WO2011076734A1 - Composés, composition pharmaceutique et procédés pour utilisation dans le traitement de maladies inflammatoires - Google Patents

Composés, composition pharmaceutique et procédés pour utilisation dans le traitement de maladies inflammatoires Download PDF

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WO2011076734A1
WO2011076734A1 PCT/EP2010/070236 EP2010070236W WO2011076734A1 WO 2011076734 A1 WO2011076734 A1 WO 2011076734A1 EP 2010070236 W EP2010070236 W EP 2010070236W WO 2011076734 A1 WO2011076734 A1 WO 2011076734A1
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methyl
amino
thiazol
phenyl
acid
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PCT/EP2010/070236
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Hamid Hoveyda
Cyrille Evangelos Brantis
Guillaume Dutheuil
Ludivine Zoute
Didier Schils
Jérôme BERNARD
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Euroscreen S.A.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention concerns methods and compounds useful in treating and/or preventing inflammatory diseases. More specifically, the invention relates to the use of selective GPR43 agonists or partial agonist and their pharmacologically acceptable salts and solvates thereof, previously described in international patent application No. PCT/EP2009/066536 filed on December 2009 in the name of the present Applicant, for the preparation of a medicament for the treatment and/or prevention of inflammatory diseases.
  • the present invention comprises compounds useful in treating and/or preventing diseases, such as Tumor Necrosis Factor a (TNF-a), IL- ⁇ , IL-6 and/or IL-8 mediated diseases and other resulting diseases.
  • diseases such as Tumor Necrosis Factor a (TNF-a), IL- ⁇ , IL-6 and/or IL-8 mediated diseases and other resulting diseases.
  • TNF-a Tumor Necrosis Factor a
  • IL- ⁇ IL-6
  • IL-8 mediated diseases and other resulting diseases.
  • the compounds of the invention are useful for the treatment and/or prevention of diseases or conditions involving inflammation.
  • TNF-a is upstream in the cytokine cascade of inflammation. As a result, elevated levels of TNF-a may lead to elevated levels of other inflammatory and proinflammatory cytokines, such as IL-1, IL-6 and IL-8.
  • TNF-a and Interleukin-1 are pro-inflammatory cytokines secreted by a variety of cells, including monocytes and macrophages, in response to many inflammatory stimuli (e.g. lipopolysaccharide-LPS) or external cellular stress (e.g., osmotic shock and peroxide).
  • inflammatory stimuli e.g. lipopolysaccharide-LPS
  • external cellular stress e.g., osmotic shock and peroxide
  • Elevated levels of TNF-a and/or IL-1 over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; inflammatory bowel disease (IBD) including but not limited to Crohn's disease, ulcerative colitis and colitis; Pagets disease; osteoporosis; multiple myeloma; uveitilis; acute and chronic myelogenous leukemia; pancreatic ⁇ cell destruction; rheumatoid spondylitis; osteoarthritis; gouty arthritis and other arthritis conditions; gout; adult respiratory distress syndrome (ARDS); chronic pulmonary inflammation diseases; silicosis; pulmonary sarcoidosis; psoriasis; allergic rhinitis; anaphylaxis; contact dermatitis; pancreatitis; non-alcoholic steato hepatitis (NASH); asthma; muscle degeneration; cachexia such as cachexia secondary to infection or malignancy
  • TNF-a and IL-1 appear to play a role in pancreatic ⁇ cell destruction and diabetes.
  • Pancreatic ⁇ cells produce insulin which helps mediate blood glucose homeostasis. Deterioration of pancreatic ⁇ cell functional abnormalities may occur in patients with type II diabetes.
  • TNF-a TNF-a promotes the release of other cytokines (IL- ⁇ , IL-6) and also chemokines, which promote neutrophil infiltration into the infarct area (Flivtein, Stroke 25, 1481 (1994).
  • IL- ⁇ cytokines
  • chemokines which promote neutrophil infiltration into the infarct area
  • IL-1 is a more potent inducer of stromelysin than TNF-a (Firestein, Am. J. Pathol. 140, 1309 (1992)).
  • neutrophil, lymphocyte, and monocyte emigration has been observed. The emigration is attributed to the induction of chemokines (e.g., IL-8), and the up-regulation of adhesion molecules (Dinarello, Eur. Cytokines Netw. 5, 517-531 (1994)).
  • IL-8 has been implicated in exacerbating and/or causing many disease states in which massive neutrophil infiltration into sites of inflammation or injury (e.g., ischemia) is mediated by the chemotactic nature of IL-8, including, but not limited to, the following: asthma, inflammatory bowel disease (IBD), psoriasis, adult respiratory distress syndrome, cardiac and renal reperfusion injury, thrombosis and glomerulonephritis.
  • IBD inflammatory bowel disease
  • psoriasis psoriasis
  • adult respiratory distress syndrome e.g., pulmonary distress syndrome
  • cardiac and renal reperfusion injury e.g., thrombosis and glomerulonephritis.
  • IL-8 also has the ability to active neutrophils. Thus, reduction in IL-8 levels may lead to diminished neutrophil infiltration.
  • TNF-cc and IL-1 affect a wide variety of cell and tissues and these cytokines as well as other leukocytes derived cytokine, such as IL-6 and IL-8, are important and critical inflammatory mediators of a wide variety of diseases states and conditions.
  • the inhibition of these cytokines is of benefit in controlling, reducing and alleviating many of these disease states mediated by these cytokines.
  • TNF-a Several approaches have been taken to block the effect of TNF-a.
  • TNF-a e.g. TNFR-55 or TNFR-75
  • TNFR-55 or TNFR-75 soluble receptors for TNF-a
  • cA2 a monoclonal antibody specific to TNF-a
  • cA2 has demonstrated improvement in swollen joint count in a Phase II human trial of rheumatoid arthritis (Feldmann et al; Immunological Reviews, pp. 195-223 (1995)).
  • These approaches block the effects of TNF-a and IL-1 by either protein sequestration or receptor antagonism.
  • GPR43 (also named FFA2R) belongs to a subfamily of G-Protein- Coupled Receptors (GPCRs), including GPR40 and GPR41 that have been identified as receptors for free fatty acids (Le Poul et al, J. Biol Chem. 278, 25481-489, 2003; Covington et al., Biochemical Society transaction 34, 770-773, 2006).
  • GPCRs G-Protein- Coupled Receptors
  • the 3 family members share 30 to 40% sequences identity with specificity toward different fatty acids carbon chain length, with short chain fatty acids ((SCFAs): six carbons molecules or shorter) activating GPR41 and GPR43 and medium and long chain fatty acids activating GPR40 (Rayasam et al., Expert Opinion on therapeutic targets, 11 661-671, 2007 ).
  • C2 acetate and C3 propionate are the most potent activators of GPR43.
  • GPR43 is strongly expressed in peripheral blood mononuclear cell (PBMC), bone marrow, and polymorphonuclear cells such as neutrophils.
  • PBMC peripheral blood mononuclear cell
  • the involvement of GPR43 in leukocyte function is supported by the induction of its mRNA during the differentiation and activation of monocytes and neutrophils cells (Le Poul et al, J. Biol. Chem., 2003, 278: 25481-25489; Senga et al, Blood, 2003, 101 : 1185-1187).
  • Recent studies have shown that both acetate and propionate decreased LPS-stimulated TNF-a release from neutrophils.
  • propionate dose-dependently suppressed IL-6 mRNA and protein release from colitis mouse colon organ cultures are examples of colitis mouse colon organ cultures.
  • TNF-a and members of the interleukin family are known to play a key role in the pathogenesis of IBD (Fuss, Curr Drug Targets Inflamm allergy 2003, 2: 101-112; Tedelind et al, World J Gastroenterol 2007, 13(20): 2826-2832). Further, GPR43 has been described to regulate the anti-inflammatory responses by SCFA in various in vivo model such as colitis, rheumatoid arthritis and asthma through a regulation of the neutrophil physio lo logy.
  • GPR43 agonists or partial agonists may be of therapeutic value for the treatment and/or prevention of inflammatory diseases.
  • the invention relates to the use of compounds of general formula
  • Ar 1 is a 5- to 6-membered aryl or heteroaryl group, 3- to 8-membered cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, or a linear or branched C3-C6 alkyl group, each of the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or alkyl groups being optionally substituted by one or more groups selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkoxyalkoxy, alkylamino, amino
  • R 1 is H, halo, allyl, or a C 1 -C 4 alkyl group, which may optionally be substituted by one or more groups selected from halo or C 1 -C 4 alkyl;
  • L 2 is a C 1 -C3 alkylene, C 2 -C 4 alkenylene, C3-C6 cylcloalkylene, each of which being optionally substituted by one or more groups selected from halo, alkyl, alkoxy, or haloalkyl; or L 2 is -0-CH 2 -; or
  • R is H or linear or branched alkyl, aryl, acyloxy alkyl, dioxolene, R 3 is H, methyl or ethyl, and R 4 is hydroxyl -S0 2 CH 3j -S0 2 cyclopropyl or -S0 2 CF 3 ;
  • D is CO or S0 2 ;
  • R 2 is H, linear or branched C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 haloalkyl, C 2 - C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylalkyl, aryl, arylalkyl, heteroarylalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, or aralkyloxyalkyl; each of the alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroarylalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, and aralkyloxyalkyl groups being optionally substituted by one or more substituents selected from halo, cyano,
  • Ar 2 is a 5- or 6-membered heterocyclic group or a 5- or 6-membered heteroaryl group, optionally substituted by one or more substituents selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, alkenyl, alkynyl, heteroalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, alkylcarbonylaminoalkyl, acylamino, carbamoyl, hydroxycarbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, halo
  • L 3 is a single bond, C 1 -C 3 alkylene, C 1 -C 3 cycloalkylene C 1 -C 3 alkenylene or carbonylamino;
  • Ar 3 is an aryl, heteroaryl, or C 1 -C4 alkyl group, each of which being optionally substituted by one or more groups selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, ary
  • the invention provides methods for treating and/or preventing in a patient the development of an inflammatory disease, including, but not limited to, rheumatoid arthritis; inflammatory bowel disease (IBD) including but not limited to Crohn's disease, ulcerative colitis and colitis; Pagets disease; osteoporosis; multiple myeloma; uveitilis; acute and chronic myelogenous leukemia; pancreatic ⁇ cell destruction; rheumatoid spondylitis; osteoarthritis; gouty arthritis and other arthritis conditions; gout; adult respiratory distress syndrome (ARDS); chronic pulmonary inflammation diseases; silicosis; pulmonary sarcoidosis; psoriasis; allergic rhinitis; anaphylaxis; contact dermatitis; pancreatitis; asthma; muscle degeneration; cachexia such as cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome; Reiter's syndrome; type I
  • ischemia reperfusion injury comprising the administration of a pharmaceutically effective amount of a compound of formula (I) or pharmaceutically acceptable salt or solvate thereof to a patient in need thereof.
  • the compounds of the invention or pharmaceutically acceptable salts and solvates thereof are those described above in respect to formula (I) with the following provisos:
  • Ar 2 -L 3 -Ar 3 is not 4-(4-butylphenyl)thiazol-2-yl, 4-(4-ethylphenyl)thiazol-2-yl, 4- (para-tolyl)thiazol-2-yl, 4-phenylthiazol-2-yl, 4-(4-propylphenyl)thiazol-2-yl, 4- (4-(sec-butyl)phenyl)thiazol-2-yl, 4-(4-isopropylphenyl)thiazol-2-yl, 4-(4- isobutylphenyl)thiazol-2-yl, 4-(4-(tert-butyl)phenyl)thiazol-2-yl, 4-(4- butylphenyl)-5 -methylthiazo 1-2-yl, 4-(4-ethylphenyl)-5 -methylthiazo 1-2-yl, 5 - methyl-4-(para-tolyl)thiazol-2-y
  • Ar 2 is not 5-cyano-thiazolyl; the compound of formula I is none of.
  • the compound of the invention is not 6-((4-(2- chlorophenyl)thiazol-2-yl)carbamoyl)cyclohex-3-enecarboxylic acid.
  • the invention relates to the use of compounds of formula (I) as well as pharmaceutically acceptable salts and solvates thereof for the preparation of a medicament for the treatment and/or prevention of inflammatory diseases or in other terms to methods for treating and/or preventing in a patient the development of an inflammatory disease, comprising the administration of a pharmaceutically effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof to a patient in need thereof.
  • Preferred compounds of formula I and pharmaceutically acceptable salts and solvates thereof are those wherein
  • Z is -COOR, wherein R is defined as above in respect to formula I, preferably Z is COOH; and/or
  • R 1 is hydrogen, halogen, or a group selected from C 1-4 alkyl optionally substituted by one or more substituents selected from halogen, allyl or alkyl; preferably R 1 is selected from hydrogen, fluoro, methyl, or ethyl, the methyl or ethyl group being optionally substituted with one or more substituents selected from fluoro or alkyl, more preferably R 1 is hydrogen, fluoro or methyl, and most preferably R 1 is hydrogen, and L 2 is as defined above in respect to formula I, preferably L 2 is cyclopropylene, ethenylene, n-propylene, -CH 2 C(R'R")-, or -C(R'R")-, wherein R' and R" are independently selected from H, halogen, methyl, and ethyl, more preferably L 2 is cyclopropylene, ethenylene, methylene, -CHMe-, -CHF-; even more
  • R 1 and L 2 together are a 5- to 6-membered saturated or unsaturated carbocyclic or heterocyclic group, preferably a non aromatic, saturated or partially unsaturated, 5- to 6-membered carbocyclic group, under the condition that -L 1 -Ar 1 is H, more preferably R 1 and L 2 together are a cyclohexyl or cyclohexenyl group, under the condition that -L 1 -Ar 1 is H, even more preferably R 1 and L 2 together are selected from the group consisting of
  • dotted line is present or absent, preferably present; D is attached at position a and Z is attached at position b under the condition that -L 1 -Ar 1 is H; and/or
  • R 2 is H, linear or branched C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, allyl, propargyl, cyclopropyl, cyclopentyl, cyclopentylmethyl, cyclopropylmethyl, 1 ,1,1- trifluoroethyl, -C 2 H 4 CO 2 CH 3 , -CH 2 C0 2 CH 3 , or -CH 2 CONH 2 , benzyl, benzyloxyethyl, methoxyethyl, preferably R 2 is H, methyl, ethyl, allyl, cyclopropyl, hydroxyethyl, -C 2 H 4 C0 2 CH 3 , -CH 2 C0 2 CH 3, -CH 2 CONH 2 , more preferably R 2 is methyl or cyclopropyl; and/or Ar 1 is a 5- to 6-membered aryl or heteroaryl group, or a 5- to 6-membere
  • Still other preferred compounds of formula I are those wherein D is S0 2 and Ar 1 ,
  • Ar Ar J , R , IT, L , If, I ,and Z are as defined above in respect to formula I.
  • preferred compounds of Formula I are those of formula la:
  • Ar 1 , Ar", Ar J , R , R", L , If and f are as defined above in respect to formula I.
  • Preferred compounds of formula la are those wherein
  • Ar 1 , Ar", Ar J , R", L 1 and f are as defined above in respect to formula I.
  • preferred compounds of Formula I are those of formula lb:
  • X is S or O, preferably X is S;
  • Y is CH or N, preferably Y is CH;
  • L 3 is attached to the heterocyclic group X c 1 either in position 4 or 5, preferably in position 4; and if Y is CH, R 5 is H, halo, hydroxyl, linear or branched C 1 -C3 alkyl, C 1 -C3 hydroxyalkyl, C 1 -C3 haloalkyl, preferably H, methyl, F, CI, or CF 3 , more preferably H or F and R 5 is attached to the heterocyclic group either in position 4, if L 3 is attached in position 5, or in position 5, if L 3 is attached in position 4; preferably R 5 is attached in position 5; if Y is N, R 5 is absent and L 3 is attached in position 5; and
  • Ar 1 and L 1 are as defined above in respect to formula I, preferably Ar 1 is a 5- to 6-membered aryl, preferably phenyl, or heteroaryl group, preferably furanyl, thiophenyl, oxazolyl, isoxazolyl, or thiazolyl optionally substituted by one or more groups selected from halogen, trifluoromethyl, cyano, methoxy trifluoromethoxy, and methoxyethoxy, and L 1 is a single bond, C 1 -C 2 alkylene, or C 2 alkenylene, each optionally being substituted by one or more substituents selected from halo, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, preferably L 1 is a single bond, or Ci-C 2 alkylene, optionally substituted by C 1 -C 2 alkyl, more preferably L 1 is -CH 2 - ; or Ar 1 is a linear or branched C3-C6
  • Ar 3 is as defined above in respect to formula I, preferably Ar 3 is an aryl or heteroaryl group, optionally substituted by one or more substituents selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, cyano, 5 or 6 membered heteroaryl such as pyridinyl, phenyl, methylcarbonylamino, -NH-SO2CF3, and L 3 is a single bond or C1-C2 alkylene; or Ar 3 is a C1-C4 alkyl group and L 3 is a single bond, more preferably Ar 3 is an aryl, preferably phenyl, or heteroaryl group, preferably thiophenyl, more preferably thiophen-2-yl, furanyl, more preferably furan-2-yl, each of said aryl or heteroaryl being optionally substituted by one or more substituents selected from halo, C1-C4 alkyl
  • R 1 is as defined above in respect to formula I, preferably R 1 is hydrogen, halogen, allyl, or a group selected from C 1 -4 alkyl optionally substituted by one or more substituents selected from halogen or alkyl; more preferably R 1 is selected from hydrogen, fluoro, or methyl or ethyl, the methyl or ethyl group being optionally substituted with one or more substituents selected from fluoro or alkyl, even more preferably R 1 is hydrogen, fluoro or methyl, and most preferably R 1 is hydrogen, and L 2 is as defined above in respect to formula I, preferably L 2 is cyclopropylene, ethenylene, n-propylene, -C(R'R")-, wherein R' and R" are independently selected from H, halogen, methyl, and ethyl, more preferably L 2 is cyclopropylene, ethenylene, methylene, -CHMe-, -CHF-
  • D is attached at position a and Z is attached at position b under the condition that -iZ-Ar 1 is H; and/or R 1 and L 2 together are a non aromatic, saturated or partially unsaturated, carbocyclic group, under the condition that -L 1 -Ar 1 is H, preferably R 1 and L 2 together are a cyclohexyl or cyclohexenyl group, under the condition that -L 1 -Ar 1 is H, more preferably R 1 and L 2 together are selected from the group consisting of
  • dotted line is present or absent, preferably present; D is attached at position a and Z is attached at position b under the condition that -L 1 -Ar 1 is H; and/or
  • Z is as defined above in respect to formula I, preferably Z is -COOR, wherein R is defined as above in respect to formula I, more preferably Z is COOH; and R 2 is as defined above in respect to formula I, preferably R 2 is H, linear or branched C 1 -C 4 alkyl, C 1 -C 2 hydroxyalkyl, allyl, propargyl, cyclopropyl, cyclopentyl, cyclopentylmethyl, cyclopropylmethyl, benzyl, benzyloxyethyl, methoxyethyl, 1 , 1 ,1-trifluoroethyl, -C 2 H 4 CO 2 CH 3 , -CH 2 C0 2 CH 3 , or -CH 2 CONH 2 , more preferably R 2 is H, methyl, ethyl, allyl, cyclopropyl, hydroxyethyl, - C 2 H 4 CO 2 CH 3 , -CH 2 CO 2 CH
  • Preferred compounds of formula lb are those wherein Z is -COOR, preferably COOH, and R, Ar 1 , Ar 2 , Ar 3 , R 1 , R 2 , L 1 , L 2 and L 3 are as defined above in respect to formula I.
  • Particularly preferred compounds of formula lb are those of formula Ib-1
  • L , If, If, Ar", X, Y, Z, R , R", and R" are as defined above in respect to formula lb, preferably L 1 is methylene, optionally substituted by C 1 -C 2 alkyl or halo, preferably by methyl or fluoro, even more preferably L 1 is methylene; and
  • R 6 , R 7 , R' 6 , R' 7 and R 8 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, heteroaryloxycarbonyl,
  • Preferred compounds of formula lb- 1 are those of formula lb- la wherein L 2 , L 3 , Ar 3 , X, Y, R 2 , R 5 , R 6 , R 7 , R' 6 , R' 7 and R 8 are as defined above in respect to formula lb- 1.
  • L , L% I , Ar", X, Y, Z, R , R" and R" are as defined above in respect to formula lb, preferably L 1 is methylene;
  • B 1 , B 2 and B 3 are independently CF 2 , O, NR a , CO, or S0 2 , wherein R a is H or alkyl, preferably linear or branched C 1 -C 4 alkyl; C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylaminocarbonyl, C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkylcarbonyl, C 3 -C 6 cycloalkylsulfonyl, C 3 -C 6 cycloalkylaminocarbonyl, aryl, arylcarbonyl, arylsulfonyl or arylaminocarbonyl, heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl or heteroarylammocarbonyl; preferably B 1 , B 2 and B 3 are O and R 9 , R 10 , R
  • A is -(CH 2 ) compassion-0-, -(CH 2 ) admir-NR a -, -(CH 2 ) n -S0 2 -, or -(CH 2 ) m -, wherein n is equal to 0 or 1 , m is equal to 1 or 2, and R a is as defined above in respect to formula Ib-2b, preferably R a is H or alkyl, preferably linear or branched C1-C4 alkyl; C1-C4 alkylcarbonyl, C1-C4 alkylsulfonyl, more preferably linear or branched C1-C4 alkyl; and
  • A is -(CH 2 ) compassion-0-, -(CH 2 ) admir-NR a -, -(CH 2 ) n -S0 2 -, or -(CH 2 ) m -, wherein n is equal to 0 or 1 , m is equal to 1 or 2, and R a is as defined above in respect to formula Ib-2b, preferably R a is H or alkyl, preferably linear or branched C1-C4 alkyl; C1-C4 alkylcarbonyl, C1-C4 alkylsulfonyl, more preferably linear or branched C1-C4 alkyl; and
  • R 16 , R 17 , R 18 and R 19 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, heteroarylcarbonyloxy, heteroarylcarbonyl,
  • R or R and R or R and R together form an alkylenedioxy group or a
  • R 16 17 17 18 18 19 haloalkylenedioxy group or R and R or R and R or R together form a cycloalkyl, aryl, heterocyclyl or heteroaryl moiety fused to the phenyl group they are attached to, each of said substituents being optionally substituted by one or more further substituents selected from halo, alkoxy, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonyl, aralkyl, aryl, arylamino, aryloxy, cyano, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocyclyl, hydroxyl, oxo, or sulfonyl, preferably R 16 , R 17 , R 18 and R 19 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, halo
  • Preferred compounds of formula Ib-4 are those of formula Ib-4a
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , X, Y and Z are as defined above in respect to formula lb- 4,
  • R 20 and R' 20 are independently selected from H, halo (preferably -F and -CI), cyano, C 1 -C 3 alkyl, cyclopropyl, haloalkyl, alkoxy, haloalkoxy, alkoxycarbonylamino, or the two substituents form an alkylenedioxy group or a haloalkylenedioxy group, preferably R 20 and R 20 are H, halo preferably fluoro or chloro, haloalkyl, preferably -CF 3 or -CHF 2 , alkoxy preferably methoxy, haloalkoxy preferably -OCF 3 or -OCHF 2 ;
  • Ar 4 is 5 or 6 membered aryl, preferably phenyl, 5 or 6 membered heteroaryl, preferably furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, more preferably furan-3-yl, thiophen-3-yl, pyridinyl, still more preferably pyridin- 3-yl, each of said 5 or 6 membered aryl or 5 or 6 membered heteroaryl groups being optionally fused to one or more 5 or 6 membered cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, thus forming a fused ring system, and the latter fused ring system being optionally substituted by one or more further substituents selected from halo, hydroxyl, oxo, alkyl, and/or each of said 5 or 6 membered aryl or 5 or 6 membered heteroaryl groups being optionally substitute
  • Preferred compounds of formula Ib-4a are those of formula Ib-4b
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , and Z are as defined above in respect to formula lb, and Ar 4 , R 20 and R' 20 , are as defined above in respect to formula Ib-4a.
  • Preferred compounds of formula Ib-4b are those of formula Ib-4c
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , and Z are as defined above in respect to formula lb;
  • R 20 and R' 20 are as defined above in respect to formula Ib-4a;
  • R and R are independently selected from H, halo, preferably fluoro or chloro, alkoxy, preferably methoxy, preferably R 21 and R 22 are H;
  • R 23 is selected from H, halo, cyano, hydroxyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, alkylaminoalkoxy, preferably dimethylaminoethoxy, cycloalkyloxy, cycloalkylalkyloxy, heterocyclyloxy, aryloxy, aralkyloxy, alkylamino, alkylaminoalkyl, cycloalkylamino, arylamino, aralkylamino, alkylaminocarbonyl, heteroarylcarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, alkylsulfonyl, preferably C1-C3 alkylsulfonyl, more preferably methylsul
  • Y 1 is C-R 24 and R 24 and R 23 together form a 5 or 6 membered cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, preferably 2-oxopyrrolidinyl, morpholinyl, 2- oxopiperidinyl, furanyl, pyrrolyl, imidazolyl, thus forming a fused ring system, the latter fused ring system being optionally substituted by one or more group selected from oxo, alkyl or halo; and
  • Y 2 is N or C-R 25 where R 25 is H, halo, alkoxy, alkyl, heterocyclyl, preferably pyrrolidinyl, imidazolinyl, piperidinyl or morpholinyl, more preferably 2- oxopyrrolidin-l-yl, 2-oxoimidazolin-l-yl, 2-oxopiperidin-lyl or morpholin-4-yl, each of said substituents being optionally substituted by one or more further substituents selected from halo, preferably chloro or fluoro, oxo, alkyl, preferably methyl, preferably R 25 is H, halo, methoxy, more preferably H, chloro or fluoro, or
  • Y is C-R and R and R together form a 5 or 6 membered cycloalkyl, aryl, heterocyclyl or heteroaryl moiety, preferably 2-oxopyrrolidinyl, morpholinyl, 2- oxopiperidinyl, furanyl, pyrrolyl, imidazolyl, furanyl, thus forming a fused ring system, the latter fused ring system being optionally substituted by one or more group selected from oxo, alkyl or halo, under the condition that R 24 and R 23 together do not form a 5 or 6 membered cycloalkyl, aryl, heterocyclyl or heteroaryl moiety.
  • Preferred compounds of formula Ib-4c are those of formula Ib-4d
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , and Z are as defined above in respect to formula lb;
  • R 20 and R' 20 are as defined above in respect to formula Ib-4a; and
  • R , R , R" and R" are as defined above in respect to formula Ib-4c.
  • Preferred compounds of formula Ib-4d are those of formula Ib-4e
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , and Z are as defined above in respect to formula lb;
  • R 20 and R' 20 are as defined above in respect to formula Ib-4a; and
  • R , R , R" and R" are as defined above in respect to formula Ib-4c.
  • Other preferred compounds of formula Ib-4d are those of Ib-4f
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , and Z are as defined above in respect to formula lb;
  • R 20 and R' 20 are as defined above in respect to formula Ib-4a; and
  • R , R , R" and R" are as defined above in respect to formula Ib-4c. Still other preferred compounds of formula Ib-4d are those of formula Ib-4g
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , and Z are as defined above in respect to formula lb;
  • R 20 and R' 20 are as defined above in respect to formula Ib-4a; and
  • R , R , R" and R" are as defined above in respect to formula Ib-4c.
  • Other preferred compounds of formula Ib-4c are those of formula Ib-4d'
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , and Z are as defined above in respect to formula lb;
  • R 20 and R' 20 are as defined above in respect to formula Ib-4a; and
  • R , R , R" and R" are as defined above in respect to formula Ib-4c.
  • Preferred compounds of formula Ib-4d' are those of formula Ib-4e'
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , and Z are as defined above in respect to formula lb;
  • R 20 and R' 20 are as defined above in respect to formula Ib-4a; and
  • R , R , R" and R" are as defined above in respect to formula Ib-4c.
  • Other preferred compounds of formula Ib-4d' are those of formula Ib-4f
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , and Z are as defined above in respect to formula lb;
  • R 20 and R' 20 are as defined above in respect to formula Ib-4a; and
  • R , R , R and R are as defined above in respect to formula Ib-4c.
  • Still other preferred compounds of formula Ib-4d' are those of formula Ib-4g'
  • R , R , R" and R" are as defined above in respect to formula Ib-4c.
  • preferred compounds of formula Ib-4a are those of formula Ib-4h,
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , and Z are as defined above in respect to formula lb; and Ar 4 , R 20 and R' 20 , are as defined above in respect to formula Ib-4a.
  • Preferred compounds of formula Ib-4h are those of formula Ib-4i
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , and Z are as defined above in respect to formula lb;
  • R 20 and R' 20 are as defined above in respect to formula Ib-4a; and
  • R , R , R , Y and Y are as defined above in respect to formula Ib-4c.
  • Preferred compounds of formula Ib-4i are those of formula Ib-4j
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , and Z are as defined above in respect to formula lb;
  • R 20 and R' 20 are as defined above in respect to formula Ib-4a;
  • R , R , R" and R" are as defined above in respect to formula Ib-4c.
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 , X, Y, and Z are as defined above in respect to formula lb;
  • R , R , R , R , R are independently selected from H, halo, cyano, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, acylamino, carbamoyl, alkoxycarbamoyl, cycloalkylcarbamoyl, alkylcarbamoylamino, cycloalkylaminocarbamoyl, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfony
  • R , R , R i0 are independently selected from H, halo, preferably chloro or fluoro, more preferably chloro, cyano, alkyl, preferably methyl, haloalkyl, preferably - CF 3 or -CHF 2 , cycloalkyl, preferably cyclopropyl, alkoxy, preferably methoxy or isopropyloxy, haloalkoxy, preferably -OCF 3 or -OCHF 2 , alkoxycarbamoyl, or
  • R , R' , R , R' 27 , R 28 are independently selected from H, halo, preferably chloro or fluoro, more preferably chloro, haloalkyl, preferably -CF 3 or -CHF 2 , alkoxy, preferably methoxy.
  • Preferred compounds of formula Ib-4k are those of formula Ib-41
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 and Z are as defined above in respect to formula lb; and R 26 , R' 26 , R 27 , R' 27 and R 28 are as defined above in respect to formula Ib-4k.
  • Preferred compounds of formula Ib-41 are those of formula Ib-4m
  • R' iD and R i are as defined above in respect to formula Ib-4k, preferably R' and are independently selected from H, halo, haloalkyl, haloalkoxy, preferably chloro, fluoro CF 3 , CHF 2 , OCF 3 or OCHF 2 , preferably R' 26 is chloro and R 27 is selected from H, halo, CF 3 , CHF 2 , OCF 3 or OCHF 2 , preferably chloro and fluoro.
  • Other preferred compounds of formula Ib-41 are those of formula Ib-4n,
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 and Z are as defined above in respect to formula lb;
  • R' , 11" and R i0 are as defined above in respect to formula Ib-4k, preferably R' , R 27 and R 28 are independently selected from H, halo, haloalkyl, haloalkoxy, preferably chloro, fluoro, CF 3 , or CHF 2 , preferably OCF 3 or OCHF 2 .
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 and Z are as defined above in respect to formula lb;
  • R and R' are as defined above in respect to formula Ib-4k, preferably R and R' 27 are independently selected from H, halo, haloalkyl, haloalkoxy, preferably chloro, fluoro, CF 3 , CHF 2 OCF 3 or OCHF 2 .
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 and Z are as defined above in respect to formula lb;
  • R" and R i0 are as defined above in respect to formula Ib-4k, preferably R and R 28 are independently selected from H, halo, haloalkyl, alkoxy, haloalkoxy, preferably chloro, fluoro, CF 3 , CHF 2 , methoxy, OCF 3 or OCHF 2 .
  • Still other preferred compounds of formula Ib-41 are those of formula Ib-4q
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 and Z are as defined above in respect to formula lb; and R and R are as defined above in respect to formula Ib-4k, preferably R and are independently selected from H, halo, haloalkyl, alkoxy, haloalkoxy, preferably chloro, fluoro, CF 3 , or CHF 2 , methoxy, OCF 3 or OCHF 2 .
  • preferred compounds of formula I are those of formula Ic
  • Ar , Ar , R , R , L , L , L and Z are as defined above in respect to formula I;
  • R 6 , R 7 , R' 6 , R' 7 and R 8 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, arylcarbonyloxy, hetero
  • Preferred compounds of formula Ic are those wherein
  • Z is -COOH; R 1 is H;
  • L 2 is cyclopropylene, ethenylene, methylene, -CHMe-, -CHF-;
  • L 1 is as defined above in respect to formula I, preferably methylene, ethylene, or a single bond; and Ar 2 , Ar 3 , R 2 , R 6 , R 7 , R' 6 , R' 7 R 8 and L 3 are as defined above in respect to formula I.
  • Particularly preferred compounds of formula Ic are those of formula Ic-1
  • Ar 2 , Ar 3 , R 2 , R 6 , R 7 , R' 6 , R' 7 R 8 , L 2 , L 3 , and Z are as defined above in respect to formula Ic.
  • Preferred compounds of formula Ic-1 are those wherein Z is -COOH;
  • L 2 is cyclopropylene, ethenylene, methylene, -CHMe-, -CHF-;
  • Ar 2 , Ar 3 , R 2 , R 6 , R 7 , R' 6 , R' 7 R 8 , and L 3 are as defined above in respect to formula Ic.
  • preferred compounds of formula I are those of formula Id
  • Ar 2 , Ar 3 , R, R 2 and L 3 are as defined above in respect to formula I.
  • Preferred compounds of formula Id are those of formula Id-1
  • dotted line is present or absent, preferably the dotted line is present;
  • X is S or O;
  • Y is CH or N;
  • L 3 is attached to the heterocyclic group either in position 4 or 5, preferably in position 4;
  • R 5 is halo, hydroxyl, linear or branched C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 haloalkyl, preferably F, CI, or CF 3 and R 5 is attached to the heterocyclic group either in position 4, if L 3 is attached in position 5, or in position 5, if L 3 is attached in position 4; preferably R 5 is attached in position 5; If Y is N, R 5 is absent and L 3 is attached in position 5; and
  • Ar 3 is as defined above in respect to formula I, preferably Ar 3 is an aryl or heteroaryl group, optionally substituted by one or more substituents selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, cyano, 5 or 6 membered heteroaryl such as pyridinyl, phenyl, methylcarbonylamino, -NH-SO 2 CF 3 , and L 3 is a single bond or C 1 -C 2 alkylene; or Ar 3 is a C 1 -C 4 alkyl group and L 3 is a single bond, more preferably Ar 3 is an aryl, preferably phenyl, or heteroaryl group, preferably thiophenyl, more preferably thiophen-2-yl, furanyl, more preferably furan-2-yl, each of said aryl or heteroaryl being optionally substituted by one or more substituents selected from halo,
  • R is as defined above in respect to formula I;
  • R 2 is as defined above in respect to formula I, preferably R 2 is H, linear or branched C1-C4 alkyl, C1-C2 hydroxyalkyl, allyl, propargyl, cyclopropyl, cyclopentyl, cyclopentylmethyl, cyclopropylmethyl, benzyl, benzyloxyethyl, methoxyethyl, 1,1,1-trifluoroethyl, -C2H4CO2CH3, -CH 2 C0 2 CH 3 , or -CH 2 CONH 2 , more preferably R 2 is H, methyl, ethyl, allyl, cyclopropyl, hydroxyethyl, - C 2 H 4 C0 2 CH 3 , -CH 2 C0 2 CH 3 , or -CH 2 CONH 2 , more preferably R 2 is methyl or cyclopropyl.
  • preferred compounds of Formula I are those of formula Ie: wherein
  • Y is CH or N
  • R 14 and R 15 are independently H, halo, cyano, hydroxyl, linear or branched C 1 -C3 alkyl, C 1 -C3 hydroxyalkyl, C 1 -C3 haloalkyl, preferably H, F, CI, or CF 3 , more preferably H;
  • Ar 1 and L 1 are as defined above in respect to formula I, preferably as defined in respect to formula lb, more preferably Ar 1 is a 5- to 6-membered aryl or heteroaryl group, optionally substituted by one or more groups selected from halogen, trifluoromethyl, cyano, and methoxy, and L 1 is a methylene group, C 1 -C 2 alkylene, or C 2 alkenylene; or Ar 1 is a linear or branched C 3 -C 6 alkyl group, optionally substituted by one or more groups selected from halogen, trifluoromethyl, cyano, and methoxy, and L 1 is a methylene group;
  • Ar 3 is as defined above in respect to formula I, preferably Ar 3 is an aryl or heteroaryl group, optionally substituted by one or more substituents selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, cyano, 5 or 6 membered heteroaryl such as pyridinyl, phenyl, methylcarbonylamino, -NH-S0 2 CF 3 , and L 3 is a single bond or C 1 -C 2 alkylene; or Ar 3 is a C 1 -C 4 alkyl group and L 3 is a single bond, more preferably Ar 3 is an aryl, preferably phenyl, or heteroaryl group, preferably thiophenyl, more preferably thiophen-2-yl, furanyl, more preferably furan-2-yl, each of said aryl or heteroaryl being optionally substituted by one or more substituents selected from halo
  • R 1 is as defined above in respect to formula I, preferably R 1 is hydrogen, halogen, or a group selected from C 1 -4 alkyl optionally substituted by one or more substituents selected from halogen or alkyl; more preferably R 1 is selected from hydrogen, fluoro, or methyl or ethyl, the methyl or ethyl group being optionally substituted with one or more substituents selected from fluoro or alkyl, even more preferably R 1 is hydrogen, fluoro or methyl, and most preferably R 1 is hydrogen, and L 2 is as defined above in respect to formula I, preferably L 2 is cyclopropylene, ethenylene, n-propylene, or -C(R'R")-, wherein R' and R" are independently selected from H, halogen, methyl, and ethyl, more preferably L 2 is cyclopropylene, ethenylene, methylene, -CHMe-, -CHF-, even more
  • Z is as defined above in respect to formula I, preferably Z is -COOR, wherein R is defined as above in respect to formula I; preferably Z is COOH and
  • R 2 is as defined above in respect to formula I, preferably R 2 is H, linear or branched C 1 -C 4 alkyl, C 1 -C 2 hydroxyalkyl, allyl, propargyl, cyclopropyl, cyclopentyl, cyclopentylmethyl, cyclopropylmethyl, benzyl, benzyloxyethyl, methoxyethyl, 1 , 1 ,1-trifluoroethyl, -C 2 H 4 CO 2 CH 3 , -CH 2 C0 2 CH 3 , or -CH 2 CONH 2 , more preferably R 2 is H, methyl, ethyl, allyl, cyclopropyl, hydroxyethyl, -
  • R 2 is methyl or cyclopropyl.
  • Preferred compounds of formula Ie are those wherein Z is -COOR and R, Ar 1 ,
  • Ar Ar J , R , R", L , If and 1 are as defined above in respect to formula I, preferably L 1 is a methylene group and Ar 1 is phenyl.
  • preferred compounds of Formula I are those of formula If
  • Ar 1 , Ar 3 , L 1 , L 2 , L 3 , R 1 , R 2 , R 14 , R 15 , Y and Z are as defined above in respect to formula Ie.
  • preferred compounds of Formula I are those of formula Ig:
  • B 4 is O or S or N-R b where R b is H or alkyl, preferably linear or branched C 1 -C 4 alkyl; C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylsulfonyl, C 1 -C4 alkylaminocarbonyl, C3-C6 cycloalkyl; preferably O or S, more preferably O,
  • R 9 , R 9 , and R 11 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbony
  • Ar Ar J , L , If, If, R , R", and Z are as defined above in respect to formula I.
  • preferred compounds of Formula I are those of formula Ih:
  • B 5 is CH 2 or O preferably O
  • R 9 , R 10 , R' 9 , R' 10 , R 11 , R 12 and R" 13 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclyloxy
  • Ar Ar J , L , If, If, R , R", and Z are as defined above in respect to formula I.
  • preferred compounds of Formula I are those of formula Ii
  • R 9 , R 9 and R 12 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, heteroaryloxycarbonyl, alkylcarbonyloxy, cyclo
  • R 9 , R' 9 , R 10 , R' 10 , R 11 , R 12 and R" 13 are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbony
  • Ar Ar J , L , If, If, R , R", and Z are as defined above in respect to formula I.
  • preferred compounds of Formula I are those of formula Ik:
  • R 29 is H, halo, alkyl, haloalkyl preferably -CF 3 or -CF 2 H, alkoxy, haloalkoxy preferably -OCF 3 or -OCF 2 H, cyano, preferably R 29 is H, F, -CF 3 , alkyl preferably methyl, more preferably R 29 is H, F or methyl; and
  • Ar Ar L , If, If, R , R", and Z are as defined above in respect to formula I.
  • preferred compounds of Formula I are those of formula II:
  • R and R are independently selected from H, halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyloxy, heterocyclylcarbonyloxy, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloalkylcarbonyl
  • Ar Ar J , L , If, If, R , R", and Z are as defined above in respect to formula I.

Abstract

La présente invention concerne des composés de formule (I) utiles dans le traitement et/ou la prévention de maladies inflammatoires.
PCT/EP2010/070236 2009-12-21 2010-12-20 Composés, composition pharmaceutique et procédés pour utilisation dans le traitement de maladies inflammatoires WO2011076734A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014175832A1 (fr) * 2013-04-26 2014-10-30 Agency For Science, Technology And Research Modulateurs de la voie wnt
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
CN112209922A (zh) * 2019-07-12 2021-01-12 湖南大学 阿魏酰胺衍生物及其医药用途与晶体结构
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
WO2021160109A1 (fr) * 2020-02-13 2021-08-19 劲方医药科技(上海)有限公司 Composé de dihydronaphtyridinone, son procédé de préparation et son utilisation médicale
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
RU2809869C1 (ru) * 2020-02-13 2023-12-19 Генфлит Терапьютикс (Шанхай) Инк. Соединение на основе дигидронафтиридинона, и способ его получения, и его применение в медицине

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07149745A (ja) * 1993-11-30 1995-06-13 Hisamitsu Pharmaceut Co Inc 新規な２−アミノチアゾール誘導体
WO1996033176A1 (fr) 1995-04-18 1996-10-24 The Du Pont Merck Pharmaceutical Company Nouveaux composes d'acides hydroxamiques et d'aminocarboxylates servant d'inhibiteurs des metalloproteases et du tnf
WO2000026202A1 (fr) * 1998-10-30 2000-05-11 Pharmacia & Upjohn S.P.A. Derives 2-amino-thiazole, leur procede de preparation et leur utilisation en tant qu'agents antitumoraux
WO2003006443A2 (fr) * 2001-07-11 2003-01-23 Boehringer Ingelheim Pharma Gmbh & Co. Kg Derives d'acide carboxylique, medicaments contenant ces composes, leur utilisation et leur production
WO2004041813A1 (fr) * 2002-10-30 2004-05-21 Vertex Pharmaceuticals Incorporated Compositions utiles en tant qu'inhibiteurs de rock et d'autres proteines kinases
WO2004085388A2 (fr) * 2003-03-24 2004-10-07 Bristol-Myers Squibb Company Inhibiteurs de tyrosine kinase cycliques
WO2005026137A2 (fr) * 2003-09-06 2005-03-24 Vertex Pharmaceuticals Incorporated Modulateurs de transporteurs a cassette de liaison a l'atp
US20050143384A1 (en) * 2003-10-30 2005-06-30 Eric Sartori Amide thiadiazole inhibitors of plasminogen activator inhibitor-1
WO2005103022A1 (fr) * 2004-04-20 2005-11-03 Transtech Pharma, Inc. Derives de thiazole et de pyrimidine substitues, modulateurs des recepteurs de la melanocortine
WO2007117494A1 (fr) * 2006-04-05 2007-10-18 Vertex Pharmaceuticals Incorporated Désazapurines utiles comme inhibiteurs des kinases janus
WO2009044250A1 (fr) * 2007-10-02 2009-04-09 Palobiofarma, S.L. Nouveaux composés comme antagonistes des récepteurs a1 de l'adénosine
WO2010066682A1 (fr) * 2008-12-08 2010-06-17 Euroscreen S.A. Composés, composition pharmaceutique et méthodes pour application au traitement de troubles métaboliques

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07149745A (ja) * 1993-11-30 1995-06-13 Hisamitsu Pharmaceut Co Inc 新規な２−アミノチアゾール誘導体
WO1996033176A1 (fr) 1995-04-18 1996-10-24 The Du Pont Merck Pharmaceutical Company Nouveaux composes d'acides hydroxamiques et d'aminocarboxylates servant d'inhibiteurs des metalloproteases et du tnf
WO2000026202A1 (fr) * 1998-10-30 2000-05-11 Pharmacia & Upjohn S.P.A. Derives 2-amino-thiazole, leur procede de preparation et leur utilisation en tant qu'agents antitumoraux
WO2003006443A2 (fr) * 2001-07-11 2003-01-23 Boehringer Ingelheim Pharma Gmbh & Co. Kg Derives d'acide carboxylique, medicaments contenant ces composes, leur utilisation et leur production
WO2004041813A1 (fr) * 2002-10-30 2004-05-21 Vertex Pharmaceuticals Incorporated Compositions utiles en tant qu'inhibiteurs de rock et d'autres proteines kinases
WO2004085388A2 (fr) * 2003-03-24 2004-10-07 Bristol-Myers Squibb Company Inhibiteurs de tyrosine kinase cycliques
WO2005026137A2 (fr) * 2003-09-06 2005-03-24 Vertex Pharmaceuticals Incorporated Modulateurs de transporteurs a cassette de liaison a l'atp
US20050143384A1 (en) * 2003-10-30 2005-06-30 Eric Sartori Amide thiadiazole inhibitors of plasminogen activator inhibitor-1
WO2005103022A1 (fr) * 2004-04-20 2005-11-03 Transtech Pharma, Inc. Derives de thiazole et de pyrimidine substitues, modulateurs des recepteurs de la melanocortine
WO2007117494A1 (fr) * 2006-04-05 2007-10-18 Vertex Pharmaceuticals Incorporated Désazapurines utiles comme inhibiteurs des kinases janus
WO2009044250A1 (fr) * 2007-10-02 2009-04-09 Palobiofarma, S.L. Nouveaux composés comme antagonistes des récepteurs a1 de l'adénosine
WO2010066682A1 (fr) * 2008-12-08 2010-06-17 Euroscreen S.A. Composés, composition pharmaceutique et méthodes pour application au traitement de troubles métaboliques

Non-Patent Citations (41)

* Cited by examiner, † Cited by third party
Title
"groups or molecules which have chemical and physical similarities producing similar biological effects", CHEM. SOC. REV., vol. 8, 1979, pages 563
ARIENTI ET AL., J. MED. CHEM., vol. 48, no. 6, 2005, pages 1882
ATKINSON ET AL., J. ORG. CHEM., vol. 64, 1999, pages 3467
BARTOLI ET AL., J. MED. CHEM., vol. 41, 1998, pages 1855 - 68
C.G. WERMUTH: "The Practice of Medicinal Chemistry"
CHANDRASEKHAR ET AL., CLINICAL IMMUNOL IMMUNOPATHOL., vol. 55, 1990, pages 382
CHEM. RES. TOXICOL., 2007, pages 1954 - 1965
CLAREMON ET AL., TET. LETT., vol. 28, 1988, pages 2155
COVINGTON ET AL., BIOCHEMICAL SOCIETY TRANSACTION, vol. 34, 2006, pages 770 - 773
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 12 May 1984 (1984-05-12), CHERNYKH, V. P. ET AL: "Synthesis and interactions of heteroamides of ethylenedicarboxylic acids and their esters", XP002599069, retrieved from STN Database accession no. 1983:53789 *
DATABASE WPI Week 199533, Derwent World Patents Index; AN 1995-248282, XP002599068 *
DINARELLO, EUR. CYTOKINES NETW., vol. 5, 1994, pages 517 - 531
DRYSDALE ET AL., J. MED. CHEM., vol. 35, 1992, pages 2573 - 2581
E. L. ELIEL; S. H. WILEN; L. N. MANDER: "Stereochemistry of Organic Compounds", 1994, WILEY- INTERSCIENCE
EVANS ET AL., J. ORG. CHEM., vol. 64, 1999, pages 6411 - 6417
FARMATSEVTICHNII ZHURNAL (KIEV) , (5), 64-5 CODEN: FRZKAP; ISSN: 0367-3057, 1982 *
FELDMANN ET AL., IMMUNOLOGICAL REVIEWS, 1995, pages 195 - 223
FIRESTEIN, AM. J. PATHOL., vol. 140, 1992, pages 1309
FLEURSTEIN, STROKE, vol. 25, 1994, pages 1481
FUSS, CURR DRUG TARGETS INFLAMM ALLERGY, vol. 2, 2003, pages 101 - 112
H.L. FRIEDMAN: "Symposium on Chemical-Biological correlations", 1951, NATIONAL COUNCIL PUBLICATION
I. LANGMUIR, J. AM. CHEM. SOC., vol. 41, 1919, pages 1549
J. AM. CHEM. SOC., vol. 120, 1998, pages 12459
LAROCK, R. C.: "Comprehensive Org Transf", 1999, WILEY, pages: 709 - 719
LE POUL ET AL., J. BIOL CHEM., vol. 278, 2003, pages 25481 - 489
LE POUL ET AL., J. BIOL. CHEM., vol. 278, 2003, pages 25481 - 25489
LILJEBRIS ET AL., J. MED. CHEM., vol. 45, 2002, pages 1785 - 1798
MASLOWSKI ET AL., NATURE, vol. 461, no. 7268, 2009, pages 1282 - 1286
MASLOWSKI KENDLE M ET AL: "Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43", NATURE (LONDON), vol. 461, no. 7268, October 2009 (2009-10-01), pages 1282, XP002599070, ISSN: 0028-0836 *
MATTHEWS ET AL., J. COMB. CHEM., vol. 2, 2000, pages 19 - 23
PERETTO ET AL., J. MED. CHEM., vol. 48, 2005, pages 5705 - 5720
RAYASAM ET AL., EXPERT OPINION ON THERAPEUTIC TARGETS, vol. 11, 2007, pages 661 - 671
RODRIGUEZ ET AL., TETRAHEDRON, vol. 38, no. 24, 1997, pages 4221
RUDOLPH, J., TETRAHEDRON, vol. 56, 2000, pages 3161
SENGA ET AL., BLOOD, vol. 101, 2003, pages 1185 - 1187
SWAIN ET AL., J. MED. CHEM., vol. 34, 1991, pages 140 - 151
TARAROV ET AL., J. CHEM. SOC. PERKIN TRANS., vol. 1, 1997, pages 3101 - 3106
TEDELIND ET AL., WORLD J GASTROENTEROL, vol. 13, no. 20, 2007, pages 2826 - 2832
TETRAHEDRON, vol. 1, 1957, pages 9635
WALLACE ET AL., ORG. PROC. RES.& DEV., vol. 8, 2004, pages 738 - 743
WHITE ET AL., J. MED. CHEM., vol. 39, 1996, pages 4382 - 95

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