas in a patient with atherosclerotic disease manifest by clinical signs such as angina, claudication, Sons, one that has suffered a mycardial infarction, stroke or transient ischemic attack, or one diagnosed by angiography, sonography or MRI.
  • the compounds of formula (I) also serve to prevent or reduce the risk of developing atherosclerosis, as well as for halting or slowing the progression of atherosclerotic disease 5 once it has become clinically evident, comprising the administration of a prophylactically or therapeutically effective amount, as appropriate, of a compound of formula (I) to a mammal, including a human, who is at risk of developing atherosclerosis or who already has atherosclerotic disease.
  • Atherosclerosis encompasses vascular diseases and conditions that are recognized and 0 understood by physicians practicing in the relevant fields of medicine.
  • Atherosclerotic cardiovascular disease including restenosis following revascularization procedures, coronary . heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease including multi-infarct dementia, and peripheral vessel disease including erectile dysfunction are all clinical manifestations of atherosclerosis and are 5 therefore encompassed by the terms "atherosclerosis” and "atherosclerotic disease”.
  • the present compounds of formula (I) are also useful for the prophylaxis and/or treatment of clinical conditions associated with atherosclerosis such as inherited or induced hypercholesterolemia as well as inherited or induced reduced sensitivity to insulin (insulin 0 resistance syndrome also known as metabolic syndrome) and associated metabolic disorders .
  • clinical conditions will include, but will not be limited to, general obesity, abdominal obesity, arterial hypertension, hyperinsulinaemia, type 2 diabetes, type 1 diabetes and other more rare forms of diabetes mellitus and the dyslipidaemia characteristically appearing with insulin resistance.
  • This dyslipidaemia also known as the atherogenic 5 lipoprotein profile, is characterised by moderately elevated non-esterified fatty acids, elevated VLDL triglyceride rich particles, high ApoB levels, low HDL levels associated with low apoAI levels in the presence of small, dense, LDL particles, phenotype B.
  • the compounds of formula (I) are expected to be useful in treating patients with combined or 0 mixed hyperlipidemias and dyslipidemias, especially low HDL levels with or without other manifestations of the metabolic syndrome.
  • the compounds of formula (I) are expected to be useful in treating patients with low HDL levels of other reasons than metabolic syndrome or type 2 diabetes. Treatment with the compounds of formula (I) are expected to lower the cardiovascular morbidity and mortality associated with atherosclerosis due to their antidyslipidaemic as well as antiinflammatory properties.
  • the cardiovascular disease conditions include macro- angiopathies of various internal organs causing myocardial infarction, congestive heart failure, cerebrovascular disease and peripheral arterial insufficiency.
  • the insulin sensitizing effect of the compounds of formula (I) is also expected to prevent or delay the development of type 2 diabetes from the metabolic syndrome .and diabetes of pregnancy. Therefore the development of long-term complications associated with chronic hyperglycaemia in diabetes mellitus such as the micro-angiopathies causing renal disease, retinal damage and peripheral vascular disease of the lower limbs are expected to be delayed.
  • the compounds of formula (I) may also be useful- for the prevention or treatment of inflammation and neurodegenerative diseases or neurological disorders. Accordingly, this invention also provides a method for preventing or. treating inflammation in the CNS, reducing amyloid pathology and a method for preventing or treating neurodegenerative diseases or disorders characterized by neuron degeneration, neuron injury or impaired plasticity or inflammation in the CNS.
  • the neurodegenerative diseases or conditions characterized by neuron degeneration and inflammation will include but will not be limited to stroke, Alzheimer's disease, fronto-temporal dementias (taupathies), peripheral neuropathy, Parkinson's disease, dementia with Lewy bodies, Huntington's disease, amyotrophic lateral sclerosis and multiple sclerosis.
  • the compounds of formula ( ⁇ ) are useful in preventing or treating inflammatory conditions or diseases.
  • diseases or conditions will include but will not be limited to atherosclerotic diseases such as angina pectoris and myocardial infarction but also rheumatoid arthristis, juvenile rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis, degenerative joint disease, one or more connective tissue diseases, ankylosing spondolytis, bursitis, Sjogren's syndrome, psoriasis, psoriatic arthritis, neuraligia, synovitis, glomerulonephritis, vasculitis or sarcoidosis as well as inflammatory bowel diseases such as Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, indeterminant colitis, irritable bowel disorder, irritable
  • Compounds of formula (I) may also be used in other inflammatory conditions of the lung including asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease and pneumonia bronchitis. Furthermore the compounds of formula (I) may be useful in treatment of various conditions outside the cardiovascular system whether or not associated with insulin resistance, like polycystic ovarian syndrome, obesity and cancer.
  • the present invention provides a method of treating and/or preventing rheumatoid arthritis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing juvenile rheumatoid arthritis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing systemic lupus erythematosus comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing osteoarthritis comprising the administration of an effective amount of a compound of formula (I) to a ⁇ mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing degenerative joint disease comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing one or more connective tissue diseases comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing ankylosing spondolytis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing bursitis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing Sjogren's syndrome comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing psoriasis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing psoriatic arthritis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing neuraligia comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing synovitis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing glomerulonephritis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing vasculitis or sarcoidosis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing Coeliac disease comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing proctitis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing eosinopilic gastro- enteritis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing mastocytosis comprising the administration of an effective amount of a compound of formula ( ⁇ ) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing microscopic colitis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing indeterminant colitis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method ⁇ f treating and/or preventing irritable bowel disorder comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing inflammatory bowel disease comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing Crohn's disease comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing ulcerative colitis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing irritable bowel syndrome comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing the insulin resistance syndrome and/or metabolic disorders (as defined above) comprising the administration of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing type 2 diabetes comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing cardiovascular disease comprising the administration of an effective amount of a compound of formula (I) to a - mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing atherosclerosis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing hypercholesterolemia comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing conditions associated with a need for improving reverse cholesterol transport comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing conditions associated with a need for decreasing intestinal cholesterol absorption comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing conditions associated with a need for increasing HDL-cholesterol levels comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • a mammal particularly a human
  • the present invention provides a method of treating and/or preventing conditions associated with a need for decreasing LDL-cholesterol levels comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing inflammatory conditions comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing Alzheimer's disease comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing arteriosclerosis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing conditions associated with a need for improving HDL function comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing hyperlipidemic conditions comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing dyslipidemic conditions comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides a method of treating and/or preventing dyslipidemia comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
  • the present invention provides the use of a compound of formula (I) as a medicament.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of rheumatoid arthritis.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of juvenile rheumatoid arthritis.
  • the present invention provides the use of a compound of formula (I) in the_ manufacture of a medicament for the treatment and/or prohylaxis of systemic lupus erythematosus.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of osteoarthritis.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of degenerative joint disease. In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of one or more connective tissue diseases.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of ankylosing spondolytis.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of bursitis.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of Sjogren's syndrome.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of psoriasis.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of psoriatic arthritis.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of neuraligia.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of synovitis.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of glomerulonephritis.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of vasculitis or sarcoidosis.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of Coeliac disease. In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of proctitis.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of eosinopilic gastroenteritis.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of mastocytosis.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of microscopic colitis.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of indeterminant colitis.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of irritable bowel disorder.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a. medicament for the treatment and/or prohylaxis of inflammatory bowel disease.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of Crohn's disease.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of ulcerative colitis.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of irritable bowel syndrome.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of dyslipidemic conditions. In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of insulin resistance syndrome and/or metabolic disorders.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prophylaxis of cardiovascular disease.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prophylaxis of atherosclerosis.
  • the present invention provided the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prophylaxis of hypercholesterolemia.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prophylaxis of conditions associated with a need for improving reverse cholesterol transport.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prophylaxis of conditions associated with a need for decreasing intestinal cholesterol absorption.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prophylaxis of conditions associated with a need for increasing HDL-cholesterol levels.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prophylaxis of conditions associated with a need for decreasing LDL-cholesterol levels.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prophylaxis of inflammatory conditions. In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prophylaxis of Alzheimer's disease.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prophylaxis of arteriosclerosis.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prophylaxis of type 2 diabetes.
  • the present invention provides the use of a compound of formula (I) in the . manufacture of a medicament for the treatment and/or prophylaxis of conditions associaieo with a need for improving HDL function.
  • the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prophylaxis of hyperlipidemic conditions.
  • the present invention provides the use of a compound of formula (I) in the 0 manufacture of a medicament for the treatment and/or prophylaxis of dyslipidemia.
  • the compounds of the invention may be combined with another therapeutic agent that is useful in the treatment of disorders associated with the development and progress of atherosclerosis such as hypertension, hyperlipidaemias, dyslipidaemias, diabetes, inflammation and obesity.
  • the compounds of the invention may be combined with another therapeutic agent that decreases the ratio of LDL:HDL or an agent that causes a decrease in 0 circulating levels of LDL-cholesterol.
  • the compounds of the invention may also be combined with therapeutic agents used to treat complications related to micro-angiopathies.
  • the compund of formula (I) may be administered in association with cholesterol biosynthesis inhibitors, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • Suitable cholesterol biosynthesis inhibitors include HMG CoA reductase inhibitors, squalene synthesis inhibitors and squalene epoxidase inhibitors.
  • Suitable squalene synthesis inhibitor are squalestatin 1, TAK-475, compounds described in WO2005012284 and a suitable squalene epoxidase inhibitor is NB- 598.
  • the compund of formula (I) may be administrated in association with an HMG CoA reductase inhibitor, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • an HMG CoA reductase inhibitor or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof are statins well known in the art.
  • statins are selected from the group consisting of atorvastatin, fluvastatin, pitavastatin, lovastatin, mevastatin, nicostatin, nivastatin, pravastatin and simvastatin, or a pharmaceutically acceptable salt, especially sodium or calcium, solvate, solvate of such a salt or a prodrug thereof.
  • a particular statin is atorvastatin, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a more particular statin is atorvastatin calcium salt.
  • a particularly preferred statin is, however, rosuvastatin, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a preferable particular statin is rosuvastatin calcium salt.
  • cholesterol biosynthesis inhibitors also includes chemical modifications of the HMG CoA reductase inhibitors, squalene synthesis inhibitors and squalene epoxidase inhibitors, such as esters, prodrugs and metabolites, whether active or inactive.
  • the compund of formula (I) may be administered in association with an inhibitor of the ileal bile acid transport system (IBAT inhibitor), or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • IBAT inhibitor an inhibitor of the ileal bile acid transport system
  • Suitable compounds possessing IBAT inhibitory activity have been described, see for instance the compounds described in WO 93/16055, WO 94/18183, WO 94/18184, WO 96/05188, WO 96/08484, WO 96/16051, WO 97/33882, WO 98/07449, WO 98/03818, WO 98/38182, WO 99/32478, WO 99/35135, WO 98/40375, WO 99/35153, WO 99/64409, WO 99/64410, WO 00/01687, WO 00/47568, WO 00/61568, WO 00/62810, WO 01/68906, DE 19825804, WO 00/38725, WO 00/38726, WO 00/38727, WO 00/38728, WO 00/38729, WO 01/68906, WO 01/66533, WO 02/32428, WO 02/
  • Benzodiazepines and the compounds described in the claims, particularly claim 1, of WO 00/01687, WO 96/08484 and WO 97/33882 are incorporated herein by reference.
  • Other suitable classes of EBAT inhibitors are the 1,2-benzothiazepines, 1,4-benzothiazepines and 1,5-berizothiazepines.
  • a further suitable class of EBAT inhibitors is the 1,2,5- benzothi adi azepines .
  • IBAT inhibitory activity is (3i?,5i?)-3-butyl-3- , ethyl- 1 , 1 -dioxido-5-phenyl-2,3 ,4,5-tetrahydro- 1 ,4-benzothiazepin-8-yl ⁇ -D- glucopyranosiduronic acid (EP 864 582).
  • a further suitable compound possessing EBAT inhibitory activity is S-8921 (EP 597 107).
  • the compund of formula (I) may be administered in association with a cholesterol absorption antagonist , or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, for example AVE-5530 or for example azetidinones such as ezetrol (zetia, ezetimibe) and those described in US 5,767,115 which are 0 incorporated herein by reference.
  • a cholesterol absorption antagonist or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, for example AVE-5530 or for example azetidinones such as ezetrol (zetia, ezetimibe) and those described in US 5,767,115 which are 0 incorporated herein by reference.
  • Suitable compounds possessing cholesterol absorption antagonist activity have been described, see for instance the compounds described in WO 02/50027, WO 02/66464, WO 04/005247, WO 04/000803, WO 04/000804, WO 04/000805, WO05021495, WO05021497 and WO05033100 which are incorporated herein by reference.
  • the compund of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with a bile acid sequestrant or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • Suitable bile acid sequestrants include HBS-107, cholestyramine (Questran ® , LoCholest ® ), cholestemide (Cholebine ® ), colesevelam (Welchol ® ), cholestipol (Colestid ® ) and cosevelam hydrochloride.
  • the compound of formula (I) may be administered in association with other agents that increase reverse cholesterol transport by other means than increasing expression of ABG-transporters, eg. ApoA-1 mimetica.
  • ApoA-1 mimetica include D-F4, ETC 216, ETC 642, RTC 588, ETC 1001, Apo Al Milano, D-4F and AVP-26452. • .
  • the compound of formula (I) may be administered in association with a peroxisome proliferator-activated receptor (PPAR) modulating agent.
  • PPAR modulating agents include a PPAR alpha and/or gamma and/or delta agonist, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • Suitable PPAR alpha'and/or gamma and/or delta agonists, pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof are well known in the art.
  • a PPAR alpha and/or gamma and/or delta agonist refers to muraglitazar (BMS 298585), rivoglitazone (CS-OIl), netoglitazone (MCC-555), balaglitazone (DRF-2593, NN-2344), clofibrate (Atromid-S ® ), fenofibrate, bezafibrate (Oralipin ® ), gemfibrozil (Lopid ® ), ciprofibrate (Ciprol ® ), pioglitazone (Actos ® ), rosiglitazone (Avandia ® ), AVE- 0847, AVE-8134, CLX-0921, DRP-10945, DRF-4832, E-3030, K-Hl, KRP-101, LBM-642 (oxeglitazar), LY-518674, LY-674, naveglitazar (LY
  • a PPAR alpha and/or gamma and/or delta agonist refers to tesaglitazar ((S)-2-ethoxy-3-[4-(2- 5 ⁇ 4-methanesulphonyl-oxyphenyl ⁇ ethoxy)phenyl]propanoic acid) and pharmaceutically acceptable salts thereof.
  • the compound of formula (I) may be administered in 10 association with a pyruvate dehydrogenase kinase (PDK) inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • PDK pyruvate dehydrogenase kinase
  • the compound of formula (I) may be administered in ; i 5 association with a cholesteryl ester transfer protein (CETP) inhibitor, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, for example JTT-705, ⁇ torcetrapib (CP-529414) and those referenced and described in WO 00/38725 page 7 line- 22 - page 10, line 17 which are incorporated herein by reference.
  • CETP cholesteryl ester transfer protein
  • the compound of formula (I) may be administered in association with a microsomal transfer protein (MTP) inhibitor, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, for example implipatide, CP-346086, JTT-130 and those described in WO 03/004020, WO 03/002533, WO 02/083658
  • MTP microsomal transfer protein
  • the compound of formula (I), or a pharmaceutically 30 acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with an agonist to the receptor HM74A (nicotinic acid receptor).
  • HM74A agonists are e g compounds described in WO2005011677, WO2004032928, WO2004033431 or a nicotinic acid derivative, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, including slow release and combination products, for example, nicotinic acid (niacin), acipimox, nicofuranose, NIASPAN® and niceritrol.
  • the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with a acyl coenzymA: cholesterol O-acyltransferase (ACAT) inhibitor, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, for example CS-505, eflucimibe (F-12511), K-604 and SMP-797.
  • ACAT cholesterol O-acyltransferase
  • the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with modulators of nuclear hormone receptors such as farnesoid X receptor (FXR), or pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof for example EMT-747, or modulators of nuclear receptors such as retenoid X receptor (RXR), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • modulators of nuclear hormone receptors such as farnesoid X receptor (FXR), or pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof for example EMT-747
  • modulators of nuclear receptors such as retenoid X receptor (RXR)
  • RXR retenoid X receptor
  • the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with a phytosterol compound, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, for example stands and FM- VP4.
  • the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with other therapies for the treatment of metabolic syndrome or type 2 diabetes and its associated complications, these include biguanide drugs, for example metformin, phenformin and buformin, insulin (synthetic insulin analogues, amylin) and oral antihyperglycemics (these are divided into prandial glucose regulators and alpha-glucosidase inhibitors).
  • An example of an alpha-glucosidase inhibitor is acarbose or voglibose or miglitol.
  • An example of a prandial glucose regulator is repaglinide or nateglinide.
  • the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with a sulfonylurea for example: glimepiride, glibenclamide (glyburide), gliclazide, glipizide, gliquidone, chloropropamide, tolbutamide, acetohexamide, glycopyramide, carbutamide, glibonuride, glisoxepid, glybuthiazole, glibuzole, glyhexamide, glymidine, glypinamide, phenbutamide, tolcylamide and tolazamide.
  • a sulfonylurea for example: glimepiride, glibenclamide (glyburide), gliclazide, glipizide, gliquidone, chloropropamide, tolbutamide, acetohexamide, glycopyramide, carbutamide, glibon
  • the sulfonylurea is glimepiride or glibenclamide (glyburide). More preferably the sulfonylurea is glimepiride. Therefore the present invention includes administration of a compound of the present invention in conjunction with one, two or more existing therapies described in this paragraph.
  • the doses of the other existing therapies for the treatment of type 2 diabetes and its associated complications will be those known in the art and approved for use by regulatory bodies for example the FDA and may be found in the Orange Book published by the EDA. Alternatively smaller doses may be used as a result of the benefits derived from the combination.
  • the compound of formula (I), or a pharmaceutically • acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with an antihypertensive compound for example althiazide, benzthiazide, captopril, carvedilol, chlorothiazide sodium, clonidine hydrochloride, cyciothiazide, delapril hydrochloride, dilevalol hydrochloride, doxazosin mesylate, fosinopril sodium,- guanfaeine hydrochloride, methyidopa, metoprolol succinate, moexipril hydrochloride, monatepil maleate, pelanserin hydrochloride, phenoxybenzemine hydrochloride, prazosin hydrochloride, primidolol, quinapril hydrochloride, quinaprilat, ramipril, terazo
  • the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with an angiotensin converting enzyme (ACE) inhibitor.
  • ACE angiotensin converting enzyme
  • Particular ACE inhibitors or pharmaceutically acceptable salts, solvates, solvate of such salts or prodrugs thereof, including active metabolites, which can be used in combination with a compound of formula (I) include but are not limited to, the following compounds: alacepril, alatriopril, ancovenin, benazepril, benazepril hydrochloride, benazeprilat, benzoylcaptopril, captopril, captopril- cysteine, captopril-glutathione, ceranopril, cilazapril, cilazaprilat, delapril, delapril-diacid, enalapril, enalaprilat,
  • ACE inhibitors are ramipril, ramiprilat, lisinopril, enalapril and enalaprilat. More preferred ACE inhibitors are ramipril and ramiprilat.
  • the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with an angiotensin II receptor antagonist.
  • Preferred angiotensin II receptor antagonists, pharmaceutically acceptable salts, solvates, solvate of such salts or a prodrugs thereof for use in combination with a compound of formula (I) include, but are not limited to, compounds: candesartan, candesartan cilexetil, losartan, valsartan, irbesartan, telmisartan and eprosartan.
  • Particularly preferred angiotensin II receptor antagonists or pharmaceutically acceptable derivatives thereof are candesartan and candesartan cilexetil, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with an andrenergic blocker.
  • Andrenergic blocker include an alpha andrenergic blocker, or a beta andrenergic blocker, or a mixed alpha/beta andrenergic blocker or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • Examples of andrenergic blockers are bretylium tosylate, dihydroergotamine so mesylate, phentolamine mesylate, solypertine tartrate, zolertine hydrochloride, carvedilol, labetalol hydrochloride, fenspiride hydrochloride, labetalol hydrochloride, proroxan, alfuzosin hydrochloride, acebutolol, acebutolol hydrochloride, alprenolol hydrochloride, atenolol, bunolol hydrochloride, carteolol hydrochloride, celiprolol hydrochloride, cetamolol hydrochloride, cicloprolol hydrochloride, dexpropranolol hydrochloride, diacetolol hydrochloride, dilevalol hydrochloride, esmolol hydrochloride, exaprolol hydrochlor
  • the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with an andrenergic stimulant for example combination product of chlorothiazide and methyldopa, the combination product of methyidopa hydrochlorothiazide and methyldopa, clonidine hydrochloride, clonidine, the combination product of chlorthalidone and clonidine hydrochloride and guanfacine hydrochloride, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • an andrenergic stimulant for example combination product of chlorothiazide and methyldopa, the combination product of methyidopa hydrochlorothiazide and methyldopa, clonidine hydrochloride, clonidine, the combination product of chlorthalidone and clonidine hydrochloride and guanfacine
  • the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with calcium channel blocker for example clentiazem maleate, amlodipine besylate, isradipine, nimodipine, felodipine, nilvadipine, nifedipine, teludipine hydrochloride, diltiazem hydrochloride, belfosdil, verapamil hydrochloride or fostedil, or an AT-I blocker, or a saluretic, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • calcium channel blocker for example clentiazem maleate, amlodipine besylate, isradipine, nimodipine, felodipine, nilvadipine, nifedipine, teludipine hydrochloride, diltiaze
  • the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with a diuretic for example the combination product of hydrochlorothiazide and spironolactone and the combination product of hydrochlorothiazide and triamterene, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • a diuretic for example the combination product of hydrochlorothiazide and spironolactone and the combination product of hydrochlorothiazide and triamterene, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with a vasodilator for example coronary vasodilators (for example fostedil, azaclorzine hydrochloride, chromonar hydrochloride, clonitrate, diltiazem hydrochloride, dipyridamole, droprenilamine, erythrityl tetranitrate, isosorbide dinitrate, isosorbide mononitrate, lidoflazine, mioflazine hydrochloride, mixidine, molsidomine, nicorandil, nifedipine, nisoldipine, nitroglycerine, oxprenolol hydrochloride, pentrinitrol, perhexiline maleate, prenylamine, propatyl nitrate, terodiline hydroch
  • the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with a anti-anginal agents for example amlodipine besylate, amlodipine maleate, betaxolol hydrochloride, bevantolol hydrochloride, butoprozine hydrochloride, carvedilol, cinepazet maleate, metoprolol succinate, molsidomine, monatepil maleate, primidolol, ranolazine hydrochoride, tosifen or verapamil hydrochloride or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • a anti-anginal agents for example amlodipine besylate, amlodipine maleate, betaxolol hydrochloride, bevantolol hydrochloride, butoprozine hydrochloride, carvedilol, cinepaze
  • the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with an anti-coagulants selected from argatroban, bivalirudin, dalteparin sodium, desirudin, dicumarol, Iyapolate sodium, nafamostat mesylate, phenprocoumon, tinzaparin sodium and warfarin sodium or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof .
  • an anti-coagulants selected from argatroban, bivalirudin, dalteparin sodium, desirudin, dicumarol, Iyapolate sodium, nafamostat mesylate, phenprocoumon, tinzaparin sodium and warfarin sodium or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof .
  • the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with an antithrombotic agents for example anagrelide hydrochloride, bivalirudin, cilostazol, dalteparin sodium, danaparoid sodium, dazoxiben hydrochloride, efegatran sulfate, enoxaparin sodium* fluretofen, ifetr ⁇ ban, ifetroban sodium, lamifiban, lotrafiban hydrochloride, napsagatran, orbofiban acetate, roxifiban acetate, sibrafiban, tinzaparin sodium, trifenagrel, abciximab and zolimomab aritox or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • an antithrombotic agents for example anagrelide hydrochloride, bival
  • the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with other agents that act as or deliver a Factor Ha agonist for example 3DP-4815, AZD-0837, melagatran, ximelagatran, ART-123, lepirudin, AVE-5026, bivaluridin, dabigatran etexilate, E-4444, odiparcil, ardeparin sodium, pegmusirudin, LB-30870, dermatan sulfate, argatroban, MCC-977, desirudin, deligoparin sodium, PGX-100, idraparinux sodium, SR-123781, SSR-182289A, SCH-530348, TRB50, TGN-167, TGN-255, and compounds described in WO94/29336, WO97/23499 and WO02/44145, which are incorporated
  • the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with a fibrinogen receptor antagonists for example roxifiban acetate, fradafiban, orbofiban, lotraf ⁇ ban hydrochloride, tirofiban, xemilofiban, monoclonal antibody 7E3 and sibrafiban or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • a fibrinogen receptor antagonists for example roxifiban acetate, fradafiban, orbofiban, lotraf ⁇ ban hydrochloride, tirofiban, xemilofiban, monoclonal antibody 7E3 and sibrafiban or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with a platelet inhibitors for example cilostezol, clopidogrel bisulfate, epoprostenol, epoprostenol sodium, ticlopidine hydrochloride, aspirin, ibuprofen, naproxen, sulindae, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone and piroxicam, dipyridamole or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • a platelet inhibitors for example cilostezol, clopidogrel bisulfate, epoprostenol, epoprostenol sodium, ticlopidine hydrochloride, aspirin, ibuprofen, naproxen, sulindae, indom
  • the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with a platelet aggregation inhibitors for example acadesine, beraprost, beraprost sodium, ciprostene calcium, itezigrel, lifarizine, lotrafiban hydrochloride, orbofiban acetate, oxagrelate, fradafiban, orbofiban, tirofiban and xemilofiban or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • a platelet aggregation inhibitors for example acadesine, beraprost, beraprost sodium, ciprostene calcium, itezigrel, lifarizine, lotrafiban hydrochloride, orbofiban acetate, oxagrelate, fradafiban, orbofiban, tirofiban and
  • the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with a hemorrheologic agents for example pentoxifylline or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with lipoprotein associated coagulation inhibitors; or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with a Factor Vila inhibitor or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with a Factor Xa inhibitor or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • the compound of formula (I), or a pharmaceutically acceptable salt or solvate theieof, or a solvate of such a salt may be administered in association with a low molecular weight heparin for example enoxaparin, nardroparin, dalteparin, certroparin, parnaparin, reviparin and tinzaparin or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • a low molecular weight heparin for example enoxaparin, nardroparin, dalteparin, certroparin, parnaparin, reviparin and tinzaparin or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administered in association with an anti-obesity compound, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, for example a pancreatic lipase inhibitor e.g.
  • orlistat EP 129,748
  • ATL-962 ATL-962
  • GT-389255 an appetite (satiety) controlling substance for example sibutramine (Meridia ® , Reductil ® , GB 2,184,122 and US 4,929,629), PYY 3-36 (amylin), APD-356, 1426, Axokine, T-71, a cannabinoid 1 (CBl) antagonist or inverse agonist, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, for example rimonabant (EP 656354), AVE-1625, CP945598, SR-147778, SLV-319, and as described in WOO 1/70700, or a Fatty Acid Synthesis (FAS) inhibitor, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof or a melanin concentrating hormone (MCH) antagonist, or pharmaceutically acceptable salts, solvates, solvates
  • the compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administrated in association with an anti-inflammatory agent such as glucocorticoids, non-steroidal antiinflammatory agents (NSAID) or intestinal anti-inflammatory agents, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • an anti-inflammatory agent such as glucocorticoids, non-steroidal antiinflammatory agents (NSAID) or intestinal anti-inflammatory agents, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • Suitable glucocorticoids will include, but will not be limited to betametason, dexametason, methyl prednisolon, prednisolon, prednison, triamcino ⁇ on, hydrocortison, cortison and budesonid.
  • Suitable nonsteroidal anti-inflammatory agents will include, but will not be limited to indometacin, diclofenac, ibuprofen as well as acetylsalicylic acid.
  • Suitable intestinal anti-inflammatory agents will include, but will not be limited to amino salicylates such as sulfasalazin, mesalazin, olsalazin and balsalazid.
  • the compounds of formula (I); or. a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt may be administrated in association with a cholinesterase inhibitor or an N-methyl-D-aspartate (NMDA) receptor antagonist, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, such as donepezil, rivastigmin or galantamin or memant ⁇ v
  • a method of treating and/or preventing metabolic disorders in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for the treatment and/or prohylaxis of type 2 diabetes and its associated complications in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method of treating and/or preventing hyperlipidemic conditions in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • Tn aa additional featuie of the invention there is provided a method for the treatment and/or prohylaxis of dyslipidemia in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for the treatment and/or prohylaxis of the insulin resistance syndrome in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for the treatment and/or prohylaxis of cardiovascular disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for the treatment and/or prohylaxis of atherosclerosis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for the treatment and/or prohylaxis of hypercholesterolemia in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing conditions associated with a need for improving reverse cholesterol transport in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing conditions associated with a need for decreasing intestinal cholesterol absorption in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing conditions associated with a need for increasing HDL-cholesterol levels in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing conditions associated with a need for decreasing LDL-cholesterol levels in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically - acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug' thereof.
  • a method for the treatment and/or prohylaxis of inflammatory conditions in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for the treatment and/or prohylaxis of Alzheimer's disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for the treatment and/or prohylaxis of arteriosclerosis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a p.-odrug thereof.
  • a method for treating and/or preventing conditions associated with a need for impioving HDL function in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing rheumatoid arthritis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing juvenile rheumatoid arthritis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing systemic lupus erythematosus in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing osteoarthritis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula
  • a method for treating and/or preventing degenerative joint disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing one or more connective tissue diseases in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing ankylosing spondolytis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt, or a prodrug thereof.
  • a method for treating and/or preventing bursitis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration'with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing Sjogren's syndrome in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing psoriasis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or 5 preventing psoriatic arthritis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable 0 salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing neuraligia in a warm-blooded animal, such as man, in need of such treatment comprising administering to said animal an effective amount of a compound of fomr ⁇ la 5 (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the - other compounds described in this combination section, or a pharmaceutically acceptable salt, ' solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or, preventing synovitis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the 5 other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing glomerulonephritis in a warm-blooded animal, such as man, in need of such 0 treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing vasculitis or sarcoidosis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing Coeliac disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt' or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing proctitis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing eosinopilic gastroenteritis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing mastocytosis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing microscopic colitis in a warm-blooded animal, such as man, in need of -:uch treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing indeterminant colitis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing inflammatory bowel disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing Crohn's disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing ulcerative colitis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing irritable bowel syndrome in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt; in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method for treating and/or preventing dyslipidemic conditions in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • kits comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • kits comprising: a) a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in a first unit dosage form; • ⁇ . b) one of the other compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof; in a second unit dosage form; and c) container means for containing said first and second dosage forms.
  • kits comprising: a) a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, together with a pharmaceutically acceptable diluent or carrier, in a first unit dosage form; ' ' ' b) one of the other compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in a second unit dosage form; and c) container means for containing said first and second dosage forms.
  • a compound of the 5 formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of one or more connective tissue diseases in a warm-blooded animal, such as man.
  • a combination treatment comprising the administration of an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, 0 optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration of an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warm-blooded animal, such as man in need of such therapeutic treatment.
  • X which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , OR b , SR b , S(O)R", SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR 3 , OC(O)R b , S0 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , NR a C(0)NR a R a , or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b or NR a C(0)NR
  • R 10 is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , . S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR c C(0)R b , C(O)OR 3 , OC(O)R b r SO 2 NR 3 R 3 , NR a SO 2 R b , NR 3 C(O)OR", OC(O)NR 3 R 3 or NR 3 C(O)NR 3 R 3 ;
  • R 2 represents phenyl which is optionally substituted by one or more of the following: halogen (Cl, F 5 1, B.r),
  • R 3 represents ' ⁇
  • X which is optionally substituted by one or more of the following: F, OH, CN, NR a R ⁇ 0R b ,
  • M and Het 3 P wherein M and Het 3 each optionally is substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NR 3 R 3 , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR 3 R 3 , OC(O)R b , C(O)OR 3 , SO 2 NR a R a , NR a SO 2 R b , OC(O)NR 3 R 3 ,
  • Ci-C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b ,.
  • E represents a saturated or unsaturated non-aromatic monocyclic ring composed of 3, 4, 5, 6, 7 or 8 carbon atoms or a saturated or unsaturated non-aromatic or partly aromatic bicyclic ring composed of 4, 5, 6, 7, 8, 9 or 10 carbon atoms, and the ring binds, unless otherwise specified, through its non-aromatic part to nitrogen in 4-position on the isothiazol-3(2H)-thione 1,1- dioxide;
  • A represents an aromatic monocyclic ring composed of 3, 4, 5, 6, 7 or 8 carbon atoms or an aromatic bicyclic ring composed of 4, 5, 6, 7, 8, 9 or 10 carbon atoms;
  • P binds to nitrogen in 4-position on the isothiazol-3(2H)-thione 1,1-dioxide and represents a straight or branched, saturated or unsaturated alkyl group having 1 to 6 carbon atoms wherein the alkyl group is optionally interrupted or ended by O, NR a , S, S(O), SO 2 , C(O), OC(O), C(O)O, NR 3 C(O), C(O)NR 3 , S0 2 NR a , NR 3 SO 2 and/or P is optionally substituted by one or more of the following: F, OH, CN, NR a R a , C(O)R 0 , 0R b , SR b , S(O)R b , SO 2 R b ,
  • Q represents a saturated or unsaturated non-aromatic monocyclic ring composed of 3, 4, 5, 6, 7, 8 carbon atoms, which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , phenyld alkyl, C(O)NR 3 R 3 , NR a C(0)R b , C(O)OR a , OC(O)R b , SO 2 NR 3 R 3 , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , NR 2 C(O)NR 3 R 3 , or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , OR b , SR
  • T binds to M, Het ⁇ A or Het 1 and represents an alkyl group having 1 carbon atom or optionally consists of one or more of the following: O, NR a , S, S(O), SO 2 , C(O), OC(O), C(O)O, NR 3 C(O), C(0)NR a , SO 2 NR a or NR 3 SO 2 ;
  • Het 1 represents a saturated or unsaturated non-aromatic 3-10 membered monocyclic ring in which one or more of the atoms in the ring is an element other than carbon, for example nitrogen, oxygen or.
  • the ring optionally is substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , phenylQ alkyl, C(0)NR a R ⁇ NR 3 C(0)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(0)0R b , 0C(0)NR a R a , NR a C(O)NR a R a , or C 1 -QaIkVl which is optionally substituted by one or more, of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b ,
  • Het 4 represents a saturated or unsaturated non-aromatic 3-10 membered monocyclic ring or a saturated or unsaturated non-aromatic or partly aromatic 4-10 membered bicyclic ring in which one or more of the atoms in the monocyclic or bicyclic ring is an element other than carbon, for example nitrogen, oxygen or sulfur, and the ring binds, unless otherwise specified, through its non-aromatic part to nitrogen in 4-position on the isothiazol-3(2H)-thione 1,1- dioxide;
  • ⁇ et 5 represents an aromatic 3-10 membered monocyclic ring or an aromatic 4-10 membered bicyclic ring in which one or more of the atoms in the monocyclic or bicyclic ring is an element other than carbon, for example nitrogen, oxygen or sulfur;
  • R a independently represents ⁇ or a straight or branched. saturated or unsaturated C 1 -C 4 alkyl chain optionally substituted by one or more F;
  • R b independently represents a straight or branched, saturated or unsaturated Q-Qalkyl chain optionally substituted by one or more F;
  • R c independently represents ⁇ or a straight or branched, saturated or unsaturated Q-Csalkyl chain optionally substituted by one or more F. . . .
  • R 1 represents
  • X which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , OR b ,
  • SR b S(O)R b , SO 2 R b , C(O)R b , or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , OR b , SR b , S(O)R b , SO 2 R b or C(O)R b ; cycloalkyl or heterocyclyl each optionally substituted by one or more of the following: F, OH,
  • CN NR a R a , OR b , SR b , S(O)R b , SO 2 R b , C(O)R b , or C 1 -QaIkVl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , OR b , SR b , S(O)R b , SO 2 R b or C(O)R b ; phenyl or heteroaryl each optionally substituted by one or more of the following: halogen (Cl, F, I, Br), OH, CN, NO 2 , NR a R a , OR b , SR b , S(O)R b , SO 2 R b , C(O)R b , or Q-Qalkyl optionally substituted by one or more of the following: F, OH, CN, NR a R a , OR b ,
  • cycloalkylY or heterocyclylY wherein cycloalkyl or heterocyclyl each optionally is substituted by one or more of the following: F, OH, CN, NR a R a , OR b , SR b , S(O)R b , SO 2 R b ,
  • CN NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b ; phenylY or heteroarylY wherein phenyl or heteroaryl each optionally is substituted by one or more of the following: halogen (Cl, F, I, Br), OH, CN, NO 2 , NR a R a , 0R b , SR b , S(O)R b ,
  • R 2 represents phenyl which is optionally substituted by one or more of the following: halogen (Cl, F, I, Br),
  • R 1 represents
  • X which is optionally substituted by one or more of the following: F, OH, CN, NR a R ⁇ 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , C(0)NR a R a , NR a C(0)R b , C(O)OR a , OC(O)R b , SO 2 NR a R ⁇ .
  • NR a S0 2 R b NR a C(0)0R b , 0C(0)NR a R a , NR a C(O)NR a R a , or d-C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b ,
  • R 1 represents
  • X which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , or d-C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b or C(0)R b .
  • Further aspect 5 which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b or C(0)R b .
  • R 3 represents X which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , OR b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(0)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , NR a C(O)NR a R a , or d-C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R
  • R 3 represents ⁇ • " ; .-; . MP or Het 3 P wherein M and Het 3 each optionally is substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NR a R a , OR b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR a R a , OC(O)R b , C(O)OR ⁇ SO 2 NR a R a , NR a SO 2 R b , OC(O)NR a R a , NR a C(O)OR b , NR a C(0)NR a R a , Q, QT, Het 1 , Het J T, R, RT, Het 2 , Het 2 T, or Ci-C 4 alkyl which is optionally substituted by one or
  • E or Het 4 each optionally substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NR a R ⁇ 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(O)R b , C(O)NR 3 R 3 , OC(O)R b , C(O)OR 3 , SO 2 NR 3 R 3 , NR a S0 2 R b , OC(O)NR a R a , NR 3 C(O)OR 5 , NR 3 C(O)NR 3 R 3 , Q, QZ, Het 1 , Het'Z, R, RZ, Het 2 , Het 2 Z, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b
  • R represents
  • X which is optionally substituted by one Or more of the following: F, OH, CN, NR 3 R a , 0R b ,
  • NR 3 SO 2 R NR 3 C(0)0R b , OC(O)NR 3 R 3 , NR 3 C(O)NR 3 R 3 , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR 3 R 3 , 0R b , SR b , S(O)R b , SO 2 R b ,
  • E or Het 4 each optionally substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(0)R b , C(O)NR a R a , 0C(0)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , 0C(0)NR a R a , NR a C(O)OR b , NR a C(0)NR a R a , Q, QZ, Het 1 , HeI 1 Z, R, RZ, Het 2 , Het 2 Z, or d-C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a ,
  • R 3 represents
  • -X which is optionally substituted by one or more of the following: F, OH, CN, NR a R ⁇ OR b ,
  • NR a SO 2 R b NR a C(O)OR b , OC(O)NR a R a , NR a C(0)NR a R a , or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b ,
  • M and Het each optionally is substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(0)R b , C(O)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR 3 R 3 , NR 3 SO 2 R 5 , 0C(0)NR a R a , NR a C(O)OR b , NR a C(0)NR a R a , Q, QT, Het 1 , Het 1 !
  • R, RT, Het 2 , Het 2 T, or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NR 3 R 3 , OR b , SR b , S(O)R b , SO 2 R ⁇ C(O)R b , NR a C(0)R b , C(O)NR 3 R 3 , OC(O)R b , C(O)OR 3 , SO 2 NR 3 R 3 , NR a S0 2 R b , NR a C(0)0R b , OC(O)NR 3 R 3 or NR 3 C(O)NR 3 R 3 , and wherein M or Her 3 each optionally is substituted on the aromatic ring by one or more of the following: halogen (Cl, F, Br, I), OH, CN, NR 3 R a , OR b , SR b , S(O)R b ,
  • NR a C(O)OR b OSO 2 R b , SO 2 NR a C(O)R b , NR 3 C(O)NR 3 R 3 , Q, QT, Het 1 , HeI 1 T, R, RT, Het 2 , Het 2 T, or Q ⁇ alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(C)R b , C(O)NR 3 R 3 , OC(O)R b , C(O)OR 3 , SO 2 NR 3 R 3 , NR a SO 2 R b , NR a C(0)0R b , OC(O)NR 3 R 3 or NR a C(0)NR a R 3 .
  • R 3 represents E or Het 4 each optionally substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NR 3 R 3 , 0R b , SR b , S(O)R b , SO 2 R b , C(0)R b , NR a C(0)R b , C(0)NR 3 R a , OC(O)R b , C(O)OR 3 , SO 2 NR 3 R 3 , NR a S0 2 R b , OC(O)NR 3 R 3 , NR a C(O)OR b , NR 3 C(O)NR 3 R 3 , Q, QZ, Het J , Het'z, R, RZ, Het 2 , Het 2 Z, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR 3 R 3 , 0R b ,
  • X which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , OR b , SR b , S(O)R b , SO 2 R b , C(O)R b , NR a C(0)R b , C(0)NR a R a , OC(O)R b , C(O)OR a , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , NR a C(O)NR a R a , or C 1 -QaIkVl which is optionally substituted by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b , SO 2 R b , C(O)R b or NR
  • Furthei aspect 15 A compound according to further aspect 4 or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, wherein R 3 represents
  • M and Her 3 each optionally is substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NR a R a , 0R b , SR b , S(O)R b ; SO 2 R b , C(0)R b , NR a C(0)R b , C(O)NR a R a , OC(O)R b , C(O)OR 3 , S0 2 NR a R a , NR a SO 2 R b , 0C(0)NR a R a , NR a C(0)0R b , NR a C(O)NR a R a , Q, QT, Het 1 , HeI 1 T, R, RT, Het 2 , Het 2 T, or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a
  • Specific compounds of the invention are 4-( ⁇ l-[3-chloro-5- (trifluoromethyl)pyridin-2-yl]piperidin-4-yl ⁇ amino)-2-isopropyl-5-phenylisothiazole-3(2H)- thione 1,1 -dioxide and 2-isopropyl-5-phenyl-4-[(4-phenylbutyl)amino]isothiazole-3(2H)- thione 1,1 -dioxide or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt.
  • R , R and R are as defined in further aspect 1, with Lawesson's reagent optionally in the presence of an inert organic solvent such as toluene.
  • R 3 NH 2 v ⁇ wherein R 3 is as defined in further aspect 1, optionally in the presence of an inert organic solvent such as acetonitrile.
  • a pharmaceutical formulation comprising a compound according to any one of further aspects 1-17 in admixture with pharmaceutically acceptable adjuvants, diluents and/or carriers.
  • Further aspect 36 A method of treating and/or preventing lipid disorders (dyslipidemia) whether or not associated with insulin resistance comprising the administration of a- compound according to any one of further aspects 1-17 to a mammal in need thereof.
  • a method for treatment and/or prophylaxis of cardiovascular disease comprising administering to a mammal, including man, in need of such a treatment an effective amount of a compound as defined in any of further aspects 1-17.
  • a method of treating and/or preventing atherosclerosis comprising.the administration of an effective amount of a compound of formula 1 according to any one of further aspects 1-17 to a mammal in need thereof.
  • a method for treatment and/or prophylaxis of hypercholesterolemia comprising administering to a mammal, including man, in need of such a treatment an effective amount of a compound as defined in any of further aspects' 1-17.
  • Further aspect 40 A method for treatment and/or prophylaxis of conditions associated with a need for improving reverse cholesterol transport comprising administering to a mammal, including man, in need of such a treatment an effective amount of a compound as defined in any of further aspects 1-17.
  • Further aspect 41 A method for treatment and/or prophylaxis of conditions associated with a need for decreasing intestinal cholesterol absorption comprising administering to a mammal, including man, in need of such a treatment an effective amount of a compound as defined in any of further aspects 1-17.
  • a method for treatment and/or prophylaxis of conditions associated with a need for increasing HDL-cholesterol levels comprising administering to a mammal, including man, in need of such a treatment an effective amount of a compound as defined in any of further aspects 1-17.
  • a method for treatment and/or prophylaxis of conditions associated with a need for decreasing LDL- cholesterol levels comprising administering to a mammal, including man, in need of such a treatment an effective amount of a compound as defined in any of further aspects 1-17. ⁇ • .
  • a method for treatment and/or prophylaxis of inflammatory conditions comprising administering to a mammal, including man, in need of such a treatment an ⁇ effective amount of a compound as defined in any of further aspects 1-17.
  • a method for treatment and/or prophylaxis of Alzheimer's disease comprising administering to a mammal, including man, in need of such a treatment an effective amount of a compound as defined in any of further aspects 1-17.
  • a method for treatment and/or prophylaxis of arteriosclerosis comprising administering to a mammal, including man, in need of such a treatment an effective amount of a compound as defined in any of further aspects 1-17.
  • a method for treatment and/or prophylaxis of type 2 diabetes comprising administering to a mammal, including man, in need of such a treatment an effective amount of a compound as defined in any of further aspects 1-17.
  • a method for treatment and/or prophylaxis of conditions associated with a need for improving HDL function comprising administering to a mammal, including man, in need of such a treatment an effective amount of a compound as defined in any of further aspects 1-17.
  • X denotes a straight or branched, saturated or unsaturated alkyl group having 1 to 6 carbon atoms wherein said alkyl group may optionally be interrupted by O, S, S(O), SO 2 , C(O), NR a , OC(O), C(O)O, NR 3 C(O), C(O)NR 3 , SO 2 NR 3 OrNR 3 SO 2 .
  • Y denotes a straight or branched, saturated or unsaturated alkyl group having 1 to 3 carbon atoms wherein said alkyl group binds tc nitrogen in 2-position in the isothiazol- 3(2H)-thione 1,1-dioxide and may optionally be interrupted or ended by O, S, S(O), SO 2 , C(O), OC(O), C(O)O, NR C C(O), C(O)NR C , NR C and/or Y is optionally substituted by one or more of the following: OH, F, CN, NR a R a , d-C 4 alkyl, 0R b , SR b , S(O)R 5 or SO 2 R b .
  • Y the term “ended by O, S, S(O), SO 2 , C(O), OC(O), C(O)O, NR 0 C(O), C(O)NR 0 , NR 0 " means that the alkyl group has as the last position O, S, S(O), SO 2 , C(O), OC(O), C(O)O, NR 0 C(O), C(O)NR 0 or NR 0 before it binds further to phenyl, heteroaryl, cycloalkyl or heterocyclyl.
  • Z denotes a straight or branched, saturated or unsaturated alkyl group having 1 to 6 carbon atoms wherein said alkyl group binds to E or Her 4 and one of the following: Q, Het 1 , R or Het 2 , and may optionally be interrupted or ended by O, S, S(O), SO 2 , C(O), OC(O), C(O)O, NR 3 C(O), C(O)NR 3 , NR 3 , SO 2 NR 3 , NR 3 SO 2 , optionally consists only of one of the following: O, S, S(O), SO 2 , C(O), OC(O), C(O)O, NR 3 C(O), C(O)NR 3 , NR 3 , SO 2 NR 3 , NR a SO 2 and/or Z is optionally substituted by one or more of the following: OH, F, CN, NR°R C , C(O)R 0 , 0R b
  • M denotes a saturated or unsaturated non-aromatic monocyclic ring composed of 3, 4, 5, 6, 7 or 8 carbon atoms or a saturated or unsaturated non-aromatic or partly aromatic bicyclic ring composed of 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • E denotes a saturated or unsaturated non-aromatic monocyclic ring composed of 3, 4, 5, 6, 7 or 8 carbon atoms or a saturated or unsaturated non-aromatic or partly aromatic bicyclic ring composed of 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the ring binds, unless otherwise specified, through its non-aromatic part to nitrogen in 4-position on the isothiazol-3(2H)- thione 1,1-dioxide.
  • A denotes an aromatic monocyclic ring composed of 3, 4, 5, 6, 7 or 8 carbon atoms or ar aromatic bicyclic ring composed of 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • P denotes a straight or branched, saturated or unsaturated alkyl group having 1 to 6 carbon atoms wherein the alkyl group binds to nitrogen in 4-position on the isothiazol- 3(2H)-thione I 5 I -dioxide- and is optionally interrupted or ended by O, NR 3 , S, S(O), SO 2 , C(O), OC(O), C(O)O, NR 3 C(O), C(O)NR 3 , SO 2 NR 3 , NR 3 SO 2 and/or P is optionally substituted by one or more of the following: F, OH, CN, NR a R a , C(O)R C , OR b , SR b , S(O)R b , SO 2 R b , phenyl, phenylQ-Csalkyl, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following: F, OH, CN
  • Q denotes a saturated or unsaturated non-aromatic monocyclic ring composed of 3, 4, 5, 6, 7, 8 carbon atoms, which is optionally substituted by one or more of the following: F, OH, CN, NR 3 R 3 , 0R b , SR b , S(O)R b , SO 2 R b , C(0)R b , phenyld alkyl, C(O)NR 3 R 3 , NR 3 C(0)R b , C(O)OR 3 , OC(O)R b , SO 2 NR a R ⁇ NR a SO 2 R b , NR a C(0)0R b , OC(O)NR 3 R 3 , NR 3 C(O)NR 3 R 3 , or Q ⁇ alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR a R 3 , 0R b , SR b , S(O)
  • Q examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctanyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl and cyclooctadienyl.
  • R denotes a phenyl group which is optionally substituted by one or more of the following: halogen (Cl, F, I, Br), OH, CN, NO 2 , NR a R a , OR b , SR b , S(O)R b , SO 2 R b , C(O)R b , phenyldalkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , 0C(0)NR a R a , OS0 2 R b , NR a C(O)NR a R a , SO 2 NHC(O)R b , or d-C 4 alkyl which is optionally substituted by one or more of the following: hal
  • T denotes an alkyl group having 1 carbon r j;om or optionally consists of one or more of the following: O, NR a , S, S(O), SO 2 , C(O), OC(O), C(O)O, NR 8 C(O), C(0)NR a , SO 2 NR 3 or NR 3 SO 2 .
  • T binds to M, Het 3 , A or Het 5 .
  • C 1 alkyl denotes an alkyl group having 1 carbon atom.
  • An example Of said alkyl includes, but is not limited to, methyl.
  • d-Csalkyl denotes a straight or branched, saturated or unsaturated alkyl group having 1 to 3 carbon atoms.
  • C 1 -C 4 alkyl denotes a straight or branched, saturated or unsaturated alkyl group having 1 to 4 carbon atoms.
  • cycloalkyl denotes a saturated or unsaturated non-aromatic monocyclic ring composed of 3, 4, 5, 6, 7, 8 carbon atoms, and includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctanyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl and cyclooctadienyl.
  • heterocyclyl denotes a saturated or unsaturated non-aromatic 3-8 membered monocyclic ring in which one or more of the atoms in the ring is an element other than carbon, for example nitrogen, oxygen or sulfur.
  • sulfur shall be understood to include sulphoxide (S(O)) and sulphone (SO 2 ).
  • nitrogen shall be understood to include nitrogen oxide (NO).
  • heteroaryl denotes an aromatic 3-8 membered monocyclic ring in which one or more of the atoms in the ring is an element other than carbon, for example nitrogen, oxygen and sulfur.
  • sulfur shall be understood to include sulphoxide (S(O)) and sulphone (SO 2 ).
  • nitrogen shall be understood to include nitrogen oxide (NO).
  • Het 1 denotes a saturated or unsaturated non-aromatic 3-10 membered monocyclic ring in which one or more of the atoms in the ring is an element other than carbon, for example nitrogen, oxygen or sulfur, and wherein the ring optionally is substituted by one or more of the.
  • Het 2 denotes an aromatic 3-10 membered monocyclic ring in which one or more of the atoms in the ring is an element other than carbon, for example nitrogen, oxygen and sulfur, and which is substituted by one or more of the following: halogen (Cl, F, I, Br), OH, CN, NO 2 , NR a R a , OR b , SR b , S(O)R b , SO 2 R b , C(O)R b , phenylQalkyl, C(O)NR a R a , NR a C(0)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(0)0R b , 0C(0)NR a R a , OSO 2 R b , NR a C(0)NR a R a R , SO 2 NHC
  • Het 3 denotes a saturated or unsaturated non-aromatic 3-10 membered monocyclic ring or a saturated or unsaturated non-aromatic or partly aromatic 4-10 membered bicyclic ring in which one or more of the atoms in the monocyclic or bicyclic ring is an element other than carbon, for example nitrogen, oxygen or sulfur.
  • sulfur shall be understood to include sulphoxide (S(O)) and sulphone (SO 2 ).
  • nitrogen shall be understood to include nitrogen oxide (NO).
  • Het 4 denotes a saturated or unsaturated non-aromatic 3-10 membered monocyclic ring or a saturated or unsaturated non-aromatic or partly aromatic 4-10 membered bicyclic ring in which one or more of the atoms in the monocyclic or bicyclic ring is an element other than carbon, for example nitrogen, oxygen or sulfur.
  • sulfur shall be understood to include sulphoxide (S(O)) and sulphone (SO 2 ).
  • nitrogen shall be understood to include nitrogen oxide (NO).
  • the ring binds, unless otherwise specified, through its non- aromatic part to nitrogen in 4-position on the isothiazol-3(2H)-thione 1,1-dioxide.
  • ⁇ et 5 denotes an aromatic 3-10 membered monocyclic ring or an aromatic 4-10 membered bicyclic ring in which one or more of the atoms in the monocyclic or bicyclic ring is an element other than carbon, for example nitrogen, oxygen or sulfur.
  • sulfur shall be understood to include sulphoxide (S(O)) and sulphone (SO 2 ).
  • nitrogen shall be understood to include nitrogen oxide (NO).
  • R a independently represents ⁇ or a straight or branched, saturated or unsaturated Q ⁇ alkyl chain optionally substituted by one or more F.
  • R b independently represents a straight or branched, saturated or unsaturated C 1 -C 4 alkyl chain optionally substituted by one or more F.
  • R c independently represents ⁇ or a straight or branched, saturated or unsaturated C; t -C 3 alkyl chain optionally substituted by one or more F.
  • Flash column chromatography employed normal phase silica gel 60 (0.040-0.063 mm, Merck) or 1ST IsolutedOSPE columns normal phase silica gel or Biotage Horizon HPFC System using silica FLASH+ HPFC Cartridges.
  • HPLC purifications were performed on either a Gilson preparative HPLC system with a UV triggered fraction collector, equipped with an ACE C8 5 ⁇ m 250 mm x 20 mm column, or a Kromasil C18 column, or on a Waters preparative HPLC system equipped with a Kromasil C8 10 ⁇ m 250 mm x 21.2 mm column, or on a Waters preparative HPLC system equipped with an ACE C8 5 ⁇ m 250 mm x 50 mm column or an ACE C8 5 ⁇ m 250 mm x 20 mm column, or on a Waters FractionLynx HPLC system with a mass triggered fraction collector, equipped with a ACE C8 5 ⁇ m 100 mm x 21.2 mm column; using MeCNMH 4 O Ac buffer system with a gradient from 100% mobilphase A (5% MeCN + 95% 0.1 M NH 4 OAc) to 100% mobilphase B (100% MeCN) unless otherwise stated.
  • LBD Ligand Binding Domain
  • SRC-I human Steroid Receptor Co-Activator-1
  • LXRalpha or LXRbeta enhances the affinity of LXR towards SRC-I and thereby brings Eu 3+ and APC in close proximity.
  • Eu 3+ is 10 excited at 337 nm and emitts light at 620 nm. This emission, when in close proximity, excites APC to emit light at 665 nm.
  • the assay mix has the following final concentrations; LXRalpha mix: 0.06 ⁇ g/mL Eu-labelled anti-6x His Ab, 1.15/ ⁇ g/mL Streptavidin APC, 30 nM SRC-I peptide and 0.9 ⁇ g/mL LXRalpha in buffer and LXRbeta mix; 0.06 ⁇ g/mL Eu-labelled anti-6x His Ab, 1.15 ⁇ g/mL Streptavidin APC, 90 nM SRC-I peptide and 0.2 ⁇ g/mL LXRbeta in buffer. Time-resolved fluorescence readings were done in a Wallac Victor reader at 665 nm followed by reading at
  • the LXR ligand, 22-R Hydroxycholesterol or an internal compound at 50 ⁇ M was used as the 100% control.
  • Expression vectors were prepared by inserting the ligand binding domain cDNA 30 (complementary DNA) of human LXRalpha (amino acid 205-447) and LXRbeta (amino acid 216-461) in frame with, 3' to the yeast GAL4 transcription factor DNA binding domain and the nuclear localization signal from the T-antigen of Polyoma Virus in the eucaryotic expression vector pSG5 (Stratagene).
  • the resulting expression vectors pSGGAL-LXRalpha and pSGGAL-LXRbeta were used in cotransfection experiments together with the pGL3 luciferase reporter plasmid containing a minimal S V40 promoter (Promega) and five copies of the UAS GAL4 recognition site.
  • 2.5 ⁇ g pSGGAL-LXRalpha or beta were mixed with 25 ⁇ g pGL3 5xUAS and 22.5 ⁇ g pBluscript (Stratagene) in 0.95 mL ice cold PBS containing approx. 4-9 milj.
  • U2/OS osteosarcoma cells were used in cotransfection experiments together with the pGL3 luciferase reporter plasmid containing a minimal S V40 promoter (Promega) and five copies of the UAS GAL4 recognition site.
  • 2.5 ⁇ g pSGGAL-LXRalpha or beta were mixed with 25 ⁇ g pGL3 5xUAS and
  • the cell/DNA mixture was electroporated in 0.4 cm cuvettes at 960 ⁇ F, 230 V using a BioRad electroporator and diluted to 0.32 milj cells /mL in complete DMEM [Dulbecco's Modified Eagle Medium w/o phenol red, (Gibco 11880-028) including 10% FBS (Foetal Bovine Serum), 1% PEST (Penicillin Streptomycin), 2OmM Hepes, 2mM L-Glutamine and 0.36% Glucose Gibco 31966-021] medium. Cells from at least two electroporations were pooled in order to avoid variations between different electroportations.
  • DMEM Dulbecco's Modified Eagle Medium w/o phenol red, (Gibco 11880-028) including 10% FBS (Foetal Bovine Serum), 1% PEST (Penicillin Streptomycin), 2OmM Hepes, 2mM L-Glutamine and 0.36%
  • Stainless steel beads (Cat. No. 69989, QIAGEN) were added to collection micro tubes, one bead per tube, (Cat. No.19560, QIAGEN), while the tubes were kept on dry ice. Tissues were transferred .to the collection micro tubes after which 750 ⁇ l QIAzol (Cat. No.79306, QIAGEN) was added and then the tubes were placed in a Mixer Mill and homogenized for 2 x 5 minutes at 25 Hz. After homogenization the 96-well plate was centrifuged at 6000 x g for one minute at 4 0 C in a Sigma 4K-15C centrifuge.
  • RNA was eluted in 150 ⁇ l with a concentration of 50- 200ng/ ⁇ l and 10 ⁇ l of this was analyzed by agarose gel electrophoresis ( ⁇ on denaturating 1% TBE gel) to verify RNA quality.
  • cDNA synthesis was performed using the High-Capacity Archive Kit (Cat. No 4322171, Applied Biosystems) according to the manufacturers recommendations, by random primers, in a total reaction volume of 50 ⁇ l/sample.
  • Gene expression mRNA levels were determined by real-time PCR (7500 Real-time PCR system, Applied Biosystems). Taqman universal PCR master mix (Cat.No. 4305719, Applied Biosystems) was used in a 25 ⁇ l reaction containing 40OnM of each target primer, 10OnM of each of the control primers (36B4), 20OnM of the target probe, 10OnM of the control probe (36B4) and 2.5-10ng of sample cDNA. The threshold cycles (Ct) for the endogenous control gene 36B4 and target genes were determined and relative mRNA levels were calculated using the comparative Ct method and expressed as fold induction.
  • SREBPIc Probe 5'-FAM-CAGCTCATCAACAACCAAGACAGTGACTTCC-TAMRA-S', 36B4 Forward; 5 ' -GAGGAATCAGATGAGGATATGGGA-S', 36B4 Reverse; 5'-AAGCAGGCTGACTTGGTTGC-S', 36B4 Probe; 5'-VIC-TCGGTCTCTCGACTAATCCCGCCAA-TAMRA-S'.
  • selectivity values were determined to discriminate between the primary intestinal up regulation of LXR target genes and the unwanted plasma and hepatic TG elevations, respectively.
  • the compounds of formula I have an EC 50 of less than 50 ⁇ mol/1 for LXR ⁇ and/or ⁇ in coactivator recruitment assays and/or reporter gene assays.
  • the compounds of Example 1 and Example 2 have EQo's for LXR ⁇ of 3.1 ⁇ mol/1 and 10.5 ⁇ mol/1 in the reporter gene assay.
  • the compounds of the present invention exhibit favourable pharmacological effects in vivo.
  • the compounds of the present invention also has a promising toxicological profile

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Abstract

The present invention relates to certain novel compounds of the formula (I) to processes for preparing such compounds, to their the utility in modulation of nuclear hormone receptors Liver X Receptor (LXR) α (NR1H3) and/or β (NR1H2) and in treating and/or preventing clinical conditions including cardiovascular diseases such as atherosclerosis; inflammatory diseases, Alzheimer's disease, lipid disorders (dyslipidemias) whether or not associated with insulin resistance, type 2 diabetes and other manifestations of the metabolic syndrome, to methods for their therapeutic use and to pharmaceutical compositions containing them.

Description

NON-ANILINIC DERIV ATIVES OF ISOTHIAZOL-3f2HVTHIONE 1.1 -DIOXIDES AS LIVER X RECEPTOR MODULATORS
Field of the invention
The present invention relates to certain novel substituted 4-(amino)isothiazol-3(2H)-thione 1,1-dioxides, to processes for preparing such compounds, to their the utility in modulation of nuclear hormone receptors Liver X Receptor (LXR) α (NR1Η3) and/or β (NR1H2) and in treating and/or preventing clinical conditions including cardiovascular diseases such as atherosclerosis; inflammatory diseases, Alzheimer's disease, lipid disorders (dyslipidemias) whether or not associated with insulin resistance, type 2 diabetes and other manifestations of the metabolic syndrome, to methods for their therapeutic use and to pharmaceutical compositions containing them.
Background of the invention
Abnormalities of cholesterol and fatty acid homeostasis, that are reflected as diverse dyslipidemias, are causal of atherosclerosis and consequently cardiovascular disease (CVD). This disease is one of the major health problems in industrialized countries and is reaching the same prevalence in adults in developing nations. Most studies show that statins reduce low density lipoproteins (LDL) cholesterol by 25-30% and the relative risk of coronary events by approximately 30%. While this beneficial effect is significant, effectively 70% of the treated cohort remains with unchanged risk. This has prompted intense research in order to identify other common abnormalities of lipid metabolism that if efficiently treated could improve the results of current CVD therapy.
The nuclear hormone receptors LXR α and β use oxysterols as natural ligands. They appear to act as cholesterol sensors with target genes that are required for cholesterol efflux from macrophages, like ATP binding cassette transporter Al (ABCAl) and apoE, as well as gene products, like cholesterol ester transferase protein (CETP) and phospholipid transport protein (PLTP), that are required for the function of high density lipoprotein (HDL) in the reverse cholesterol transport. In the liver, LXR ligands seem to stimulate the hepatobiliary secretion of cholesterol, a pathway controlled by the ABCG5 and ABCG8. The s-ame cholesterol transporters appear to reduce cholesterol absorption in enterocytes, therefore influencing total body cholesterol balance. These effects of LXR stimulation could help to explain its remarkable anti-atherosclerotic properties observed in animal models.
Recently the synthetic LXR ligands GW3965 (Glaxo) and T-0901317 (Tularik) were reported to increase glucose tolerance in fat fed obese mouse, which was interpreted to result from reduced hepatic gluconeogenesis and increased glucose uptake in adipocytes Lafitte BA et al. (Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5419-24). Activation of LXR' s improves glucose tolerance through coordinated regulation of glucose metabolism in liver and adipose tissue.
JP2001163786A discloses the synthesis of certain novel 2-(substituted alkyl)-4-(substituent)- 5~(sub3tit.uent)isothiazol"3(2H)-one 1,1-dioxides wherein the 4- or 5-posititins are substituted by e.g. Η, lower alky! or carboxyl. These compounds are reported to have matrixmetalloproteirjase (MMP) inhibitory activity (especially matrixmetalloprotemase-13 (MMP-13) inhibitory activity) and aggrecanase inhibitory activity, and are useful in the prevention or treatment of arthritis (especially osteoarthritis) and for inhibiting metastasis, infiltration or proliferation of cancer (especially breast cancer).
EP1069110A1 discloses the synthesis of certain novel 2-(substituted alkyl)-4-(substituenl)-5~ (substituent)isothiazol-3(2H)-one 1,1-dioxides wherein the 4- or 5-positions are substituted by e.g. Η, lower alkyl or carboxyl. These compounds are reported to have matrixmetalloproteinase-13 (MMP-13) inhibitory activity and aglycanase inhibitory activity, and are useful for treating arthritic disorders such as reumatoid arthritis.
WO9708143A1 discloses the synthesis of 2-(substituted alkyl)-4-(substituent)-5-
(substituent)isothiazol-3(2H)-one 1,1-dioxides wherein the substituents in 4- or 5-positions are selectioned from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, carbamoyl substituted with an alkyl of 1 to 3 carbon atoms, acetoxy, carboxy, hydroxy, amino, amino substituted with an alkyl of 1 to 3 carbon atoms, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or halo, or the 4 and/or 5 positions are unsubstituted, and their use for reducing levels of Tumor Necrosis Factor (TNF ) in mammals. In the application WO05/005417 it is disclosed that certain novel l-(substituted alkyl)-3 amino-4 phenyl- lH-pyrrole-2,5-dione derivatives have utility in the modulation of nuclear hormone receptors Liver X Receptor (LXR) α (NR1Η3) and/or β (NR1H2) and in treating and/or preventing clinical conditions including cardiovascular diseases.
In the application WO05/005416 it is disclosed that certain novel 5-thioxo-l,5-dihydro-2H- pyrrol-2-one and lH-pyrrole-2,5-dithione derivatives have utility in the modulation of nuclear hormone receptors Liver X Receptor (LXR) α (NR1Η3) and/or β (NR1H2) and in treating and/or preventing clinical conditions including cardiovascular diseases.
WO05/035551 discloses certain novel 2-(substituent)-4-(substituent.)-5- (substituent)isothiazol-3(2H)-one 1,1 dioxide,?. These compounds are reported to modulate the activity of a target protein such as a phosphatase.
The term "LXR modulator" as used herein, refers to the ability of a compound to modulate the biological activity of LXRα and/or LXRβ via increase or decrease of the function and/or expression of LXRα and/or LXRβ, where LXRα and/or LXRβ function may include transcription regulatory activity and/or protein-binding. Modulation may occur in vitro or in vivo. Modulation, as described herein, includes antagonism, agonism, partial antagonism and/or partial agonism of a function or characteristic associated with LXRα and/or LXRβ, either directly or indirectly, and/or the upregulation or downregulation of LXRα and/or LXRβ expression, either directly or indirectly. More specifically, such an LXR modulator either enhances or inhibits the biological activities of LXR via the function and/or expression of LXR. If such a modulator partially or completely enhances the biological activities of LXR via the function and/or expression of LXR, it is a partial or full LXR agonist, respectively. It is the object of the present invention to provide LXR modulators. Another object of this invention is to provide LXR modulator compounds being LXR agonists. It should be noted that to show activity in the specific Test Methods described herein, the LXR modulator compound must bind to the ligand binding domain of the LXR and recruit either the specific peptide derived from the co-activator protein, SRCl, to the modulator compound-bound LXR complex in the described Co-activator recruitment assay, or one or more of the nuclear hormone receptor co-factors present in the U2OS cell-based method described herein. The compounds of this invention that form an LXR-modulator compound- complex may recruit at least one or more of the other >80 known different nuclear hormone receptor cofactors in any other cell-based method prepared and assayed according to known procedures. Compounds according to formula (I), that do not recruit the SRCl-derived peptide or any of the co-factors present in the in cell-based method described herein, is however anticipated to bind to LXR and the LXR-modulator compound-complex so formed will recruit at least one or more of the other >80 known different nuclear receptor cofactors present in other cellular system. The LXR modulator compound-complex may also displace co-repressors, such as NcOR, with simultaneous recruitment of a co-activator or may only displace a co-repressor without co-activator recruitment, leading to partial activation of certain LXR regulated genes. Recruiter peptides derived from any of these other nuclear hormone receptor cofactors may be similarly prepared and assayed according to known procedures!.
Description of i,he invention According to a first aspect of the invention there is provided a compound of formula I:
Figure imgf000005_0001
formula I or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, wherein R1 represents
X which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, C(0)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(0)NRaRa, or d-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb or NRaC(O)NRaRa; cycloalkyl or heterocyclyl each optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, C(0)NRaRa, NRaC(0)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(0)0Rb, OC(O)NRaRa, NRaC(O)NRaRa, or C1- C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb , C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa; phenyl or heteroaryl each optionally substituted by one or more of the following: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(0)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, OSO2Rb, NRaC(0)NRaRa, SO2NHC(O)Rb, or C1-C4alkyl optionally substituted by one or more of the following: F, OH, CN, NRaR\ 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa; cycloalkylY or heterocyclylY wherein cycloalkyl or heterocyclyl each optionally is substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(0)Rb, C(0)NRaRa, NRaC(0)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaS02Rb, NRaC(0)0Rb, OC(O)NRaRa, NRaC(0)NRaRa, or C i-Qalky} which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(0)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb,:NRaC(O)ORb, 0C(0)NRaRa or NRaC(0)NRaRa; phenylY or heteroarylY wherein phenyl or heteroaryl each optionally is substituted by one or more of the following: halogen (Cl, F, I, Br), OH3 CN, NO2, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(0)Rb, C(0)NRaRa, NRaC(O)Rb, C(0)0Ra, OC(O)Rb, SO2NRaRa, NRaS02Rb, NRaC(0)0Rb, OC(O)NRaRa, OSO2Rb, NRaC(O)NRaRa, SO2NHC(O)Rb, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, C(0)NRaRa, NRcC(0)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(0)0Rb, 0C(0)NRaRa or NRaC(O)NRaRa; R2 represents phenyl which is optionally substituted byone or more of the following: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, C(0)NRaRa, NRaC(0)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaS02Rb, NRaC(O)ORb, 0C(0)NRaRa, OSO2Rb, NRaC(0)NRaRa, SO2NHC(O)Rb, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, C(0)NRaRa, NRaC(0)Rb, C(O)ORa, OC(O)Rb, NRaS02Rb, SO2NRaRa, NRaC(0)0Rb, OC(O)NRaRaor NRaC(0)NRaRa; R3 represents
X which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(0)Rb, NRaC(0)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, S02NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(O)NRaRa, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb or NRaC(O)NRaRa;
MP or Het3P wherein M and Her3 each optionally is substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or CrC4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa, and wherein M or Het3 each optionally is substituted on the aromatic ring by one or more of the. following: halogen (Cl, F, Br, I), OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)OEb, NRaC(O)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QT, Het1, He^T, R, RT, Het2, Het2T, or Ci-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa: AP or Het5P wherein A and Het5 each optionally is substituted by one or more of the following: halogen (F, Cl, Br, I), OH, CN, NO2, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa,
NRaC(O)ORb, OSO2Rb, SO2NRaC(O)Rb, NRaC(O)NRaRa, Q, QT, Het1, HBt1T, R, RT, Het2, Het2T, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN1 NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa; E or Het4 each optionally substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, Q, QZ, Het1, HCt1Z, R, RZ, Het2, Het2Z, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2R5, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa, and E or Het4 each optionally is substituted on the aromatic ring by one or more of the folowing: halogen(F, Cl, Br, I), OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, OSO2Rb, SO2NRaC(0)Rb, Q, QZ, Het1, HCt1Z, R, RZ, Het2, , Het2Z, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaR\ ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa.
The following definitions shall apply throughout the specification and the appended claims unless specifically stated otherwise:
The term "X" denotes a straight or branched, saturated or unsaturated alkyl group having 1 to 6 carbon atoms wherein said alkyl group may optionally be interrupted by O, S, SiRbRb, S(O), SO2, C(O), NRa, OC(O), C(O)O, NHaC(0), C(0)NRa, S02NRa or NRaS02. It shall be understood that when X is present more than once in the same compound then the value may be the same or different. Examples of said "X" include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, tert-bntyl, isobutyl, pentyl, hexyl, vinyl, isopropenyl, allyl, but-2- enyl, ethynyl, 2-propynyl, 2-methoxyethyl, 3-methylpropyl, methylthiomethyl, 3- hydroxypropyl, 2-(2-methoxyethoxy)ethyl, 3-(2-methoxyethoxy)propyl, 2,2-dimethylpropyl, 2-hydroxy ethyl, 2,2,2-trifluoroethyϊ, 2,3-dihydroxypropyl, 2-cyanoethyl and methyl ethanoylglycinate.
The term "Y" denotes a straight or branched, saturated or unsaturated alkylene group having 1 to 3 carbon atoms wherein said alkylene group binds to nitrogen in 2-position in the isothiazol-3(2H)-thione 1,1-dioxide and may optionally be interrupted or ended by one of the following: O, S, SiRbRb, S(O), SO2, C(O), OC(O), C(O)O, NRCC(O), C(O)NRC, NRC and/or Y is optionally substituted by one or more of the following independently selected from: OH, F, CN, NRaRa, CrC4alkyl, 0Rb, SRb, SiRbRbRb, S(O)Rb or SO2Rb. In the definition of "Y" the term "ended by O, S, SiRbRb, S(O), SO2, C(O), OC(O), C(O)O, NR0C(O), C(O)NR0, NRC" means that the alkylene group has as the last position O, S, SiRbRb, S(O), SO2, C(O), OC(O), C(O)O, NR0C(O), C(O)NR0 or NR0 before it binds further to phenyl, heteroaryl, cycloalkyl or heterocyclyl. Examples of said "Y" include, but are not limited to, methylene, ethylene, propylene, 2-methylethylene, and 1-methylethylene. The term "Z" denotes a straight or branched, saturated or unsaturated alkylene group having 1 to 6 carbon atoms wherein said alkylene group binds to E or Het4 and one of the following: Q, Het1, R or Het2, and may optionally be interrupted or ended by one of the following: O, S, SiRbRb, S(O), SO2, C(O), OC(O), C(O)O, C(0)CRa, NR3C(O), C(0)NRa, NRa, SO2NRa, NRaSO2, or is one of the following: O, S, SiRbRb, S(O), SO2, C(O), OC(O), C(O)O, NRaC(0), C(0)NRa, NRa , SO2NRa, NRaSO2 and/or Z is optionally substituted by one or more of the following independently selected from: OH, F, CN, NRCRC, C(O)RC, 0Rb, SRC, SiRbRbRb, S(O)RC, SO2RC, phenyl, phenylQ-Csalkyl, or Q-Qalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, NRaRa, SRb, SiRbRbRb, S(O)Rb, SO2Rb, ORb. In the definition of "Z" the term "ended by O, S, SiRbRb, S(O), SO2, C(O), OC(O), C(O)O, NRaC(O), C(O)NRa, NRa, SO2NRa, NRaSO2" means that the alkylene group has as the last position O, S, SiRbRb, S(O), SO2, C(O), OC(O), C(O)O, NRaC(0), C(0)NRa, NRa, SO2NRa or NRaSO2 before it binds further to E, Het4, Q, Het1, R or Het2. Examples of said "Z" include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, O, S, S(O), SO2, C(O), OC(O), C(O)O, C(O)CH2, CH2C(O), C(O)(CrC4alkyl), NHC(O), C(O)NH, NH, SO2NH, NHSO2, N(C1-QaIkVl)C(O), C(O)N(C1- C4alkyl), N(C1-QaIkVl) , SO2N(C1-QaIkVl), N(C1-C4alkyl)SO2, 1-methylpropylene, 2- methylpropylene and 3-methylpropylene. In the definition of Z it is to be understood that specific values bind in the order written, i.e. from left to right. For example, when Z is C(O)CH2 then C(O) in said C(O)CH2 binds to E or Het4 and CH2 in said C(O)CH2 binds to Q, Het1, R or Het2.
The term "M" denotes a saturated or unsaturated non-aromatic monocarbocyclic ring composed of 3, 4, 5, 6, 7 or 8 carbon atoms or a saturated or unsaturated non-aromatic or partly aromatic bicyclic ring system composed of 8, 9 or 10 carbon atoms. Examples of said "M" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctanyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl, cyclooctadienyl, decaline, hydrindane, indane, indene, and bicyclo[4.2.0]octa-l,3,5-triene.
The term "E" denotes a saturated or unsaturated non-aromatic monocarbocyclic ring composed of 3, 4, 5, 6, 7 or 8 carbon atoms or a saturated or unsaturated non-aromatic or partly aromatic bicyclic ring system composed of 8, 9 or 10 carbon atoms. The ring binds, unless otherwise specified, through its non-aromatic part to nitrogen in 4-position on the isothiazol-3(2H)-thione 1,1-dioxide. Examples of said "E" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctanyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl, cyclooctadienyl, decaline, hydrindane, indane, indene andbicyclo[4.2.0]octa-l,3,5-triene.
The term "A" denotes an aromatic monocyclic ring composed of 6 carbon atoms or an aromatic bicyclic ring system composed of 10 carbon atoms. Examples of said "A" include, but are not limited to, phenyl, naphtalene and azulene.
The term "P" denotes a straight or branched, saturated or unsaturated alkylene group having 1 to 6 carbon atoms wherein the alkylene group binds to nitrogen in 4-position on the isothiazol-3(2H)-thione 1,1-dioxide and is optionally interrupted or ended by one of the following: O, NRa, S, SiRbRb, S(O), SO2, C(O), OC(O), C(O)O, NRaC(0), C(0)NRa, S02NRa, NRaSO2 and/or P is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, C(O)RC, 0Rb, SRb, SiR13RV, S(O)Rb, SO2R15, phenyl, phenylQ-Csalkyl, or CrQalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, NRaRa, SRb, SiRbRbRb, S(O)Rb, SO2Rb or 0Rb. In the definition of "P" the term "ended by O, NRa, S, SiRV, S(O), SO2, C(O), OC(O), C(O)O, NRaC(0), C(0)NRa, S02NRa, NRaSO2" means that the alkylene group has as the last position O, NRa, S, SiRV, S(O), SO2, C(O), OC(O), C(O)O, NR2C(O), C(0)NRa, SO2NR3 or NRaS02" before it binds further to M, Het3, A or Het5. Examples of said "P" include, but are not limited to, methylene, ethylene, propylene, butylene, ethyleneoxy, propyleneoxy, butyleneoxy, ethyleneamino, ethylenethio, propylenethio, CH2C(O)NHCH2, CH2C(O)O, CH2CH2C(O)O-CH2CH2CH2C(O)O, CH2C(O)OCH2, CH2C(O)OCH2CH2, CH2CH2OCOCH2, CH2C(O)OCH(CH3)CH2, 1-methylpropylene, 2-methylpropylene and 3- methylpropylene. In the definition of P it is to be understood that the specific values bind in the order written, i.e. from left to right. For example, when P is ethyleneoxy then it is the oxygen that binds to M, Het3, A or Het5.
The term "Q" denotes a saturated or unsaturated non-aromatic monocyclic ring composed of 3, 4, 5, 6, 7 or 8 carbon atoms, which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, phenylQalkyl, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(O)NRaRa, or CrC4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, NRaSO2Rb, SO2NRaRa, NRaC(O)ORb, OC(O)NRaRaor NRaC(O)NRaRa. Examples of said "Q" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctanyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl and cyclooctadienyl.
The term "R" denotes a phenyl group which is optionally substituted by one or more of the following independently selected from: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, 0Rb, SRb, SiR13RV, S(O)Rb, SO2Rb, C(O)Rb, phenylCialkyl, C(O)NRaRa, NRaC(O)Rb, C(O)OR3, OC(O)Rb, SO2NRaRa, NRaS02Rb, NRaC(0)0Rb, OC(O)NRaRa, OSO2Rb, NR3C(O)NR3R3, S02NHC(0)Rb, or Q-Qalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb,
C(O)Rb, C(0)NRaRa, NRaC(0)Rb, C(O)ORa, OC(O)Rb, NRaS02Rb, S02NRaRa, NRaC(0)0Rb, OC(O)NRaRaor NRaC(0)NRaRa.
The term "T" denotes methylene or is one of the following: O, NRa, S, SiRbRb, S(O), SO2, C(O), OC(O), C(O)O, NRaC(0), C(0)NRa, S02NRa or NRaS02. T binds to M, Her3, A or Het5 and one of the following: Q, Het1, R or Het2. Examples of said "T" include; but are not limited to, methylene, O, NRa, S, SiRV, S(O), SO2, C(O), OC(O), C(O)O, NR3C(O), C(O)NR3, SO2NR3 and NR3SO2.
The term "Qalkyl" denotes an alkyl group having 1 carbon atom. An example of said alkyl includes, but is not limited to, methyl.
The term "Q-Csalkyl" denotes a straight or branched, saturated or unsaturated alkyl group having 1 to 3 carbon atoms. Examples of said alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, vinyl, isopropenyl, allyl, ethynyl, and 2-proρynyl.
The term "CrQalkyl" denotes a straight or branched, saturated or unsaturated alkyl group having 1 to 4 carbon atoms. Examples of said alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, tert-butyl, vinyl, isopropenyl, allyl, but-2-enyl, ethynyl, 2-propynyl, and but-2-ynyl.
The term "halogen" denotes fluoro, chloro, bromo and iodo groups.
The term "cycloalkyl" denotes a saturated or unsaturated non-aromatic monocyclic ring composed of 3, 4, 5, 6, 7 or 8 carbon atoms. Examples of said "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctanyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl and cyclooctadienyl.
The term "heterocyclyl" denotes a saturaced or unsaturated non-aromatic 3, 4, 5, 6, 7 or 8 membered monocyclic ring in which one or more of the atoms in the ring is an element other than carbon independently selected from one or more of for example nitrogen, oxygen or sulfur. The term "sulfur" shall be understood to include sulphoxide (S(O)) and sulphone (SO2). The term "nitrogen" shall be understood to include nitrogen oxide (NO). Examples of said "heterocyclyl" include, but are not limited to, aziridine, azetidine, 2- pyrroline, 3- pyrroline, pyrrolidine, imidazoline, piperidine, piperazine, 2-pyrazoline, oxirane, oxetane, tetrahydrofuran, tetrahydropyian, 1,4-dioxaiie, 1,3-dioxolane, 1,2-oxathiolane, morpholine, 3- pyrazoline, pyrazolidine, 2H-pyrane, 4H-pyrane, 1,4-dithiane, 1,4-oxathiane and thiomorpholine.
The term "heteroaryl" denotes an aromatic 5 or 6 membered monocyclic ring in which one or more of the atoms in the ring is an element other than carbon independently selected from one or more of for example nitrogen, oxygen and sulfur. The term "sulfur" shall be understood to include sulphoxide (S(O)) and sulphone (SO2). The term "nitrogen" shall be understood to include nitrogen oxide (NO). Examples of said "heteroaryl" include, but are not limited to, furan, pyrrole, pyrazine, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, pyridine-1-oxide, isoxazole, oxazole, isothiazole, thiazole, thiophene, 1,2,4-triazole, furazane, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,5-thiadiazole, 1,2,4-thiadiazole and 1,2,3-thiadiazole. The term "Het1" denotes a saturated or unsaturated non-aromatic 3, 4, 5, 6, 7, 8, 9, or 10 membered monocyclic ring in which one or more of the atoms in the ring is an element other than carbon independently selected from one or more of for example nitrogen, oxygen or sulfur, and wherein the ring optionally is substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, phenyldalkyl, C(O)NRaRa, NRaC(O)Rb, C(O)OR3, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(O)NRaRa, or Q-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)OR3, OC(O)Rb, NRaSO2Rb, SO2NR3R3, NRaC(O)ORb, OC(O)NRaRaor NRaC(O)NRaRa. The term "sulfur" shall be understood to include sulphoxide (S(O)) and sulphone (SO2). The term "nitrogen" shall be understood to include nitrogen oxide (NO). Examples of said "Eet1" include, but are not limited to aziridine, azetidine, 2- pyrroline, 3-pyrroline, pyrrolidine, imidazoline, piperidine, piperazine, 2-pyrazoline, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, 1,4- dioxane, 1,3-dioxolane, 1,2-oxathiolane, morpholine, 3-pyrazoline, pyrazolidine, 2H-pyrane, 4H-pyrane, 1,4-dithiane, 1,4-oxathiane and thiomorpholine.
The term "Het2" denotes an aromatic 5 or 6 membered monocyclic ring in which one or more of the atoms in the ring is an element other than carbon independently selected from one or more of for example nitrogen, oxygen and sulfur, and which is substituted by one or more of the following independently selected from: halogen (Cl, F, I, Br), OH, CN, NO2, NRaR\ 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, phenylCialkyl, C(O)NR3R3, NRaC(0)Rb, C(O)OR3, OC(O)Rb, SO2NR3Ra, NRaS02Rb, NRaC(O)ORb, OC(O)NR3R3, OSO2Rb, NRaC(0)NRaRa, SO2NHC(O)Rb, or Q-Qalkyl optionally substituted by one or more of the following independently selected from: F, OH, CN, NR3R3, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb,
C(0)Rb, C(O)NR3R3, NR3C(0)Rb, C(O)OR3, OC(O)Rb, NRaSO2Rb, SO2NR3R3, NRaC(0)0Rb, OC(0)NRaRaor NR3C(O)NR3R3. The term "sulfur" shall be understood to include sulphoxide (S(O)) and sulphone (SO2). The term "nitrogen" shall be understood to include nitrogen oxide (NO). Examples of said "Het2" include, but are not limited to, furan, pyrrole, pyrazine, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, pyridine- 1 -oxide, isoxazole, oxazole, isothiazole, thiazole, thiophene, 1,2,4-triazole, furazane, 1,2,3-oxadiazole, 1,2,4- oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,5-thiadiazole, 1,2,4-thiadiazole and 1,2,3- thiadiazole. The term "Het3" denotes a saturated or unsaturated non-aromatic 3, 4, 5, 6, 7, 8, 9 or 10 membered monocyclic ring or a saturated or unsaturated non-aromatic or partly aromatic 9 or 10 membered bicyclic ring system in which one or more of the atoms in the monocyclic ring or bicyclic ring system is an element other than carbon independently selected from one or more of for example nitrogen, oxygen or sulfur. The term "sulfur" shall be understood to include sulphoxide (S(O)) and sulphone (SO2). The term "nitrogen" shall be understood to include nitrogen oxide (NO). Examples of said "Het3" include, but are not limited to aziridine, azetidine, 2- pyrroline, 3-pyrroline, pyrrolidine, imidazoline, piperidine, piperazine, 2- pyrazoline, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, 1,3-dioxolane, 1,2-oxathiolane, morpholine, 3-pyrazoline, pyrazolidine, 2H-pyrane, 4H-pyrane, 1,4-dithiane, 1,4-oxathiane, thiomόtpholiαe, indoiine, l,3-dihydro-2-benzofuran, 2,3-dihydro-l- benzofuran, 1,3-benzodioxole, 2;3-dihydro-l,4-benzodioxine, chroman and isochroman.
The term "Het4" denotes a saturated or unsaturated non-aromatic 3, 4, 5, 6, 7, 8, 9 or 10 membered monocyclic ring or a saturated or unsaturated non-aromatic or partly aromatic 9 or 10 membered bicyclic ring system in which one or more of the atoms in the monocyclic ring or bicyclic ring system is an element other than carbon independently selected from one or more of for example nitrogen, oxygen or sulfur. The term "sulfur" shall be understood to include sulphoxide (S(O)) and sulphone (SO2). The term "nitrogen" shall be understood to include nitrogen oxide (NO). The ring binds, unless otherwise specified, through its non- aromatic part to nitrogen in 4-position on the isothiazol-3(2H)-thione 1,1-dioxide. Examples of said "Ηet4" include, but are not limited to, aziridine, azetidine, 2- pyrroline, 3-pyrroline, pyrrolidine, imidazoline, piperidine, piperazine, 2-pyrazoline, oxirane, oxetane, tetrahydrofuran, furan, tetrahydropyran, 1,4-dioxane 1,3-dioxolane, 1,2-oxathiolane, morpholine, 3-pyrazoline, pyrazolidine, isoxazole, 2Η-pyrane, 4H-pyrane, 1,4-dithiane, 1,4- oxathiane, thiomorpholine, indoiine, l,3-dihydro-2-benzofuran, 2,3-dihydro-l-benzofuran, 1,3-benzodioxole, 2,3-dihydro-l,4-benzodioxine, chroman and isochroman.
The term "Het5" denotes an aromatic 5 or 6 membered monocyclic ring or an aromatic 9 or 10 membered bicyclic ring in which one or more of the atoms in the monocyclic ring or bicyclic ring system is an element other than carbon independently selected from one or more of for example nitrogen, oxygen or sulfur. The term "sulfur" shall be understood to include sulphoxide (S(O)) and sulphone (SO2). The term "nitrogen" shall be understood to include nitrogen oxide (NO). Examples of said "Het5" include, but are not limited to, furan, pyrrole, pyrazine, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, pyridine-1-oxide, isoxazole, oxazole, isothiazole, thiazole, thiophene, 1,2,4-triazole, furazane, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,5-thiadiazole, 1,2,4-thiadiazole 1,2,3-thiadiazole, benzofuran, isobenzofuran, indole, isoindole, benzothiophene, benzo[c]thiophene, benzimidazole, purine, indazole, benzoxazole, benzisoxazole, bnezthiazole, quinoline, quinoxaline, quinazoline, cinnoline and isoquionoline.
Ra independently represents H or a straight or branched, saturated or unsaturated Q^alkyl chain optionally substituted by one or more F.
Rb independently represents a straight or branched, saturated or unsaturated Q-C^alkyl chain optionally substituted by one or more F.
Rc independently represents H or a straight or branched, saturated or unsaturated Q-Csalkyl chain optionally substituted by one or more F. . .
It shall be understood that when a substitutent bears more than one of Ra, Rυ or Rc then each of these may be the same or different. For example, NRaRa includes amino, alkylamino and dialkylamino. Furthermore, it shall be understood that when different substituents in the same compound bear more than one of Ra, Rb or Rc then each of these may be the same or different.
Further values of R1, R2 and R3 in compounds of formula (I) now will follow. It will be understood that such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.
In a first group of compounds of formula I R1 represents
X which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(O)NRaRa, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb or NRaC(O)NRaRa; cycloalkyl or heterocyclyl each optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2R5, C(O)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)OR3, OC(O)Rb, S02NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(0)NRaRa, or C1- C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 5 0Rb, SRb, S(O)Rb, SO2R5, C(O)Rb , C(O)NR3R3, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(0)0Rb, OC(O)NRaRa or NRaC(O)NRaRa; phenyl or heteroaryl each optionally substituted by one or more of the following: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(0)Rb, C(0)NRaRa, NRaC(0)Rb, C(O)ORa, OC(O)Rb, S02NRaRa, NRaSO2Rb, NRaC(0)0Rb, 0C(0)NRaRa, OSO2Rb, 0 NRaC(0)NRaRa, SO2NHC(O)Rb, or CrC4alkyl optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(0)Rb,
■ C(O)OR3.. OC(O)Rb, SO2NR11R3, NRaSO2Rb, NRaC(0)0Rb, OC(O)NRaRa or NRaC(O)NRaRa; cycloalkylY or heterocyπiylY wherein cycloalkyl or heterocyclyl each optionally is substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, 5 C(O)Rb, C(O)NR3R3, NRaC(0)Rb, C(O)ORa, OC(O)Rb, SO2NRaR3, NR3SO2Rb, NRaC(0)0Rb, OC(O)NR3R3, NRaC(0)NRaRa, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR3R3, ORb, SRb, S(O)Rb, SO2Rb, C(0)Rb, C(O)NR3R3, NRaC(0)Rb, C(O)OR3, OC(O)Rb, SO2NR3R3, NR3SO2R", NR3C(0)0Rb, OC(O)NRaR3 or NR3C(O)NR3R3; 0 phenylY or heteroarylY wherein phenyl or heteroaryl each optionally is substituted by one or . more of the following: halogen (Cl, F, I, Br), OH, CN, NO2, NR3R3, 0Rb, SRb, S(O)Rb, SO2Rb, C(0)Rb, C(O)NR3R3, NR3C(O)R", C(O)OR3, OC(O)Rb, SO2NR3R3, NRaSO2Rb, NR3C(O)OR", OC(O)NR3R3, OSO2R", NR3C(O)NR3R3, SO2NHC(O)R", or CrC4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR3R3, 0Rb, SRb, 5 S(O)Rb, SO2R", C(O)R", C(O)NR3R3, NRcC(0)Rb, C(O)OR3, OC(O)R", SO2NR3R3, NR3SO2R", NR3C(O)OR", 0C(0)NR3Ra or NR3C(O)NR3R3; R2 represents phenyl which is optionally substituted byone or more of the following: halogen (Cl, F, I, Br), OH, CN, NO2, NR3R3, OR", SRb, S(O)Rb, SO2Rb, C(O)R", C(O)NR3R3, NR3C(O)R", 0 C(O)OR3, OC(O)Rb, SO2NR3R3, NR3SO2R13, NR3C(O)OR", OC(O)NR3R3, OSO2R",
NR3C(O)NR3R3, SO2NHC(O)Rb, or CrQalkyl which is optionally substituted by one or more of the following: F, OH, CN, NR3R3, 0Rb, SRb, S(O)Rb, SO2R5, C(O)Rb, C(O)NR3R3, NRaC(O)Rb, C(O)OR3, 0C(0)Rb, NRaSO2Rb, SO2NRaRa, NRaC(O)ORb, OC(O)NRaRaor NRaC(O)NRaRa; R3 represents
X which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NR3C(O)OR", OC(O)NRaRa, NRaC(O)NRaRa, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb or NRaC(0)NRaRa; MP or Het3P wherein M and Het3 each optionally is substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(0)NRaRa, Q, QT, Het1, HSt1T.. R.. RT, Het2, Het2!', or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaR\ • and wherein M or Het3 each optionally is substituted on the aromatic ring by one or more of the following: halogen (Cl, F, Br, I), OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, 0C(0)NRaRa, NRaC(0)0Rb, NRaC(O)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QT, Het1, Het1!1, R, RT, Het2, Het2T, or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, , CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(0)0Rb, OC(O)NRaRa or NRaC(O)NRaRa; AP or Het5P wherein A and Het5 each optionally is substituted by one or more of the following: halogen (F, Cl, Br, I), OH, CN, NO2, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, S02NRaRa, NRaS02Rb, 0C(0)NRaRa, NRaC(O)ORb, OSO2Rb, SO2NRaC(O)Rb, NRaC(0)NRaRa, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or d-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, 0C(0)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(0)0Rb, OC(O)NRaRa or NRaC(O)NRaRa; E or Het4 each optionally substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NRaR\ 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaS02Rb, 0C(0)NRaRa, NRaC(0)0Rb, NRaC(O)NRaRa, Q, QZ, Het1, HeI1Z, R, RZ, Het2, Het2Z, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa, and E or Het4 each optionally is substituted on the aromatic ring by one or more of the folowing: halogen (F, Cl, Br, I), OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb,
NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa,
NRaC(O)ORb, NRaC(0)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QZ, Het1, HtSt1Z, R, RZ, Het2,
Het2Z, or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH,
CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaR\ OC(O)Rb, C(O)ORa, S02NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaRa.
ϊn a second gi'oαp of compounds of formula I
R1 represents
X which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, or Ci-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb or C(O)Rb; cycloalkyl or heterocyclyl each optionally substituted by one or more of the following: F, OH,
CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, or CrC4alkyl which is optionally substituted , by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb or C(O)Rb; phenyl or heteroaryl each optionally substituted by one or more of the following: halogen (Cl,
F, I, Br), OH, CN, NO2, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(0)Rb, or CrC4alkyl optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb,
C(O)Rb; cycloalkylY or heterocyclylY wherein cycloalkyl or heterocyclyl each optionally is substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb,
C(O)Rb, or Cϊ-C4alkyl which is optionally substituted by one or more of the following: F, OH,
CN, NRaR\ 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb; phenylY or heteroarylY wherein phenyl or heteroaryl each optionally is substituted by one or more of the following: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(0)Rb, or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb;
R2 represents phenyl which is optionally substituted by one or more of the following: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, or CrC4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, R3 is the same as in the first group of compounds of formula I.
In a third group of compounds of formula I
R1 represents
X which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(0)Rb, C(O)ORa, OC(O)Rb, S02NRaRa,
NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(O)NRaRa, or d-C4alkyl which is optionally substituted by one or more of the following: F, OH7 CK NRaR\ 0Rb, SRb, S(O)Rb, SO2Rb,
C(O)Rb or NRaC(O)NRaRa,
R2 is the same as in the second group of compounds of formula L R3 is the same as in the first group of compounds of formula I.
In a fourth group of compounds of formula I R1 represents
X which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, or Q-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)R\ SO2Rb or C(O)Rb, R2 is the same as in the second group of compounds of formula I, R3 is the same as in the first group of compounds of formula I.
In a fifth group of compounds of formula I
R1 is the same as in the first group of compounds of formula I,
R2 is the same as in the first group of compounds of formula I, and
R3 represents
X which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa,
NRaS02Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(0)NRaRa, or Ci-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb,
C(O)Rb or NRaC(0)NRaRa. In a sixth group of compounds of formula I R is the same as in the first group of compounds of formula I, R is the same as in the first group of compounds of formula I, and R3 represents
MP or Het3P wherein M and Het3 each optionally is substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, Q, QT, Het1, HetlrT, R, RT, Het2, HeI2T, or CrC4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO?.NRaRa, NR"SO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa, and wherein M or Het3 each optionally is substituted on the aromatic ring by one or more of the following: halogen (Cl, F, Br, I), OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaS02Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(0)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaRa; AP or Het5P wherein A and Het5 each optionally is substituted by one or more of the following: halogen(F, Cl, Br, I), OH, CN, NO2, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(0)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, 0C(0)NRaRa, NRaC(O)ORb, OSO2Rb, SO2NRaC(O)Rb, NRaC(0)NRaRa, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or CrC4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, S02NRaRa, NRaSO2Rb, NRaC(O)ORb, 0C(0)NRaRa or NRaC(O)NRaRa.
In a seventh group of compounds of formula I R1 is the same as in the first group of compounds of formula I, R is the same as in the first group of compounds of formula I, and R3 represents
E or Het4 each optionally substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)Rb, C(O)OR2, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, Q, QZ, Het1, Hd1Z, R, RZ, Het2, Het2Z, or CrC4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, 0C(0)NRaRa or NRaC(0)NRaRa, and E or Het4 each optionally is substituted on the aromatic ring by one or more of the following: halogen (F, Cl, Br, I), OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(0)0Rb, NRaC(O)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QZ, Het1, HeI1Z, R, RZ, Het2, Het2Z, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NR3R3, NRaSO2Rb ? NRaC(O)ORb, OC(O)NR3R3 or NRaC(O)NRaRa.
In an 8th group of compounds of formula I R1 is the same as in the second group of compounds of formula I,
R2 is the same as in the second group of compounds of formula I, and
R3 represents .
X which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb,
SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)Rb, C(O)OR3, SO2NR3R3, NRaS02Rb, NR3C(0)0Rb, 0C(0)NRaR3, NR3C(O)NR3R3, or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NR3Ra, 0Rb, SRb, S(O)Rb, SO2Rb,
C(O)Rb or NR3C(O)NR3R3.
In a 9th group of compounds of formula I R1 is the same as in the second group of compounds of formula I,
R2 is the same as in the second group of compounds of formula I, and
R3 represents
MP or Het3P wherein M and Het3 each optionally is substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NR3R3, 0Rb, SRb, S(O)Rb, SO2Rb, C(0)Rb, NRaC(0)Rb, C(O)NR3R3, OC(O)Rb, C(O)OR3, SO2NR3R3, NRaSO2Rb, OC(O)NR3R3,
NR3C(0)0Rb, NR3C(O)NR3R3, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NR3R3, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa, and wherein M or Het3 each optionally is substituted on the aromatic ring by one or more of the following: halogen (Cl, F, Br, I), OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or C!-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa; AP or Het5P wherein A and Het5 each optionally is substituted by one or more of the following: halogen (F, Cl, Br, I), OH, CN, NO2, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb 5 C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaR'\ NRaC(O)ORb, OSO2Rb, SO2NRaC(O)Rb, NRaC(O)NRaRa, Q, QT, Het1, Het!T, R, RT, Het2, IiSt2T, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(Θ)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaRa.
In a 10th group of compounds of formula I
R1 is the same as in the second group of compounds of formula I, R2 is the same as in the second group of compounds of formula I, and R3 represents
E or Het4 each optionally substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, S02NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(0)NRaRa, Q, QZ, Het1, HeI1Z, R, RZ, Het2, Het2Z, or Q^alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, S02NRaRa, NRaS02Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaRa, and E or Het4 each optionally is substituted on the aromatic ring by one or more of the following: halogen (F, Cl, Br, I), OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(0)Rb, NRaC(0)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaR\ OSO2Rb, SO2NRaC(O)Rb, Q, QZ, Het1, HeI1Z, R, RZ, Het2, Het2Z, or CrC4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa;
In an 11th group of compounds of formula I R1 is the same as in the third group of compounds of formula I, R2 is the same as in the third group of compounds of formula I, and R3 represents
X which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(O)NRaRa, or CrC4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb orNRaC(O)NRaRa,
In a 12th group of compounds of formula I R1 is the same as in the third group of compounds of formula I, R2 is the same as in the third group of compounds of formula I, and R3 represents
MP or Het3P wherein M and Het3 each optionally is substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(0)0Rb, 0C(0)NRaRa or NRaC(O)NRaRa, and wherein M or Het3 each optionally is substituted on the aromatic ring by one or more of the following: halogen (Cl, F, Br, I), OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(0)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or Ci-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa; AP or Het5P wherein A and Het5 each optionally is substituted by one or more of the following: halogen (F, Cl, Br, I), OH, CN, NO2, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NR3R3, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, OSO2Rb, SO2NRaC(O)Rb, NRaC(O)NRaRa, Q, QT, Het1, HeI1T, R, RT, Het2, HCt2T, or C1-C4BIlCyI which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NR3R3, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa.
In a 13th group of compounds of formula I
R1 is the same as in the third group of compounds of formula I,
R2 is the same as in the third group of compounds of formula I, and R3 represents
E or Het4 each optionally substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Fb, NRaC(O)Rb, 0(0)NRaRa,
OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRr,
- Q, QZ, Het1, HCt1Z, R, RZ, Het2, Het2Z, or CrC4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(0)0Rb, OC(O)NRaRa or NRaC(0)NRaRa, and E or Het4 each optionally is substituted on the aromatic ring by one or more of the ' • following: halogen (F, Cl, Br, I), OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa,
NRaC(O)ORb, NRaC(0)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QZ, Het1, Het'Z, R, RZ, Het2, Het2Z, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaRa;
In a 14th group of compounds of formula I R1 is the same as in the fourth group of compounds of formula I, R2 is the same as in the fourth group of compounds of formula I, and R3 represents X which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, NRaC(0)0Rb, 0C(0)NRaR3, NRaC(O)NRaRa, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb or NRaC(O)NRaRa.
In a 15 group of compounds of formula I R1 is the same as in the fourth group of compounds of formula I, R2 is the same as in the fourth group of compounds of formula I, and R3 represents
MP or Het3P wherein M and Het3 each optionally is substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(0)NRaRa, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or CrC4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaRa, and wherein M or Het3 each optionally is substituted on the aromatic ring by one or more of the following: halogen (Cl, F, Br, I), OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, 0C(0)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QT, Het1, Het:T, R, RT, Het2, Het T, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa; AP or Het5P wherein A and Het5 each optionally is substituted by one or more of the following: halogen (F, Cl, Br, I), OH, CN, NO2, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(0)NRaRa, OC(O)Rb, C(O)OR3, SO2NR3R3, NR3SO2Rb, OC(O)NR3R3, NRaC(0)0Rb, OSO2Rb, SO2NR3C(O)R", NR3C(O)NR3R3, Q, QT, Het1, HCt1T, R, RT, Het2, Het2T, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NR3R3, OC(O)Rb, C(O)OR3, SO2NR3R3, NR3SO2Rb, NRaC(0)0Rb, OC(O)NR3R3 OrNR3C(O)NR3R3.
In a 16th group of compounds of formula I
R1 is the same as in the fourth group of compounds of formula I, R2 is the same as in the fourth group of compounds of formula I, and R3 represents E or Het4 each optionally substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, Q, QZ, Het1, HCt1Z, R, RZ, Het2, Het2Z, or CrC4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa, and E or Het4 each optionally is substituted on the aromatic ring by one or more of the following: halogen (F, Cl, Br, I), OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa,
NRaC(O)ORb, NRaC(0)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QZ, Het1, HeI1Z, R, RZ, Het2, Het2Z, or CrC4alkyl which is optionally substituted by one or more ofthe following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)Rb/ C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRf .
Further embodiments of the invention
According to another embodiment of the invention there is provided a compound of general formula (I)
Figure imgf000026_0001
formula (I) or a pharmaceutically acceptable salt thereof, wherein
R1 represents X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(O)NRaRa, or CrC4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaR\ 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb or NRaC(O)NRaRa; or R1 is cycloalkyl or heterocyclyl each optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(0)Rb, C(O)ORa,
OC(O)R5, S02NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(0)NRaRa, or C1-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb , C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaS02Rb, NRaC(O)ORb, 0C(0)NRaRa or
NRaC(0)NRaRa; or R1 is phenyl or hetercaryl each optionally substituted by one or more of the following independently selected from: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, 0Rb, SRb 5 SiR13R13R", S(O)Rb, SO2Rb, C(0)Rb, C(O)NRaRa, NRaC(0)Rb, C(O)ORa, OC(O)Rb, S02NRaRa, NRaSO2Rb, NRaC(O)ORb,
OC(O)NRaRa, OSO2Rb, NRaC(0)NRaRa, SO2NHC(O)Rb, or C1-C4^yI optionally substituted by one or more of the following independently selected from: F, OH, CN, OT<aRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C(0)NRaRa, NRaC(O)Rb, C(0)0Ra, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(0)0Rb, OC(O)NRaRa or NRaC(O)NRaRa; or R1 is cycloalkylY or heterocyclylY wherein cycloalkyl or heterocyclyl each optionally is substituted by one or more of the following independently selected from: F, OH, CN, NRaRa,' 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C(0)NRaRa, NRaC(0)Rb, C(O)ORa, OC(O)Rb, S02NRaRa, NRaSO2Rb, NRaC(0)0Rb, 0C(0)NRaRa, NRaC(O)NRaRa, or CrC4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C(0)NRaRa, NRaC(0)Rb, C(O)ORa, OC(O)Rb, S02NRaR\ NRaS02Rb, NRaC(0)0Rb, 0C(0)NRaRa or NRaC(O)NRaRa; or R1 is phenylY or heteroarylY wherein phenyl or heteroaryl each optionally is substituted by one or more of the following independently selected from: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(0)Rb, C(0)NRaRa, NRaC(O)Rb, C(O)OR3, 0C(0)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, OSO2Rb, NRaC(O)NRaRa, SO2NHC(O)Rb, or Ci-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRcC(O)Rb, C(O)OR3, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or
NRaC(O)NRaRa; R2 represents phenyl which is optionally substituted by one or more of the following independently selected from: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(0)Rb, C(O)NRaRa, NRaC(O)Rb,
C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, 0C(0)NRaRa, OSO2Rb, NRaC(O)NRaRa, SO2NHC(O)Rb, or Q-dalkyl which is optionally •' substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiR13R15R13, S(O)Rb, SO2Rb, C(O)Kb, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, NRaSO2Rb, SO2NRaRa, NRaC(O)ORb,
OC(O)NRaRaor NRaC(0)NRaRa; R3 represents
X which is optionally substituted by one or more of ihe following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa,
NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(0)NRaRa, or C1-C4aikyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiR13RV5S(O)R", SO2Rb, C(O)Rb or NRaC(O)NRaRa; or R3 is MP or Het3P wherein M and Het3 each optionally is substituted on the non- aromatic ring by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, 0C(0)NRaRa, NRaC(0)0Rb, NRaC(O)NRaRa, Q, QT, Het1, HetlrT, R, RT, Het2, Het2T, or C1- C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(0)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(0)0Rb, OC(O)NRaRa or NRaC(0)NRaRa, and wherein M or Het3 each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen (Cl, F, Br, I), OH, CN, NRaRa, ORb, SRb, SiR13R13R13, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q,
QT, Het1, HetlrT, R, RT, Het2, Het2T, or Q-Qalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa; or R3 is AP or Het5P wherein A and Het5 each optionally is substituted by one or more of the following independently selected from: halogen (F, Cl, Br, I), OH, CN, NO2, NRaRa, 0Rb, SRb, SiRbRbRb S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(0)NRaRa : OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, 0C(0)NRaRa, NRaC(0)0Rb, OSO2Rb, SO2NRaC(O)Rb, NRaC(O)NRaRa, Q, QT, Het1, HetJT,
R, RT, Het2, Het2T, or C1-C-IaIlCyI which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(0)0Ra, ■ SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, 0C(0)NRaRa or NRaC(O)NRaRa; or R3 is E or Het4 each optionally substituted on the non-aromatic ring by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)R\ SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(0)0Rb, NRaC(0)NRaRa, Q, QZ, Het1, HBt1Z, R, RZ, Het2, Het2Z, or Ci-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, S02NRaRa, NRaSO2Rb, NRaC(0)0Rb, OC(O)NRaRa or NRaC(O)NRaRa, and E or Het4 each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen (F, Cl, Br, I), OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, 0C(0)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QZ, Het1, HeI1Z, R, RZ, Het2, Het2Z, or Ci-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb,S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or
NRaC(O)NRaRa.
Further values of R1, R2 and R3 will now follow. It will be understood that such values may be r used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.
In a first embodiment of the invention there -is provided a class of compounds of formula I wherein
R1 represents X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRB, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(O)NRaRa, or Q-Qalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaR\ 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb,
C(O)Rb or NRaC(O)NRaRa; or R1 is cycloalkyl or heterocyclyl each optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa,
NRaC(0)NRaRa, or Q-Qalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb , C(O)NRaRa, NRaC(0)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaS02Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaRa; or R1 is phenyl or heteroaryl each optionally substituted by one or more of the following independently selected from: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, OSO2Rb, NRaC(O)NRaRa, SO2NHC(O)Rb, or C1-C4EIlCyI optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiR13RV, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NR3R3, NRaSO2Rb,
NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa; or R1 is cycloalkylY or heterocyclylY wherein cycloalkyl or heterocyclyl each optionally is substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa,
NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(O)NRaRa, or d-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(0)0Rb, OC(O)NRaRa or NRaC(0)NRaRa; or R1 is phenylΥ or heteroarylY wherein phenyl or heteroaryl each optionally is substituted by one or more of the following independently selected from: halogen (Ci, F, I, Br), OH, CN, NO2, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(0)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)OR3, OC(O)Rb, SO2NR3R3, NRaS02Rb, NRaC(0)0Rb, OC(O)NR3R3, OSO2Rb, NR3C(O)NR1R3,
SO2NHC(O)Rb, or C!-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaR3, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NR3R3, NRcC(0)Rb, C(O)OR3, OC(O)Rb, SO2NR3R3, NRaSO2Rb, NRaC(O)ORb, OC(O)NR3R3 or NR3C(O)NR3R3;
R2 represents phenyl which is optionally substituted by one or more of the following independently selected from: halogen (Cl, F, I, Br), OH, CN, NO2, NRaR3, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NR3R3, NRaC(0)Rb, C(O)OR3, OC(O)R5, SO2NR3R3, NRaSO2Rb, NRaC(0)0Rb, OC(O)NR3R3,
OSO2Rb, NR3C(O)NR3R3, SO2NHC(O)Rb, or C1-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR3R\ 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NR3R3, NRaC(O)Rb, C(O)ORa, OC(O)Rb, NRaSO2Rb, SO2NRaRa, NRaC(O)ORb, OC(O)NRaRaor NRaC(O)NRaRa; R3 represents
X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb,
SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(O)NRaRa, or Ci-C4BIlCyI which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiR15RV5S(O)R13, SO2Rb, C(O)Rb or NRaC(O)NRaRa; or R3 is MP or Het3P wherein M and Her3 each optionally is substituted on the non- aromatic ring by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, 0C(0)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, Q, QT, Het1 , HeI1T, R, RT, Het2, Het2T, or C1-
C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa orNRaC(O)NRaRa, and wherein M or Het3 each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen (Cl, F, Br, I), OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QT, Het1, HCt1T, R, RT, Het2, Het2T, or C1-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaS02Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaRa; or R is AP or Het P wherein A and Het each optionally is substituted by one or more of the following independently selected from: halogen (F, Cl, Br, I), OH, CN, NO2, NRaRa, 0Rb, SRb, SiRbRbRb S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, 0C(0)NRaRa, NRaC(O)ORb, OSO2Rb, SO2NRaC(O)Rb, NRaC(O)NRaRa, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or Ci-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or
NRaC(0)NRaRa; or R3 is E or Het4 each optionally substituted on the non-aromatic ring by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NR1SO2R", OC(O)NRaRa, NRaC(O)ORb,
. NRaC(0)NRaRa, Q, QZ, Het1, HeI1Z, R, RZ, Het2, Het2Z, or C1-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb,
C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NR1R*, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa, and E or Het4 each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen (F, Cl, Br, I), OH,
■ CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(0)Rb, NRaC(0)Rb,
C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, 0C(0)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QZ, Het1, Het1 Z,
R, RZ, Het2, Het2Z, or C1-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb,S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaRa.
In a second embodiment of the invention there is provided a class of compounds of formula
(I) wherein
R1 represents X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, or d-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaR\ 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb or C(O)Rb; or R1 is cycloalkyl or heterocyclyl each optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, or CrC4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiR5RV, S(O)Rb, SO2Rb or C(O)Rb; or R1 is phenyl or heteroaryl each optionally substituted by one or more of the following independently selected from: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, or CrC4alkyl optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiR6R13R5, S(O)Rb, SO2Rb, C(O)Rb; or R1 is cycloalkylY or heterocyctyl Y wherein cycloalkyl or heterocyclyl each optionally is substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb,
C(O)Rb, or C1-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(0)Rb; or R1 is phenylY or heteroarylY wherein phenyl or heteroaryl each optionally is substituted by one or more of the following independently selected from: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(0)Rb, or Q-Qalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(0)Rb; R2 represents phenyl which is optionally substituted by one or more of the following independently selected from: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, or d-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb,
R is the same as for the first embodiment. In a third embodiment of the invention there is provided a class of compounds of formula (I) wherein
R1 represents
X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiR13RV, S(O)Rb,
SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa,
NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(O)NRaRa, or C1-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb or NRaC(O)NRaRa,
R2 is the same as for the second embodiment , and
RJϊs the same as for the first embodiment.
In a fourth embodiment of the invention there is provided a class of compounds of formula (I) wherein
R1 represents X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb,
SO2Rb, C(O)Rb, or Ci-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb,
SiRbRbRb, S(O)Rb, SO2Rb or C(O)Rb, R2 is the same as for the second embodiment, and R3 is the same as for the first embodiment.
In a fifth embodiment of the invention there is provided a class of compounds of formula (I) wherein
R1 is the same for the first embodiment, R2 is the same as for the first embodiment, and R3 represents X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(O)NRaRa, or C1-QaIkVl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb or NRaC(O)NRaRa.
In a sixth embodiment of the invention there is provided a class of compounds of formula (I) wherein
R1 is the same as for the first embodiment, R2 is the same as for the first embodiment, and R3 represents MP or Het3P wherein M and Het3 each optionally is substituted on the non- aromatic ring by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb ; SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, Q5 QT, Het1, HCt1T, R, RT, Het2, Het2T, or C1- C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(0)0Rb, OC(O)NRaRa or NRaC(0)NRaRa, and wherein M or Het3 each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen (Cl, F, Br,
I), OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, 0C(0)NRaRa, NRaC(O)ORb, NRaC(0)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or Q-C4alkyl which is optionally substituted by one or more of the following independently selected from: F,
OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, S02NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa; or R3 is AP or Het5P wherein A and Het5 each optionally is substituted by one or more of the following independently selected from: halogen (F, Cl, Br, I), OH, CN,
NO2, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb,
C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa,
NRaC(O)ORb, OSO2Rb, SO2NRaC(O)Rb, NRaC(0)NRaRa, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or Ci-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NR3R8, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaRa.
In a seventh embodiment of the invention there is provided a class of compounds of formula (I) wherein
R1 is the same as for the first embodiment, R2 is the same as for the first embodiment, and R3 represents
E or Het4 each optionally substituted on the non-aromatic ring by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb,
• . . SiR13RV, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb. . C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaR\ NRaC(O)ORb;
NRaC(O)NRaRa, Q, QZ, Het1, HfJt1Z, R, RZ, Het2, Het2Z, or C1-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rh,
C(O)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NR3R3, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa orNRaC(O)NRaRa, and E or Het4 each optionally is substituted on the aromatic ring by one or more of the folowing independently selected from: halogen (F, Cl, Br, I), OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)Rb, C(O)OR3, S02NRaRa, NRaSO2Rb, 0C(0)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QZ, Het1, HeI1Z,
R, RZ, Het2, Het2Z, or C1-QaIkVl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NR3R3, NRaSO2Rb, NRaC(O)ORb, OC(O)NR3R3 or NR3C(O)NR3R3.
In an 8th embodiment of the invention there is provided a class of compounds of formula (I) wherein R1 is the same as for the second embodiment,
R2 is the same as for the second embodiment, and
R3 represents
X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb,
SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa,
NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(O)NRaRa, or Q-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb or NRaC(O)NRaRa.
In a 9th embodiment of the invention there is provided a class of compounds of formula (I) wherein
R1 is the same as for the second -embodiment, - R2 is the same as for the second embodiment, and R3 represents
MP or Het3P wherein M and Het" each optionally is substituted on the non- aromatic ring by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa,
NRaC(O)ORb, NRaC(O)NRaR\ Q, QT, Het1, HetlrT, R, RT, Het2, Het2T, or C1- C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaRa, and wherein M or Het3 each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen (Cl, F, Br, I), OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q,
QT, Het1, HeI1T, R, RT, Het2, Het2T, or C1-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa; or R3 is AP or HetsP wherein A and Het5 each optionally is substituted by one or more of the following independently selected from: halogen (F, Cl, Br, I), OH, CN, NO2, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb,
C(O)NRaRa, OC(O)Rb, C(O)OR8, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa,
NRaC(O)ORb, OSO2Rb, SO2NRaC(O)Rb, NRaC(0)NRaRa, Q, QT, Het1, Het1!1,
R, RT, Het2, HeI2T, or C1-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaR\ 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb,
C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or
NRaC(0)NRaRa.
'In a 10th embodiment of the invention there is provided a class of compounds of foπriula (I) wherein
R1 is the same as for the second embodiment,
R2 is the same as for the second embodiment, and - ■ ■ -
R3 represents
• E or Het4 each optionally substituted on the non-aromatic ring by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb,
SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb,
C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb,
NRaC(0)NRaRa, Q, QZ, Het1, HeI1Z, R, RZ, Het2, Het2Z, or CrC4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb,
C(O)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa,
NRaSO2Rb, NRaC(O)ORb, 0C(0)NRaRa or NRaC(O)NRaRa, and E or Het4 each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen (F, Cl, Br, I), OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb,
C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa,
NRaC(0)0Rb, NRaC(O)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QZ, Het1, He^Z,
R, RZ, Het2, Het2Z, or C1-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRVR13, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa.
In an 11th embodiment of the invention there is provided a class of compounds of formula (I) wherein
R1 is the same as for the third embodiment,
R2 is the same as for the third embodiment, and R3 represents
X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb 5 NRaC(O)ORb, OC(O)NRaRa, NRaC(O)NRaRa, or Q-Qalkyl which is optionally substituted 'by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb or NRaC(O)NRaRa.
In a 12th embodiment of the invention there is provided a class of compounds of formula (I) wherein
R1 is the same as for the third embodiment, R2 is the same as for the third embodiment, and R3 represents
MP or Het3P wherein M and Het3 each optionally is substituted on the non- aromatic ring by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, Q, QT, Het1, HetlrT, R, RT, Het2, Het2T, or C1- C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaRa, and wherein M or Het3 each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen (Cl, F, Br, I), OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q,
QT, Het1, HetlrT, R, RT, Het2, Het2T, or Q-Qalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa; or R3 is AP or Het5P wherein A and Het5 each optionally is substituted by one or more of the following independently selected from: halogen (F, Cl, Br, I), OH, CN, NO2, NRaRa, 0Rb, SRb, SiRW, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, OSO2Rb, SO2NRaC(O)Rb, NRaC(0)NRaRa, Q, QT, Het1 , HBt1T,
R, RT, Het2, Het2T, or C1-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, GN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(0)NRaR\ OC(O)Rb, C(O)ORa, SO2NRaRa, NRaS02Rb, NRaC(O)ORb, 0C(0)NRaRa or NRaC(O)NRaRa.
In a 13th embodiment of the invention there is provided a class of compounds of formula (I) wherein
R1 is the same as for the third embodiment, R2 is the same as for the third embodiment, and
R3 represents
E or Het4 each optionally substituted on the non-aromatic ring by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb,
NRaC(O)NRaRa, Q, QZ, Het1, HeI1Z, R, RZ, Het2, Het2Z, or Q-Qalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa, and E or Het4 each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen (F, Cl, Br, I), OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb,
C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QZ, Het1, HeI1Z, R, RZ, Het2, Het2Z, or Ci-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb,
C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaRa.
In a 14th embodiment of the invention there is provided a class of compounds of formula (I) wherein
R1 is the same as for the fourth embodiment, R is the same as for the fourth embodiment, and R3 represents
X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb,
SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(O)NRaRa, or Q-Qalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb or NRaC(0)NRaRa.
In a 15th embodiment of the invention there is provided a class of compounds of formula (I) wherein
R1 is the same as for the fourth embodiment, R2 is the same as for the fourth embodiment, and R3 represents
MP or Het3P wherein M and Het3 each optionally is substituted on the non- aromatic ring by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or C1- C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb,
SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, 0C(0)NRaRa or NRaC(O)NRaRa, and wherein M or Het3 each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen (Cl, F, Br, I), OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb,
NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaB.a, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, OSO2Rb : SO2NRaC(O)Rb, Q, QT, Het1, He^T, R, RT, Het2, Het2T, or Cr-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiR15R13R5, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb,
C(O)NRaRa, OC(O)Rb, C(O)OR2, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaRa; or R3 is AP or Het5P wherein A and Het5 each optionally is substituted by one or more of the following independently selected from: halogen (F, Ci, Br, I), OH, CN, NO2, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb,
C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(0)0Rb, OSO2Rb, SO2NRaC(O)Rb, NRaC(O)NRaRa, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or C1-C4^IkVl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb,
C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaRa.
In a 16th embodiment of the invention there is provided a class of compounds of formula (I) wherein
R1 is the same as for the fourth embodiment, R is the same as for the fourth embodiment, and R3 represents E or Het4 each optionally substituted on the non-aromatic ring by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, Q, QZ, Het1, HeI1Z, R, RZ, Het2, Het2Z, or d-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa, and E or Het4 each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen (F, Cl, Br, I), OH, CN, NRaRa. 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORh, NR-aC(O)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QZ, Het1, HCt1Z, R, RZ, Het2, Het2Z, or C1-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaRa.
The compounds of formula I have activity as medicaments. In particular the compounds of formula (I) are LXR agonists.
Specific compounds of the invention are 4-({ l-[3-chloro-5-(trifluoromethyl)pyridin-2- yl]piperidin-4-yl}amino)-2-isopropyl-5-phenylisothiazole-3(2H)-thione 1,1-dioxide and 2- isopropyl-5-phenyl-4-[(4-phenylbutyl)amino]isothiazole-3(2H)-thione 1,1-dioxide or a pharmaceutically acceptable salt thereof.
In another aspect of the invention, there is provided a compound according to formula (V) in which R isopropyl and R is phenyl. In another aspect of the invention, there is provided a compound according to formula (VI) in which R1 is isopropyl, R2 is phenyl and L is a leaving group such as for instance Cl, Br, I, methanesulfonate (MsO) or trifluoromethanesulfonate (OTf).
Certain compounds of the present invention may exist as tautomers or stereoisomers (e.g. racemate, enantiomer, diastereomer or E- or Z-isomer). It is to be understood that the present invention encompasses all such tautomers or stereoisomers.
Certain compounds of the present invention may exist as solvates or hydrates. It is to be understood that the present invention encompasses all such solvates or hydrates.
The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention. :
A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, nitric, methansulphonic, sulphuric, phosphoric, trifluoroacetic, pαra-toluene sulphonic, 2-mesitylen sulphonic, citric, acetic, tartaric, fumaric, lactic, succinic, malic, malonic, maleic, 1,2-ethanedisulphonic, adipic, aspartic, benzenesulphonic, benzoic, ethanesulphonic or nicotinic acid. In addition a suitable pharmaceutically acceptable salt of a compound of the invention, is, for example, a base-addition salt of a compound of the invention which is sufficiently acidic, for example, a metal salt, for example, sodium, potassium, calcium, magnesium, zinc or aluminum, an ammonium salt, a salt with an organic base which affords a physiologically acceptable cation, which includes quartenery ammonium hydroxides, for example methylamine, ethylamine, diethylamine, trimethyl amine, tert- butylamine, triethylamine, dibenzylamine, N,N-dibenzylethylamine, cyclohexylethylamine, tris-(2-hydroxyethyl)amine, hydroxyethyl diethylamine, (IR, 2S)-2-hydroxyinden-l-amine, morpholine, N-methylpiperidine, N-ethylpiperidine, piperazine, methylpiperazine, adamantylamine, choline hydroxide, tetrabutylammonium hydroxide, tris- (hydroxymethyl)methylamine hydroxide, L-arginine, N-methyl D-glucamine, lysine or arginine.
The compound of the formula (I), or other compounds disclosed herein, may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the formula (I). Examples of pro-drugs include in vivo hydrolysable esters and in vivo hydrolysable amides of a compound of the formula (I).
Methods of preparation
The compounds of the invention may be prepared as outlined in the Schemes below. However, the invention is not limited to these methods. The compounds may also be prepared as described for structurally related compounds in the prior art. The reactions can be carried out according to Standard procedures or as described in the experimental section.
Figure imgf000046_0001
Scheme I In Scheme I "reagent" means a reagent that can transform the hydroxy group in the compound of formula (V) into a leaving group L. Examples of such leaving groups are for instance Cl, Br, I, methanesulfonate (OMs) or trifluoromethanesulfonate (OTf).
In Scheme I R1, R2 and R3 are as defined above.
The expression "inert organic solvent" refers to a solvent which does not react with the starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product. Examples of such solvents are for instance dimethylformamide, methylene chloride and acetonitrile.
The individual reactions steps in Scheme I may be performed while heating either using conventional means such as heating the reaction mixture on an oil bath, or heating the reaction mixture in a microwave oven.
Furthermore, it shall be understood that the R1 group in a compound of formula (I) can be replaced by another R1 group, e.g. cyclopentyl. For example, when R1 is tert-bnty\ it can be removed by deprotection with trifluoroacetic acid, and the resulting compound can subsequently be reacted with an alkylating agent containing the new R1 group.
It shall be understood that in some of the reactions in this application it may be necessary to use protecting group for functionalities such as for example hydroxyl groups, amino groups, and carboxyl groups. Further representative protecting groups can be found in T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley and Sons, Inc., New York (1999), which is incorporated hereby by reference in its entirety.
It shall be understood that the diethyl oxalate used for making compound (V) in Scheme I can be exchanged for equivalent reagents such as e.g. methyl oxalyl chloride.
It shall be understood that the potassium fø/t-butoxide used in the Scheme above can be exchanged for equivalent reagents such as e.g. lithium tørt-butoxide. Compounds of formula (II) and (IV) are commercially available or may be prepared as described in the experimental part in this patent application or by methods known by those skilled in the art.
5 Compounds of formula (VII) are commercially available or may be prepared as described in the experimental part in this patent application or by methods known by those skilled in the art.
Certain compounds of formula (V) or (VI) are believed to be novel and are claimed herein as 0 useful intermediates in the preparation of compounds of formula (I).
It is to be understood that when R1 or R3 represent nitrogen oxides in compounds of formula I these are prepared from the corresponding amines and an oxidizing agent such as metachloropeibenzoic acid (MCPBA) optionally in the presence of an inert organic solvent 5 such as dichloromethane.
■ Persons skilled in the art will appreciate that, in order to obtain compounds of the invention in an alternative and in some occasions, more convenient manner, the individual process steps mentioned hereinbefore may be performed in a different order, and/or the individual reactions 0 may be performed at different stage in the overall route (i.e. chemical transformations may be performed upon different intermediates to those associated hereinbefore with a particular reaction).
5 Pharmaceutical preparations
The compounds of the invention will normally be administered via the oral, parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable salt or solvate 0 thereof, or a solvate of such a salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses. Suitable daily doses of the compounds of the invention in therapeutical treatment of humans are about 0.0001-100 mg/kg body weight, preferably 0.01-10 mg/kg body weight.
Oral formulations are preferred particularly tablets or capsules which may be formulated by methods known to those skilled in the art to provide doses of the active compound in the range of 0.007 mg to 700 mg for example 1 mg, 3 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg and 250 mg.
According to a further aspect of the invention there is thus provided a pharmaceutical formulation including any of the compounds of the invention, or pharmaceutically acceptable derivatives thereof, in admixture with pharmaceutically acceptable excipients, oils which may be glycerides, diluents and/or carriers.
Pharmacological properties The compounds of formula (I) are useful for normalization of cholesterol homeostasis, decreasing intestinal cholesterol absorption, improving reverse cholesterol transport, improving HDL functionality, increasing HDL-cholesterbl levels, decreasing LDL-cholesterol levels, decreasing cholesterol content of apoB -containing lipoproteins, stimulating cholesterol efflux from vascular cells and/or decreasing the inflammatory response of vascular cells. As a consequence of these properties the compounds of formula (I) are expected to have anti- atherosclerotic effects.
The compounds of formula (I) are useful in the prevention or treatment of cardiovascular disease in a mammal, particularly a human. The compounds of formula (I) are useful in the prevention or treatment of atherosclerosis in a mammal, particularly a human. Cardiovascular disease includes but is not limited to conditions associated with atherosclerosis, arteriosclerosis, hypercholesterolemia, and other kinds of dyslipidemia that increase the risk for cardiovascular disease. In particular the compounds of formula (I) are useful in the treatment or prevention of cardiovascular disease, especially those involving atherosclerosis, hypercholesterolemia and dyslipidemia.
The compounds of formula (I) also serve to prevent lipid accumulation in, or remove lipids from, tissue deposits such as atherosclerotic plaques or xanthomas in a patient with atherosclerotic disease manifest by clinical signs such as angina, claudication, bruits, one that has suffered a mycardial infarction, stroke or transient ischemic attack, or one diagnosed by angiography, sonography or MRI.
The compounds of formula (I) also serve to prevent or reduce the risk of developing atherosclerosis, as well as for halting or slowing the progression of atherosclerotic disease 5 once it has become clinically evident, comprising the administration of a prophylactically or therapeutically effective amount, as appropriate, of a compound of formula (I) to a mammal, including a human, who is at risk of developing atherosclerosis or who already has atherosclerotic disease.
Atherosclerosis encompasses vascular diseases and conditions that are recognized and 0 understood by physicians practicing in the relevant fields of medicine. Atherosclerotic cardiovascular disease including restenosis following revascularization procedures, coronary . heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease including multi-infarct dementia, and peripheral vessel disease including erectile dysfunction are all clinical manifestations of atherosclerosis and are 5 therefore encompassed by the terms "atherosclerosis" and "atherosclerotic disease".
• The present compounds of formula (I) are also useful for the prophylaxis and/or treatment of clinical conditions associated with atherosclerosis such as inherited or induced hypercholesterolemia as well as inherited or induced reduced sensitivity to insulin (insulin 0 resistance syndrome also known as metabolic syndrome) and associated metabolic disorders .These clinical conditions will include, but will not be limited to, general obesity, abdominal obesity, arterial hypertension, hyperinsulinaemia, type 2 diabetes, type 1 diabetes and other more rare forms of diabetes mellitus and the dyslipidaemia characteristically appearing with insulin resistance. This dyslipidaemia, also known as the atherogenic 5 lipoprotein profile, is characterised by moderately elevated non-esterified fatty acids, elevated VLDL triglyceride rich particles, high ApoB levels, low HDL levels associated with low apoAI levels in the presence of small, dense, LDL particles, phenotype B.
The compounds of formula (I) are expected to be useful in treating patients with combined or 0 mixed hyperlipidemias and dyslipidemias, especially low HDL levels with or without other manifestations of the metabolic syndrome.
The compounds of formula (I) are expected to be useful in treating patients with low HDL levels of other reasons than metabolic syndrome or type 2 diabetes. Treatment with the compounds of formula (I) are expected to lower the cardiovascular morbidity and mortality associated with atherosclerosis due to their antidyslipidaemic as well as antiinflammatory properties. The cardiovascular disease conditions include macro- angiopathies of various internal organs causing myocardial infarction, congestive heart failure, cerebrovascular disease and peripheral arterial insufficiency. The insulin sensitizing effect of the compounds of formula (I) is also expected to prevent or delay the development of type 2 diabetes from the metabolic syndrome .and diabetes of pregnancy. Therefore the development of long-term complications associated with chronic hyperglycaemia in diabetes mellitus such as the micro-angiopathies causing renal disease, retinal damage and peripheral vascular disease of the lower limbs are expected to be delayed.
The compounds of formula (I) may also be useful- for the prevention or treatment of inflammation and neurodegenerative diseases or neurological disorders. Accordingly, this invention also provides a method for preventing or. treating inflammation in the CNS, reducing amyloid pathology and a method for preventing or treating neurodegenerative diseases or disorders characterized by neuron degeneration, neuron injury or impaired plasticity or inflammation in the CNS. The neurodegenerative diseases or conditions characterized by neuron degeneration and inflammation will include but will not be limited to stroke, Alzheimer's disease, fronto-temporal dementias (taupathies), peripheral neuropathy, Parkinson's disease, dementia with Lewy bodies, Huntington's disease, amyotrophic lateral sclerosis and multiple sclerosis.
The compounds of formula (ϊ) are useful in preventing or treating inflammatory conditions or diseases. These diseases or conditions will include but will not be limited to atherosclerotic diseases such as angina pectoris and myocardial infarction but also rheumatoid arthristis, juvenile rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis, degenerative joint disease, one or more connective tissue diseases, ankylosing spondolytis, bursitis, Sjogren's syndrome, psoriasis, psoriatic arthritis, neuraligia, synovitis, glomerulonephritis, vasculitis or sarcoidosis as well as inflammatory bowel diseases such as Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, indeterminant colitis, irritable bowel disorder, irritable bowel syndrome and distal proctitis. Compounds of formula (I) may also be used in other inflammatory conditions of the lung including asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease and pneumonia bronchitis. Furthermore the compounds of formula (I) may be useful in treatment of various conditions outside the cardiovascular system whether or not associated with insulin resistance, like polycystic ovarian syndrome, obesity and cancer.
The present invention provides a method of treating and/or preventing rheumatoid arthritis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing juvenile rheumatoid arthritis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing systemic lupus erythematosus comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing osteoarthritis comprising the administration of an effective amount of a compound of formula (I) to a ■ mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing degenerative joint disease comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing one or more connective tissue diseases comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing ankylosing spondolytis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof. The present invention provides a method of treating and/or preventing bursitis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing Sjogren's syndrome comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing psoriasis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing psoriatic arthritis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing neuraligia comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing synovitis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing glomerulonephritis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing vasculitis or sarcoidosis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof. The present invention provides a method of treating and/or preventing Coeliac disease comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing proctitis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing eosinopilic gastro- enteritis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing mastocytosis comprising the administration of an effective amount of a compound of formula (ϊ) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing microscopic colitis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing indeterminant colitis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method αf treating and/or preventing irritable bowel disorder comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing inflammatory bowel disease comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof. The present invention provides a method of treating and/or preventing Crohn's disease comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing ulcerative colitis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing irritable bowel syndrome comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing the insulin resistance syndrome and/or metabolic disorders (as defined above) comprising the administration of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing type 2 diabetes comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing cardiovascular disease comprising the administration of an effective amount of a compound of formula (I) to a - mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing atherosclerosis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing hypercholesterolemia comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing conditions associated with a need for improving reverse cholesterol transport comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing conditions associated with a need for decreasing intestinal cholesterol absorption comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing conditions associated with a need for increasing HDL-cholesterol levels comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof. >. ■
The present invention provides a method of treating and/or preventing conditions associated with a need for decreasing LDL-cholesterol levels comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing inflammatory conditions comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing Alzheimer's disease comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing arteriosclerosis comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing conditions associated with a need for improving HDL function comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof. The present invention provides a method of treating and/or preventing hyperlipidemic conditions comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing dyslipidemic conditions comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
The present invention provides a method of treating and/or preventing dyslipidemia comprising the administration of an effective amount of a compound of formula (I) to a mammal (particularly a human) in need thereof.
In a further aspect the present invention provides the use of a compound of formula (I) as a medicament. ■
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of rheumatoid arthritis.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of juvenile rheumatoid arthritis.
In a further aspect the present invention provides the use of a compound of formula (I) in the_ manufacture of a medicament for the treatment and/or prohylaxis of systemic lupus erythematosus.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of osteoarthritis.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of degenerative joint disease. In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of one or more connective tissue diseases.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of ankylosing spondolytis.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of bursitis.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of Sjogren's syndrome.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of psoriasis.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of psoriatic arthritis.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of neuraligia.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of synovitis.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of glomerulonephritis.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of vasculitis or sarcoidosis.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of Coeliac disease. In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of proctitis.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of eosinopilic gastroenteritis.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of mastocytosis.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of microscopic colitis.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of indeterminant colitis.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of irritable bowel disorder.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a. medicament for the treatment and/or prohylaxis of inflammatory bowel disease.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of Crohn's disease.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of ulcerative colitis.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of irritable bowel syndrome.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of dyslipidemic conditions. In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prohylaxis of insulin resistance syndrome and/or metabolic disorders.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prophylaxis of cardiovascular disease.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prophylaxis of atherosclerosis.
In a further aspect the present invention provided the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prophylaxis of hypercholesterolemia.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prophylaxis of conditions associated with a need for improving reverse cholesterol transport.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prophylaxis of conditions associated with a need for decreasing intestinal cholesterol absorption.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prophylaxis of conditions associated with a need for increasing HDL-cholesterol levels.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prophylaxis of conditions associated with a need for decreasing LDL-cholesterol levels.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prophylaxis of inflammatory conditions. In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prophylaxis of Alzheimer's disease.
5 In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prophylaxis of arteriosclerosis.
In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prophylaxis of type 2 diabetes. 0
In a further aspect the present invention provides the use of a compound of formula (I) in the . manufacture of a medicament for the treatment and/or prophylaxis of conditions associaieo with a need for improving HDL function.
5 In a further aspect the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prophylaxis of hyperlipidemic conditions.
■ In a further aspect the present invention provides the use of a compound of formula (I) in the 0 manufacture of a medicament for the treatment and/or prophylaxis of dyslipidemia.
Combination Therapy
5 The compounds of the invention may be combined with another therapeutic agent that is useful in the treatment of disorders associated with the development and progress of atherosclerosis such as hypertension, hyperlipidaemias, dyslipidaemias, diabetes, inflammation and obesity. The compounds of the invention may be combined with another therapeutic agent that decreases the ratio of LDL:HDL or an agent that causes a decrease in 0 circulating levels of LDL-cholesterol. In patients with diabetes mellitus the compounds of the invention may also be combined with therapeutic agents used to treat complications related to micro-angiopathies. In another aspect of the present invention, the compund of formula (I) , or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with cholesterol biosynthesis inhibitors, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof. Suitable cholesterol biosynthesis inhibitors include HMG CoA reductase inhibitors, squalene synthesis inhibitors and squalene epoxidase inhibitors. Suitable squalene synthesis inhibitor are squalestatin 1, TAK-475, compounds described in WO2005012284 and a suitable squalene epoxidase inhibitor is NB- 598. In this aspect of the invention, the compund of formula (I) , or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administrated in association with an HMG CoA reductase inhibitor, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof. Suitably the HMG CoA reductase inhibitor, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof are statins well known in the art. Particular statins are selected from the group consisting of atorvastatin, fluvastatin, pitavastatin, lovastatin, mevastatin, nicostatin, nivastatin, pravastatin and simvastatin, or a pharmaceutically acceptable salt, especially sodium or calcium, solvate, solvate of such a salt or a prodrug thereof. A particular statin is atorvastatin, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof. A more particular statin is atorvastatin calcium salt. A particularly preferred statin is, however, rosuvastatin, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof. A preferable particular statin is rosuvastatin calcium salt.
In the present application, the term "cholesterol biosynthesis inhibitors" also includes chemical modifications of the HMG CoA reductase inhibitors, squalene synthesis inhibitors and squalene epoxidase inhibitors, such as esters, prodrugs and metabolites, whether active or inactive.
In another aspect of the present invention, the compund of formula (I) , or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt,, may be administered in association with an inhibitor of the ileal bile acid transport system (IBAT inhibitor), or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
Suitable compounds possessing IBAT inhibitory activity have been described, see for instance the compounds described in WO 93/16055, WO 94/18183, WO 94/18184, WO 96/05188, WO 96/08484, WO 96/16051, WO 97/33882, WO 98/07449, WO 98/03818, WO 98/38182, WO 99/32478, WO 99/35135, WO 98/40375, WO 99/35153, WO 99/64409, WO 99/64410, WO 00/01687, WO 00/47568, WO 00/61568, WO 00/62810, WO 01/68906, DE 19825804, WO 00/38725, WO 00/38726, WO 00/38727, WO 00/38728, WO 00/38729, WO 01/68906, WO 01/66533, WO 02/32428, WO 02/50051, WO 03/040124, WO 03/040127, 5 WO03/043992, WO03/061604, WO 04/020421, WO 04/076430, EP 864582, EP 489423, EP 549 967, EP 573 848, EP 624 593, EP 624 594, EP 624 595 and EP 624 596 and the contents of these patent applications are incorporated herein by reference.
Further suitable compunds possessing EBAT inhibitory activity have been described in WO 94/24087, WO 98/56757, WO 00/20392, WO 00/20393, WO 00/20410, WO 00/20437, WO
10 01/34570, WO 00/35889, WO 01/68637, WO 02/08211, WO 03/020710, WO 03/022825, . WO 03/022830, WO 03/022286, WO 03/091232, WO 03/106482, JP 10072371 , US 5070103, EP 251 315, EP 417 725, EP 869 121, EP 1 070 703 and EP 597 107 and the contents of these patent applications are incorporated herein by reference. Particular classes of IBAT inhibitors suitable for use in the present invention are
15 benzodiazepines, and the compounds described in the claims, particularly claim 1, of WO 00/01687, WO 96/08484 and WO 97/33882 are incorporated herein by reference. Other suitable classes of EBAT inhibitors are the 1,2-benzothiazepines, 1,4-benzothiazepines and 1,5-berizothiazepines. A further suitable class of EBAT inhibitors is the 1,2,5- benzothi adi azepines .
20 One particular suitable compound possessing IBAT inhibitory activity is (3i?,5i?)-3-butyl-3- , ethyl- 1 , 1 -dioxido-5-phenyl-2,3 ,4,5-tetrahydro- 1 ,4-benzothiazepin-8-yl β-D- glucopyranosiduronic acid (EP 864 582). A further suitable compound possessing EBAT inhibitory activity is S-8921 (EP 597 107).
5 In another aspect of the present invention, the compund of formula (I) , or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with a cholesterol absorption antagonist , or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, for example AVE-5530 or for example azetidinones such as ezetrol (zetia, ezetimibe) and those described in US 5,767,115 which are 0 incorporated herein by reference. Suitable compounds possessing cholesterol absorption antagonist activity have been described, see for instance the compounds described in WO 02/50027, WO 02/66464, WO 04/005247, WO 04/000803, WO 04/000804, WO 04/000805, WO05021495, WO05021497 and WO05033100 which are incorporated herein by reference. In another aspect of the present invention, the compund of formula (I) , or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with a bile acid sequestrant or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof. Suitable bile acid sequestrants include HBS-107, cholestyramine (Questran® , LoCholest® ), cholestemide (Cholebine® ), colesevelam (Welchol® ), cholestipol (Colestid® ) and cosevelam hydrochloride.
In another aspect of the present invention, the compound of formula (I) , or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with other agents that increase reverse cholesterol transport by other means than increasing expression of ABG-transporters, eg. ApoA-1 mimetica. See for instance the compounds described in WO-2004094471 which are incorporated herein by reference. Suitable apoA-1 mimetica include D-F4, ETC 216, ETC 642, RTC 588, ETC 1001, Apo Al Milano, D-4F and AVP-26452. • .
In another aspect of the invention, the compound of formula (I) , or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with a peroxisome proliferator-activated receptor (PPAR) modulating agent. PPAR modulating agents include a PPAR alpha and/or gamma and/or delta agonist, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof. Suitable PPAR alpha'and/or gamma and/or delta agonists, pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof are well known in the art. These include the compounds described in WO 01/12187, WO 01/12612, WO 99/62870, WO 99/62872, WO 99/62871, WO 98/57941, WO 01/40170, WO 04/000790, WO 04/000295, WO 04/000294, WO 03/051822, WO 03/051821, WO 02/096863, WO 04/056748, WO 03/051826, WO 02/085844, WO 01/40172, J Med Chem, 1996, 39, 665, Expert Opinion on Therapeutic Patents, 10 (5), 623-634 (in particular the compounds described in the patent applications listed on page 634) and J Med Chem, 2000, 43, 527 which are all incorporated herein by reference. Particularly a PPAR alpha and/or gamma and/or delta agonist refers to muraglitazar (BMS 298585), rivoglitazone (CS-OIl), netoglitazone (MCC-555), balaglitazone (DRF-2593, NN-2344), clofibrate (Atromid-S® ), fenofibrate, bezafibrate (Oralipin® ), gemfibrozil (Lopid® ), ciprofibrate (Ciprol® ), pioglitazone (Actos® ), rosiglitazone (Avandia® ), AVE- 0847, AVE-8134, CLX-0921, DRP-10945, DRF-4832, E-3030, K-Hl, KRP-101, LBM-642 (oxeglitazar), LY-518674, LY-674, naveglitazar (LY-818), LY-929, 641597, GW-590735, GW-677954, GW-501516, metaglidasan (MBX-102), MBX-2044, ONO-5129, PLX-204, R- 483 (BM131258), R-119702, , T-131 (AMG-131), TAK-559 or TAK-654. Particularly a PPAR alpha and/or gamma and/or delta agonist refers to tesaglitazar ((S)-2-ethoxy-3-[4-(2- 5 {4-methanesulphonyl-oxyphenyl}ethoxy)phenyl]propanoic acid) and pharmaceutically acceptable salts thereof.
In yet another aspect of the invention, the compound of formula (I) , or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in 10 association with a pyruvate dehydrogenase kinase (PDK) inhibitor, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In another aspect of the invention, the compound of formula (I) , or a pharmaceutically ■ ' acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in ; i 5 association with a cholesteryl ester transfer protein (CETP) inhibitor, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, for example JTT-705, ■ torcetrapib (CP-529414) and those referenced and described in WO 00/38725 page 7 line- 22 - page 10, line 17 which are incorporated herein by reference.
20 In another aspect of the invention, the compound of formula (I) , or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with a microsomal transfer protein (MTP) inhibitor, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, for example implipatide, CP-346086, JTT-130 and those described in WO 03/004020, WO 03/002533, WO 02/083658
25 and WO 00/242291, and the contents of these patent applications are incorporated herein by reference, or those described in Science, 282, 751-54, 1998 which are incorporated herein by reference.
In another aspect of the invention, the compound of formula (I), or a pharmaceutically 30 acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with an agonist to the receptor HM74A (nicotinic acid receptor). Examples of HM74A agonists are e g compounds described in WO2005011677, WO2004032928, WO2004033431 or a nicotinic acid derivative, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, including slow release and combination products, for example, nicotinic acid (niacin), acipimox, nicofuranose, NIASPAN® and niceritrol.
In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with a acyl coenzymA: cholesterol O-acyltransferase (ACAT) inhibitor, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, for example CS-505, eflucimibe (F-12511), K-604 and SMP-797.
In yet another aspect of the invention, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with modulators of nuclear hormone receptors such as farnesoid X receptor (FXR), or pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof for example EMT-747, or modulators of nuclear receptors such as retenoid X receptor (RXR), or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In another aspect of the invention,1 the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with a phytosterol compound, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, for example stands and FM- VP4.
In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with other therapies for the treatment of metabolic syndrome or type 2 diabetes and its associated complications, these include biguanide drugs, for example metformin, phenformin and buformin, insulin (synthetic insulin analogues, amylin) and oral antihyperglycemics (these are divided into prandial glucose regulators and alpha-glucosidase inhibitors). An example of an alpha-glucosidase inhibitor is acarbose or voglibose or miglitol. An example of a prandial glucose regulator is repaglinide or nateglinide.
In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with a sulfonylurea for example: glimepiride, glibenclamide (glyburide), gliclazide, glipizide, gliquidone, chloropropamide, tolbutamide, acetohexamide, glycopyramide, carbutamide, glibonuride, glisoxepid, glybuthiazole, glibuzole, glyhexamide, glymidine, glypinamide, phenbutamide, tolcylamide and tolazamide. Preferably the sulfonylurea is glimepiride or glibenclamide (glyburide). More preferably the sulfonylurea is glimepiride. Therefore the present invention includes administration of a compound of the present invention in conjunction with one, two or more existing therapies described in this paragraph. The doses of the other existing therapies for the treatment of type 2 diabetes and its associated complications will be those known in the art and approved for use by regulatory bodies for example the FDA and may be found in the Orange Book published by the EDA. Alternatively smaller doses may be used as a result of the benefits derived from the combination.
In another aspect of the invention, the compound of formula (I), or a pharmaceutically • acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with an antihypertensive compound for example althiazide, benzthiazide, captopril, carvedilol, chlorothiazide sodium, clonidine hydrochloride, cyciothiazide, delapril hydrochloride, dilevalol hydrochloride, doxazosin mesylate, fosinopril sodium,- guanfaeine hydrochloride, methyidopa, metoprolol succinate, moexipril hydrochloride, monatepil maleate, pelanserin hydrochloride, phenoxybenzemine hydrochloride, prazosin hydrochloride, primidolol, quinapril hydrochloride, quinaprilat, ramipril, terazosin hydrochloride, candesartan, candesartan cilexetil, telmisartan, amlodipine besylate, amlodipine maleate and bevantolol hydrochloride, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with an angiotensin converting enzyme (ACE) inhibitor. Particular ACE inhibitors or pharmaceutically acceptable salts, solvates, solvate of such salts or prodrugs thereof, including active metabolites, which can be used in combination with a compound of formula (I) include but are not limited to, the following compounds: alacepril, alatriopril, ancovenin, benazepril, benazepril hydrochloride, benazeprilat, benzoylcaptopril, captopril, captopril- cysteine, captopril-glutathione, ceranopril, cilazapril, cilazaprilat, delapril, delapril-diacid, enalapril, enalaprilat, enapril, epicaptopril, foroxymithine, fosfenopril, fosenopril, fosenopril sodium, fosinopril, fosinopril sodium, fosinoprilat, fosinoprilic acid, hemorphin-4, imidapril, indolapril, indolaprilat, lisinopril, lyciumin A, lyciumin B, moexipril, moexiprilat, muracein A, muracein B, muracein C, pentopril, perindopril, perindoprilat, pivalopril, pivopril, quinapril, quinapril hydrochloride, quinaprilat, ramipril, ramiprilat, spirapril, spirapril . hydrochloride, spiraprilat, spiropril,- spiropril hydrochloride, temocapril, temocapril hydrochloride, teprotide, trandolapril, trandolaprilat, zofenopril and zofenoprilat. Preferred ACE inhibitors are ramipril, ramiprilat, lisinopril, enalapril and enalaprilat. More preferred ACE inhibitors are ramipril and ramiprilat.
In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with an angiotensin II receptor antagonist. Preferred angiotensin II receptor antagonists, pharmaceutically acceptable salts, solvates, solvate of such salts or a prodrugs thereof for use in combination with a compound of formula (I) include, but are not limited to, compounds: candesartan, candesartan cilexetil, losartan, valsartan, irbesartan, telmisartan and eprosartan. Particularly preferred angiotensin II receptor antagonists or pharmaceutically acceptable derivatives thereof are candesartan and candesartan cilexetil, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with an andrenergic blocker. Andrenergic blocker include an alpha andrenergic blocker, or a beta andrenergic blocker, or a mixed alpha/beta andrenergic blocker or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof. Examples of andrenergic blockers are bretylium tosylate, dihydroergotamine so mesylate, phentolamine mesylate, solypertine tartrate, zolertine hydrochloride, carvedilol, labetalol hydrochloride, fenspiride hydrochloride, labetalol hydrochloride, proroxan, alfuzosin hydrochloride, acebutolol, acebutolol hydrochloride, alprenolol hydrochloride, atenolol, bunolol hydrochloride, carteolol hydrochloride, celiprolol hydrochloride, cetamolol hydrochloride, cicloprolol hydrochloride, dexpropranolol hydrochloride, diacetolol hydrochloride, dilevalol hydrochloride, esmolol hydrochloride, exaprolol hydrochloride, flestolol sulfate, labetalol hydrochloride, levobetaxolol hydrochloride, levobunolol hydrochloride, metalol hydrochloride, metoprolol, metoprolol tartrate, nadolol, pamatolol sulfate, penbutolol sulfate, practolol, propranolol hydrochloride, sotalol hydrochloride,, timolol, timolol maleate, tiprenolol hydrochloride, tolamolol, bisoprolol, bisoprolol fumarate and nebivolol or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with an andrenergic stimulant for example combination product of chlorothiazide and methyldopa, the combination product of methyidopa hydrochlorothiazide and methyldopa, clonidine hydrochloride, clonidine, the combination product of chlorthalidone and clonidine hydrochloride and guanfacine hydrochloride, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with calcium channel blocker for example clentiazem maleate, amlodipine besylate, isradipine, nimodipine, felodipine, nilvadipine, nifedipine, teludipine hydrochloride, diltiazem hydrochloride, belfosdil, verapamil hydrochloride or fostedil, or an AT-I blocker, or a saluretic, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with a diuretic for example the combination product of hydrochlorothiazide and spironolactone and the combination product of hydrochlorothiazide and triamterene, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with a vasodilator for example coronary vasodilators (for example fostedil, azaclorzine hydrochloride, chromonar hydrochloride, clonitrate, diltiazem hydrochloride, dipyridamole, droprenilamine, erythrityl tetranitrate, isosorbide dinitrate, isosorbide mononitrate, lidoflazine, mioflazine hydrochloride, mixidine, molsidomine, nicorandil, nifedipine, nisoldipine, nitroglycerine, oxprenolol hydrochloride, pentrinitrol, perhexiline maleate, prenylamine, propatyl nitrate, terodiline hydrochloride, tolamolol and verapamil), or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof. In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with a anti-anginal agents for example amlodipine besylate, amlodipine maleate, betaxolol hydrochloride, bevantolol hydrochloride, butoprozine hydrochloride, carvedilol, cinepazet maleate, metoprolol succinate, molsidomine, monatepil maleate, primidolol, ranolazine hydrochoride, tosifen or verapamil hydrochloride or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with an anti-coagulants selected from argatroban, bivalirudin, dalteparin sodium, desirudin, dicumarol, Iyapolate sodium, nafamostat mesylate, phenprocoumon, tinzaparin sodium and warfarin sodium or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof .
In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with an antithrombotic agents for example anagrelide hydrochloride, bivalirudin, cilostazol, dalteparin sodium, danaparoid sodium, dazoxiben hydrochloride, efegatran sulfate, enoxaparin sodium* fluretofen, ifetrόban, ifetroban sodium, lamifiban, lotrafiban hydrochloride, napsagatran, orbofiban acetate, roxifiban acetate, sibrafiban, tinzaparin sodium, trifenagrel, abciximab and zolimomab aritox or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with other agents that act as or deliver a Factor Ha agonist for example 3DP-4815, AZD-0837, melagatran, ximelagatran, ART-123, lepirudin, AVE-5026, bivaluridin, dabigatran etexilate, E-4444, odiparcil, ardeparin sodium, pegmusirudin, LB-30870, dermatan sulfate, argatroban, MCC-977, desirudin, deligoparin sodium, PGX-100, idraparinux sodium, SR-123781, SSR-182289A, SCH-530348, TRB50, TGN-167, TGN-255, and compounds described in WO94/29336, WO97/23499 and WO02/44145, which are incorporated hereby by reference.
In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with a fibrinogen receptor antagonists for example roxifiban acetate, fradafiban, orbofiban, lotrafϊban hydrochloride, tirofiban, xemilofiban, monoclonal antibody 7E3 and sibrafiban or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with a platelet inhibitors for example cilostezol, clopidogrel bisulfate, epoprostenol, epoprostenol sodium, ticlopidine hydrochloride, aspirin, ibuprofen, naproxen, sulindae, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone and piroxicam, dipyridamole or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with a platelet aggregation inhibitors for example acadesine, beraprost, beraprost sodium, ciprostene calcium, itezigrel, lifarizine, lotrafiban hydrochloride, orbofiban acetate, oxagrelate, fradafiban, orbofiban, tirofiban and xemilofiban or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with a hemorrheologic agents for example pentoxifylline or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof. In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with lipoprotein associated coagulation inhibitors; or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof. In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with a Factor Vila inhibitor or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with a Factor Xa inhibitor or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt or solvate theieof, or a solvate of such a salt, may be administered in association with a low molecular weight heparin for example enoxaparin, nardroparin, dalteparin, certroparin, parnaparin, reviparin and tinzaparin or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administered in association with an anti-obesity compound, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, for example a pancreatic lipase inhibitor e.g. orlistat (EP 129,748), ATL-962, GT-389255 or an appetite (satiety) controlling substance for example sibutramine (Meridia® , Reductil® , GB 2,184,122 and US 4,929,629), PYY 3-36 (amylin), APD-356, 1426, Axokine, T-71, a cannabinoid 1 (CBl) antagonist or inverse agonist, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, for example rimonabant (EP 656354), AVE-1625, CP945598, SR-147778, SLV-319, and as described in WOO 1/70700, or a Fatty Acid Synthesis (FAS) inhibitor, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof or a melanin concentrating hormone (MCH) antagonist, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, for example 856464 and as described in WO 04/004726. In another aspect of the invention, the compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administrated in association with an anti-inflammatory agent such as glucocorticoids, non-steroidal antiinflammatory agents (NSAID) or intestinal anti-inflammatory agents, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof. Suitable glucocorticoids will include, but will not be limited to betametason, dexametason, methyl prednisolon, prednisolon, prednison, triamcinoϊon, hydrocortison, cortison and budesonid. Suitable nonsteroidal anti-inflammatory agents will include, but will not be limited to indometacin, diclofenac, ibuprofen as well as acetylsalicylic acid. Suitable intestinal anti-inflammatory agents will include, but will not be limited to amino salicylates such as sulfasalazin, mesalazin, olsalazin and balsalazid.
In another aspect of the invention, the compounds of formula (I); or. a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, may be administrated in association with a cholinesterase inhibitor or an N-methyl-D-aspartate (NMDA) receptor antagonist, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof, such as donepezil, rivastigmin or galantamin or memantπv
Therefore in an additional feature of the invention, there is provided a method of treating and/or preventing metabolic disorders in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
Therefore in an additional feature of the invention, there is provided a method for the treatment and/or prohylaxis of type 2 diabetes and its associated complications in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
Therefore in an additional feature of the invention, there is provided a method of treating and/or preventing hyperlipidemic conditions in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
Tn aa additional featuie of the invention, there is provided a method for the treatment and/or prohylaxis of dyslipidemia in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for the treatment and/or prohylaxis of the insulin resistance syndrome in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for the treatment and/or prohylaxis of cardiovascular disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for the treatment and/or prohylaxis of atherosclerosis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for the treatment and/or prohylaxis of hypercholesterolemia in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing conditions associated with a need for improving reverse cholesterol transport in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing conditions associated with a need for decreasing intestinal cholesterol absorption in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing conditions associated with a need for increasing HDL-cholesterol levels in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing conditions associated with a need for decreasing LDL-cholesterol levels in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically - acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug' thereof.
In an additional feature of the invention, there is provided a method for the treatment and/or prohylaxis of inflammatory conditions in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for the treatment and/or prohylaxis of Alzheimer's disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for the treatment and/or prohylaxis of arteriosclerosis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a p.-odrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing conditions associated with a need for impioving HDL function in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing rheumatoid arthritis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing juvenile rheumatoid arthritis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing systemic lupus erythematosus in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing osteoarthritis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula
(I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing degenerative joint disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing one or more connective tissue diseases in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing ankylosing spondolytis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt, or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing bursitis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration'with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing Sjogren's syndrome in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing psoriasis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or 5 preventing psoriatic arthritis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable 0 salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing neuraligia in a warm-blooded animal, such as man, in need of such treatment .. which comprises administering to said animal an effective amount of a compound of fomrøla 5 (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the - other compounds described in this combination section, or a pharmaceutically acceptable salt, ' solvate, solvate of such a salt or a prodrug thereof.
0 In an additional feature of the invention, there is provided a method for treating and/or, preventing synovitis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the 5 other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing glomerulonephritis in a warm-blooded animal, such as man, in need of such 0 treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing vasculitis or sarcoidosis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention,. there is provided a method for treating and/or preventing Coeliac disease. in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt' or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing proctitis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing eosinopilic gastroenteritis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof. In an additional feature of the invention, there is provided a method for treating and/or preventing mastocytosis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing microscopic colitis in a warm-blooded animal, such as man, in need of -:uch treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing indeterminant colitis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing inflammatory bowel disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof. In an additional feature of the invention, there is provided a method for treating and/or preventing Crohn's disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing ulcerative colitis in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing irritable bowel syndrome in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt; in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
In an additional feature of the invention, there is provided a method for treating and/or preventing dyslipidemic conditions in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in simultaneous, sequential or separate administration with an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier.
According to a further aspect of the present invention there is provided a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
According to a further aspect of the present invention there is provided a kit comprising: a) a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in a first unit dosage form; • ■ . b) one of the other compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof; in a second unit dosage form; and c) container means for containing said first and second dosage forms.
According to a further aspect of the present invention there is provided a kit comprising: a) a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, together with a pharmaceutically acceptable diluent or carrier, in a first unit dosage form; ' ' ' b) one of the other compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in a second unit dosage form; and c) container means for containing said first and second dosage forms.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the the treatment and/or prophylaxis of metabolic disorders and its associated complications in a warm-blooded animal, such as man. According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the the treatment and/or prophylaxis of metabolic syndrome or type 2 diabetes and its associated complications in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of dyslipidemia in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of hyperlipidaemic conditions in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of cardiovascular disease in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of atherosclerosis in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt- and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of hypercholesterolemia in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of a conditions associated with a need for improving reverse cholesterol transport in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of a conditions associated with a need for decreasing intestinal cholesterol absorption in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), of such or a pharmaceutically acceptable salt or solvate thereof, or a solvate a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of a conditions associated with a need for increasing HDL-cholesterol levels in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of a conditions associated with a need for decreasing LDL-cholesterol levels in a warm-blooded animal, such as man. . .
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of inflammatory conditions in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of Alzheimer's disease in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of arteriosclerosis in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of a conditions associated with a need for improving HDL function in a warm-blooded animal, such as man. According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of rheumatoid arthritis in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of juvenile rheumatoid arthritis in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of systemic lupus erythematosus in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of osteoartrithis in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of degenerative joint disease in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the 5 formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of one or more connective tissue diseases in a warm-blooded animal, such as man. 0
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of-the other compounds described in this combination section, or a pharmaceutically ■ acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a 5- medicament for use in the treatment and/or prophylaxis of ankylosing spondolytis in a • warm-blooded animal, such as man.
.. ... . .. ( . . . . ..
According to another feature of the invention there is provided the use of a compound of the formula (I), or a'pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, 0 and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of bursitis in a warm-blooded animal, such as man.
5 According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of Sjogren's syndrome in a 0 warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of psoriasis in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of psoriatic arthritis in a warm-blooded animal, such as man. . • .
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of neuraligia in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or' a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of synovitis in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of glomerunephritis in a warm-blooded animal, such as man. According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of vasculitis or sarcoidosis in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of Coeliac disease in a.warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically ■ acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of proctitis in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of eosinopilic gastroenteritis in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of mastocytosis in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate, of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of microscopic colitis in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt ora prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of indeterminant colitis in a warm-blooded animal, such as man,
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of inflammatory bowel disease in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of Crohn's disease in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of ulcerative colitis in a warm-blooded animal, such as man. 5
According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a 0 medicament for use in the treatment and/or prophylaxis of irritable bowel syndrome in a warm-blooded animal, such as man.
According to another feature of the invention there is provided the use of a- compound of the • "formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, 5 and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of dyslipidemic conditions in a warm-blooded animal, such as man.
0 According to another feature of the invention there is provided the use of a compound of the ■ " formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, and one of the other compounds described in this combination section, or a pharmaceutically - acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment and/or prophylaxis of insuline resistance syndrome in a 5 warm-blooded animal, such as man.
According to a further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, 0 optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration of an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warm-blooded animal, such as man in need of such therapeutic treatment.
Further aspects of the invention
Further aspect 1. A compound of general formula I
Figure imgf000094_0001
or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, wherein R1 represents
X which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)R", SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)OR3, OC(O)Rb, S02NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(0)NRaRa, or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb or NRaC(0)NRaRa; cycloalkyl or heterocyclyl each optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(0)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)R", S02NRaRa, NRaSO2Rb, NRaC(0)0Rb, 0C(0)NRaRa, NRaC(0)NRaRa, or C1- C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb , C(O)NRaRa, NRaC(0)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaS02Rb, NRaC(O)ORb, 0C(0)NRaRa or NRaC(O)NRaRa; phenyl or heteroaryl each optionally substituted by one or more of the following: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, C(0)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)R", S02NRaRa, NRaSO2Rb, NRaC(0)0Rb, 0C(0)NRaRa, OSO2Rb, NRaC(0)NRaRa, SO2NHC(O)Rb, or d-C4alkyl optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(0)Rb, C(0)NRaRa, NRaC(0)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(0)0Rb, 0C(0)NRaRa or NRaC(O)NRaRa; cycloalkylY or heterocyclylY wherein cycloalkyl or heterocyclyl each optionally is substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(O)NRaRa, or d-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or 5 NRaC(O)NRaRa; phenylY or heteroarylY wherein phenyl or heteroaryl each optionally is substituted by one or more of the following: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, OSO2Rb, NRaC(0)NRaRa, SO2NHC(O)Rb, or CrC4alkyl which
10 is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, . S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRcC(0)Rb, C(O)OR3, OC(O)Rb r SO2NR3R3, NRaSO2Rb, NR3C(O)OR", OC(O)NR3R3 or NR3C(O)NR3R3; R2 represents phenyl which is optionally substituted by one or more of the following: halogen (Cl, F5 1, B.r),
. 15 OH, CN, NO2, NR3R3, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, C(0)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NR3R3, NR3SO2Rb, NRaC(0)0Rb, OC(O)NR3R3, OSO2Rb, NR3C(O)NR3R3, SO2NHC(O)Rb, or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NR3R3, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NR3R3, NRaC(0)Rb, C(O)OR3, OC(O)Rb, NRaSO2Rb, SO2NR3R3, NRaC(0)0Rb, OC(O)NR3ROr
20 NR3C(O)NR3R3;
R3 represents ' ■
X which is optionally substituted by one or more of the following: F, OH, CN, NRaR\ 0Rb,
• SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NR3R3, NR3SO2Rb, NRaC(O)ORb, OC(O)NR3R3, NR3C(O)NR3R3, or Cx-C4alkyl which is optionally
25 substituted by one or more of the following: F, OH, CN, NR3R3, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb or NR3C(O)NR3R3;
MP or Het3P wherein M and Het3 each optionally is substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NR3R3, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NR3R3, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, OC(O)NR3R3,
30 NR3C(0)0Rb, NR3C(O)NR3R3, Q, QT, Het1, Het1!1, R, RT, Het2, Het2T, or CrC4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR3R3, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NR3C(0)Rb, C(O)NR3R3, OC(O)Rb, C(O)ORa, SO2NR3R3, NR3SO2Rb, NR3C(O)ORb, OC(O)NR3R3 or NR3C(O)NR3R3, and wherein M or Het3 each optionally is substituted on the aromatic ring by one or more of the following: halogen (Cl, F, Br, I), OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QT, Het1, Het1!, R, RT, Het2, Het2T, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa; AP or Het P wherein A and Het5 each optionally is substituted by one or more of the following: halogen (F, Cl, Br, I), OH, CN, NO2, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, OSO2Rb, SO2NRaC(O)Rb, NRaC(O)NRaRa, Q, QT, Het1, Het!T, R, RT, Het2, Het2T, or Ci-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb,. C(O)NRaRa, OC(O)Rb, C(O)OR\ SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaRa; E or Het4 each optionally substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, Q, QZ, Het1, Het]Z, R, RZ, Het2, Het2Z, or 0!-04311CyI which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa, and E or Het4 each optionally is substituted on the aromatic ring by one or more of the folowing: halogen (F, Cl, Br, I), OH, CN, NRaR\ 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QZ, Het1, Het*Z, R, RZ, Het2, Het2Z, or Q^alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaRa; and in the above definitions X represents a straight or branched, saturated or unsaturated alkyl group having 1 to 6 carbon atoms wherein said alkyl group may optionally be interrupted by O, S, S(O), SO2, C(O), NRa, OC(O), C(O)O, NR3C(O), C(0)NRa, SO2NRa or NR3SO2; Y binds to nitrogen in 2-position in the isothiazol-3(2H)-thione 1,1 -dioxide and represents a straight or branched, saturated or unsaturated alkyl group having 1 to 3 carbon atoms wherein said alkyl group may optionally be interrupted or ended by O, S, S(O), SO2, C(O), OC(O), C(O)O, KR0C(O), C(O)NR0, NRC and/or Y is optionally substituted by one or more of the following: OH, F, CN, NRaRa, d-C4alkyl, 0Rb, SRb, S(O)Rb or SO2Rb; Z binds to E or Het4 and one of the following: Q, Het1, R or Het2, and represents a straight or branched, saturated or unsaturated alkyl group having 1 to 6 carbon atoms wherein said alkyl group may optionally be interrupted or ended by O, S, S(O), SO2, C(O), OC(O), C(O)O, NRaC(O), C(0)NRa, NR\ S02NRa, NRaS02, optionally consists only of one of the following: O, S, S(O), SO2, C(O), OC(O), C(O)O, NRaC(0), C(O)NRa, NRa , S02NRa, NR3SO2 and/or Z is optionally substituted by one or more of the following: OH, F, CN, NRCRC, C(O)R0, 0Rb, SR0, S(O)R0, SO2R0, phenyl, ρhenylCi-C3alkyl, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, NR3R3, SRb, S(O)Rb, SO2Rb, ORb; M represents a saturated or unsaturated non-aromatic monocyclic ring composed of 3, 4, 5, 6, 7 or 8 carbon atoms or a saturated or unsaturated non-aromatic or partly aromatic bicyclic ring composed of 4, 5, 6, 7, 8, 9 or 10 carbon atoms;
E represents a saturated or unsaturated non-aromatic monocyclic ring composed of 3, 4, 5, 6, 7 or 8 carbon atoms or a saturated or unsaturated non-aromatic or partly aromatic bicyclic ring composed of 4, 5, 6, 7, 8, 9 or 10 carbon atoms, and the ring binds, unless otherwise specified, through its non-aromatic part to nitrogen in 4-position on the isothiazol-3(2H)-thione 1,1- dioxide;
A represents an aromatic monocyclic ring composed of 3, 4, 5, 6, 7 or 8 carbon atoms or an aromatic bicyclic ring composed of 4, 5, 6, 7, 8, 9 or 10 carbon atoms; P binds to nitrogen in 4-position on the isothiazol-3(2H)-thione 1,1-dioxide and represents a straight or branched, saturated or unsaturated alkyl group having 1 to 6 carbon atoms wherein the alkyl group is optionally interrupted or ended by O, NRa, S, S(O), SO2, C(O), OC(O), C(O)O, NR3C(O), C(O)NR3, S02NRa, NR3SO2 and/or P is optionally substituted by one or more of the following: F, OH, CN, NRaRa, C(O)R0, 0Rb, SRb, S(O)Rb, SO2Rb, phenyl, phenylQ-Csalkyl, or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, NR3R3, SRb, S(O)Rb, SO2Rb or ORb;
Q represents a saturated or unsaturated non-aromatic monocyclic ring composed of 3, 4, 5, 6, 7, 8 carbon atoms, which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, phenyld alkyl, C(O)NR3R3, NRaC(0)Rb, C(O)ORa, OC(O)Rb, SO2NR3R3, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NR2C(O)NR3R3, or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, C(0)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, NRaSO2Rb, SO2NRaRa, NRaC(O)ORb, OC(O)NRaRaor NRaC(O)NRaRa; R represents a phenyl group which is optionally substituted by one or more of the following: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, phenylCialkyl, C(O)NRaRa, NRaC(0)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, 0C(0)NRaRa, OSO2Rb, NRaC(O)NRaRa, SO2NHC(O)Rb, or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, NRaSO2Rb, SO2NRaRa, NRaC(O)ORb, OC(0)NRaRaor NRaC(O)NRaRa;
T binds to M, Het\ A or Het1 and represents an alkyl group having 1 carbon atom or optionally consists of one or more of the following: O, NRa, S, S(O), SO2, C(O), OC(O), C(O)O, NR3C(O), C(0)NRa, SO2NRa or NR3SO2; Het1 represents a saturated or unsaturated non-aromatic 3-10 membered monocyclic ring in which one or more of the atoms in the ring is an element other than carbon, for example nitrogen, oxygen or. sulfur, and wherein the ring optionally is substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, phenylQ alkyl, C(0)NRaR\ NR3C(0)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(0)0Rb, 0C(0)NRaRa, NRaC(O)NRaRa, or C1-QaIkVl which is optionally substituted by one or more, of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(0)Rb, C(O)ORa, OC(O)Rb, NRaSO2Rb, SO2NRaRa, NRaC(0)0Rb, OC(O)NRaRaor NRaC(0)NRaRa; Het2 represents an aromatic 3-10 membered monocyclic ring in which one or more of the atoms in the ring is an element other than carbon, for example nitrogen, oxygen and sulfur, and which is substituted by one or more of the following: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, phenylQ alkyl, C(O)NRaRa, NRaC(0)Rb, C(O)OR3, OC(O)Rb, SO2NR3R3, NRaSO2Rb, NRaC(0)0Rb, 0C(0)NRaRa, OSO2Rb, NR3C(O)NR3R3, S02NHC(0)Rb, or CrC4alkyl optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(0)Rb, C(O)NR3R3, NR3C(0)Rb, C(O)OR3, OC(O)Rb, NRaS02Rb, SO2NR3R3, NR3C(0)0Rb, OC(O)NRaRaor NRaC(0)NRaRa; Het3 represents a saturated or unsaturated non-aromatic 3-10 membered monocyclic ring or a saturated or unsaturated non-aromatic or partly aromatic 4-10 membered bicyclic ring in which one or more of the atoms in the monocyclic or bicyclic ring is an element other than carbon, for example nitrogen, oxygen or sulfur;
Het4 represents a saturated or unsaturated non-aromatic 3-10 membered monocyclic ring or a saturated or unsaturated non-aromatic or partly aromatic 4-10 membered bicyclic ring in which one or more of the atoms in the monocyclic or bicyclic ring is an element other than carbon, for example nitrogen, oxygen or sulfur, and the ring binds, unless otherwise specified, through its non-aromatic part to nitrogen in 4-position on the isothiazol-3(2H)-thione 1,1- dioxide;
Ηet5 represents an aromatic 3-10 membered monocyclic ring or an aromatic 4-10 membered bicyclic ring in which one or more of the atoms in the monocyclic or bicyclic ring is an element other than carbon, for example nitrogen, oxygen or sulfur;
Ra independently represents Η or a straight or branched. saturated or unsaturated C1-C4alkyl chain optionally substituted by one or more F;
Rb independently represents a straight or branched, saturated or unsaturated Q-Qalkyl chain optionally substituted by one or more F; and
Rc independently represents Η or a straight or branched, saturated or unsaturated Q-Csalkyl chain optionally substituted by one or more F. . . .
Further aspect 2. A compound according to further aspect 1 or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, wherein
R1 represents
X which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb,
SRb, S(O)Rb, SO2Rb, C(O)Rb, or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb or C(O)Rb; cycloalkyl or heterocyclyl each optionally substituted by one or more of the following: F, OH,
CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, or C1-QaIkVl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb or C(O)Rb; phenyl or heteroaryl each optionally substituted by one or more of the following: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, or Q-Qalkyl optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb,
C(O)Rb; cycloalkylY or heterocyclylY wherein cycloalkyl or heterocyclyl each optionally is substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb,
C(O)Rb, or d-C4alkyl which is optionally substituted by one or more of the following: F, OH,
CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb; phenylY or heteroarylY wherein phenyl or heteroaryl each optionally is substituted by one or more of the following: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, 0Rb, SRb, S(O)Rb,
SO2Rb, C(O)Rb, or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb;
R2 represents phenyl which is optionally substituted by one or more of the following: halogen (Cl, F, I, Br),
OH, CN, NO2, NRaR\ ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, or CrC4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb,
C(O)Rb. ■ • •
Further aspect 3. A compound according to further aspect 2 or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, wherein • •
R1 represents
X which is optionally substituted by one or more of the following: F, OH, CN, NRaR\ 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, C(0)NRaRa, NRaC(0)Rb, C(O)ORa, OC(O)Rb, SO2NRaR\ .
NRaS02Rb, NRaC(0)0Rb, 0C(0)NRaRa, NRaC(O)NRaRa, or d-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb,
C(O)Rb or NRaC(0)NRaRa.
Further aspect 4. A compound according to further aspect 3 or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, wherein
R1 represents
X which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, or d-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb or C(0)Rb. Further aspect 5. A compound according to further aspect 1 or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, wherein R3 represents X which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(O)NRaRa, or d-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb or NRaC(0)NRaRa.
Further aspect 6. A compound according to further aspect 1 or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, . . . wherein
R3 represents ■ • " ; .-; . MP or Het3P wherein M and Het3 each optionally is substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR\ SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(0)NRaRa, Q, QT, Het1, HetJT, R, RT, Het2, Het2T, or Ci-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa, and wherein M or Het3 each optionally is substituted on the aromatic ring by one or more of the following: halogen (Cl, F, Br, I), OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaS02Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(0)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QT, Het1, HeI1T, R, RT, Het2, He-2T, or Ci-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(0)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaS02Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaRa; AP or Het5P wherein A and Het5 each optionally is substituted by one or more of the following: halogen (F, Cl, Br, I), OH, CN, NO2, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaS02Rb, OC(O)NRaRa, NRaC(0)0Rb, OSO2Rb, SO2NRaC(O)Rb, NRaC(O)NRaRa, Q, QT, Het1, HetJT, R, RT, Het2, HGt2T, or Ci-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NR3R3, NRaSO2Rb, NRaC(O)ORb, 0C(0)NRaRa or NRaC(O)NRaRa.
Further aspect 7. A compound according to further aspect 1 or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, wherein R3 represents
E or Het4 each optionally substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NRaR\ 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NR3R3, OC(O)Rb, C(O)OR3, SO2NR3R3, NRaS02Rb, OC(O)NRaRa, NR3C(O)OR5, NR3C(O)NR3R3, Q, QZ, Het1, Het'Z, R, RZ, Het2, Het2Z, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2R5, C(O)Rb, NEaC(O)Rb, C(O)NR3R3, OC(O)Rb, C(O)OR3, SO2NR3R3, NRaS02Rb, NR3C(O)ORb, OC(O)NR3R3 or NR3C(O)NR3R3 * and E or Het4 each optionally is substituted on the aromatic ring by one or more of the folowing: halogen (F, Cl, Br, I), OH, CN, NR3R3, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NR3C(O)Rb, C(O)NR3R3, OC(O)Rb, C(O)ORa, SO2NR3R3, NRaS02Rb, OC(O)NR3R3, NRaC(0)0Rb, NR8C(O)NR3R3, OSO2Rb, SO2NR3C(O)Rb, Q, QZ, Het1, HeI1Z, R, RZ, Het2, Het2Z, or C1-C4-UkVl which is optionally substituted by one or more of the following; F, OK, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NR3R3, OC(O)R0, C(O)OR3, SO2NR3R3, NR3SO2R", NR3C(0)0Rb, OC(O)NR3R3 OrNR3C(O)NR3R3.
Further aspect 8. A compound according to further aspect 2 or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, wherein
R represents
X which is optionally substituted by one Or more of the following: F, OH, CN, NR3Ra, 0Rb,
SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NR3R3, OC(O)Rb, C(O)OR3, SO2NR3R3,
NR3SO2R", NR3C(0)0Rb, OC(O)NR3R3, NR3C(O)NR3R3, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR3R3, 0Rb, SRb, S(O)Rb, SO2Rb,
C(O)Rb or NR3C(O)NR3R3. Further aspect 9. A compound according to further aspect 2 or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, wherein R3 represents MP or Het3P wherein M and Het3 each optionally is substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, Q, QT, Het1, HetJT, R, RT, Het2, Het2T, or CrC4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaR\ NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa, and wherein M or Het3 each optionally is substituted on the aromatic ring by one or more of the following: halogen (Cl, F, Br, I), OH, CN, NRaR3, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa ? NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(0)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or Q-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2R13, C(Θ)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaR\ NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa; AP or Het5P wherein A and Het5 each optionally is substituted by one or more of the following: halogen (F, Cl, Br, I), OH, CN, NO2, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa,' NRaC(0)0Rb, OSO2Rb, SO2NRaC(O)Rb, NRaC(O)NRaRa, Q, QT, Het1, Het!T, R, RT, Het2, Het2T, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, S02NRaRa, NRaS02Rb, NRaC(O)ORb, 0C(0)NRaRa or NRaC(O)NRaRa.
Further aspect 10. A compound according to further aspect 2 or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, wherein R3 represents
E or Het4 each optionally substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, 0C(0)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, 0C(0)NRaRa, NRaC(O)ORb, NRaC(0)NRaRa, Q, QZ, Het1, HeI1Z, R, RZ, Het2, Het2Z, or d-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa, and E or Het4 each optionally is substituted on the aromatic ring by one or more of the following: halogen (F, Cl, Br, I), OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QZ, Het1, HeI1Z, R, RZ, Het2, Het2Z, or Q-C^lkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa.
Further aspect 11. A compound according to further aspect 3 or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, wherein "
R3 represents
-X which is optionally substituted by one or more of the following: F, OH, CN, NRaR\ ORb,
SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa,
NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(0)NRaRa, or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb,
C(O)Rb or NRaC(0)NRaRa.
Further aspect 12. A compound according to further aspect 3 or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, wherein R3 represents
MP or Het P wherein M and Het each optionally is substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NR3R3, NR3SO2R5, 0C(0)NRaRa, NRaC(O)ORb, NRaC(0)NRaRa, Q, QT, Het1, Het1!1, R, RT, Het2, Het2T, or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NR3R3, ORb, SRb, S(O)Rb, SO2R\ C(O)Rb, NRaC(0)Rb, C(O)NR3R3, OC(O)Rb, C(O)OR3, SO2NR3R3, NRaS02Rb, NRaC(0)0Rb, OC(O)NR3R3 or NR3C(O)NR3R3, and wherein M or Her3 each optionally is substituted on the aromatic ring by one or more of the following: halogen (Cl, F, Br, I), OH, CN, NR3Ra, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, OSO2R5, SO2NRaC(O)Rb, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or Ci-C4.aU.yl which is optionally substituted by one or more of the following: F, -OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NR3R3, NRaSO2Rb, NR3C(0)0Rb, 0C(0)NRaRa or NR3C(O)NR3R3; AP or Het5P wherein A and Het5 each optionally is substituted by one or more of the following: halogen (F, Cl, Br, I), OH, CN, NO2, NR3Ra, 0Rb, SRb, S(O)Rb, SO2Rb, C(0)Rb, NRaC(0)Rb, C(O)NR3R3, OC(O)Rb, C(O)ORa, SO2NR3R3, NRaSO2Rb, 0C(0)NRaRa,
NRaC(O)ORb, OSO2Rb, SO2NRaC(O)Rb, NR3C(O)NR3R3, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or Q^alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(C)Rb, C(O)NR3R3, OC(O)Rb, C(O)OR3, SO2NR3R3, NRaSO2Rb, NRaC(0)0Rb, OC(O)NR3R3 or NRaC(0)NRaR3.
Further aspect 13. A compound according to further aspect 3 or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, wherein
R3 represents E or Het4 each optionally substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NR3R3, 0Rb, SRb, S(O)Rb, SO2Rb, C(0)Rb, NRaC(0)Rb, C(0)NR3Ra, OC(O)Rb, C(O)OR3, SO2NR3R3, NRaS02Rb, OC(O)NR3R3, NRaC(O)ORb, NR3C(O)NR3R3, Q, QZ, HetJ, Het'z, R, RZ, Het2, Het2Z, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR3R3, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NR3C(0)Rb, C(O)NR3R3, OC(O)Rb, C(O)ORa, SO2NR3R3, NRaSO2Rb, NRaC(0)0Rb, OC(O)NR3R3 or NR3C(O)NR3R3, and E or Het4 each optionally is substituted on the aromatic ring by one or more of the following: halogen (F, Cl, Br, I), OH, CN, NR3R3, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NR3R3, OC(O)Rb, C(O)OR3, SO2NR3R3, NRaSO2Rb, OC(O)NRaRa, NR3C(O)ORb, NR3C(O)NR3R3, OSO2Rb, SO2NRaC(O)Rb, Q, QZ, Het1, HeI1Z, R, RZ, Het2, Het2Z, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR3R3, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NR3C(0)Rb, C(O)NR3R3, OC(O)R5, C(O)OR3, SO2NR3R3, NRaSO2Rb, NRaC(0)0Rb, OC(O)NR3R3 or NR3C(O)NR3R3. Further aspect 14. A compound according to further aspect 4 or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, wherein R3 represents
X which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(O)NRaRa, or C1-QaIkVl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb or NRaC(O)NRaRa.
Furthei aspect 15. A compound according to further aspect 4 or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, wherein R3 represents
MP or Het3P wherein M and Her3 each optionally is substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb; SO2Rb, C(0)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, S02NRaRa, NRaSO2Rb, 0C(0)NRaRa, NRaC(0)0Rb, NRaC(O)NRaRa, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(0)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, 0C(0)NRaRa or NRaC(O)NRaRa, and wherein M or Het3 each optionally is substituted on the aromatic ring by one or more of the following: halogen (Cl, F, Br, I), OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(0)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, 0C(0)NRaRa, NRaC(0)0Rb, NRaC(O)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QT, Het1, Het^, R, RT, Het2, Het2T, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaR\ 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(0)0Rb, 0C(0)NRaRa or NRaC(0)NRaRa; AP or Het5P wherein A and Het5 each optionally is substituted by one or more of the following: halogen (F, Cl, Br, I), OH, CN, NO2, NRaR\ 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, S02NRaRa, NRaSO2Rb, 0C(0)NRaRa, NRaC(0)0Rb, OSO2Rb, S02NRaC(0)Rb, NRaC(O)NRaRa, Q, QT, Het1, He^T, R, RT, Het2, Het2T, or C1-C4-UlCyI which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaRa.
Further aspect 16. A compound according to further aspect 4 or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, wherein R3 represents E or Het4 each optionally substituted on the non-aromatic ring by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaR\ NRaS02Rb 0C(0)NRaRa, NRaC(O)ORb, NRaC(0)NRaRa, Q, QZ, Het1, HetxZ, R, RZ, Her2, HBt2Z, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaR3, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NR3R2, NRaSO2Rb, NRaC(0)0Rb, 0C(0)NRaRa or NR3C(O)NR3R3, and E or Het4 each optionally is substituted on the aromatic ring by one or more of the following: halogen (F, Cl, Br, I), OH, CN, NR3R3, ORb, SRb, S(O)Rb, SO2R5, C(O)Rb, NRaC(0)Rb, C(O)NR3R3, OC(O)Rb, C(O)OR3, SO2NR3R3, NRaSO2Rb, OC(O)NR3R3, NR3C(O)OR", NR3C(O)NR3R3, OSO2Rb, SO2NRaC(O)Rb, Q, QZ, Het1, HBt1Z, R, RZ, Het2, Het2Z, or d-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NR3R3, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NR3R3, OC(O)Rb, C(O)OR3, SO2NR3R3, NRaSO2Rb, NR3C(O)ORb, OC(O)NR3R3 or NRaC(0)NRaRa.
Further aspect 17. Specific compounds of the invention are 4-({ l-[3-chloro-5- (trifluoromethyl)pyridin-2-yl]piperidin-4-yl}amino)-2-isopropyl-5-phenylisothiazole-3(2H)- thione 1,1 -dioxide and 2-isopropyl-5-phenyl-4-[(4-phenylbutyl)amino]isothiazole-3(2H)- thione 1,1 -dioxide or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt.
Further aspect 18. A process for the preparation of a compound according to any one of further aspects 1-17, wherein R1, R2 or R3 are as defined in further aspect 1, comprising the step of reacting a compound of formula VIII,
Figure imgf000108_0001
vm
1 O *3 wherein R , R and R are as defined in further aspect 1, with Lawesson's reagent optionally in the presence of an inert organic solvent such as toluene.
Further aspect 19. A process for the preparation of a compound of formula VIΪI, wherein R1 and R2 are as defined in further aspect 1 and L is a leaving group such as Cl, Br, L methanesulfonate or trifluoromethanesulfonate, with a compound of formula VII,
R3NH2 vπ wherein R3 is as defined in further aspect 1, optionally in the presence of an inert organic solvent such as acetonitrile.
Further aspect 20. A pharmaceutical formulation comprising a compound according to any one of further aspects 1-17 in admixture with pharmaceutically acceptable adjuvants, diluents and/or carriers.
Further aspect 21. The use of a compound according to any one of further aspects 1-17 in therapy.
Further aspect 22. The use of a compound according to any of further aspects 1-17 for the manufacture of a medicament for the modulation of the nuclear hormone receptors LXR α and/or β.
Further aspect 23. The use of a compound according to any one of further aspects 1-17 in the manufacture of a medicament for the treatment and/or prophylaxis of cardiovascular disease. Further aspect 24. The use of a compound according to any one of further aspects 1-17 in the manufacture of a medicament for the treatment and/or prophylaxis of atherosclerosis.
Further aspect 25. The use of a compound according to any one of further aspects 1-17 in the manufacture of a medicament for the treatment and/or prophylaxis of hypercholesterolemia.
Further aspect 26. The use of a compound according to any one of further aspects 1-17 in the manufacture of a medicament for the treatment and/or prophylaxis of conditions associated with a need for improving reverse cholesterol transport.
Further aspect 27. The use of a compound according to any one of further aspects 1-17 in the manufacture of a medicament fo^ the treatment and/or prophylaxis of conditions associated with a need for decreasing intestinal cholesterol absorption.
Further aspect 28. The use of a compound according to any one of further aspects 1-17 in the manufacture of a medicament for the treatment and/or prophylaxis of conditions associated with a need for increasing HDL-cholesterol levels.
Further aspect 29. The use of a compound according to any one of further aspects 1-17 in the manufacture of a medicament for the treatment and/or prophylaxis of conditions associated with a need for decreasing LDL-cholesterol levels.
Further aspect 30. The use of a compound according to any one of further aspects 1-17 in the manufacture of a medicament for the treatment and/or prophylaxis of inflammatory conditions.
Further aspect 31. The use of a compound according to any one of further aspects 1-17 in the manufacture of a medicament for the treatment and/or prophylaxis of Alzheimer's disease.
Further aspect 32. The use of a compound according to any one of further aspects 1-17 in the manufacture of a medicament for the treatment and/or prophylaxis of arteriosclerosis. Further aspect 33. The use of a compound according to any one of further aspects 1-17 in the manufacture of a medicament for the treatment and/or prophylaxis of type 2 diabetes.
Further aspect 34. The use of a compound according to any one of further aspects 1-17 in the manufacture of a. medicament the treatment and/or prophylaxis of conditions associated with a need for improving HDL function.
Further aspect 35. The use of a compound according to any one of further aspects 1-17 in the manufacture of a medicament for the treatment and/or prophylaxis of lipid disorders (dyslipidemia) whether or not associated with insulin resistance.
Further aspect 36. A method of treating and/or preventing lipid disorders (dyslipidemia) whether or not associated with insulin resistance comprising the administration of a- compound according to any one of further aspects 1-17 to a mammal in need thereof.
Further aspect 37. A method for treatment and/or prophylaxis of cardiovascular disease comprising administering to a mammal, including man, in need of such a treatment an effective amount of a compound as defined in any of further aspects 1-17.
Further aspect 38. A method of treating and/or preventing atherosclerosis comprising.the administration of an effective amount of a compound of formula 1 according to any one of further aspects 1-17 to a mammal in need thereof.
Further aspect 39. A method for treatment and/or prophylaxis of hypercholesterolemia comprising administering to a mammal, including man, in need of such a treatment an effective amount of a compound as defined in any of further aspects' 1-17.
Further aspect 40. A method for treatment and/or prophylaxis of conditions associated with a need for improving reverse cholesterol transport comprising administering to a mammal, including man, in need of such a treatment an effective amount of a compound as defined in any of further aspects 1-17. Further aspect 41. A method for treatment and/or prophylaxis of conditions associated with a need for decreasing intestinal cholesterol absorption comprising administering to a mammal, including man, in need of such a treatment an effective amount of a compound as defined in any of further aspects 1-17.
Further aspect 42. A method for treatment and/or prophylaxis of conditions associated with a need for increasing HDL-cholesterol levels comprising administering to a mammal, including man, in need of such a treatment an effective amount of a compound as defined in any of further aspects 1-17.
Further aspect 43. A method for treatment and/or prophylaxis of conditions associated with a need for decreasing LDL- cholesterol levels comprising administering to a mammal, including man, in need of such a treatment an effective amount of a compound as defined in any of further aspects 1-17. ■ • .
Further aspect 44. A method for treatment and/or prophylaxis of inflammatory conditions comprising administering to a mammal, including man, in need of such a treatment an } effective amount of a compound as defined in any of further aspects 1-17.
Further aspect 45. A method for treatment and/or prophylaxis of Alzheimer's disease comprising administering to a mammal, including man, in need of such a treatment an effective amount of a compound as defined in any of further aspects 1-17.
Further aspect 46. A method for treatment and/or prophylaxis of arteriosclerosis comprising administering to a mammal, including man, in need of such a treatment an effective amount of a compound as defined in any of further aspects 1-17.
Further aspect 47. A method for treatment and/or prophylaxis of type 2 diabetes comprising administering to a mammal, including man, in need of such a treatment an effective amount of a compound as defined in any of further aspects 1-17.
Further aspect 48. A method for treatment and/or prophylaxis of conditions associated with a need for improving HDL function comprising administering to a mammal, including man, in need of such a treatment an effective amount of a compound as defined in any of further aspects 1-17.
For the further aspects 1-48 above the definitions mentioned hereinbefore or the following definitions shall apply:
The term "X" denotes a straight or branched, saturated or unsaturated alkyl group having 1 to 6 carbon atoms wherein said alkyl group may optionally be interrupted by O, S, S(O), SO2, C(O), NRa, OC(O), C(O)O, NR3C(O), C(O)NR3, SO2NR3 OrNR3SO2.
The term "Y" denotes a straight or branched, saturated or unsaturated alkyl group having 1 to 3 carbon atoms wherein said alkyl group binds tc nitrogen in 2-position in the isothiazol- 3(2H)-thione 1,1-dioxide and may optionally be interrupted or ended by O, S, S(O), SO2, C(O), OC(O), C(O)O, NRCC(O), C(O)NRC, NRC and/or Y is optionally substituted by one or more of the following: OH, F, CN, NRaRa, d-C4alkyl, 0Rb, SRb, S(O)R5 or SO2Rb. In the definition of "Y" the term "ended by O, S, S(O), SO2, C(O), OC(O), C(O)O, NR0C(O), C(O)NR0, NR0" means that the alkyl group has as the last position O, S, S(O), SO2, C(O), OC(O), C(O)O, NR0C(O), C(O)NR0 or NR0 before it binds further to phenyl, heteroaryl, cycloalkyl or heterocyclyl.
The term "Z" denotes a straight or branched, saturated or unsaturated alkyl group having 1 to 6 carbon atoms wherein said alkyl group binds to E or Her4 and one of the following: Q, Het1, R or Het2, and may optionally be interrupted or ended by O, S, S(O), SO2, C(O), OC(O), C(O)O, NR3C(O), C(O)NR3, NR3, SO2NR3, NR3SO2, optionally consists only of one of the following: O, S, S(O), SO2, C(O), OC(O), C(O)O, NR3C(O), C(O)NR3, NR3 , SO2NR3, NRaSO2 and/or Z is optionally substituted by one or more of the following: OH, F, CN, NR°RC, C(O)R0, 0Rb, SR0, S(O)R0, SO2R0, phenyl, phenylCi-C3alkyl, or d-C4alkyl which is optionally substituted by one or more of the following: F, OH, NR3R3, SRb, S(O)Rb, SO2Rb, ORb. In the definition of "Z" the term "ended by O, S, S(O), SO2, C(O), OC(O), C(O)O, NR3C(O), C(O)NR3, NR3, SO2NR3, NR3SO2" means that the alkyl group has as the last position O, S, S(O), SO2, C(O), OC(O), C(O)O, NR3C(O), C(O)NR3, NRa, SO2NR3 or NR3SO2 before it binds further to E, Het4, Q, Het1, R or Het2.
Ill The term "M" denotes a saturated or unsaturated non-aromatic monocyclic ring composed of 3, 4, 5, 6, 7 or 8 carbon atoms or a saturated or unsaturated non-aromatic or partly aromatic bicyclic ring composed of 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
The term "E" denotes a saturated or unsaturated non-aromatic monocyclic ring composed of 3, 4, 5, 6, 7 or 8 carbon atoms or a saturated or unsaturated non-aromatic or partly aromatic bicyclic ring composed of 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The ring binds, unless otherwise specified, through its non-aromatic part to nitrogen in 4-position on the isothiazol-3(2H)- thione 1,1-dioxide.
The term "A" denotes an aromatic monocyclic ring composed of 3, 4, 5, 6, 7 or 8 carbon atoms or ar aromatic bicyclic ring composed of 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
The term "P" denotes a straight or branched, saturated or unsaturated alkyl group having 1 to 6 carbon atoms wherein the alkyl group binds to nitrogen in 4-position on the isothiazol- 3(2H)-thione I5I -dioxide- and is optionally interrupted or ended by O, NR3, S, S(O), SO2, C(O), OC(O), C(O)O, NR3C(O), C(O)NR3, SO2NR3, NR3SO2 and/or P is optionally substituted by one or more of the following: F, OH, CN, NRaRa, C(O)RC, ORb, SRb, S(O)Rb, SO2Rb, phenyl, phenylQ-Csalkyl, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, NRaRa, SRb, S(O)Rb, SO2Rb or 0Rb. In the definition of "P" the term "ended by O, NRa, S, S(O), SO2, C(O), OC(O), C(O)O, NR3C(O), C(O)NR3, SO2NR3, NR3SO2" means that the alkyl group has as the last position O, NRa, S, S(O), SO2, C(O), OC(O), C(O)O, NRaC(0), C(O)NR3, SO2NR3 or NR3SO2" before it binds further to M, Het3, A or Het5.
The term "Q" denotes a saturated or unsaturated non-aromatic monocyclic ring composed of 3, 4, 5, 6, 7, 8 carbon atoms, which is optionally substituted by one or more of the following: F, OH, CN, NR3R3, 0Rb, SRb, S(O)Rb, SO2Rb, C(0)Rb, phenyld alkyl, C(O)NR3R3, NR3C(0)Rb, C(O)OR3, OC(O)Rb, SO2NRaR\ NRaSO2Rb, NRaC(0)0Rb, OC(O)NR3R3, NR3C(O)NR3R3, or Q^alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaR3, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NR3R3, NR3C(0)Rb, C(O)OR3, OC(O)Rb, NR3SO2R13, SO2NR3R3, NRaC(O)ORb, OC(O)NR3R3Or NR3C(O)NR3R3. Examples of such Q include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctanyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl and cyclooctadienyl.
The term "R" denotes a phenyl group which is optionally substituted by one or more of the following: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, phenyldalkyl, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, 0C(0)NRaRa, OS02Rb, NRaC(O)NRaRa, SO2NHC(O)Rb, or d-C4alkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaR\ 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(0)Rb, C(O)ORa, OC(O)Rb, NRaSO2Rb, SO2NRaRa, NRaC(O)ORb, OC(O)NRaRaor NRaC(O)NRaRa.
The term "T" denotes an alkyl group having 1 carbon r j;om or optionally consists of one or more of the following: O, NRa, S, S(O), SO2, C(O), OC(O), C(O)O, NR8C(O), C(0)NRa, SO2NR3 or NR3SO2. T binds to M, Het3, A or Het5.
The term "C1 alkyl" denotes an alkyl group having 1 carbon atom. An example Of said alkyl includes, but is not limited to, methyl.
The term "d-Csalkyl" denotes a straight or branched, saturated or unsaturated alkyl group having 1 to 3 carbon atoms.
The term "C1-C4alkyl" denotes a straight or branched, saturated or unsaturated alkyl group having 1 to 4 carbon atoms.
The term "cycloalkyl" denotes a saturated or unsaturated non-aromatic monocyclic ring composed of 3, 4, 5, 6, 7, 8 carbon atoms, and includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctanyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl and cyclooctadienyl.
The term "heterocyclyl" denotes a saturated or unsaturated non-aromatic 3-8 membered monocyclic ring in which one or more of the atoms in the ring is an element other than carbon, for example nitrogen, oxygen or sulfur. The term "sulfur" shall be understood to include sulphoxide (S(O)) and sulphone (SO2). The term "nitrogen" shall be understood to include nitrogen oxide (NO).
The term "heteroaryl" denotes an aromatic 3-8 membered monocyclic ring in which one or more of the atoms in the ring is an element other than carbon, for example nitrogen, oxygen and sulfur. The term "sulfur" shall be understood to include sulphoxide (S(O)) and sulphone (SO2). The term "nitrogen" shall be understood to include nitrogen oxide (NO).
The term "Het1" denotes a saturated or unsaturated non-aromatic 3-10 membered monocyclic ring in which one or more of the atoms in the ring is an element other than carbon, for example nitrogen, oxygen or sulfur, and wherein the ring optionally is substituted by one or more of the. following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, phenylQalkyl, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, 0C(0)NRaRa, NRaC(0)NRaRa, or Q-Qalkyl which is optionally substituted by one or more of the following: F, OH, CN, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(0)Rb, C(0)NRaRa, NRaC(0)Rb, C(O)ORa, OC(O)Rb, NRaS02Rb, SO2NRaRa, NRaC(0)0Rb, OC(O)NRaRaor NRaC(0)NRaRa. The term "sulfur" shall be understood to include sulphoxide (S(O)) and sulphone (SO2). The term "nitrogen" shall be understood to include nitrogen oxide (NO).
The term "Het2" denotes an aromatic 3-10 membered monocyclic ring in which one or more of the atoms in the ring is an element other than carbon, for example nitrogen, oxygen and sulfur, and which is substituted by one or more of the following: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, ORb, SRb, S(O)Rb, SO2Rb, C(O)Rb, phenylQalkyl, C(O)NRaRa, NRaC(0)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(0)0Rb, 0C(0)NRaRa, OSO2Rb, NRaC(0)NRaRa, SO2NHC(O)Rb, or CrC4alkyl optionally substituted by one or more of the following: F, OH, CN, NRaRa, 0Rb, SRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(0)Rb, C(O)ORa, OC(O)Rb, NRaS02Rb, SO2NRaRa, NRaC(O)ORb, OC(O)NRaRaor NRaC(0)NRaRa. The term "sulfur" shall be understood to include sulphoxide (S(O)) and sulphone (SO2). The term "nitrogen" shall be understood to include nitrogen oxide (NO).
The term "Het3" denotes a saturated or unsaturated non-aromatic 3-10 membered monocyclic ring or a saturated or unsaturated non-aromatic or partly aromatic 4-10 membered bicyclic ring in which one or more of the atoms in the monocyclic or bicyclic ring is an element other than carbon, for example nitrogen, oxygen or sulfur. The term "sulfur" shall be understood to include sulphoxide (S(O)) and sulphone (SO2). The term "nitrogen" shall be understood to include nitrogen oxide (NO).
The term "Het4" denotes a saturated or unsaturated non-aromatic 3-10 membered monocyclic ring or a saturated or unsaturated non-aromatic or partly aromatic 4-10 membered bicyclic ring in which one or more of the atoms in the monocyclic or bicyclic ring is an element other than carbon, for example nitrogen, oxygen or sulfur. The term "sulfur" shall be understood to include sulphoxide (S(O)) and sulphone (SO2). The term "nitrogen" shall be understood to include nitrogen oxide (NO). The ring binds, unless otherwise specified, through its non- aromatic part to nitrogen in 4-position on the isothiazol-3(2H)-thione 1,1-dioxide.
The term "Ηet5" denotes an aromatic 3-10 membered monocyclic ring or an aromatic 4-10 membered bicyclic ring in which one or more of the atoms in the monocyclic or bicyclic ring is an element other than carbon, for example nitrogen, oxygen or sulfur. The term "sulfur" shall be understood to include sulphoxide (S(O)) and sulphone (SO2). The term "nitrogen" shall be understood to include nitrogen oxide (NO).
Ra independently represents Η or a straight or branched, saturated or unsaturated Q^alkyl chain optionally substituted by one or more F.
Rb independently represents a straight or branched, saturated or unsaturated C1-C4alkyl chain optionally substituted by one or more F.
Rc independently represents Η or a straight or branched, saturated or unsaturated C;t-C3alkyl chain optionally substituted by one or more F.
The invention is illustrated, but not limited, by the following Examples.
The naming of the compounds in this patent application was made either using a program from ACD Labs (version 6.0/Name, 6.0 Name batch or labs 8.0/Name) or using the function Autonom 2000 Name in the program Isis Draw. Examples
Abbreviations
DCM dichloromethane DMF N, N'-dimethylformamide
DMSO dimethylsulfoxide
EtOAc ethyl acetate
EtOH ethanol
HPLC high performance liquid chromatography LC-MS liquid chromatography mass spectroscopy
MeCN acetonitrile
NMR nuclear magnetic resonance
TEA triethylamine
TFA trifluoroacetic acid THF tetrahydrofuran
UV ultra violet rt room temperature h hour(s) mins minutes b broad bs broad singlet d doublet dd double doublet m multiplet s singlet t triplet sep septett
General Experimental Procedures Phase Separator from 1ST was used. Flash column chromatography employed normal phase silica gel 60 (0.040-0.063 mm, Merck) or 1ST IsolutedOSPE columns normal phase silica gel or Biotage Horizon HPFC System using silica FLASH+ HPFC Cartridges. HPLC purifications were performed on either a Gilson preparative HPLC system with a UV triggered fraction collector, equipped with an ACE C8 5 μm 250 mm x 20 mm column, or a Kromasil C18 column, or on a Waters preparative HPLC system equipped with a Kromasil C8 10 μm 250 mm x 21.2 mm column, or on a Waters preparative HPLC system equipped with an ACE C8 5 μm 250 mm x 50 mm column or an ACE C8 5 μm 250 mm x 20 mm column, or on a Waters FractionLynx HPLC system with a mass triggered fraction collector, equipped with a ACE C8 5μm 100 mm x 21.2 mm column; using MeCNMH4O Ac buffer system with a gradient from 100% mobilphase A (5% MeCN + 95% 0.1 M NH4OAc) to 100% mobilphase B (100% MeCN) unless otherwise stated. 1H NMR and 13C NMR measurements were performed on a BRUKER ACP 300 or on a Varian Unity Plus 400, 500 or 600 spectrometer, operating at 1H frequencies of 300, 400, 500, 600 MHz, respectively, and 13C frequencies of 75, 100, 125 and 150 MHz, respectively. Chemical shifts are given in 8 values (ppm) with the solvents used as internal standard, unless otherwise stated. Microwave heating was performed using single node heating in a Smith Creator or Emrys Optimizer from Personal Chemistry, Uppsala, Sweden. Mass spectral data were obtained using a Micromass LCT or Waters Q-Tof micro system and, where appropriate, either positive ion data or negative ion data were collected
Synthesis of Starting Materials and Intermediates N-Isopropyl-1-phenylmethanesulfonamide The title compound was prepared as described in the reference below:
Orazi, Orfeo O.; Corral, Renee A.; Bravo, Rodolfo; J.Heterocycl.Chem.; 23; 1986; 1701- 1708.
4-Chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide Step A. Methyl[(benzylsulfonyl)(isopropyl)amino](oxo)acetate
A mixture of N-isopropyl-1-phenylmethanesulfonamide (1.Og, 4.7mmol) and methyl oxalyl chloride (2.0 mL, 21,6 mmol) was heated at 1200C for Ih. Evaporation gave methyl[(benzylsulfonyl)(isopropyl)amino](oxo)acetate which was used directly in the next reaction without any purification. Step B. 4-Hydroxy-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide Potassium tert-butoxido (1.5g, 13.4mmol) was added to a solution of crude methyl[(benzylsulfonyl)(isopropyl)amino](oxo)acetate (2.Og, 21.6mmol) in DMF (15mL). After 17 hours the mixture was evaporated and the residue was purified by silica gel column chromatography using a 4:1 mixture of EtOAc and MeOH as eluant, to give the title compound (0.5g, 40%) as a solid. Step C
DMF (25mL) and oxalyl chloride (0.2mL, 2.29mmol) were added separately to a solution of 4-hydroxy-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.5g, 1.87mmol) in DCM (25mL) at 0 °C. The reaction mixture was then heated at 500C for 4h, water was added and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with water, then brine and evaporated. The residue was purified by silica gel column chromatography using a 4:1 mixture of hexane and EtOAc as eluant to give the title compound (0.25 g, 46 %) as a solid; 1H NMR (200 MHz, CDCl3): δ 8.10-7.94 (m, 2H), 7.61- 7.50 (m, 3H), 4.50 (sep, IH), 1.61 (s, 3H), 1.65 (s, 6H).
4-({l-[3-CMoro-5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}amino)-2-isopi'opyl-5- plieiiylisøthiazol-3(2iϊ)-one 1,1-dioxide A solution of 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.20Og, 0.700mmol), TEA (0.106g, 1.050mmol) and l-[3-chloro-5-(trifluoromethyl)ρyridin-2- yl]piperidiri-4-amine (0.294g, 1.050mmol) in MeCN ( mL) was heated at 1200C for 30 mins in a microwave reactor. The residue was purified by silica gel column chromatography (Horizons Biotage) using a 1:1 mixture of heptane and EtOAc as eluant, to give the title compound (0.344 g, 93 %); 1H NMR (500 MHz, CDCl3): δ 8.34-8.33 (m, IH), 7.74-7.72 (m, IH), 7.57-7.54 (m, 2H), 7.49-7.46 (m, 3H), 5.27 (d, IH), 4.47-4.39 (m, IH), 3.85-3.78 (m, 2H), 3.24-3.14 (m IH), 2.55-2.48 (m 2H), 1.82-1.76 (m 2H), 1.60 (d 6H), 1.56-1.48 (m 2H); 13C lNMR (125 MHz, CDCl3): 5 160.0, 158.7, 143.1, 136.2, 134.5, 131.8, 130.2, 129.0, 125.3, 121.3, 120.6, 120.3, 107.1, 66.1, 50.3, 47.9, 47.4, 32.4, 20.4; Mass Spectrum: M-H+ 529.
2-Isopropyl-5-phenyl-4-[(4-phenylbutyl)amino]isothiazol-3(2/T)-one 1,1-dioxide A solution of 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150g, 0.521mmol), TEA (0.079g, 0.782mmol) and 4-phenylbutylamine (0.117g, 0.782mmol) in MeCN (3mL) was heated at 1200C for 5 mins in a microwave reactor. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (Horizons Biotage) using a 75:25 mixture of heptane and EtOAc as eluant, to give the title compound (0.174 g, 84 %); 1HNMR (500 MHz, CDCl3): δ 7.52-7.48 (m, 2H), 7.45-7.41 (m, 3H), 7.30- 7.26 (m, 2H), 7.22-7.17 (m, IH), 7.10-7.06 (m, 2H), 5.28-5.23 (m, IH), 4.45-4.38 (m, IH), 2.89-2.84 (m 2H), 2.49-2.44 (m 2H), 1.59 (d 6H), 1.43-1.38 (m 4H); 13C NMR (125 MHz, CDCl3): 6 158.8, 141.8, 135.6, 131.8, 129.8, 128.8, 128.6, 128.5, 126.2, 125.3, 106.8, 47.7, 44.2, 35.4, 29.2, 28.3, 20.4; Mass Spectrum: M-H+ 399.
5 Synthesis of Examples
Example 1
4-({l-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yI}amino)-2-isopropyl-5- 10 phenylisothiazole-θtøJΪMhione 1,1-dioxide
A solution of 4-({ l-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}amino)-2- isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.185g, O.350mmol) and 2,4-bis(4- methoxyphenyl)-l,3,2,4-dithiadiphosphetane 2,4-disulfide (0.17Og, 0.420mmol) in Toluene (3 mL) was heated at 130°C for 80mins in a microwave reactor. The residue was purified by
15 column chromatography (Horizons Biotage) using a 85:15 mixture of heptane and EtOAc as eluant, to give the title compound (0.135 g, 71 %); 1H NMR (500 MHz, CDCl3): δ 8.36-8.33 (m, IH), 7.74-7.72 (m, IH), 7.58-7.53 (m, 2H), 7.50-7.46 (m, 3H), 6.09 (br d, IH), 5.07-4.99 (m, IH), 3.82-3.75 (br m, 2H), 3.25-3.16 (m IH), 2.61-2.55 (m 2H), 1.83-1.77 (m 2H), 1.70 (d 6H), 1.60-1.52 (m 2H); 13C NMR (125 MHz, CDCl3): 6 184.5, 160.1, 143.1, 136.2, 135.1,
20 131.9, 130.2, 129.0, 125.3, 121.3, 101.8, 53.4, 50.4, 47,3, 32.2, 19.3.
Example 2 2-Isopropyl-5-phenyl-4-[(4-phenylbutyl)amino]isothiazole-3(2JΪ)-thione 1,1-dioxide
A solution of 2-isopropyl-5-phenyl-4-[(4-phenylbutyl)amino]isothiazol-3(2H)-one 1,1- 25 dioxide (0.174g, 0.437mmol) and 2,4-bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane 2,4- disulfide (0.117g, 0.782mmol) in toluene (4mL) was heated at 130°C for 20 mins and then at 14O0C for lOmins in a microwave reactor. The residue was purified by silica gel column chromatography (Horizons Biotage) using a 85:15 mixture of heptane and EtOAc as eluant, to give the title compound (0.122g, 67%); 1H NMR (500 MHz, CDCl3): δ 7.51-7.48 (m, 2H), 30 7.46-7.42 (m, 3H), 7.31-7.27 (m, 2H), 7.23-7.18 (m, IH), 7.12-7.08 (m, 2H), 6.05-6.01 (m, IH), 5.06-4.99 (m, IH), 2.88-2.83 (m 2H), 2.51-2.46 (m 2H), 1.70 (d 6H), 1.45-1.41 (m 4H); 13C NMR (125 MHz, CDCl3): δ 184.6, 141.8, 136.2, 131.9, 129.7, 128.8, 128.6, 128.5, 126.2, 125.3, 101.3, 53.2, 44.8, 44.7, 35.5, 29.1, 28.4, 19.3; Mass Spectrum: M-H+ 415. Biological activity Co-Activator recruitment assay
The Ligand Binding Domain (LBD) of human LXRalpha (amino acid 205-447) and LXRbeta (amino acid 216-461) was produced by recombinant techniques in E coli. A 5 fragment of the human Steroid Receptor Co-Activator-1 (SRC-I) was produced as a synthetic peptide. An anti-6xHis-antibody coupled with Europium (Eu3+) was used to recognize the His-tag on the LXR-LBD and Allophycocyanin (APC) coupled to streptavidin was used to recognize the biotinylated SRC-I. Agonist binding to LXRalpha or LXRbeta enhances the affinity of LXR towards SRC-I and thereby brings Eu3+ and APC in close proximity. Eu3+ is 10 excited at 337 nm and emitts light at 620 nm. This emission, when in close proximity, excites APC to emit light at 665 nm.
Compounds (1OmM) in DMSO were diluted (1/3) in DMSO in 10 concentrations. ; This dilution plates were further diluted in buffer {20mM
T 5 [Tris(hydroxymethyl)aminomethane] pH 7.5, 0.125% CHAPS {3-[(3-
Cholamidopropyl)dimethylammonio]-l-propanesulfonate}, 2mM DTT (Dithiothreitol) and 0.05% BSA (Bovine Serum Albumin)} in order to reduce DMSO concentration, 0.5 μl to 13.5 μl. To this, 6 μl assay mix was added, giving an maximal assay concentration of 83 μM, and the plates (384-well V-groove plates) were incubated at room temperature for 60 to 80 min..
20 The assay mix has the following final concentrations; LXRalpha mix: 0.06 μg/mL Eu-labelled anti-6x His Ab, 1.15/ιg/mL Streptavidin APC, 30 nM SRC-I peptide and 0.9 μg/mL LXRalpha in buffer and LXRbeta mix; 0.06 μg/mL Eu-labelled anti-6x His Ab, 1.15μg/mL Streptavidin APC, 90 nM SRC-I peptide and 0.2 μg/mL LXRbeta in buffer. Time-resolved fluorescence readings were done in a Wallac Victor reader at 665 nm followed by reading at
25 615 nm. The LXR ligand, 22-R Hydroxycholesterol or an internal compound at 50μM was used as the 100% control.
Transactivation assay
Expression vectors were prepared by inserting the ligand binding domain cDNA 30 (complementary DNA) of human LXRalpha (amino acid 205-447) and LXRbeta (amino acid 216-461) in frame with, 3' to the yeast GAL4 transcription factor DNA binding domain and the nuclear localization signal from the T-antigen of Polyoma Virus in the eucaryotic expression vector pSG5 (Stratagene). The resulting expression vectors pSGGAL-LXRalpha and pSGGAL-LXRbeta were used in cotransfection experiments together with the pGL3 luciferase reporter plasmid containing a minimal S V40 promoter (Promega) and five copies of the UAS GAL4 recognition site. 2.5 μg pSGGAL-LXRalpha or beta were mixed with 25 μg pGL3 5xUAS and 22.5 μg pBluscript (Stratagene) in 0.95 mL ice cold PBS containing approx. 4-9 milj. U2/OS osteosarcoma cells. After a five minute incubation on ice the cell/DNA mixture was electroporated in 0.4 cm cuvettes at 960 μF, 230 V using a BioRad electroporator and diluted to 0.32 milj cells /mL in complete DMEM [Dulbecco's Modified Eagle Medium w/o phenol red, (Gibco 11880-028) including 10% FBS (Foetal Bovine Serum), 1% PEST (Penicillin Streptomycin), 2OmM Hepes, 2mM L-Glutamine and 0.36% Glucose Gibco 31966-021] medium. Cells from at least two electroporations were pooled in order to avoid variations between different electroportations. 25 μl diluted, electroporated cells, were seeded into 384- well plates (0.8 x i04 cells/well) and the cells were' allowed to adhere for 2 h at 370C, 5% CO2 in u cell culture incubator. Compounds (1OmM) in DMSO were diluted (1/3) in DMSO in 10 concentrations. This dilution plates were further diluted in complete DMEM w/o phenol red (2.5μl to 97.5μl) in order to reduce DMSO concentration. 7 μl of this was added to the electroporated cells in 384-well plates and incubation was continued for 48 h in a cell culture incubator, after which cells were lysed by adding 32 μl/well LucLite luciferase substrate. Luciferase activity was measured as Luminescence in the Wallac Victor reader after 15 min. incubation at room temperature. The LXR ligand, Tularik T0901317, or an internal standard, at lμM was used as the 100% control.
In vivo assay
Separation of the desired antiatherogenic and the undesired lipogenic effects of LXR ligands was tested in normal C57 BL6 mice where the test agents are administered for three days (4 doses) in different or fixed oral doses. Gavage was performed once daily about noon, except the last dose that was given at 0700 hours, 3 hours before anaesthesia. 30 Mice were used in each screen and these were divided into five groups with six animals in each. One group was control group and the remaining 4 groups were treated with test agents in fixed or different doses. The test agents were given by gavage once daily for three days in four doses totally.
Blood samples were then obtained under anaesthesia for determination of plasma levels of TG. The liver was removed for determination of liver weight and TG content. 20- 50mg tissue, liver or intestine (first 2-3 cm distal the stomach) was snap-frozen in liquid nitrogen at necropsy for later analysis of any up regulation of LXR target genes, primarily ABCAl, ABCGl, SREBPIc and FAS. The tissues are kept in a -8O0C freezer until analysis.
Stainless steel beads (Cat. No. 69989, QIAGEN) were added to collection micro tubes, one bead per tube, (Cat. No.19560, QIAGEN), while the tubes were kept on dry ice. Tissues were transferred .to the collection micro tubes after which 750μl QIAzol (Cat. No.79306, QIAGEN) was added and then the tubes were placed in a Mixer Mill and homogenized for 2 x 5 minutes at 25 Hz. After homogenization the 96-well plate was centrifuged at 6000 x g for one minute at 40C in a Sigma 4K-15C centrifuge. 150/il chloroform was added to all samples, which were shaken vigorously for 15 seconds and incubated at room temperature for 2-3 minutes and centrifuged again at 6000 x g for 15 minutes. 200μl of the upper aqueous phase was transferred to Square-well tubes (Cat. No.19573, QIAGEN) and one volume of 70% ethanol wits added and mixed by pipetting up and down. After a 10 minute incubation on ice 250μl samples was loaded oneo the wells of a 96-well" culture cluster plate (Cat. No. 3595, Corning Incorporated) RNA was purified using an ABI Prism 6700 or ABI Prism 6100 according to the manufacturers recommendations. RNA was eluted in 150μl with a concentration of 50- 200ng/μl and 10μl of this was analyzed by agarose gel electrophoresis (ήon denaturating 1% TBE gel) to verify RNA quality. cDNA synthesis was performed using the High-Capacity Archive Kit (Cat. No 4322171, Applied Biosystems) according to the manufacturers recommendations, by random primers, in a total reaction volume of 50μl/sample.
Gene expression mRNA levels were determined by real-time PCR (7500 Real-time PCR system, Applied Biosystems). Taqman universal PCR master mix (Cat.No. 4305719, Applied Biosystems) was used in a 25μl reaction containing 40OnM of each target primer, 10OnM of each of the control primers (36B4), 20OnM of the target probe, 10OnM of the control probe (36B4) and 2.5-10ng of sample cDNA. The threshold cycles (Ct) for the endogenous control gene 36B4 and target genes were determined and relative mRNA levels were calculated using the comparative Ct method and expressed as fold induction.
The following primer and probes were used: ABCAl Forward; 5'- AAGGGTTTCTTTGCTC AGATTGTC-3', ABCAl Reverse; 5'- TGCCAAAGGGTGGC ACA-3', ABCAl Probe;
5'-FAM-CCAGCTGTCTTTGTTTGCATTGCCC -TAMRA-3', ABCGl Forward; 5'- CC ATGA ATGCC AGC AGCTACT-3', ABCGl Reverse; 5'- CACTGACACGCACACGGACT-3', ABCGl Probe; 5 '-FAM-TGCCGCAATGACGGAGCCC-TAMRA-S ', FAS Forward; 5'-GGCATCATTGGGCACTCCTT-S', FAS Reverse; 5'-GCTGCAAGCACAGCCTCTCT-S', FAS Probe; 5'-FAM-CCATCTGCATAGCCACAGGCAACCTC-TAMRA-S', SREBPIc Forward; 5'-GGAGCCATGGATTGCACATT-S', . SREBPIc Reverse; 5'-CCTGTCTCACCCCCAGCATA-S',
SREBPIc Probe; 5'-FAM-CAGCTCATCAACAACCAAGACAGTGACTTCC-TAMRA-S', 36B4 Forward; 5'-GAGGAATCAGATGAGGATATGGGA-S', 36B4 Reverse; 5'-AAGCAGGCTGACTTGGTTGC-S', 36B4 Probe; 5'-VIC-TCGGTCTCTCGACTAATCCCGCCAA-TAMRA-S'.
From dose-response relationships » selectivity values (relative potencies) were determined to discriminate between the primary intestinal up regulation of LXR target genes and the unwanted plasma and hepatic TG elevations, respectively.
The compounds of formula I have an EC50 of less than 50 μmol/1 for LXRα and/or β in coactivator recruitment assays and/or reporter gene assays. For example, the compounds of Example 1 and Example 2 have EQo's for LXRα of 3.1 μmol/1 and 10.5 μmol/1 in the reporter gene assay. In addition the compounds of the present invention exhibit favourable pharmacological effects in vivo. The compounds of the present invention also has a promising toxicological profile

Claims

CLAIMS LA compound of general formula (I)
Figure imgf000125_0001
or a pharmaceutically acceptable salt thereof, wherein R1 represents
X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NR2R", NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NR3R3, NRaC(O)NRaRa, or C1-C4alkyl which is optionally substituted by one or more, of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb or NRaC(O)NRaRa; cycloalkyl or heterocyclyl each optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb > S(O)Rb, SO2Rb, C(0)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)OR3, OC(O)Rb, SO2NRaRa, NRaS02Rb, NRaC(O)ORb, 0C(0)NRaRa, NRaC(O)NRaRa, or Q-Qalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb , C(0)NRaRa, NRaC(0)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(0)0Rb, 0C(0)NRaRa or NRaC(O)NRaRa; phenyl or heteroaryl each optionally substituted by one or more of the following independently selected from: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C(0)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, 0C(0)NRaRa, OSO2Rb, NRaC(0)NRaRa, SO2NHC(O)Rb, or Ci-Qalkyl optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb,
C(O)Rb, C(0)NRaRa, NRaC(0)Rb, C(O)OR3, OC(O)Rb, SO2NRaRa, NRaS02Rb, NRaC(0)0Rb, 0C(0)NRaRa or NRaC(O)NRaRa; cycloalkylY or heterocyclylY wherein cycloalkyl or heterocyclyl each optionally is substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(O)NRaRa, or Ci-Qalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NR3C(O)Rb, C(O)OR3, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaRa; phenylY or heteroarylY wherein phenyl or heteroaryl each optionally is substituted by one or more of the following independently selected from: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)OR3, OC(O)Rb, SO2NR3R3, NRaSO2Rb, NR3C(O)ORb, OC(O)NR3R3, OSO2Rb, NRaC(0)NRaRa, SO2NHC(O)Rb, or C1-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRW, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRcC(O)Rb, C(O)OR3, OC(O)Rb, SO2NR3R3, NR3SO2R13, NRaC(0)0Rb, OC(O)NR3R3 or NRaC(O)NRaRa; R represents . . , phenyl which is optionally substituted by one or more of the following independently selected from: halogen (Cl, F, I, Bi), OH, CN, NO2, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NR3R3, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NR3R3, NRaSO2Rb, NRaC(0)0Rb, OC(O)NR3R3, OSO2Rb, NRaC(0)NRaRa, SO2NHC(O)Rb, or CrC4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR3Ra, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NR3R3, NRaC(0)Rb, C(O)OR3, OC(O)Rb, NRaSO2Rb, SO2NR3R3, NRaC(0)0Rb, OC(O)NR3R3Or NR3C(O)NR3R3; R3 represents
X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NR3R3, OC(O)Rb, C(O)OR3, SO2NR3R3, NR3SO2Rb, NRaC(O)ORb, OC(O)NR3R3, NR3C(O)NR3R3, or Ci-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR3R3, 0Rb, SRb, SiRV3R13, S(O)Rb, SO2R5, C(O)Rb or NR3C(O)NR3R3; MP or Het3P wherein M and Het3 each optionally is substituted on the non-aromatic ring by one or more of the following independently selected from: F, OH, CN, NR3R3, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)R13, NR3C(O)R13, C(O)NR3R3, OC(O)Rb, C(O)OR3, SO2NR3R3, NR3SO2R13, OC(O)NR3R3, NRaC(O)ORb, NR3C(O)NR3R3, Q, QT, Het1, Het1!, R, RT, Het2, Het2T, or C1-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaRa, and wherein M or Het3 each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen (Cl, F, Br, I), OH5 1CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QT, Het1, Het!T, R, RT, Het2, Het2T, or C1-C4BIlCyI which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa; AP or Het5P wherein A and Het5 each optionally is substituted by one or more of the following independently selected from: halogen (F, Cl, Br, I), OH, CN, NO2, NRaRa, ORb, SRb, SiRVRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NE11R8, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, OSO2Rb, SO2NRaC(O)Rb, NRaC(O)NRaRa, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or Q-dalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa; E or Het4 each optionally substituted on the non-aromatic ring by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, Q, QZ, Het1, HCt1Z, R, RZ, Het2, Het2Z, or C1- C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)R5, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa, and E or Het4 each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen (F, Cl, Br, I), OH, CN, NRaRa, ORb, SRb, SiR15R15R13, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QZ, Het1, Het!Z, R, RZ, Het2, Het2Z, or CrC4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, Sθ2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa; and in the above definitions
X represents a straight or branched, saturated or unsaturated alkyl group having 1 to 6 carbon atoms wherein said alkyl group may optionally be interrupted by O, S, SiRbRb, S(O), SO2, C(O), NRa, OC(O), C(O)O, NR3C(O), C(O)NR3, S02NRa or NR3SO2; Y which binds to the nitrogen in the 2-position of the isothiazol-3(2H)-thione 1,1-dioxide and represents a straight or branched, saturated or unsaturated alkylene group having 1 to 3 carbon atoms wherein said alkyl group may optionally be interrupted or ended by one of the following: O, S, SiRbRb, S(O), SO2, C(O), OC(O), C(O)O, NRCC(O), C(O)NRC, NRC and/or Y is optionally substituted by one or more of the following independently selected from: OH, F, CN,. NRaRa, Cre4alkyϊ, 0Rb, SRb, SiRVR13, S(O)Rb or SO2Rb;
Z binds to E or Het4 and one of the following: Q, Het1, R or Het2, and represents a straight or branched, saturated or unsaturated alkylene group having 1 to 6 carbon atoms wherein said alkylene group may optionally be interrupted or ended by one of the following: O, S, SiRbRb, S(O), SO2, C(O), OC(O), C(O)O, NRaC(0), C(0)NRa, NRa, SO2NR3, NR3SO2, or is one of the following: O, S, SXRV, S(O), SO2, C(O), OC(O), C(O)O, NR3C(O), C(O)NR3, NR3 , SO2NRa, NR3SO2 and/or Z is optionally substituted by one or more of the following independently selected from: OH, F, CN, NRCRC, C(O)RC, ORb, SRC, SiRbRbRb, S(O)RC, SO2RC > phenyl, phenylQ-Csalkyl, or C1-C4alkyl which is optionally substituted by one or more of the following: F, OH, NRaRa, SRb, SiR5R6R5, S(O)Rb, SO2Rb, 0Rb; M represents a saturated or unsaturated non-aromatic monocarbocyclic ring composed of 3, 4, 5, 6, 7 or 8 carbon atoms or a saturated or unsaturated non-aromatic or partly aromatic bicyclic ring system composed of 8, 9 or 10 carbon atoms; E represents a saturated or unsaturated non-aromatic monocarbocyclic ring composed of 3, 4, 5, 6, 7 or 8 carbon atoms or a saturated or unsaturated non-aromatic or partly aromatic bicyclic ring system composed of 8, 9 or 10 carbon atoms, and the ring binds, unless otherwise specified, through its non-aromatic part to nitrogen in 4-position on the isothiazol- 3(2H)-thione 1,1-dioxide; A represents an aromatic monocyclic ring composed of 6 carbon atoms or an aromatic bicyclic ring system composed of 4 10 carbon atoms;
P binds to nitrogen in 4-position on the isothiazol-3(2H)-thione 1,1-dioxide and represents a straight or branched, saturated or unsaturated alkylene group having 1 to 6 carbon atoms wherein the alkylene group is optionally interrupted or ended by one of the following: O, NR3, S, SiR5R5, S(O), SO2, C(O), OC(O), C(O)O, NR3C(O), C(O)NR3, SO2NR3, NR3SO2 and/or P is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR3R3, C(O)RC, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2R5, phenyl, phenylQ- Caalkyl, or d-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, NR3R3, SRb, SiR5RV, S(O)Rb, SO2R5 or 0Rb; Q represents a saturated or unsaturated non-aromatic monocyclic ring composed of 3, 4, 5, 6, 7 or 8 carbon atoms, which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR3R3, 0Rb, SR5, SiR5R5R5, S(O)R5, SO2Rb, C(O)R5, phenyldalkyl, C(O)NR3R3, NRaC(O)Rb, C(O)OR3, 0C(0)Rb, SO2NR3R3,
NR3SO2R5, NR3C(O)OR5, OC(O)NR3R3, NR3C(O)NR3R3, or d-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, OR5, SR5, SiR5R5R5, S(O)R5, SO2R5, C(O)R5, C(0)NR'"R3; NRaG(0)Rb, C(O)OR3, OC(O)R5, NR3SO2R5, SO2NR3R3, NR3C(O)OR5, OC(O)NR3R3Or NRaC(0)NR3R3; R represents a phenyl group which is optionally substituted by one or more of the following independently selected from: halogen (Cl, F, I, Bi), OH, CN, NO2, NRaRa, OR5, SR5, SiR5R5R5, S(O)R5, SO2R5, C(O)R5, phenyldalkyl, C(O)NR3R3, NR3C(O)R5, C(O)OR3, OC(O)R5, SO2NR3R3, NR3SO2R5, NR3C(O)OR5, OC(O)NR3R8, OSO2R5, NR3C(O)NR3R3, SO2NHC(O)R5, or Q-Qalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR3R3, OR5, SR5, SiR5R5R5, S(O)R5, SO2R5,
C(O)R5, C(O)NR3R3, NR3C(O)R5, C(O)OR3, OC(O)R5, NR3SO2R5, SO2NR3R3, NR3C(O)OR5, OC(O)NR3R3Or NR3C(O)NR3R3;
T binds to M, Het3, A or Het5 and one of the following: Q, Het1, R or Het2; and represents methylene or is one of the following: O, NR3, S, SiR5R5, S(O), SO2, C(O), OC(O), C(O)O, NR3C(O), C(O)NR3, SO2NR3 Or NR3SO2;
Het1 represents a saturated or unsaturated non-aromatic 3, 4, 5, 6, 7, 8, 9 or 10 membered monocyclic ring in which one or more of the atoms in the ring is an element other than carbon independently selected from one or more of for example nitrogen, oxygen or sulfur, and wherein the ring optionally is substituted by one or more of the following independently selected from: F, OH, CN, NR3R3, OR5, SR5, SiR5R5R5, S(O)R5, SO2R5, C(O)R5, phenyldalkyl, C(O)NR3R3, NR3C(O)R5, C(O)OR3, OC(O)R5, SO2NR3R3, NR3SO2R5, NR3C(O)OR5, OC(O)NR3R3, NR3C(O)NR3R3, or CrC4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR3R3, OR5, SR5, SiRbRbRb, S(O)Rb, SO2R", C(O)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, NRaSO2Rb, SO2NRaRa, NRaC(O)ORb, OC(O)NRaRaor NRaC(O)NRaRa; Het2 represents an aromatic 5 or 6 membered monocyclic ring in which one or more of the atoms in the ring is an element other than carbon independently selected from one or more of 5 for example nitrogen, oxygen and sulfur, and which is substituted by one or more of the • following independently selected from: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, phenyldalkyl, C(O)NRaRa, NRaC(O)Rb, C(O)OR3, OC(O)Rb, SO2NRaRa, NRaS02Rb, NRaC(O)ORb, OC(O)NRaRa, OSO2Rb, NRaC(O)NRaRa, SO2NHC(O)Rb, or C!-C4alkyl optionally substituted by one or more of the following 0 independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb,
C(O)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, NRaSO2Rb, SO2NRaRa, NRaC(O)ORb f ,OC(O}*JRaRaoi NRaC(0)NRaRa;
Het3 represents a saturated or unsaturated non-aromatic 3, 4, 5, 6, 7, 8, 9 or 10 membered monocyclic ring or a saturated or unsaturated non-aromatic or partly aromatic 9 or 10 5 membered bicyclic ring system in which one or more of the atoms in the monocyclic ring or bicyclic ring system is an element other than carbon independently selected from one or more of for example nitrogen, oxygen or sulfur; '
Het4 represents, a saturated or unsaturated non-aromatic 3, 4, 5, 6, 7, 8, 9 or 10 membered monocyclic ring or a saturated or unsaturated non-aromatic or partly aromatic 9 or 10 0 membered bicyclic ring system in which one or more of the atoms in the monocyclic ring or bicyclic ring system is an element other than carbon independently selected from one or more of for example nitrogen, oxygen or sulfur, and the ring binds, unless otherwise specified, through its non-aromatic part to nitrogen in 4-position on the isothiazol-3(2H)-thione 1,1- dioxide; 5 Ηet5 represents an aromatic 5 or 6 membered monocyclic ring or an aromatic 9 or 10 membered bicyclic ring system in which one or more of the atoms in the monocyclic ring or bicyclic ring system is an element other than carbon independently selected from one or more of for example nitrogen, oxygen or sulfur; Ra independently represents Η or a straight or branched, saturated or unsaturated Q-Qalkyl 0 chain optionally substituted by one or more F;
Rb independently represents a straight or branched, saturated or unsaturated CrC4alkyl chain optionally substituted by one or more F; and Rc independently represents H or a straight or branched, saturated or unsaturated d-C3alkyl chain optionally substituted by one or more F.
2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 represents
X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, or CrC4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb or C(O)Rb; cycloalkyl or heterocyclyl each optionally substituted by one or more of the following independently selected from: F, OH,:CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, or Q-dalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb; SRb, SiRbRbRb, S(O)Rb, SO2Rb or C(O)Rb; phenyl or heteroaryl each optionally substituted by one or more of the following independently selected from: halogen (Cl, F, I, Br), OH, CNyNO2, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, or C!-C4alkyl optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb; cycloalkylY or heterocyclylY wherein cycloalkyl or heterocyclyl each optionally is substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(0)Rb, or Q-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb; phenylY or heteroarylY wherein phenyl or heteroaryl each optionally is substituted by one or more of the following independently selected from: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, or d-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb; R2 represents phenyl which is optionally substituted by one or more of the following independently selected from: halogen (Cl, F, I, Br), OH, CN, NO2, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, or Q-Qalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiR13RV, S(O)Rb, SO2Rb, C(O)Rb.
3. A compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R1 represents
X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiR13R6R13, S(O)R*3, SO2Rb, C(O)Rb, C(O)NR3R3, NR3C(O)R", C(O)OR3, OC(O)R*3, SO2NR3R3, NR3SO2R*3, NR3C(O)OR5, OC(O)NR3R3, NRaC(0)NRaRa, or Q-Qalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, OR*3, SRb, SiRbRbRb, S(O)Rk, SQ2R*3, C(O)Rb or NRaC(0)NRaRa.
4. A compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein
R1 represents
X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, r«laRa, 0Rb, SR*3, SiRVR*3, S(O)R*3, SO2Rb, C(O)R*3, or d-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, -
CN, NRaRa, 0Rb, SR*3, SiR VR*3, S(O)R*3, SO2R*3 or C(O)R*3.
5. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 represents
X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, OR*3, SR*3, SiRbRV, S(O)R*3, SO2R*3, C(O)R*3, NR3C(O)R*3, C(O)NR3R3, OC(O)R*3, C(O)OR3, SO2NRaRa, NR3SO2R*3, NR3C(O)OR*3, OC(O)NR3R3, NRaC(0)NRaRa, or Q-Qalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR3R3, OR*3, SR*3, SiRbRbRb, S(O)R*3, SO2R*3, C(O)R*3 or NR3C(O)NR3R3.
6. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 represents
MP or HeI3P wherein M and Het3 each optionally is substituted on the non-aromatic ring by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2R5, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NR3R3, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or d-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaR\ 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)R5, C(O)ORa, SO2NRaRa, NRaSO2Rb, NR3C(O)OR5, OC(O)NRaRa or NRaC(O)NRaRa, and wherein M or Het3 each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen (Cl, F, Br, I), OH, CN, NRaRa, OR5, SR5, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)R5, C(O)OR3, SO2NR3R3, NR3SO2R", OC(O)NR3R8, NR8C(O)OR11, NR3C(O)NR3R3, OSO2Rb, SO2NRaC(O)Rb, Q, QT, Het1, HetJT, R, RT, Het2, Het2T, or CrC4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SR5, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NR3C(O)R", C(O)NR3R3, OC(O)R5, C(O)OR3, SO2NR3R3, NR3SO2Rb, NRaC(0)0Rb, OC(O)NR3R3 Or NR3C(O)NR3R3; AP or Het5P wherein A and Het5 each optionally is substituted by one or more of the following independently selected from: halogen (F, Cl, Br, I), OH, CN, NO2, NR3R3, 0Rb, SR5, SiR5R5R5, S(O)R5, SO2Rb, C(O)Rb, IVR3C(O)R5, C(O)NR3R3, OC(O)R5, C(O)OR3, SO2NR3R3, NR3SO2R5, OC(O)NR3R3, NRaC(0)0Rb, OSO2Rb, SO2NRaC(O)Rb, NR3C(O)NR3R3, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or Q-Qalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR3Ra, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NR3C(O)Rb, C(O)NR3R3, OC(O)Rb, C(O)OR3, SO2NR3R3, NR3SO2Rb, NR3C(0)0Rb, OC(O)NR3R3 Or NR3C(O)NR3R3.
7. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R represents
E or Het4 each optionally substituted on the non-aromatic ring by one or more of the following independently selected from: F, OH, CN, NR3R3, 0Rb, SR5, SiRbRbRb, S(O)Rb, SO2R5, C(O)R5, NR3C(O)R5, C(O)NR3R3, OC(O)R5, C(O)OR3, SO2NR3R3, NR3SO2R5, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, Q, QZ, Het1, HeI1Z, R, RZ, Het2, Het2Z, or C1- C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaR\ 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa, and E or Het4 each optionally is substituted on the aromatic ring by one or more of the folowing independently selected from: halogen (F, Cl, Br, I), OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)R", SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)R5, C(O)ORa, SO2NRaRa, NRaSO2Rb, 0C(0)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, OSO2Rb, SO2NR3C(O)R", Q, QZ, Het1, HeI1Z, R, RZ, Het2, Het2Z, or Q-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, OR", SRb : SiRbRbRb, S(O)R", SO2R", C(O)R", NR3C(O)R", C(O)NR8R3, OC(O)R", C(O)OR3, SO2ISR3R3, NRaSO2R", NRaC(O)ORb, 0C(0)NRaR3 or NR3C(O)NR3R3.
8. A compound according to claim 2 or a pharmaceutically acceptable salt thereof. wherein
R0 represents
X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR3R3, ORb, SRb, SiR"RbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NR3R3, OC(O)Rb, C(O)OR3, SO2NR3R3, NR3SO2R", NR3C(O)OR", OC(O)NR3R3,
NRaC(O)NR3R3, or Q-Qalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, OR", SR", SiRbRbRb, S(O)Rb,
SO2Rb, C(O)Rb or NR3C(O)NR3R3.
9. A compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R3 represents
MP or Het3P wherein M and Het3 each optionally is substituted on the non-aromatic ring by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NR3C(O)R", C(O)NRaRa, OC(O)R", C(O)OR3, SO2NR3R3, NR3SO2R", OC(O)NRaRa, NR3C(O)OR", NRaC(0)NRaRa, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or C1-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR3R3, 0Rb, SRb, SiRbRbRb, S(O)R", SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa, and wherein M or Het3 each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen (Cl, F, Br, I), OH, CN, NRaRa, ORb, SRb, 5 SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NR3R3, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QT, Het1, HetlfT, R, RT, Het2, Het2T, or CrC4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa,
10 SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa;
AP or Het5P wherein A and Het5 each optionally is substituted by one or more of the following independently selected from: halogen (F, Cl, Br, I), OH, CN, NO2, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSQ2Rb, OC(O)NR3R3, . NRaC(O)ORb, OSO2Rb, SO2NRaC(O)Rb,
15 NRaC(0)NRaRa, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or d-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)R0, SO2Rb,- C(O)Rb, NRaC(O)Rb, C(0)NRaRa, 0C(0)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaRa.
20 10. A compound according to claim 2 or a pharmaceutically acceptable salt thereof, , wherein R3 represents
E or Het4 each optionally substituted on the non-aromatic ring by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb,
25 SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NR3R3, NRaSO2Rb, OC(O)NR3R3, NRaC(O)ORb, NR3C(O)NR3R3, Q, QZ, Het1, HeI1Z, R, RZ, Het2, Het2Z, or C1- C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NR3R3, OC(O)Rb, C(O)ORa, SO2NR3R3, NRaS02Rb, NRaC(O)ORb, OC(O)NR3R3 or
30 NR3C(O)NR3R3, and E or Het4 each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen (F, Cl, Br, I), OH, CN, NR3R3, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(0)Rb, NRaC(0)Rb, C(O)NR3R3, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QZ, Het1, He^Z, R, RZ, Het2, Het2Z, or C1-C4ElRyI which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiR13RV, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, 5 SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa.
11. A compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein
R represents 0 X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiR13RV, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb,
C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, UC(O)NRaRa,
NRaC(O)NRaRa, or Q-Qalkyl which is optionally substituted by one or more of, the
• following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb 5 S(O)R6, 5 SO2Rb, C(O)Rb orNRaC(O)NRaRa. •
12. A compound according to claim 3 or a pharmaceutically acceptable salt thereof,-
' wherein
R3 represents 0 MP' or Het3P wherein M and Het3 each optionally is substituted on the non-aromatic ring by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)R5, C(O)OR3, S02NRaRa, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(0)NRaRa, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or C!-C4alkyl which is optionally substituted by one or more of the 5 following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaRa, and wherein M or Het3 each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen (Cl1 F, Br, I), OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(0)Rb, NRaC(0)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, 0C(0)NRaRa, NRaC(O)ORb, NRaC(0)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QT, Het1, Het!T, R, RT, Het2, Het2T, or C1-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NRaC(0)NRaRa; AP or Het5P wherein A and Het5 each optionally is substituted by one or more of the following independently selected from: halogen (F, Cl, Br, I), OH, CN, NO2, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NR3R3, NR3SO2R5, 0C(0)NRaRa, NRaC(0)0Rb, OSO2Rb, SO2NRaC(O)Rb, NR3C(O)NR3R3, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or Q-dalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NR3R3, OC(O)Rb, C(O)OR3, SO2NR3R3, NRaSO2Rb, NRaC(0)0Rb, 0C(0)NRaR3 or NR3C(O)NR3R3.
13. A compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein ■ .
R represents E or Het4 each optionally substituted on the non-aromatic ring by one or more of the following independently selected from: -F, OH, CN, NR3R3, ORb, SRb, SiRbRbRb, (0)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, G(0)NRaRa, OC(O)Rb, C(O)OR3, SO2NR3R3, NR3SO2Rb, OC(O)NR3R3, NR3C(0)0Rb, NRaC(O)NR3Ra, Q, QZ, Het1, Het!Z, R, RZ, Het2, Het2Z, or C1-, C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN5 NR3R3, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NR3C(0)Rb, C(O)NR3R3, OC(O)Rb, C(O)OR3, SO2NR3R3, NRaSO2Rb, NR3C(0)0Rb, OC(O)NR3R3 or NRaC(0)NR3Ra, and E or Het4 each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen (F, Cl, Br, I), OH, CN, NR3R3, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NR3C(0)Rb, C(O)NR3R3, OC(O)Rb, C(O)OR3, SO2NR3R3, NRaSO2Rb, OC(O)NR3R3, NR3C(0)0Rb, NR3C(O)NR3R3, OSO2Rb, SO2NRaC(O)Rb, Q, QZ, Het1, HBt1Z, R, RZ, Het2, Het2Z, or CrC4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR3R3, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NR3R3, OC(O)Rb, C(O)OR3, SO2NR3R3, NR3SO2Rb, NRaC(0)0Rb, OC(O)NR3R3 or NR3C(O)NR3R3.
14. A compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R3 represents
X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(O)NRaRa, or Q-Qalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb or NRaC(O)NRaRa.
15. A compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R3 represents
MP or Het3P wherein M and Het3 each optionally is substituted on the non -aromatic ring by one or more of the following independently selected from: F, OH, CN, NRaRa, QR b, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaS02Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(0)NRaRa, Q, QT, Het', HsJt1T, R, RT, Het2, Het2T, or C1-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(0)NRaRa, OC(O)Rb, C(O)ORa, S02NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa or NR3C(O)NR3R3, and wherein M or Het3 each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen (Cl, F, Br, ϊ), OH, CN, NR3R2, 0Rb, SRb,' SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaS02Rb, OC(O)NR3R3, NRaC(0)0Rb, NRaC(0)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or C1-C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(O)NR3R3, OC(O)Rb, C(O)OR3, SO2NR3R3, NRaSO2Rb, NRaC(0)0Rb, 0C(0)NRaRa Or NR3C(O)NR3R3; AP or Het5P wherein A and Het5 each optionally is substituted by one or more of the following independently selected from: halogen (F, Cl, Br, I), OH, CN, NO2, NR3R3, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(0)Rb, C(0)NRaRa, OC(O)Rb, C(O)OR3, SO2NRaRa, NRaSO2Rb, OC(O)NR3R3, NRaC(O)ORb, OSO2Rb, SO2NRaC(O)Rb, NR3C(O)NR3R3, Q, QT, Het1, HeI1T, R, RT, Het2, Het2T, or CrC4alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NRaRa, NRaSO2Rb, NR3C(O)ORb, OC(O)NRaRa or NRaC(O)NRaRa.
16. A compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein
R3 represents
E or Het4 each optionally substituted on the non-aromatic ring by one or more of the following independently selected from: F, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NRaRa, OC(O)Rb, C(O)ORa, SO2NR3R3, NRaSO2Rb, OC(O)NRaRa, NRaC(O)ORb, NRaC(O)NRaRa, Q, QZ, Het1, HetxZ, R, RZ, Het2, Het2Z, or C1- C4alkyl which is optionally substituted by one or more of the following independently selected from: F, OIT, CN, NR3R3, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NR3R3, OC(O)Rb, C(O)ORa ; SO2NR3R3, NR3SO2R*5, NR3C(0)0Rb, 0C(0)NRaRa or NRaC(O)NRaRa, . . and E or Het4 each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen (F, Cl, Br, I), OH, CN, NRaRa, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, NRaC(O)Rb, C(O)NR3R3, OC(O)Rb, C(O)OR3, S02NRaRa, NRaSO2Rb, OC(O)NR3R3, NR3C(0)0Rb, NRaC(O)NRaRa, OSO2Rb, SO2NRaC(O)Rb, Q, QZ, Het1, HeI1Z, R, RZ, Het2, Het2Z, or Q-Qalkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR3R3, 0Rb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(0)Rb, NR3C(O)Rb, C(O)NR3R3, OC(O)Rb, C(O)OR3, SO2NR3R3, NR3SO2R", NR3C(O)ORb, OC(O)NR3R3 or NRaC(0)NRaRa.
17. Specific compounds of the invention are 4-({ l-[3-chloro-5-(trifluoromethyl)pyridin-2- yl]piperidin-4-yl}amino)-2-isopropyl-5-phenylisothiazole-3(2H)-thione 1,1-dioxide and 2- isopropyl-5-phenyl-4-[(4-phenylbutyl)amino]isothiazole-3(2H)-thione 1,1-dioxide or a pharmaceutically acceptable salt thereof.
18. A process for the preparation of a compound according to any one of claims 1-17, wherein R1, R2 or R3 are as defined in claim 1, comprising the step of reacting a compound of formula
(VIII),
Figure imgf000140_0001
(VIE)
wherein R1, R2 and R3 are as defined in claim 1, with Lawesson's reagent optionally in the presence of an inert organic solvent such as toluene. 5
19. A pharmaceutical formulation comprising a compound according to any one of claims 1- 17 in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.
20. A pharmaceutical formulation comprising a compound according to any one of claims .1- 10 17, or a suitable pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.
21. A compound according to any one of claims 1-17, or a suitable pharmaceutically acceptable salt thereof, as a medicament in therapy.
15
22. A compound according to any one of claims 1-17, or a suitable pharmaceutically acceptable salt thereof, for use as a medicament in treating conditions associated with a need for modulation of nuclear hormone receptors LXR α and/or β; cardiovascular disease, atherosclerosis, hypercholesterolemia, conditions associated with a need for improving 0 reverse cholesterol transport, conditions associated with a need for decreasing intestinal cholesterol absorption, conditions associated with a need for increasing HDL-cholesterol levels, conditions associated with a need for decreasing LDL-cholesterol levels; inflammatory conditions, Alzheimer's disease, arteriosclerosis, type 2 diabetes, conditions associated with a need for improving HDL function, conditions associated with a need for improving HDL 5 function; or lipid disorders (dyslipidemia) whether or not associated with insulin resistance.
23. The use of a compound according to any of claims 1-17, or a suitable pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the modulation of the nuclear hormone receptors LXR α and/or β; cardiovascular disease; atherosclerosis, hypercholesterolemia, conditions associated with a need for improving reverse cholesterol transport, conditions associated with a need for decreasing intestinal cholesterol absorption, conditions associated with a need for increasing HDL-cholesterol levels, conditions associated with a need for decreasing LDL-cholesterol levels; inflammatory conditions, Alzheimer's disease, arteriosclerosis, type 2 diabetes, conditions associated with a need for improving HDL function, conditions associated with a need for improving HDL function; or lipid disorders (dyslipidemia) whether or not associated with insulin resistance.
24. A method of treating and/or preventing lipid disorders (dyslipidemia) whether or not associated with insulin resistance; cardiovascular disease, atherosclerosis, hypercholesterolemia, conditions associated with a need for improving reverse cholesterol transport, conditions associated with a need for decreasing intestinal cholesterol absorption, conditions associated with a.need for increasing HDL-cholesterol levels, conditions associated with a need for decreasing LDL-cholesterol levels; inflammatory conditions, Alzheimer's disease, arteriosclerosis, type 2 diabetes, or conditions associated with a need for improving HDL function comprising the administration of a thereapeutically effective amount of a compound according to any one of claims 1-17, or a suitable pharmaceutically acceptable salt thereof, to a mammal in need thereof.
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