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WO2011076732A1 - Composés, composition pharmaceutique et procédés pour utilisation dans le traitement de troubles gastro-intestinaux - Google Patents

Composés, composition pharmaceutique et procédés pour utilisation dans le traitement de troubles gastro-intestinaux Download PDF

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Publication number
WO2011076732A1
WO2011076732A1 PCT/EP2010/070234 EP2010070234W WO2011076732A1 WO 2011076732 A1 WO2011076732 A1 WO 2011076732A1 EP 2010070234 W EP2010070234 W EP 2010070234W WO 2011076732 A1 WO2011076732 A1 WO 2011076732A1
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Prior art keywords
methyl
amino
thiazol
phenyl
acid
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Inventor
Hamid Hoveyda
Cyrille Evangelos Brantis
Guillaume Dutheuil
Ludivine Zoute
Didier Schils
Graeme Fraser
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Ogeda SA
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Euroscreen SA
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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
    • A61K31/425—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
    • A61K31/415—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
    • A61K31/433—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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals

Definitions

  • the present invention concerns methods and compounds useful in treating and/or preventing gastrointestinal disorders.
  • the compounds of the invention are useful for treatment and/or prevention of gastrointestinal disorders characterized by hypermotilenemia or gastrointestinal hypermotility, including but not limited to any type of diarrhea; Irritable Bowel Syndrome (IBS); intestinal injury disorders such as short-bowel syndrome; diseases involving intestinal barrier dysfunction such as proctitis and pouchitis.
  • IBS Irritable Bowel Syndrome
  • the compounds of the invention are also useful for treatment and/or prevention of inflammatory disorders of the gastrointestinal tract, such as Inflammatory Bowel Diseases (IBD) including but not limited to colitis, Ulcerative colitis (UC) and Crohn's Disease (CD).
  • IBD Inflammatory Bowel Diseases
  • UC Ulcerative colitis
  • CD Crohn's Disease
  • the invention relates to the use of selective GPR43 agonists or partial agonists and their pharmacologically acceptable salts and solvates thereof, previously described in PCT patent application No. PCT/EP2009/066536 filed on December 2009 in the name of the present Applicant, for the preparation of a medicament useful for the treatment and/or prevention of the above-mentioned gastrointestinal disorders.
  • Gastrointestinal disorders encompass a broad scope of diseases presented frequently to primary care practitioners. These disorders include any type of diarrhea such as, cancer treatment-related diarrhea, cancer- induced diarrhea, chemotherapy- induced diarrhea, radiation enteritis, radiation- induced diarrhea, stress-induced diarrhea, chronic diarrhea, AIDS-related diarrhea, C. difficile associated diarrhea, traveller's diarrhea, diarrhea induced by graft-versus-host disease and other types of diarrhea represent a major medical issue in many areas of the word. The major medical consequences of diarrheal diseases include dehydration, acidosis, death and impaired growth.
  • IBS Irritable Bowel Syndrome
  • IBS-D Irritable Bowel Syndrome
  • IBS-C Irritable Bowel Syndrome
  • IBS-A Irritable Bowel Syndrome
  • IBS has also been referred to as spastic colon, mucous colitis, spastic colitis, nervous stomach or irritable colon.
  • IBS affects approximately 10- 15% or more of the general population. It is the most common disease diagnosed by gastroenterologists and one of the most common disorders seen by primary care physicians. The cause of IBS is unknown but a number of factor have been implicated including diet, lifestyle, depression, anxiety and infections.
  • IBD Inflammatory Bowel Disease
  • IBS Ulcerative colitis
  • CD Crohn's Disease
  • Short-chain fatty acids are the majors anions, present at about 100 mM, in the lumen of the non-ruminant mammalian large intestine. They are produced by bacterial fermentation of undigested carbohydrate from ingested dietary fiber. They are 2-carbon to 5-carbon weak acids, including acetate (C2), propionate
  • Luminal SCFAs are not only absorbed as nutrients across the intestinal epithelium, but also influence various functions of the gastrointestinal tract (Cummings et al., Cambridge University press, 1995).
  • SCFAs influence colonic blood flow (Mortensen and Hielsen in Cummings et al., Cambridge University press, 1995), fluid/electrolyte uptake (Vidyasagar and Ramakrishna J.Physiol (Lond) 2000, 539: 163-173), colonic motility (Ono et al, Jpn J. Physiol 2004, 54: 483- 493; Mitsui et al, Jpn J.
  • GPR43 (also named FFA2R) belongs to a subfamily of G-Protein-Coupled Receptors (GPCRs), including GPR40 and GPR41, that have been identified as receptor 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 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 expressed in enteroendocrine L cells of the gastrointestinal tract. Immunohistochemistry studies have shown that GPR43 immunoreactivity was fully colocalized with PYY immunoreactivity in such enteroendocrine L cells (Tazoe at al, J Physiol and Pharmacol 2008, 59: 251-262). SCFAs influence the colonic motility (inhibition of colonic brakes) via PYY release into blood circulation (Lin et al., Am J Physiol 2004, 286: 558-563; Cuche et al., Am J Physiol 200, 279: 925-930). As indicated above, the majority of PYY containing enteroendocrine cells express GPR43 as a SCFA receptor and SCFAs might stimulate PYY containing enteroendocrine cells directly, via GPR43, to release
  • GPR43 receptors on enteroendocrine L cells have also been shown to be the basis of butyrate-stimulated proglucagon gene expression leading to the release of incretin hormones such as GLP-2 (Woodward JN and Tappenden KA, Clinical Nutrition Week Poster SOS26-2), a nutritive hormone known to promote repair and remodeling of the intestinal lumen following inflammatory maladies and/or surgical injury such as in diseases like short-bowel syndrome.
  • GLP-2 Wood JN and Tappenden KA, Clinical Nutrition Week Poster SOS26-2
  • GPR43 is also strongly expressed on neutrophils. Recent studies have shown that both acetate and propionate decreased LPS-stimulated TNFa release from neutrophils, where TNFoc and members of the interleukin family are known to play a key role in the pathogenesis of IBD. In addition both acetate and propionate (i) decreased the IL-6 protein release and (ii) decreased the mRNA level of proinflammatory cytokines from colitic mouse colon organ cultures. It also been suggested that a combination of acetate, propionate and butyrate display an antiinflammatory action which could explain the protective effects of fiber-rich diets (Cavaglieri et al, Life Sciences 2003 (73): 1683-1690).
  • the anti-inflammatory response to acetate in a colitis disease model is absent in genetically-modified mice where expression of the GPR43 receptor has been deleted (i.e. GPR43- knockout mice) providing definitive evidence implicating that the antiinflammatory response to acetate is modified via specific activation of the GPR43 receptor (Maslowski et al, Nature 2009: 461, 1282-1286).
  • GPR43 agonists and partial agonists may be of therapeutic value for the treatment and/or prevention of gastrointestinal hypermotility disorders, diarrhea, Irritable Bowel Syndrome (IBS), colitis, Inflammatory Bowel Disease (IBD), intestinal injury disorders such as short-bowel syndrome as well as diseases involving intestinal barrier dysfunction such as proctitis and pouchitis.
  • IBS Irritable Bowel Syndrome
  • IBD Inflammatory Bowel Disease
  • intestinal injury disorders such as short-bowel syndrome
  • diseases involving intestinal barrier dysfunction such as proctitis and pouchitis.
  • use of compounds, as those of the present invention, showing benefit in both non- inflammatory and inflammatory gastrointestinal disorders represent a real advantage and an added value for the treatment and/or prevention of such disorders.
  • the invention relates to the use of compounds of general formula (I)
  • 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 -C4 alkyl group, which may optionally be substituted by one or more groups selected from halo or C 1 -C4 alkyl;
  • L 2 is a C 1 -C3 alkylene, C 2 -C4 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 -O-CH 2 -; or
  • R 1 and L 2 together are a 5- to 6-membered saturated or unsaturated carbocyclic or heterocyclic group, preferably a cyclohexenyl group, under the condition that -L 1 - Ar 1 is H;
  • Z is selected from the group consisting of -COOR, wherein R is H or linear or branched alkyl, aryl, acyloxyalkyl, 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
  • IBS Irritable Bowel Syndrome
  • IBS intestinal injury disorders such as short-bowel syndrome
  • diseases involving intestinal barrier dysfunction such as proctitis and pouchitis as well as for the preparation of a medicament for the treatment and /or prevention of Inflammatory Bowel Diseases (IBD) including but not limited to colitis, Ulcerative colitis (UC) and Crohn's Disease (CD).
  • IBD Inflammatory Bowel Diseases
  • the invention provides methods for treating and/or preventing in a patient the development of gastrointestinal disorders characterized by hypermotilenemia or gastrointestinal hypermotility, including but not limited to any type of diarrhea, such as, cancer treatment-related diarrhea, cancer- induced diarrhea, chemotherapy- induced diarrhea, radiation enteritis, radiation-induced diarrhea, stress-induced diarrhea, chronic diarrhea, AIDS-related diarrhea, C.
  • gastrointestinal disorders characterized by hypermotilenemia or gastrointestinal hypermotility
  • any type of diarrhea such as, cancer treatment-related diarrhea, cancer- induced diarrhea, chemotherapy- induced diarrhea, radiation enteritis, radiation-induced diarrhea, stress-induced diarrhea, chronic diarrhea, AIDS-related diarrhea, C.
  • IBS Irritable Bowel Syndrome
  • IBS intestinal injury disorders such as short-bowel syndrome
  • diseases involving intestinal barrier dysfunction such as proctitis and pouchitis as well as methods for treating and/or preventing in a patient the development of Inflammatory Bowel Diseases (IBD) including but not limited to colitis, Ulcerative colitis (UC) and Crohn's Disease (CD).
  • IBD Inflammatory Bowel Diseases
  • 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 gastrointestinal disorders or in other terms to methods for treating and/or preventing in a patient the development of gastrointestinal disorders, 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/or
  • 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 preferably L 2 is methylene; and/or
  • 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-membered
  • 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:
  • R is H or linear or branched C 1 -C4 alkyl
  • Ar 1 , Ar", Ar J , R , R", L , If and 1 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 1 are as defined above in respect to formula I.
  • preferred compounds of Formula I are those of formula lb: z lb and pharmaceutically acceptable salts, and solvates thereof, wherein 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 " ⁇ 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 al
  • 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;
  • 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-, even more preferably L 2 is methylene; or
  • D is attached at position a and Z is attached at position b under the condition that -iZ-Ar 1 is H;
  • 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;
  • R 2 is as defined above in respect to formula I, preferably R 2 is H, linear or branched C 1 -C4 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 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 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 Ci-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% L% 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 heteroarylaminocarbonyl; preferably B 1 , B 2 and B 3 are O and
  • R 9 , R 10 , R 11 , R 12 , R 13 , R' 9 , R' 10 , R' 11 , R' 12 , R' 13 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, haloalkoxy, cycloalkyloxy, heterocyclyloxy, aryloxy, amino, alkylamino, aminoalkyl, carboxy, alkoxycarbonyl, cycloalkyloxycarbonyl, heterocyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylcarbonyloxy, cycloal
  • 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 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 and R' 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.
  • 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.
  • 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-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;
  • 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, haloalkyls
  • 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
  • Preferred compounds of formula Ib-41 are those of formula Ib-4m
  • Ar 1 , L 1 , L 2 , R 1 , R 2 , R 5 and Z are as defined above in respect to formula lb;
  • 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.
  • 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 .
  • 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
  • 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;
  • R iD and R i are as defined above in respect to formula Ib-4k, preferably R and R 27 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
  • 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;
  • 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 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 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:
  • Y is CH or N
  • R 14 and R 15 are independently H, halo, cyano, hydroxyl, linear or branched Ci-C 3 alkyl, Ci-C 3 hydroxyalkyl, Ci-C 3 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, Ci-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
  • 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, - C 2 H 4 C0 2 CH 3 , -CH 2 C0 2 CH
  • Preferred compounds of formula Ie are those wherein Z is -COOR and R, Ar 1 ,
  • Ar Ar J , R , R", L , If and f 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: wherein
  • 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 -C 4 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: wherein
  • 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, heterocyclyl
  • 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 wherein
  • 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
  • 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 Ij: wherein
  • 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, cycloalkylcarbonyloxy, heterocyclyl
  • 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, halo alkoxy 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 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 and R 10 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, cycloalkylcarbon
  • Ar Ar J , L , If, If, R , R", and Z are as defined above in respect to formula I.

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Abstract

La présente invention concerne des composés de formule (I) utiles dans le traitement et/ou la prévention de troubles gastro-intestinaux.
PCT/EP2010/070234 2009-12-21 2010-12-20 Composés, composition pharmaceutique et procédés pour utilisation dans le traitement de troubles gastro-intestinaux Ceased WO2011076732A1 (fr)

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WO2013146754A1 (fr) * 2012-03-27 2013-10-03 塩野義製薬株式会社 Dérivé à noyau à cinq chaînons hétérocyclique aromatique ayant une activité inhibitrice de trpv4
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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
US12030875B2 (en) 2018-09-07 2024-07-09 PIC Therapeutics, Inc. EIF4E inhibitors and uses thereof
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