WO2010094721A1 - Dérivés de pipéridine-pyrimidine comme antagonistes des récepteurs histaminiques h4 - Google Patents

Dérivés de pipéridine-pyrimidine comme antagonistes des récepteurs histaminiques h4 Download PDF

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WO2010094721A1
WO2010094721A1 PCT/EP2010/052006 EP2010052006W WO2010094721A1 WO 2010094721 A1 WO2010094721 A1 WO 2010094721A1 EP 2010052006 W EP2010052006 W EP 2010052006W WO 2010094721 A1 WO2010094721 A1 WO 2010094721A1
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alkyl
formula
groups
group
optionally substituted
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Elena CARCELLER GONZÁLEZ
Eva María MEDINA FUENTES
Ana MORATÓ GARCÍA
Carles Ferrer Costa
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Palau Pharma, S. A.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a new series of piperidin-pyhmidine derivatives, processes to prepare them, pharmaceutical compositions comprising these compounds as well as their use in therapy.
  • Histamine is one of the most potent mediators of immediate hypersensitivity reactions. While the effects of histamine on smooth muscle cell contraction, vascular permeability and gastric acid secretion are well known, its effects on the immune system are only now beginning to become unveiled.
  • H 4 a novel histamine receptor, which was named H 4 , was cloned by several research groups working independently (Oda T et al, J Biol Chem 2000, 275: 36781 -6; Nguyen T et al, MoI Pharmacol 2001 , 59: 427-33). As the other members of its family, it is a G-protein coupled receptor (GPCR) containing 7 transmembrane segments.
  • GPCR G-protein coupled receptor
  • the H 4 receptor has low homology with the three other histamine receptors (Oda T et al); it is remarkable that it shares only a 35% homology with the H 3 receptor. While the expression of the H 3 receptor is restricted to cells of the central nervous system, the expression of the H 4 receptor has been mainly observed in cells of the haematopoietic lineage, in particular eosinophils, mast cells, basophils, dendritic cells and T-cells (Oda T et al). The fact that the H 4 receptor is highly distributed in cells of the immune system suggests the involvement of this receptor in immuno-inflammatory responses.
  • H 4 receptor is also expressed in other types of cells such as human synovial cells obtained from patients suffering from rheumatoid arthritis (Wojtecka-Lukasik E et al, Ann Rheum Dis 2006, 65 (Suppl II): 129; Ikawa Y et al, Biol Pharm Bull 2005, 28: 2016-8) and osteoarthritis (Grzybowska-Kowalczyk A et al, European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, P-11 ), and in the human intestinal tract (Sander LE et al, Gut 2006, 55: 498- 504).
  • H 4 receptor An increase in the expression of the H 4 receptor has also been reported in nasal polyp tissue in comparison to nasal mucosa of healthy people (J ⁇ k ⁇ ti A et al, Cell Biol lnt 2007, 31 : 1367-70). Recent studies with specific ligands of the H 4 receptor have helped to delimit the pharmacological properties of this receptor. These studies have evidenced that several histamine-induced responses in eosinophils such as chemotaxis, conformational change and CD11 b and CD54 up-regulation are specifically mediated by the H 4 receptor (Ling P et al, Br J Pharmacol 2004, 142:161-71 ; Buckland KF et al, Br J Pharmacol 2003, 140:1117-27).
  • the H 4 receptor In dendritic cells, the H 4 receptor has been shown to affect maturation, cytokine production and migration of these cells (Jelinek I et al, 1 st Joint Meeting of European National Societies of Immunology, Paris, France, 2006, PA-1255). Moreover, the role of the H 4 receptor in mast cells has been studied. Although H 4 receptor activation does not induce mast cell degranulation, histamine and other proinflammatory mediators are released; moreover, the H 4 receptor has been shown to mediate chemotaxis and calcium mobilization of mast cells (Hofstra CL et al, J Pharmacol Exp Ther 2003, 305: 1212-21 ).
  • H 4 receptor activation induces T-cell migration and preferentially attracts a T- lymphocyte population with suppressor/regulatory phenotype and function (Morgan RK et al, American Thoracic Society Conference, San Diego, USA, 2006, P-536), as well as regulating the activation of CD4+ T cells (Dunford PJ et al, J Immunol 2006, 176: 7062-70).
  • the distribution of the H 4 receptor suggests that it may have a role in the control of peristalsis and gastric acid secretion (Morini G et al, European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, O-10).
  • H 4 receptor antagonists have shown in vivo activity in murine models of peritonitis (Thurmond RL et al, J Pharmacol Exp Ther 2004, 309: 404-13), pleurisy (Takeshita K et al, J Pharmacol Exp Ther 2003, 307: 1072- 8) and scratching (Bell JK et al, Br J Pharmacol 2004,142 :374-80).
  • H 4 receptor antagonists have demonstrated in vivo activity in experimental models of allergic asthma (Dunford PJ et al, 2006), inflammatory bowel disease (Varga C et al, Eur J Pharmacol 2005, 522:130-8), pruritus (Dunford PJ et al, J Allergy CHn Immunol 2007, 119: 176-83), atopic dermatitis (Cowden JM et al, J Allergy Clin Immunol 2007; 119 (1 ): S239 (Abs 935), American Academy of Allergy, Asthma and Immunology 2007 AAAAI Annual Meeting, San Diego, USA), ocular inflammation (Zampeli E et al, European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, OR-36), edema and hyperalgesia (Coruzzi G et al, Eur J Pharmacol 2007, 563: 240-4), and neuropatic pain (Cowart MD et al.,J Med
  • H 4 receptor antagonist activity it would be desirable to provide novel compounds having H 4 receptor antagonist activity and which are good drug candidates.
  • preferred compounds should bind potently to the histamine H 4 receptor whilst showing little affinity for other receptors.
  • compounds should further exhibit good pharmacological activity in in vivo disease models.
  • compounds should reach the target tissue or organ when administered via the chosen route of administration and possess favourable pharmacokinetic properties. In addition, they should be non-toxic and demonstrate few side-effects.
  • One aspect of the present invention relates to the compounds of formula I
  • Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from: (i) a heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said heterocyclic group is optionally substituted with one or more Ci -4 alkyl groups; and
  • heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR 3 Rb group and is optionally substituted with one or more Ci -4 alkyl groups; wherein said heterocyclic groups (i) and (ii) are 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; or Ri represents H or Ci -4 alkyl, and R 2 represents azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, wherein R 2 is optionally substituted with one or more Ci -4 alkyl groups;
  • Ra represents H or Ci -4 alkyl
  • Rb represents H or Ci -4 alkyl; or R 3 and Rb form, together with the N atom to which they are bound, an azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group that is optionally substituted with one or more Ci -4 alkyl groups;
  • R 3 represents -COR 4 , -CONR 4 R 4 , -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 ';
  • R 4 represents Ci -8 alkyl, R 5 -Ci -8 alkyl or R 6 -C 0-8 alkyl, wherein in the Ci -8 alkyl, R 5 -
  • Ci -8 alkyl and R 6 -Co -8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups and one methylene group of the alkyl chain is optionally replaced by -O-;
  • R 4 ' represents H or Ci -8 alkyl; and optionally R 4 and R 4 ' are bound forming a -C3 -5 alkylene- group which is optionally substituted with one or more Ci -8 alkyl groups;
  • R 5 represents -CONR 4 R 7 , -NR 4 COR 7 , -NR 4 CO 2 R 7 , -NR 4 SO 2 R 7 , -SO 2 NR 4 R 7 , -
  • Re represents C 3-8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein R 6 is optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -Co -S alkyl and R 8 -Co -S alkyl;
  • R 7 represents H, Ci -8 alkyl, C 3-8 cycloalkyl-Co-s alkyl or aryl-C 0-8 alkyl, wherein in the Ci -8 alkyl, C 3-8 cycloalkyl-Co-s alkyl and aryl-C 0-8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups, and any of the C 3-8 cycloalkyl and aryl groups are optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl and hydroxyCi -8 alkyl; and optionally R 4 ' and R 7 , in a R 5 group, are bound forming a -C 3-5 alkylene- group which is optionally substituted with one or more Ci -8 alkyl
  • R 8 represents C 3-8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein R 8 is optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl and hydroxyCi -8 alkyl.
  • the compounds of formula I show high affinity for the H 4 histamine receptor.
  • another aspect of the invention relates to a compound of formula I
  • Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:
  • heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said heterocyclic group is optionally substituted with one or more Ci -4 alkyl groups; and (ii) a heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR 3 Rb group and is optionally substituted with one or more Ci -4 alkyl groups; wherein said heterocyclic groups (i) and (ii) are 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; or Ri represents H or Ci -4 alkyl, and R 2 represents azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, wherein R 2 is optionally substituted with one or more Ci -4 alkyl groups;
  • Ra represents H or Ci -4 alkyl
  • Rb represents H or Ci -4 alkyl; or R 3 and Rb form, together with the N atom to which they are bound, an azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group that is optionally substituted with one or more Ci -4 alkyl groups;
  • R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 ';
  • R 4 represents Ci -8 alkyl, R 5 -Ci -8 alkyl or R 6 -C 0-8 alkyl, wherein in the Ci -8 alkyl, R 5 - Ci -8 alkyl and Re-C 0-8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups and one methylene group of the alkyl chain is optionally replaced by -O-;
  • R 4 ' represents H or Ci -8 alkyl; and optionally R 4 and R 4 ' are bound forming a -C3 -5 alkylene- group which is optionally substituted with one or more Ci -8 alkyl groups;
  • R 5 represents -CONR 4 R 7 , -NR 4 COR 7 , -NR 4 CO 2 R 7 , -NR 4 SO 2 R 7 , -SO 2 NR 4 R 7 , -
  • R 6 represents C 3-8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein R 6 is optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -C 0-8 alkyl and R 8 -C 0-8 alkyl;
  • R 7 represents H, Ci -8 alkyl, C 3-8 cycloalkyl-C 0-8 alkyl or aryl-C 0-8 alkyl, wherein in the C1-8 alkyl, C3-8 cycloalkyl-Co-8 alkyl and aryl-Co-8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups, and any of the C3-8 cycloalkyl and aryl groups are optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl and hydroxyCi -8 alkyl; and optionally R 4 ' and R 7 , in a R 5 group, are bound forming a -C3 -5 alkylene- group which is optionally substituted with one or more Ci -8 alkyl groups
  • Another aspect of the invention relates to a pharmaceutical composition which comprises a compound of formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease mediated by the H 4 histamine receptor. More preferably, the disease mediated by the histamine H 4 receptor is an allergic, immunological or inflammatory disease or pain.
  • Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of an allergic, immunological or inflammatory disease or pain.
  • Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of an allergic, immunological or inflammatory disease.
  • the allergic, immunological or inflammatory disease is selected from respiratory diseases, ocular diseases, skin diseases, inflammatory bowel diseases, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection.
  • the allergic, immunological or inflammatory disease is selected from asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataracts, dermatitis (e.g. atopic dermatitis), psoriasis, urticaria, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection.
  • Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of pain.
  • the pain is selected from inflammatory pain, inflammatory hyperalgesia, hyperalgesia, postsurgical pain, migraine, cancer pain, visceral pain, osteoarthritis pain and neuropathic pain.
  • Another aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease mediated by the histamine H 4 receptor. More preferably, the disease mediated by the histamine H 4 receptor is an allergic, immunological or inflammatory disease or pain.
  • Another aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of an allergic, immunological or inflammatory disease or pain.
  • the allergic, immunological or inflammatory disease is selected from respiratory diseases, ocular diseases, skin diseases, inflammatory bowel diseases, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection. Still more preferably, the allergic, immunological or inflammatory disease is selected from asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataracts, dermatitis (e.g.
  • COPD chronic obstructive pulmonary disease
  • atopic dermatitis psoriasis, urticaria, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection.
  • Another aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of pain. More preferably, the pain is selected from inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-surgical pain, migraine, cancer pain, visceral pain, osteoarthritis pain and neuropathic pain.
  • Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of a disease mediated by the histamine H 4 receptor. More preferably, the disease mediated by the histamine H 4 receptor is an allergic, immunological or inflammatory disease or pain.
  • Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of an allergic, immunological or inflammatory disease or pain.
  • the allergic, immunological or inflammatory disease is selected from respiratory diseases, ocular diseases, skin diseases, inflammatory bowel diseases, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection. Still more preferably, the allergic, immunological or inflammatory disease is selected from asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataracts, dermatitis (e.g.
  • COPD chronic obstructive pulmonary disease
  • atopic dermatitis psoriasis, urticaria, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection.
  • Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of pain. More preferably, the pain is selected from inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-surgical pain, migraine, cancer pain, visceral pain, osteoarthritis pain and neuropathic pain.
  • Another aspect of the present invention relates to a method of treating or preventing an allergic, immunological or inflammatory disease in a subject in need thereof, preferably a human being, which comprises administering to said subject a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the allergic, immunological or inflammatory disease is selected from respiratory diseases, ocular diseases, skin diseases, inflammatory bowel diseases, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection.
  • the allergic, immunological or inflammatory disease is selected from asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataracts, dermatitis (e.g. atopic dermatitis), psoriasis, urticaria, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection.
  • COPD chronic obstructive pulmonary disease
  • Another aspect of the present invention relates to a method of treating or preventing pain in a subject in need thereof, preferably a human being, which comprises administering to said subject a compound of formula I or a pharmaceutically acceptable salt thereof. More preferably, the pain is selected from inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-surgical pain, migraine, cancer pain, visceral pain, osteoarthritis pain and neuropathic pain.
  • Another aspect of the present invention relates to a process for the preparation of a compound of formula I as previously defined, which comprises: 1. starting from a compound of formula Il (or an amino-protected form thereof)
  • Ri and R 2 have the meaning described for a compound of formula I, (a) when in a compound of formula I R3 represents -COR 4 , reacting a compound of formula Il with an acid or acid chloride of formula R 4 -COY, wherein Y is OH or Cl; or (b) when in a compound of formula I R3 represents -CONR 4 R 4 ', reacting a compound of formula Il with an isocyanate of formula R 4 -NCO or a carbamoyl chloride of formula R 4 R 4 -NCOW, wherein W is a leaving group; or
  • R3 represents -CO 2 R 4 , reacting a compound of formula Il with triphosgene or phosgene and subsequently reacting it with an alcohol of formula R 4 -OH; or
  • C x-y alkyl as a group or part of a group, relates to a saturated linear or branched alkyl chain, which contains from x to y carbon atoms.
  • a Ci-S alkyl group relates to a linear or branched alkyl chain which contains from 1 to 8 C atoms.
  • a Ci -4 alkyl group relates to a linear or branched alkyl chain which contains from 1 to 4 C atoms and includes the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and te/t-butyl groups.
  • the term C 0 alkyl indicates that the alkyl group is absent.
  • a haloCi-8 alkyl group means a group resulting from the substitution of one or more hydrogen atoms of a Ci-S alkyl group with one or more halogen atoms (i.e. fluorine, chlorine, bromine or iodine), which may be the same or different.
  • halogen atoms i.e. fluorine, chlorine, bromine or iodine
  • Examples include, among others, trifluoromethyl, fluoromethyl, 1 -chloroethyl, 2- chloroethyl, 1-fluoroethyl, 2-fluoroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2- trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 2,2,3,3- tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 4-fluorobutyl, nonafluorobutyl, 5,5,5-trifluoropentyl, 6,6,6-trifluorohexyl, 6,6,7,7,7- pentafluoroheptyl and 8,8,8-trifluorooctyl.
  • Ci-8 alkoxy group means a group of formula Ci-S alkyl-O-, wherein the alkyl moiety has the same meaning as defined above. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, te/t-butoxy, pentyloxy, hexyloxy, heptyloxy and octyloxy.
  • a haloCi-8 alkoxy group means a group resulting from the substitution of one or more hydrogen atoms of a Ci -8 alkoxy group with one or more halogen atoms (i.e. fluorine, chlorine, bromine or iodine), that can be the same or different.
  • halogen atoms i.e. fluorine, chlorine, bromine or iodine
  • Examples include, among others, trifluoromethoxy, fluoromethoxy, 1 -chloroethoxy, 2-chloroethoxy, 1 -fluoroethoxy, 2-fluoroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 3-fluoropropoxy, 3-chloropropoxy, 2,2,3,3- tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, heptafluoropropoxy, 4- fluorobutoxy, nonafluorobutoxy, 2-chloropentyloxy, 3-chlorohexyloxy, 2- chlorooctyloxy and 2-chloroheptyloxy.
  • Ci-8 alkylthio group means a group of formula Ci -8 alkyl-S-, wherein the alkyl moiety has the same meaning as defined above. Examples include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, te/t-butylthio, pentylthio, hexylthio, heptylthio and octylthio.
  • a C2 -4 alkynyl group means a linear or branched alkyl chain which contains from 2 to 4 carbon atoms and which further contains one or two triple bonds. Examples include, among others, the ethynyl, 1 -propynyl, 2-propynyl, 1 -butynyl, 2- butynyl, 3-butynyl and 1 ,3-butadyinyl groups.
  • a hydroxyCi-8 alkyl group relates to a group resulting from the substitution of one of more hydrogen atoms of a Ci-S alkyl group with one or more hydroxy groups.
  • the Ci -8 alkyl group is substituted with one hydroxy group. Examples include, among others, the hydroxy methyl, 1-hydroxyethyl, 2- hydroxyethyl, 1 ,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1 - hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 2- hydroxybutyl, 1 -hydroxybutyl, 2-hydroxypentyl and 3-hydroxyheptyl groups.
  • a halogen group or its abbreviation halo means fluorine, chlorine, bromine or iodine.
  • Preferred halogen groups are fluorine and chlorine, and more preferably fluorine.
  • R 6 -C 0- S alkyl groups any alkyl group is optionally substituted with one or more halogen groups, which may be the same or different.
  • This relates both to the Ci-S alkyl group, and to the Ci -8 alkyl group which forms part of the R 5 -Ci -8 alkyl group and to the Co -8 alkyl group which forms part of the R 6 -Co -8 alkyl group.
  • one methylene group of the alkyl chain of the Ci -8 alkyl, Rs-Ci -8 alkyl and R 6 -Co -8 alkyl groups i.e. one methylene group of the Ci -8 alkyl group, of the Ci -8 alkyl group which forms part of the R 5 -Ci -8 alkyl group and of the C 0- S alkyl group which forms part of the Re-C 0- S alkyl group
  • one methylene group of the alkyl chain of the Ci -8 alkyl, Rs-Ci -8 alkyl and R 6 -Co -8 alkyl groups is optionally replaced by one -O- group.
  • alkyl wherein one methylene group has been replaced by one -O- examples include, among others, methoxy methyl, ethoxy methyl, ethoxyethyl, 2-ethoxypropyl, 1 -methoxybutyl, 1- methoxypentyl, 3-propoxypropyl, 4-methoxybutyl, 4-ethoxybutyl, 5-methoxypentyl, 5-ethoxypentyl and 4-propoxybutyl.
  • R 5 -Ci -8 alkyl relates to a group resulting from the substitution of one hydrogen atom of a Ci -8 alkyl group with a R 5 group.
  • R 6 -C 0- S alkyl includes the R 6 and R 6 -Ci -8 alkyl groups.
  • R 6 -Ci-S alkyl relates to a group resulting from the substitution of one hydrogen atom of a Ci -8 alkyl group with a R 6 group.
  • R 6 is C 3- S cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and therefore an R 6 -C 0- S alkyl group includes the C 3- S cycloalkyl-C 0- s alkyl, heterocycloalkyl-Co-s alkyl, aryl-C 0- s alkyl and heteroaryl-C 0- s alkyl groups.
  • R 6 is optionally substituted with one or more groups independently selected from Ci-s alkyl, haloCi-8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -C 0-8 alkyl and R 8 -C 0-8 alkyl. Said substituents may be the same or different.
  • R 6 is optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -C 0-8 alkyl and R 8 -C 0-8 alkyl, with the condition that there is no more than one substituent selected from R 5 -C 0-8 alkyl and R 8 -C 0-8 alkyl.
  • R 6 is optionally substituted with one group independently selected from Ci -8 alkyl, halogen Ci -8 alkyl, halogen, Ci -8 alkoxy, halogen Ci -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -C 0-8 alkyl and R 8 -C 0-8 alkyl.
  • said substituents may be located at any available C atom, while in the heterocycloalkyl and heteroaryl groups said substituents may be located at any available C or N atom.
  • a C 3-8 cycloalkyl group either as a group or as part of a C 3-8 cycloalkyl-C 0-8 alkyl group, relates to a saturated carbocyclic ring of 3 to 8 carbon atoms that can be a monocyclic or a bridged bicyclic group, wherein one or two C atoms are optionally oxidized forming CO groups.
  • Examples include, among others, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentanonyl, bicyclo[2.2.1]heptanyl and bicyclo[2.2.2]octanyl groups.
  • C 3- S cycloalkyl-C 0-8 alkyl includes the C 3- S cycloalkyl and C 3-8 cycloalkyl-Ci-8 alkyl groups.
  • a C 3-8 cycloalkyl-Ci-s alkyl group means a group resulting from the substitution of one or more hydrogen atoms of a Ci -8 alkyl group with one or more C 3-8 cycloalkyl groups that can be the same or different.
  • the Ci -8 alkyl group is substituted with one or two C 3-8 cycloalkyl groups, and more preferably it is substituted with one C 3-8 cycloalkyl group.
  • the C 3-8 cycloalkyl group may substitute either one H atom on a C atom or two H atoms on the same C atom of the alkyl group (in which case the C 3-8 cycloalkyl group shares one C atom with the alkyl group), such as in the groups shown as examples below:
  • C 3-8 cycloalkyl-Ci -8 alkyl groups include, among others, the cyclopropyl methyl, cyclobutyl methyl, cyclopentyl methyl, cyclohexyl methyl, cycloheptyl methyl, cyclooctyl methyl, bicyclo[2.2.1]heptanylmethyl, dicyclopropyl methyl, (i -methyl-cyclopropyl)methyl, (i -ethyl-cyclopropyl)methyl, (1- cyclopentylmethyl-cyclopropyl)methyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2- cyclopentylethyl, 2-cyclohexylethyl, 2,2-dicyclopropyl-ethyl, 2-cyclohexyl-2- cyclopropyl-ethyl, 2-(1-methyl-cyclopropyl)ethyl, 1 -cyclopropy
  • a heterocycloalkyl group either as a group or as part of a heterocycloalkyl- Co-8 alkyl group, relates to a saturated or partially unsaturated heterocyclic ring that can be a monocyclic or a bridged bicyclic group, having from 2 to 8 carbon atoms and from 1 to 3 heteroatoms independently selected from N, O and S, and which is optionally fused with a phenyl ring. From one to three C, N or S atoms of the heterocyclic ring are optionally oxidized forming CO, NO, SO or SO2 groups, respectively.
  • heterocycloalkyl group may be attached to the rest of the molecule through any available C or N atom, including the C atoms of the phenyl ring in the case of being fused to a phenyl.
  • heterocycloalkyl groups include, among others, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrazolidinyl, isothiazolidinyl piperidinyl, morpholinyl, piperazinyl, 2-oxo- tetrahydrofuranyl, 2-oxo-[1 ,3]dioxolanyl, 2-oxo-oxazolidinyl, 2-oxo-imidazolidinyl, 2-oxo-[1 ,3]oxazinanyl, 2-oxo-piperazinyl, thiomorpholinyl, 1 ,1 -dioxo-
  • heterocycloalkyl-Co-8 alkyl includes heterocycloalkyl and heterocycloalkyl-Ci- 8 alkyl.
  • a heterocycloalkyl-Ci-s alkyl group relates to a group resulting from the substitution of one or more hydrogen atoms of a Ci-S alkyl group with one or more heterocycloalkyl groups which may be the same or different.
  • the Ci-S alkyl group is substituted with one or two heterocycloalkyl groups, and more preferably, is substituted with one heterocycloalkyl group.
  • heterocycloalkyl-Ci-s alkyl groups include, among others, pyrrol id in-2-yl methyl, pyrrol id in-3-yl methyl, morpholin-3-yl methyl, tetrahydrofuran-2-ylmethyl, (2-oxo- [1 ,3]oxazinan-6-yl)-methyl, 2-piperidin-3-yl-ethyl, 2-piperazin-1 -yl-propyl, 1-methyl- 2-piperazin-1-yl-ethyl, 2-methyl-3-(pyrrolidin-3-yl)-propyl, 3-methyl-4-piperazin-1- yl-butyl, 4-(tetrahydrofuran-3-yl)-butyl, 5-(tetrahydrofuran-3-yl)-pentyl, 6-azetidin-1 - yl-hexyl, 7-morpholin-4-yl-heptanyl and 6-methyl-8-
  • aryl -Co- 8 alkyl includes the aryl and aryl-Ci-s alkyl groups.
  • An aryl-Ci-s alkyl group means a group resulting from the substitution of one or more hydrogen atoms of a Ci-S alkyl group with one or more aryl groups which may be the same or different.
  • the Ci-S alkyl group is substituted with one or two aryl groups, and more preferably, is substituted with one aryl group.
  • aryl-Ci -8 alkyl groups include, among others, benzyl, 1 -phenylethyl, 2- phenylethyl, 1 -phenyl-1 -methyl-ethyl, 2,2-diphenyl-ethyl, 3-phenyl propyl, 2-phenyl- 1 -methyl-propyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 4-phenylhexyl, 2- methyl-3-phenylhexyl, 7-phenylheptyl, 5-phenylheptyl, 7,7-diphenyl-heptyl, 8- phenyloctyl and 7-phenyloctyl.
  • heteroaryl either as a group or part of a heteroaryl-Co-8 alkyl group, refers to an aromatic 5- or 6-membered monocyclic or 8- to 12-membered bicyclic ring containing from one to four heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • the heteroaryl group may be attached to the rest of the molecule through any available C or N atom (for example, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, pyridine-2-yl, pyridine-3-yl, pyhdine-4-yl, pyridine-5-yl, or pyhdine-6-yl).
  • heteroaryl groups include among others 1 ,2,4-oxadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,3,4-thiadiazolyl, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazolyl, pirrolyl, thiazolyl, thiophenyl, 1 ,2,3-thazolyl, 1 ,2,4-thazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, imidazopyrazinyl, imidazopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, indazolyl, indolyl, isoindolyl, is
  • heteroaryl when the examples specified refer to a bicycle in general terms, they include all possible arrangements of the atoms.
  • pyrazolopyridinyl includes groups such as 1 H-pyrazolo[3,4- £>]pyridinyl, pyrazolo[1 ,5-a]pyhdinyl, 1 /-/-pyrazolo[3,4-c]pyridinyl, 1 H-pyrazolo[4,3- c]pyridinyl and 1 /-/-pyrazolo[4,3- ⁇ b]pyridinyl;
  • imidazopyrazinyl includes groups such as 1 /-/-imidazo[4,5- ⁇ b]pyrazinyl, imidazo[1 ,2-a]pyrazinyl and imidazo[1 ,5-a]pyrazinyl and the term pyrazolopyrimidinyl includes groups such as 1 /-/-pyrazolo[3,4-c/]
  • heteroaryl-Co- 8 alkyl includes heteroaryl and heteroaryl-Ci-s alkyl.
  • a heteroaryl-Ci-s alkyl group relates to a group resulting from the substitution of one or more hydrogen atoms of a Ci -8 alkyl group with one or more heteroaryl groups which may be the same or different.
  • the Ci -8 alkyl group is substituted with one or two heteroaryl groups and, more preferably, is substituted with one heteroaryl group.
  • heteroaryl-Ci -8 alkyl examples include, among others, furan-2-ylmethyl, pyhdine-3-yl-methyl, quinolin-3-ylmethyl, oxazol- 2-ylmethyl, 1 H-pyrrol-2-ylmethyl, 1-pyridine-3-yl-ethyl, 2-pyhdine-2-yl-propyl, 3- pyridine-3-yl-propyl, 1 -methyl-2-pyhdine-3-yl-propyl, 4-pyridine-2-yl-butyl, 3- pyridine-2-yl-butyl 5-furan-2-yl-pentyl, 6-furan-2-yl-hexyl, 3-(1 H-pyrrol-2-yl)-hexyl, 7-(1 H-pyrrol-2-yl)-heptyl, 7-furan-2-yl-heptyl, 6-methyl-7-pyhdine-2-yl-heptyl, 8- furan
  • any alkyl group is optionally substituted with one or more halogen groups, which may be the same or different.
  • This relates both to the Ci -8 alkyl group and to the Co -8 alkyl group which forms part of the C3 -8 cycloalkyl-Co- ⁇ alkyl and aryl-Co-s alkyl groups.
  • R 7 when it is indicated that any of the C 3-8 cycloalkyl and aryl groups are optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C2 -4 alkynyl and hydroxyCi -8 alkyl, said substituents may be the same or different and may be located in any available carbon atom of the C3 -8 cycloalkyl or aryl groups, including the carbon which attaches the cycle to the rest of the molecule in the case of a C 3-8 cycloalkyl group.
  • R 8 when it is indicated that any of the C 3-8 cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C2 -4 alkynyl and hydroxyCi -8 alkyl, said substituents may be the same or different and may be located in any available carbon atom in the case of the C3 -8 cycloalkyl and aryl groups, or in any available carbon or nitrogen atom in the case of the heterocycloalkyl and heteroaryl groups. In the case of the C 3-8 cycloalkyl and heterocycloalkyl groups a substituent may be situated in the carbon which attaches the cycle to the rest of the molecule.
  • a -C3-5 alkylene- group in relation to the group formed by R 4 and R 4 , or to the group formed by R 4 ' and R 7 , refers to a linear alkylene chain which contains from 3 to 5 carbon atoms, i.e. a group of formula -(CH 2 )3-5-.
  • the -C3 -5 alkylene- group is optionally substituted with one or more Ci-S alkyl groups, which can be the same or different, preferably with one or more methyl groups.
  • Examples of R30 R 5 donde R 4 and R 4 ' or R 4 ' and R 7 which together form a -C3 -5 alkylene- group include, among others:
  • saturated relates to groups that do not have any double or triple bonds.
  • bridged bicyclic group refers to a bicyclic system having two common atoms (bridgeheads) connecting three acyclic chains (bridges), so that the two bridges with the higher number of atoms form then the main ring and the bridge with the lower number of atoms is the "bridge”.
  • a "fused bicyclic” group in the definition of NRiR 2 , refers to a 8- to 12- atom bicyclic system consisting of two adjacent rings sharing two atoms in common.
  • NRiR 2 Ri and R 2 together with the N atom to which they are bound can form a heterocyclic group of type (i) or (ii).
  • a heterocyclic group of type (i) is a saturated heterocyclic group which contains 2 N atoms and does not contain any other heteroatom and which can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic.
  • Examples include, among others, piperazinyl, homopiperazinyl, 2,5-diaza- bicyclo[2.2.1]heptanyl, 2,5-diaza-bicyclo[2.2.2]octanyl, octahydro-pyrrolo[1 ,2- a]pyrazinyl, octahydro-pyrrolo[3,4-b]pyhdinyl, octahydro-pyrrolo[3,2-c]pyhdinyl and octahydropyrrolo[3,4-c]pyrrolinyl.
  • Said groups can be optionally substituted with one or more Ci -4 alkyl groups, which can be the same or different and which can be placed at any available C or N atom.
  • a heterocyclic group of type (ii) is a saturated heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR 3 Rb group, and which can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic, preferably 4- to 7-membered monocyclic.
  • Examples of (ii) include, among others, 3-amino-azetidinyl, 3-methylamino-azetidinyl, 3-dimethylamino- azetidinyl, 3-amino-pyrrolidinyl, 3-methylamino-pyrrolidinyl, 3-dimethylamino- pyrrolidinyl, 4-amino-piperidinyl, 4-methylamino-piperidinyl, 4-dimethylamino- piperidinyl and 6-methylamino-3-aza-bicyclo[3.1.0]hexane-3-yl. Said groups can be further optionally substituted, as indicated above in the definition of a compound of formula I.
  • a group can be substituted with one or more, preferably 1 , 2, 3 or 4, more preferably 1 , 2 or 3, and more preferably 1 or 2 substituents, provided that said group has enough positions available susceptible of being substituted. These substituents can be the same or different, and can be located at any available position.
  • treatment is meant eliminating, reducing or ameliorating the cause or the effects of a disease.
  • treatment includes, but is not limited to, alleviation, amelioration or elimination of one or more symptoms of the disease; diminishment of the extent of the disease; stabilized (i.e. not worsening) state of disease; delay or slowing of disease progression; amelioration or palliation of the disease state; and remission of the disease (whether partial or total).
  • prevention refers to preventing the occurrence of a disease in a subject that is predisposed to or has risk factors but does not yet display symptoms of the disease. Prevention includes also preventing the recurrence of a disease in a subject that has previously suffered said disease. The invention therefore relates to the compounds of formula I as previously defined.
  • the invention relates to compounds of formula I wherein: Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:
  • heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR 3 Rb group and is optionally substituted with one or more Ci -4 alkyl groups; wherein said heterocyclic groups (i) and (ii) are 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic.
  • the invention relates to the compounds of formula I wherein R 3 and R b independently represent H or Ci -4 alkyl.
  • the invention relates to the compounds of formula I wherein R 3 and R b independently represent H, methyl or ethyl.
  • the invention relates to the compounds of formula I wherein R 3 and R b independently represent H or methyl.
  • the invention relates to compounds of formula I wherein R 3 and R b represent H. In another embodiment, the invention relates to the compounds of formula I wherein R 3 represents H and Rb represents H or Ci -4 alkyl.
  • the invention relates to the compounds of formula I wherein R 3 represents H and R b represents H, methyl or ethyl.
  • the invention relates to the compounds of formula I wherein R 3 represents H and Rb represents H or methyl.
  • the invention relates to the compounds of formula I wherein R 3 represents H and Rb represents Ci -4 alkyl.
  • the invention relates to the compounds of formula I wherein R 3 represents H and Rb represents methyl or ethyl. In another embodiment, the invention relates to the compounds of formula I wherein R 3 represents H and Rb represents methyl.
  • the invention relates to the compounds of formula I wherein Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:
  • R 3 and Rb have the meaning described above for compounds of formula I, R 0 represents H or Ci -4 alkyl, preferably H or methyl, more preferably H, and Rd represents H or Ci -4 alkyl, preferably H or methyl.
  • the invention relates to the compounds of formula I wherein Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), and R 3 , Rb, Rc and R d independently represent H or Ci -4 alkyl, preferably R 3 , Rb, Rc and R d independently represent H or methyl, and more preferably R a , Rb and Rd independently represent H or methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a), (b), (e) and (f) wherein R 3 and Rb have the meaning described above for compounds of formula I, R 0 represents H or
  • Ci -4 alkyl preferably H or methyl, more preferably H
  • R d represents H or Ci -4 alkyl, preferably H or methyl.
  • the invention relates to the compounds of formula I wherein Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a), (b), (e) and (f), and R 3 , Rb, Rc and Rd independently represent H or Ci -4 alkyl, preferably R 3 , Rb, Rc and R d independently represent H or methyl, and more preferably R a , Rb and Rd independently represent H or methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R 3 and Rb have the meaning described above for compounds of formula I and R 0 represents H or Ci -4 alkyl, preferably H.
  • the invention relates to the compounds of formula I wherein Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), and R a , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R a , Rb and R 0 independently represent H or methyl, and more preferably R a and Rb independently represent H or methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), R 3 represents H, R b represents H or Ci -4 alkyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), R a represents H, R b represents H or methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), R 3 represents H, R b represents methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), and R a , Rb and R 0 represent H.
  • the invention relates to the compounds of formula I wherein Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a)
  • R 3 and Rb have the meaning described above for compounds of formula I and R 0 represents H or Ci -4 alkyl, and preferably R 0 represents H.
  • the invention relates to the compounds of formula I wherein Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), and R a , Rb and R 0 independently represent H or Ci -4 alkyl, preferably R a , Rb and R 0 independently represent H or methyl, and more preferably R a and Rb independently represent H or methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), R 3 represents H, R b represents H or Ci -4 alkyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), R a represents H, R b represents H or methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), R 3 represents H, R b represents methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), and R a , Rb and R 0 represents H.
  • the invention relates to the compounds of formula I wherein Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b)
  • R 3 and Rb have the meaning described above for compounds of formula I and R 0 represents H or Ci -4 alkyl, and preferably R 0 represents H.
  • the invention relates to the compounds of formula I wherein Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), and R a , Rb and R 0 independently represent H or Ci -4 alkyl, preferably R a , Rb and R 0 independently represent H or methyl, and more preferably R a and Rb independently represent H or methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), R 3 represents H, R b represents H or Ci -4 alkyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), R a represents H, R b represents H or methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), R 3 represents H, R b represents methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), and R a , Rb and R 0 represent H.
  • the invention relates to the compounds of formula I wherein Ri represents H or Ci -4 alkyl and R2 represents azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, wherein R 2 is optionally substituted with one or more Ci -4 alkyl groups, and preferably Ri represents H and R 2 represents 1 -methyl- pyrrol id in-3-yl.
  • the invention relates to the compounds of formula I wherein R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or -SO 2 R 4 .
  • the invention relates to the compounds of formula I wherein R 3 represents -COR 4 .
  • the invention relates to the compounds of formula I wherein R 3 represents -CONR 4 R 4 '.
  • the invention relates to the compounds of formula I wherein R 3 represents -CO 2 R 4 . In another embodiment, the invention relates to the compounds of formula I wherein R 3 represents -SO 2 R 4 .
  • the invention relates to the compounds of formula I wherein R 3 represents -SO 2 NR 4 R 4 '.
  • the invention relates to the compounds of formula I wherein R 4 represents Ci -8 alkyl, R 5 -Ci -8 alkyl or R 6 -C 0-8 alkyl, wherein in the Ci -8 alkyl, R 5 -Ci -8 alkyl and R 6 -C 0-8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups.
  • the invention relates to the compounds of formula I wherein R 4 represents Ci -8 alkyl, R 5 -Ci -8 alkyl or R 6 - C 0-8 alkyl, wherein in the Ci -8 alkyl, R 5 -Ci -8 alkyl and R 6 -C 0-8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups, and one methylene group of the alkyl chain has been replaced by -O-.
  • the invention relates to the compounds of formula I wherein R 4 represents Ci -8 alkyl or R 6 -C 0-8 alkyl, preferably Ci -8 alkyl or R 6 -Ci -8 alkyl, wherein in the Ci -8 alkyl, R 6- C 0-8 alkyl and R 6 -Ci -8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups and one methylene group of the alkyl chain is optionally replaced by -O-.
  • the invention relates to the compounds of formula I wherein R 4 represents Ci -8 alkyl or R 6 -C 0- S alkyl, preferably Ci -8 alkyl or R 6 -Ci -8 alkyl, wherein in the Ci -8 alkyl, R 6- C 0-8 alkyl and R 6 -Ci -8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups.
  • the invention relates to the compounds of formula I wherein R 4 represents Ci -8 alkyl or R 6 -C 0-8 alkyl, preferably Ci -8 alkyl or R 6 -Ci -8 alkyl, wherein in the Ci -8 alkyl, R 6- C 0-8 alkyl and R 6 -Ci -8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups and one methylene group of the alkyl chain has been replaced by -O-.
  • the invention relates to the compounds of formula I wherein R 4 represents Ci -8 alkyl optionally substituted with one or more halogen groups, wherein one methylene group of the alkyl chain is optionally replaced by - O-.
  • the invention relates to the compounds of formula I wherein R 4 represents Ci -8 alkyl optionally substituted with one or more halogen groups.
  • the invention relates to the compounds of formula I wherein R 4 represents Ci -8 alkyl optionally substituted with one or more halogen groups, wherein one methylene group of the alkyl chain has been replaced by -O-.
  • the invention relates to the compounds of formula I wherein R 4 represents Rs-Ci -8 alkyl, wherein the alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-.
  • the invention relates to the compounds of formula I wherein R 4 represents Rs-Ci -8 alkyl, wherein the alkyl group is optionally substituted with one or more halogen groups.
  • the invention relates to the compounds of formula I wherein R 4 represents Rs-Ci -8 alkyl, wherein the alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain has been replaced by -O-.
  • the invention relates to the compounds of formula I wherein R 4 represents R 6 -C 0-8 alkyl, preferably R 6 -Ci -8 alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-.
  • the invention relates to the compounds of formula I wherein R 4 represents Re-C 0- S alkyl, preferably Re-Ci -8 alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups.
  • the invention relates to the compounds of formula I wherein R 4 represents Re-Co-8 alkyl, preferably R 6 -Ci -8 alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain has been replaced by -O-.
  • the invention relates to the compounds of formula I wherein R 4 ' represents H or Ci -8 alkyl.
  • the invention relates to the compounds of formula I wherein R 4 ' represents H.
  • the invention relates to the compounds of formula I wherein R 5 represents -OH, -NR 4 R 7 , -CONR 4 R 7 , -CO 2 Rz or -SO 2 Rz-
  • the invention relates to the compounds of formula I wherein R 5 represents -NR 4 R 7 .
  • the invention relates to the compounds of formula I wherein R 6 represents C 3- 8cycloalkyl (preferably monocyclic), aryl (preferably phenyl) or heteroaryl, wherein R 6 is optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -C 0-8 alkyl and R 8 -C 0-8 alkyl.
  • the invention relates to the compounds of formula I wherein R 6 represents aryl (preferably phenyl) or heteroaryl, which are optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl,
  • R 5 -C 0-8 alkyl and R 8 -C 0-8 alkyl are independently selected from the group consisting of R 5 -C 0-8 alkyl and R 8 -C 0-8 alkyl.
  • the invention relates to the compounds of formula I wherein R 6 represents aryl (preferably phenyl) or heteroaryl, which are optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN and C 2-4 alkynyl.
  • R 6 represents aryl (preferably phenyl) or heteroaryl, which are optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN and C 2-4 alkynyl.
  • the invention relates to the compounds of formula I wherein R 6 represents C3 -8 cycloalkyl, preferably monocyclic, optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci- 8 alkylthio, -CN, C 2-4 alkynyl, R 5 -C 0-8 alkyl and R 8 -C 0-8 alkyl.
  • the invention relates to the compounds of formula I wherein R 6 represents C3 -8 cycloalkyl, preferably monocyclic, optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN and C 2-4 alkynyl.
  • the invention relates to the compounds of formula I wherein R 6 represents heterocycloalkyl optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -C 0-8 alkyl and R 8 -C 0-8 alkyl.
  • the invention relates to the compounds of formula I wherein R 6 represents heteroaryl optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -C 0-8 alkyl and R 8 -C 0-8 alkyl.
  • the invention relates to the compounds of formula I wherein R 6 represents heteroaryl optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN and C 2-4 alkynyl.
  • the invention relates to the compounds of formula I wherein R 6 represents aryl, preferably phenyl, which is optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen,
  • the invention relates to the compounds of formula I wherein R 6 represents aryl, preferably phenyl, which is optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN and C 2-4 alkynyl.
  • R 6 represents aryl, preferably phenyl, which is optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN and C 2-4 alkynyl.
  • R 4 ' represents H or Ci -8 alkyl;
  • R 7 represents H, Ci -8 alkyl, C3 -8 cycloalkyl-C 0-2 alkyl or aryl-C 0-2 alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups and any of the C3-8 cycloalkyl and aryl groups are optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci- 8 alkylthio, -CN, C 2 A alkynyl and hydroxyCi -8 alkyl; and optionally R 4 ' and R 7 , in R 5 , are bound forming a -C3 -5 alkylene- group which is optionally substituted with one or more Ci -8 alkyl groups.
  • the invention relates to the compounds of formula I wherein R 7 represents H or Ci -8 alkyl, wherein the alkyl group is optionally substituted with one or more halogen groups; and optionally R 4 ' and R 7 , in R 5 , are bound forming a -C3 -5 alkylene- group which is optionally substituted with one or more Ci -8 alkyl groups.
  • the invention relates to the compounds of formula I wherein R 7 represents aryl-Co -8 alkyl, wherein the alkyl group is optionally substituted with one or more halogen groups and the aryl group is optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi-8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C2 -4 alkynyl and hydroxyCi -8 alkyl.
  • the invention relates to the compounds of formula I wherein R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or -SO 2 R 4 ; and
  • R 4 represents Ci -8 alkyl or R 6 -C 0-8 alkyl, preferably Ci -8 alkyl or R 6 -Ci -8 alkyl, wherein in the Ci -8 alkyl, R 6- C 0-8 alkyl and R 6 -Ci -8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups and one methylene group of the alkyl chain is optionally replaced by -O-.
  • the invention relates to the compounds of formula I wherein R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or -SO 2 R 4 ; and R 4 represents Ci -8 alkyl or R 6 -C 0-8 alkyl, preferably Ci -8 alkyl or R 6 -Ci -8 alkyl, wherein in the Ci -8 alkyl, R 6- C 0-8 alkyl and R 6 -Ci -8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups.
  • the invention relates to the compounds of formula I wherein R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or -SO 2 R 4 ; and R 4 represents Ci -8 alkyl or R 6 -C 0-8 alkyl, preferably Ci -8 alkyl or R 6 -Ci -8 alkyl, wherein in the Ci -8 alkyl, R 6- C 0-8 alkyl and R 6 -Ci -8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups and one methylene group of the alkyl chain has been replaced by -O-.
  • the invention relates to the compounds of formula I wherein R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or -SO 2 R 4 ; and
  • R 4 represents Ci -8 alkyl optionally substituted with one or more halogen groups, wherein one methylene group of the alkyl chain is optionally replaced by - O-.
  • the invention relates to the compounds of formula I wherein R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or -SO 2 R 4 ; and
  • R 4 represents Ci -8 alkyl optionally substituted with one or more halogen groups.
  • the invention relates to the compounds of formula I wherein R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or -SO 2 R 4 ; and
  • R 4 represents Ci -8 alkyl optionally substituted with one or more halogen groups, wherein one methylene group of the alkyl chain has been replaced by -O-.
  • the invention relates to the compounds of formula I wherein R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or -SO 2 R 4 ; and
  • R 4 represents R 5 -Ci-S alkyl, wherein the alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-.
  • the invention relates to the compounds of formula I wherein R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or -SO 2 R 4 ; and
  • R 4 represents R 5 -Ci -8 alkyl, wherein the alkyl group is optionally substituted with one or more halogen groups.
  • the invention relates to the compounds of formula I wherein R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or -SO 2 R 4 ; and R 4 represents Re-Co -8 alkyl, preferably R ⁇ -Ci-s alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-.
  • the invention relates to the compounds of formula I wherein R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or -SO 2 R 4 ; and R 4 represents Re-C 0- S alkyl, preferably Re-Ci -8 alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups.
  • the invention relates to the compounds of formula I wherein R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or -SO 2 R 4 ; and R 4 represents R 6 -Co -S alkyl, preferably R 6 -Ci -S alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain has been replaced by -O-.
  • the invention relates to the compounds of formula I wherein R 3 represents -CO 2 R 4 ;
  • R 4 represents Ci-S alkyl or R 6 -Co-S alkyl, preferably Ci-S alkyl or R 6 -Ci-S alkyl, wherein in the Ci-S alkyl, R 6- Co-S alkyl and R 6 -Ci-S alkyl groups any alkyl group is optionally substituted with one or more halogen groups and one methylene group of the alkyl chain is optionally replaced by -O-.
  • the invention relates to the compounds of formula I wherein R 3 represents -CO 2 R 4 ; and
  • R 4 represents Ci -8 alkyl or R 6 -C 0-S alkyl, preferably Ci -8 alkyl or R 6 -Ci -8 alkyl, wherein in the Ci -8 alkyl, R 6- C 0-8 alkyl and R 6 -Ci -8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups.
  • the invention relates to the compounds of formula I wherein R 3 represents -CO 2 R 4 ; and
  • R 4 represents Ci -8 alkyl or R 6 -C 0-8 alkyl, preferably Ci -8 alkyl or R 6 -Ci -8 alkyl, wherein in the Ci -8 alkyl, R 6- C 0-8 alkyl and R 6 -Ci -8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups and one methylene group of the alkyl chain has been replaced by -O-.
  • the invention relates to the compounds of formula I wherein R 3 represents -CO 2 R 4 ;
  • R 4 represents Ci -8 alkyl optionally substituted with one or more halogen groups, wherein one methylene group of the alkyl chain is optionally replaced by - O-.
  • the invention relates to the compounds of formula I wherein R 3 represents -CO 2 R 4 ;
  • R 4 represents Ci -8 alkyl optionally substituted with one or more halogen groups.
  • the invention relates to the compounds of formula I wherein R 3 represents -CO 2 R 4 ;
  • R 4 represents Ci -8 alkyl optionally substituted with one or more halogen groups, wherein one methylene group of the alkyl chain has been replaced by -O-.
  • the invention relates to the compounds of formula I wherein R 3 represents -CO 2 R 4 ; and
  • R 4 represents R 5 -Ci -8 alkyl, wherein the alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-.
  • the invention relates to the compounds of formula I wherein R 3 represents -CO 2 R 4 ;
  • R 4 represents R 5 -Ci-S alkyl, wherein the alkyl group is optionally substituted with one or more halogen groups.
  • the invention relates to the compounds of formula I wherein R 3 represents -CO 2 R 4 ;
  • R 4 represents R 6 -C 0-S alkyl, preferably R 6 -Ci -8 alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-.
  • the invention relates to the compounds of formula I wherein R 3 represents -CO 2 R 4 ; and
  • R 4 represents R 6 -Co-S alkyl, preferably R 6 -Ci-S alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups.
  • the invention relates to the compounds of formula I wherein R 3 represents -CO 2 R 4 ;
  • R 4 represents R 6 -C 0-S alkyl, preferably R 6 -Ci -8 alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups and one methylene group of the alkyl chain has been replaced by -O-.
  • the invention relates to the compounds of formula I wherein R 4 represents R 5 -Ci -8 alkyl, wherein the alkyl group may be optionally substituted with one or more halogen groups and one methylene group of the alkyl chain may be optionally replaced by -O-; and
  • R 5 represents -NR 4 R 7
  • the invention relates to the compounds of formula I wherein R 4 represents R 5 -Ci -8 alkyl, wherein the alkyl group may be optionally substituted with one or more halogen groups; and
  • R 5 represents -NR 4 R 7
  • the invention relates to the compounds of formula I wherein R 4 represents Re-C 0- S alkyl, preferably Re-Ci -8 alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups and one methylene group of the alkyl chain is optionally replaced by -O-; and R 6 represents C 3- 8cycloalkyl (preferably monocyclic), aryl preferably phenyl) or heteroaryl, wherein R 6 is optionally substituted with one or more groups independently selected from Ci- 8 alkyl, haloCi- 8 alkyl, halogen, Ci- 8 alkoxy, haloCi- 8 alkoxy, Ci- 8 alkylthio, -CN, C2 -4 alkynyl, R 5 -Co-S alkyl and R 8 -Co-S alkyl.
  • the invention relates to the compounds of formula I wherein R 4 represents Re-C 0- S alkyl, preferably Re-Ci -8 alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-; and
  • R 6 represents C 3- 8cycloalkyl, preferably monocyclic, optionally substituted with one or more groups independently selected from Ci- 8 alkyl, halogen Ci-s alkyl, halogen, Ci-s alkoxy, halogen Ci-s alkoxy, Ci-s alkylthio, -CN, C2- 4 alkynyl, R 5 -Co-S alkyl and R 8 -Co- S alkyl.
  • the invention relates to the compounds of formula I wherein R 4 represents Re-C 0 -S alkyl, preferably Re-Ci- 8 alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-; and
  • R 6 represents heteroaryl optionally substituted with one or more groups independently selected from Ci- 8 alkyl, halogen Ci -8 alkyl, halogen, Ci -8 alkoxy, halogen Ci -8 alkoxy, Ci-s alkylthio, -CN, C2- 4 alkynyl, R 5 -Co-S alkyl and R 8 -Co-S alkyl.
  • the invention relates to the compounds of formula I wherein R 3 represents -COR 4 , -CONR 4 R 4 , -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 , preferably -COR 4 , -CONR 4 R 4 , -CO 2 R 4 or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents Ci -8 alkyl or R 6 -C 0-8 alkyl, preferably Ci -8 alkyl or R 6 -Ci -8 alkyl, wherein in the Ci -8 alkyl, R 6- C 0-8 alkyl and R 6 -Ci -8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups and one methylene group of the alkyl chain is optionally replaced by -O-; and
  • R 6 represents aryl (preferably phenyl) or heteroaryl, which are optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci-s alkylthio, -CN, C 2 . 4 alkynyl, R 5 -Co- 8 alkyl and R 8 -Co -S alkyl.
  • the invention relates to the compounds of formula I wherein R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 ', preferably -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents Re-C 0- S alkyl, preferably Re-Ci -8 alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-; and
  • R ⁇ represents aryl (preferably phenyl) or heteroaryl, which are optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -C 0-8 alkyl and R 8 -C 0-8 alkyl.
  • the invention relates to the compounds of formula I wherein R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 ', preferably -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents Re-C 0-8 alkyl, preferably Re-Ci -8 alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-; and
  • R ⁇ represents aryl, preferably phenyl, which is optionally substituted with one or more groups independently selected from Ci -8 alkyl, halogen Ci -8 alkyl, halogen, Ci -8 alkoxy, halogen Ci -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -C 0-8 alkyl and R 8 -C 0-8 alkyl.
  • the invention relates to the compounds of formula I wherein R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 ', preferably -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents Re-C 0-8 alkyl, preferably Re-Ci -8 alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-; and
  • R ⁇ represents aryl, preferably phenyl, which is optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN and C 2-4 alkynyl.
  • the invention relates to the compounds of formula I wherein R 3 represents -CO 2 R 4 ;
  • R 4 represents R 5 -Ci -8 alkyl, wherein the alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-; and R 5 represents -NR 4 R 7 .
  • the invention relates to the compounds of formula I wherein R 3 represents -CO 2 R 4 ;
  • R 4 represents R 5 -Ci-S alkyl, wherein the alkyl group is optionally substituted with one or more halogen groups; and R 5 represents -NR 4 R 7 ; and
  • R 7 represents aryl-Co-s alkyl, preferably aryl-Ci -8 alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups, and any aryl groups are optionally substituted with one or more groups independently selected from C-1-8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci- 8 alkylthio, -
  • the invention relates to the compounds of formula I wherein R 3 represents -CO 2 R 4 ;
  • R 4 represents Ci -8 alkyl or R 6 -Co -8 alkyl, preferably Ci -8 alkyl or R 6 -Ci -8 alkyl, wherein in the Ci -8 alkyl, R 6- Co -8 alkyl and R 6 -Ci -8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups and one methylene group of the alkyl chain is optionally replaced by -O-; and R 6 represents C 3-8 cycloalkyl (preferably monocyclic), aryl (preferably phenyl) or heteroaryl, wherein R 6 is optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -Co -8 alkyl and R 8 -Co -8 alkyl.
  • the invention relates to the compounds of formula I wherein R 3 represents -CO 2 R 4 ;
  • R 4 represents Ci -8 alkyl or R 6 -Co -8 alkyl, preferably Ci -8 alkyl or R 6 -Ci -8 alkyl, wherein in the Ci -8 alkyl, R 6- C 0-8 alkyl and R 6 -Ci -8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups and one methylene group of the alkyl chain is optionally replaced by -O-; and R 6 represents aryl (preferably phenyl) or heteroaryl, wherein R 6 is optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -Co -8 alkyl and R 8 -Co -8 alkyl.
  • the invention relates to the compounds of formula I wherein R 3 represents
  • R 4 represents R 6 -C 0-S alkyl, preferably R 6 -Ci -8 alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups and one methylene group of the alkyl chain is optionally replaced by -O-; and
  • R 6 represents C 3-8 cycloalkyl, preferably monocyclic, optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -Co-S alkyl and R 8 -C 0-8 alkyl.
  • the invention relates to the compounds of formula I wherein R 3 represents -CO 2 R 4 ;
  • R 4 represents R 6 -C 0- S alkyl, preferably R 6 -Ci -8 alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-; and R 6 represents aryl (preferably phenyl) or heteroaryl, wherein R 6 is optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi-s alkyl, halogen, Ci-s alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -C 0 - S alkyl and R 8 -C 0-8 alkyl.
  • the invention relates to the compounds of formula I wherein R 3 represents -CO 2 R 4 ;
  • R 4 represents R 6 -C 0-8 alkyl, preferably R 6 -Ci -8 alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-; and
  • R 6 represents aryl, preferably phenyl, which is optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -C 0-8 alkyl and R 8 - C 0-8 alkyl.
  • the invention relates to the compounds of formula I wherein R 3 represents -CO 2 R 4 ; R 4 represents R 6 -C 0-8 alkyl, preferably R 6 -Ci -8 alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-; and
  • R 6 represents aryl, preferably phenyl, which is optionally substituted with one or more groups independently selected from Ci- ⁇ alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN and C 2-4 alkynyl.
  • the invention relates to the compounds of formula I wherein R 3 represents -CO 2 R 4 ; R 4 represents Re-C 0-8 alkyl, preferably Re-Ci -8 alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-; and
  • R ⁇ represents heteroaryl optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -C 0-8 alkyl and R 8 -C 0-8 alkyl.
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or -SO 2 R 4 , and more preferably - CO 2 R 4 ; and Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:
  • R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or -SO 2 R 4 , and more preferably - CO 2 R 4 ;
  • Ri represents H or Ci -4 alkyl and R 2 represents azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, wherein R 2 is optionally substituted with one or more Ci -4 alkyl groups, and preferably Ri represents H and R 2 represents 1 -methyl- pyrrol id in-3-yl.
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or -SO 2 R 4 , and more preferably - CO 2 R 4 ;
  • Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), wherein R 3 and Rb have the meaning described above for compounds of formula I, and R 0 and Rd independently represent H or Ci -4 alkyl, preferably R a , Rb, Rc and Rd independently represent H or Ci -4 alkyl, more preferably R a , Rb, Rc and Rd independently represent H or methyl and still more preferably R a , Rb and Rd independently represent H or methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or -SO 2 R 4 , and more preferably - CO 2 R 4 ; and Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a), (b), (e) and (f), wherein R 3 and Rb have the meaning described above for compounds of formula I, and R 0 and Rd independently represent H or Ci -4 alkyl, preferably R 3 , Rb, Rc and R d independently represent H or Ci -4 alkyl, more preferably R 3 , Rb, Rc and R d independently represent H or methyl and still more preferably R a , Rb and Rd independently represent H or methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or -SO 2 R 4 ; and more preferably - CO 2 R 4 ;
  • Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R 3 and R b have the meaning described above for compounds of formula I and R 0 represents H or Ci -4 alkyl, preferably R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, more preferably R 3 , Rb and R 0 independently represent H or methyl, still more preferably R 3 and Rb independently represent H or methyl and R 0 represents H, even more preferably R 3 represents H, R b represents H or methyl and R 0 represents H and particularly preferred R 3 represents H, R b represents methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or -SO 2 R 4 , and more preferably - CO 2 R 4 ; and Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R 3 and Rb have the meaning described above for compounds of formula I and R 0 represents H or Ci -4 alkyl, preferably R a , Rb and R 0 independently represent H or Ci -4 alkyl, more preferably R a , Rb and R 0 independently represent H or methyl, still more preferably R a and Rb independently represent H or methyl and R 0 represents H, even more preferably Ra represents H, R b represents H or methyl and R 0 represents H and particularly preferred R 3 represents H, R b represents methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein: R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or -SO 2 R 4 , and more preferably -
  • Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), wherein R 3 and Rb have the meaning described above for compounds of formula I and R 0 represents H or Ci -4 alkyl, preferably R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, more preferably
  • R a , Rb and R 0 independently represent H or methyl, still more preferably R a and Rb independently represent H or methyl and R 0 represents H, even more preferably
  • Ra represents H, R b represents H or methyl and R 0 represents H and particularly preferred R a represents H, R b represents methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 ', preferably -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents Ci -8 alkyl, R 5 -Ci -8 alkyl or R 6 -C 0-8 alkyl, wherein in the Ci -8 alkyl, R 5 -Ci -8 alkyl and R 6 -C 0-8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups and one methylene group of the alkyl chain is optionally replaced by -O-;
  • R 5 represents -NR 4 R 7 ;
  • R 6 represents C 3-8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably
  • R 6 is optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -C 0-8 alkyl and R 8 -C 0-8 alkyl; and
  • Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:
  • heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR 3 Rb group and is optionally substituted with one or more Ci -4 alkyl groups; wherein said heterocyclic groups (i) and (ii) are 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic.
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents -COR 4 , -CONR 4 R 4 , -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 , preferably -COR 4 , -CONR 4 R 4 , -CO 2 R 4 or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents Ci -8 alkyl, R 5 -Ci -8 alkyl or R 6 -C 0-8 alkyl, wherein in the Ci -8 alkyl, R 5 -Ci -8 alkyl and R 6 -C 0-8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups and one methylene group of the alkyl chain is optionally replaced by -O-;
  • R 5 represents -NR 4 R 7 ;
  • R 6 represents C 3-8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably
  • R 6 is optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -C 0-8 alkyl and R 8 -C 0-8 alkyl; and Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), wherein R 3 and Rb have the meaning described above for compounds of formula I, and R 0 and Rd independently represent H or Ci -4 alkyl, preferably R a , Rb, Rc and Rd independently represent H or Ci -4 alkyl, more preferably R a , Rb, Rc and Rd independently represent H or methyl and still more preferably R a , Rb and Rd
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 ', preferably -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 Or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents Ci -8 alkyl, R 5 -Ci -8 alkyl or R 6 -Co -8 alkyl, wherein in the Ci -8 alkyl, R 5 -Ci -S alkyl and R 6 -Co -S alkyl groups any alkyl group is optionally substituted with one or more halogen groups and one methylene group of the alkyl chain is optionally replaced by -O-; R 5 represents -NR 4 R 7 ;
  • R 6 represents C 3 -scycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably
  • R 6 is optionally substituted with one or more groups independently selected from Ci-s alkyl, haloCi-s alkyl, halogen, Ci-s alkoxy, haloCi-s alkoxy, Ci-s alkylthio, -CN, C 2-4 alkynyl, R 5 -Co-S alkyl and Rs-Co-s alkyl; and
  • Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R 3 and R b have the meaning described above for compounds of formula I and R 0 represents H or
  • Ci -4 alkyl preferably R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, more preferably R a , Rb and R 0 independently represent H or methyl, still more preferably
  • Ra and Rb independently represent H or methyl and R 0 represents H, even more preferably R a represents H, R b represents H or methyl and R 0 represents H and particularly preferred R a represents H, R b represents methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 ', preferably -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 Or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents Ci -8 alkyl, R 5 -Ci -8 alkyl or R 6 -C 0-8 alkyl, wherein in the Ci -8 alkyl, R 5 -Ci -8 alkyl and R 6 -Co -8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups and one methylene group of the alkyl chain is optionally replaced by -O-;
  • R 5 represents -NR 4 R 7 ;
  • R 6 represents C 3-8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably
  • R 6 is optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -C 0-8 alkyl and R 8 -C 0-8 alkyl; and
  • Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R 3 and Rb have the meaning described above for compounds of formula I and R 0 represents H or Ci -4 alkyl, preferably R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, more preferably
  • R a , Rb and R 0 independently represent H or methyl, still more preferably R a and Rb independently represent H or methyl and R 0 represents H, even more preferably
  • Ra represents H, R b represents H or methyl and R 0 represents H and particularly preferred R a represents H, R b represents methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents -COR 4 , -CONR 4 R 4 , -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 , preferably -COR 4 , -CONR 4 R 4 , -CO 2 R 4 Or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents Ci -8 alkyl, R 5 -Ci -8 alkyl or R 6 -C 0-8 alkyl, wherein in the Ci -8 alkyl, R 5 -Ci -8 alkyl and R 6 -C 0-8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups and one methylene group of the alkyl chain is optionally replaced by -O-; R 5 represents -NR 4 R 7 ;
  • R 6 represents C 3-8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably C 3-8 cycloalkyl, aryl or heteroaryl, wherein R 6 is optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -C 0-8 alkyl and R 8 -C 0-8 alkyl; and
  • Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), wherein R 3 and Rb have the meaning described above for compounds of formula I and R 0 represents H or Ci -4 alkyl, preferably R a , Rb and R 0 independently represent H or Ci -4 alkyl, more preferably
  • R a , Rb and R 0 independently represent H or methyl, still more preferably R a and Rb independently represent H or methyl and R 0 represents H, even more preferably Ra represents H, R b represents H or methyl and R 0 represents H and particularly preferred R 3 represents H, R b represents methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 ', preferably -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents Ci- ⁇ alkyl or R 6 -Co-S alkyl, preferably Ci- ⁇ alkyl or R 6 -Ci-S alkyl, wherein in the Ci-S alkyl, R 6- Co-S alkyl and R 6 -Ci-S alkyl groups any alkyl group is optionally substituted with one or more halogen groups and one methylene group of the alkyl chain is optionally replaced by -O-;
  • R 6 represents C 3 -scycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably
  • R 6 is optionally substituted with one or more groups independently selected from Ci-s alkyl, haloCi-s alkyl, halogen, Ci-s alkoxy, haloCi-s alkoxy, Ci-S alkylthio, -CN, C 2-4 alkynyl, R 5 -Co -S alkyl and R 8 -Co -S alkyl; and
  • Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:
  • heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR 3 Rb group and is optionally substituted with one or more Ci -4 alkyl groups; wherein said heterocyclic groups (i) and (ii) are 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic.
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 ', preferably -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents Ci-S alkyl or R 6 -Co-S alkyl, preferably Ci-S alkyl or R 6 -Ci-S alkyl, wherein in the Ci-S alkyl, R 6- Co-S alkyl and R 6 -Ci-S alkyl groups any alkyl group is optionally substituted with one or more halogen groups and one methylene group of the alkyl chain is optionally replaced by -O-;
  • R 6 represents C 3-8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably
  • R 6 is optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -Co -8 alkyl and R 8 -Co -8 alkyl; and
  • Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), wherein R 3 and Rb have the meaning described above for compounds of formula I, and R 0 and Rd independently represent H or Ci -4 alkyl, preferably R 3 , Rb, Rc and R d independently represent H or Ci -4 alkyl, more preferably R 3 , Rb, Rc and R d independently represent H or methyl and still more preferably R a , Rb and Rd independently represent H or methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 , preferably -COR 4 , -CONR 4 R 4 , -CO 2 R 4 Or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents Ci -8 alkyl or R 6 -C 0-8 alkyl, preferably Ci -8 alkyl or R 6 -Ci -8 alkyl, wherein in the Ci -8 alkyl, R 6- C 0-8 alkyl and R 6 -Ci -8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups and one methylene group of the alkyl chain is optionally replaced by -O-;
  • R 6 represents C 3-8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably
  • R 6 is optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -C 0-8 alkyl and R 8 -C 0-8 alkyl; and
  • Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R 3 and R b have the meaning described above for compounds of formula I and R 0 represents H or Ci -4 alkyl, preferably R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, more preferably R 3 , Rb and R 0 independently represent H or methyl, still more preferably R 3 and Rb independently represent H or methyl and R 0 represents H, even more preferably R 3 represents H, R b represents H or methyl and R 0 represents H and particularly preferred R a represents H, R b represents methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 ', preferably -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents Ci- ⁇ alkyl or R 6 -Co-S alkyl, preferably Ci- ⁇ alkyl or R 6 -Ci-S alkyl, wherein in the Ci-S alkyl, R 6- Co-S alkyl and R 6 -Ci-S alkyl groups any alkyl group is optionally substituted with one or more halogen groups and one methylene group of the alkyl chain is optionally replaced by -O-; R 6 represents C 3 -scycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably
  • R 6 is optionally substituted with one or more groups independently selected from Ci-s alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -Co -8 alkyl and R 8 -Co -8 alkyl; and Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R 3 and Rb have the meaning described above for compounds of formula I and R 0 represents H or Ci -4 alkyl, preferably R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, more preferably R a , Rb and R 0 independently represent H or methyl, still more preferably R a and Rb independently represent H or methyl and R
  • the invention relates to the compounds of formula I wherein: R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 ', preferably -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 Or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents Ci -8 alkyl or R 6 -C 0-8 alkyl, preferably Ci -8 alkyl or R 6 -Ci -8 alkyl, wherein in the Ci -8 alkyl, R 6- C 0-8 alkyl and R 6 -Ci -8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups and one methylene group of the alkyl chain is optionally replaced by -O-;
  • R 6 represents C 3-8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably C 3-8 cycloalkyl, aryl or heteroaryl and more preferably aryl or heteroaryl, wherein R 6 is optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi-s alkyl, halogen, Ci-S alkoxy, haloCi-s alkoxy, Ci-S alkylthio, -CN, C2 -4 alkynyl, R 5 -C 0-S alkyl and R 8 -C 0-S alkyl; and
  • Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), wherein R 3 and Rb have the meaning described above for compounds of formula I and R 0 represents H or Ci -4 alkyl, preferably R a , Rb and R 0 independently represent H or Ci -4 alkyl, more preferably
  • R a , Rb and R 0 independently represent H or methyl, still more preferably R a and Rb independently represent H or methyl and R 0 represents H, even more preferably
  • Ra represents H
  • R b represents H or methyl and R 0 represents H and particularly preferred R 3 represents H
  • R b represents methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 , preferably -COR 4 , -CONR 4 R 4 , -CO 2 R 4 or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents Ci-S alkyl, optionally substituted with one or more halogen groups, wherein one methylene group of the alkyl chain is optionally replaced by - O-; and
  • Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from: (i) a heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said heterocyclic group is optionally substituted with one or more Ci -4 alkyl groups; and
  • heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR 3 Rb group and is optionally substituted with one or more Ci -4 alkyl groups; wherein said heterocyclic groups (i) and (ii) are 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic.
  • the invention relates to the compounds of formula I wherein: R 3 represents -COR 4 , -CONR 4 R 4 , -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 , preferably -COR 4 , -CONR 4 R 4 , -CO 2 R 4 or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents Ci-S alkyl,optionally substituted with one or more halogen groups, wherein one methylene group of the alkyl chain is optionally replaced by - O-;
  • Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), wherein R 3 and Rb have the meaning described above for compounds of formula I, and R 0 and Rd independently represent H or Ci -4 alkyl, preferably R 3 , Rb, Rc and R d independently represent H or Ci -4 alkyl, more preferably R a , Rb, Rc and Rd independently represent H or methyl and still more preferably R a , Rb and Rd independently represent H or methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 ', preferably -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 Or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents Ci-S alkyl, optionally substituted with one or more halogen groups, wherein one methylene group of the alkyl chain is optionally replaced by - O-;
  • Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R 3 and Rb have the meaning described above for compounds of formula I and R 0 represents H or Ci -4 alkyl, preferably R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, more preferably R a , Rb and R 0 independently represent H or methyl, still more preferably Ra and Rb independently represent H or methyl and R 0 represents H, even more preferably R a represents H, R b represents H or methyl and R 0 represents H and particularly preferred R a represents H, R b represents methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 ', preferably -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 Or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents Ci-S alkyl, optionally substituted with one or more halogen groups, wherein one methylene group of the alkyl chain is optionally replaced by - O-;
  • Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R 3 and Rb have the meaning described above for compounds of formula I and R 0 represents H or Ci -4 alkyl, preferably R a , Rb and R 0 independently represent H or Ci -4 alkyl, more preferably R a , Rb and R 0 independently represent H or methyl, still more preferably R a and Rb independently represent H or methyl and R 0 represents H, even more preferably Ra represents H, R b represents H or methyl and R 0 represents H and particularly preferred R 3 represents H, R b represents methyl and R 0 represents H.
  • R 3 and Rb have the meaning described above for compounds of formula I and R 0 represents H or Ci -4 alkyl, preferably R a , Rb and R 0 independently represent H or Ci -4 alkyl, more preferably R a , Rb and R 0 independently represent H or methyl, still more preferably R
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 ', preferably -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 Or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents Ci-S alkyl optionally substituted with one or more halogen groups, wherein one methylene group of the alkyl chain is optionally replaced by - O-;
  • Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), wherein R 3 and Rb have the meaning described above for compounds of formula I and R 0 represents H or Ci -4 alkyl, preferably R a , Rb and R 0 independently represent H or Ci -4 alkyl, more preferably
  • R a , Rb and R 0 independently represent H or methyl, still more preferably R a and Rb independently represent H or methyl and R 0 represents H, even more preferably
  • Ra represents H
  • R b represents H or methyl and R 0 represents H and particularly preferred R 3 represents H
  • R b represents methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 ', preferably -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents Rs-Ci-S alkyl, wherein the alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-;
  • R 5 represents -CONR 4 R 7 , -NR 4 COR 7 , -NR 4 CO 2 R 7 , -NR 4 SO 2 R 7 , - SO 2 NR 4 R 7 , -NR 4 CONR 4 R 7 , -CONHSO 2 R 7 , -CO 2 R 7 , -OCOR 7 , -SO 2 R 7 , -NR 4 R 7 , - OH or 1 H-tetrazol-5-yl, preferably -NR 4 R 7 ; and
  • Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from: (i) a heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said heterocyclic group is optionally substituted with one or more Ci -4 alkyl groups; and
  • heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR 3 Rb group and is optionally substituted with one or more Ci -4 alkyl groups; wherein said heterocyclic groups (i) and (ii) are 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic.
  • the invention relates to the compounds of formula I wherein: R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 , preferably -COR 4 , -CONR 4 R 4 , -CO 2 R 4 or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents R 5 -Ci -8 alkyl, wherein the alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-;
  • R 5 represents -CONR 4 R 7 , -NR 4 COR 7 , -NR 4 CO 2 R 7 , -NR 4 SO 2 R 7 , -
  • Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), wherein R 3 and Rb have the meaning described above for compounds of formula I, and R 0 and Rd independently represent H or Ci -4 alkyl, preferably R 3 , Rb, Rc and R d independently represent H or Ci -4 alkyl, more preferably R 3 , R b , R c and R d independently represent H or methyl and still more preferably R 3 , Rb and Rd independently represent H or methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents -COR 4 , -CONR 4 R 4 , -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 , preferably -COR 4 , -CONR 4 R 4 , -CO 2 R 4 or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents R 5 -Ci -8 alkyl, wherein the alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-;
  • R 5 represents -CONR 4 R 7 , -NR 4 COR 7 , -NR 4 CO 2 R 7 , -NR 4 SO 2 R 7 , - SO 2 NR 4 R 7 , -NR 4 CONR 4 R 7 , -CONHSO 2 R 7 , -CO 2 R 7 , -OCOR 7 , -SO 2 R 7 , -NR 4 R 7 , - OH or 1 H-tetrazol-5-yl, preferably -NR 4 R 7 ; and
  • Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R 3 and R b have the meaning described above for compounds of formula I and R 0 represents H or Ci -4 alkyl, preferably R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, more preferably R a , Rb and R 0 independently represent H or methyl, still more preferably
  • Ra and Rb independently represent H or methyl and R 0 represents H, even more preferably R a represents H, R b represents H or methyl and R 0 represents H and particularly preferred R a represents H, R b represents methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 , preferably -COR 4 , -CONR 4 R 4 , -CO 2 R 4 or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents R 5 -Ci-S alkyl, wherein the alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-;
  • R 5 represents -CONR 4 R 7 , -NR 4 COR 7 , -NR 4 CO 2 R 7 , -NR 4 SO 2 R 7 , - SO 2 NR 4 R 7 , -NR 4 CONR 4 R 7 , -CONHSO 2 R 7 , -CO 2 R 7 , -OCOR 7 , -SO 2 R 7 , -NR 4 R 7 , - OH or 1 H-tetrazol-5-yl, preferably -NR 4 R 7 ; and Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R 3 and Rb have the meaning described above for compounds of formula I and R 0 represents H or Ci -4 alkyl, preferably R a , Rb and R 0 independently represent H or Ci -4 alkyl, more preferably R a , Rb and R 0 independently represent H or methyl, still more preferably R a and Rb independently represent H or methyl
  • the invention relates to the compounds of formula I wherein: R 3 represents -COR 4 , -CONR 4 R 4 , -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 , preferably -COR 4 , -CONR 4 R 4 , -CO 2 R 4 or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents R 5 -Ci-S alkyl, wherein the alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-;
  • R 5 represents -CONR 4 R 7 , -NR 4 COR 7 , -NR 4 CO 2 R 7 , -NR 4 SO 2 R 7 , - SO 2 NR 4 R 7 , -NR 4 CONR 4 R 7 , -CONHSO 2 R 7 , -CO 2 R 7 , -OCOR 7 , -SO 2 R 7 , -NR 4 R 7 , - OH or 1 H-tetrazol-5-yl, preferably -NR 4 R 7 ; and Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), wherein R 3 and Rb have the meaning described above for compounds of formula I and R 0 represents H or Ci -4 alkyl, preferably R a , Rb and R 0 independently represent H or Ci -4 alkyl, more preferably R a , Rb and R 0 independently represent H or methyl, still more preferably R a and Rb independently represent H or methyl
  • the invention relates to the compounds of formula I wherein: R 3 represents -COR 4 , -CONR 4 R 4 , -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 , preferably -COR 4 , -CONR 4 R 4 , -CO 2 R 4 or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents R 6 -Co -S alkyl, preferably R 6 -Ci -S alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-;
  • R 6 represents C 3- scycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably
  • R 6 is optionally substituted with one or more groups independently selected from Ci-s alkyl, haloCi-s alkyl, halogen, Ci-s alkoxy, haloCi-s alkoxy, Ci-S alkylthio, -CN, C 2-4 alkynyl, R 5 -Co -S alkyl and R 8 -Co -S alkyl; and Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:
  • heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said heterocyclic group is optionally substituted with one or more Ci -4 alkyl groups; and (ii) a heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR 3 Rb group and is optionally substituted with one or more Ci -4 alkyl groups; wherein said heterocyclic groups (i) and (ii) are 4- to 7-membered monocyclic, 7- to 8-nnennbered bridged bicyclic or 8- to 12-membered fused bicyclic.
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 ', preferably -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents R 6 -Co -S alkyl, preferably R 6 -Ci -S alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-;
  • R 6 represents C 3 -scycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably C 3 -scycloalkyl, aryl or heteroaryl and more preferably aryl or heteroaryl, wherein R 6 is optionally substituted with one or more groups independently selected from Ci-s alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -C 0-8 alkyl and R 8 -C 0-8 alkyl; and
  • Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), wherein R 3 and Rb have the meaning described above for compounds of formula I, and R 0 and Rd independently represent H or Ci -4 alkyl, preferably R a , Rb, Rc and Rd independently represent H or Ci -4 alkyl, more preferably R 3 , Rb, Rc and R d independently represent H or methyl and still more preferably R a , Rb and Rd independently represent H or methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein:
  • R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 ', preferably -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 Or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents R 6 -C 0-8 alkyl, preferably R 6 -Ci -8 alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-;
  • R 6 represents C 3-8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably
  • R 6 is optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -C 0-8 alkyl and R 8 -C 0-8 alkyl; and
  • Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R 3 and Rb have the meaning described above for compounds of formula I and R 0 represents H or C1-4 alkyl, preferably R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, more preferably R a , Rb and R 0 independently represent H or methyl, still more preferably Ra and Rb independently represent H or methyl and R 0 represents H, even more preferably R a represents H, R b represents H or methyl and R 0 represents H and particularly preferred R a represents H, R b represents methyl and R 0 represents H.
  • the invention relates to the compounds of formula I wherein: R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 ', preferably -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 Or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents R 6 -C 0-S alkyl, preferably R 6 -Ci -8 alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-;
  • R 6 represents C 3-8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably
  • R 6 is optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -C 0-8 alkyl and R 8 -C 0-8 alkyl; and Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R 3 and Rb have the meaning described above for compounds of formula I and R 0 represents H or Ci -4 alkyl, preferably R a , Rb and R 0 independently represent H or Ci -4 alkyl, more preferably R a , Rb and R 0 independently represent H or methyl, still more preferably R a and Rb independently represent H or methyl
  • the invention relates to the compounds of formula I wherein: R 3 represents -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 , -SO 2 R 4 or -SO 2 NR 4 R 4 ', preferably -COR 4 , -CONR 4 R 4 ', -CO 2 R 4 Or -SO 2 R 4 , and more preferably -CO 2 R 4 ;
  • R 4 represents R 6 -C 0-8 alkyl, preferably R 6 -Ci -8 alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-;
  • R 6 represents C 3-8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably
  • R 6 is optionally substituted with one or more groups independently selected from Ci -8 alkyl, haloCi -8 alkyl, halogen, Ci -8 alkoxy, haloCi -8 alkoxy, Ci -8 alkylthio, -CN, C 2-4 alkynyl, R 5 -Co -8 alkyl and R 8 -Co -8 alkyl; and
  • Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), wherein R 3 and Rb have the meaning described above for compounds of formula I and R 0 represents H or Ci -4 alkyl, preferably R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, more preferably
  • R a , Rb and R 0 independently represent H or methyl, still more preferably R a and Rb independently represent H or methyl and R 0 represents H, even more preferably
  • Ra represents H
  • R b represents H or methyl and R 0 represents H and particularly preferred R a represents H
  • R b represents methyl and R 0 represents H.
  • the present invention includes all possible combinations of the particular and preferred embodiments described above.
  • the invention relates to a compound of formula I selected from the list of examples 1 -771.
  • the invention relates to compounds according to formula I that provide more than 50% inhibition of histamine H 4 receptor activity at 10 ⁇ M, more preferably at 1 ⁇ M and even more preferably at 0.1 ⁇ M, in an H 4 receptor assay such as the one described in examples 78 or 79.
  • the compounds of the present invention contain one or more basic nitrogens and may, therefore, form salts with organic or inorganic acids.
  • these salts include: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; and salts with organic acids such as methanesulfonic acid, thfluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, fumaric acid, oxalic acid, acetic acid, maleic acid, ascorbic acid, citric acid, lactic acid, tartaric acid, malonic acid, glycolic acid, succinic acid and propionic acid, among others.
  • the compounds of the present invention may contain one or more acidic protons and, therefore, they may also form salts with bases, which also form part of the present invention.
  • these salts include: salts with inorganic cations such as sodium, potassium, calcium, magnesium, lithium, aluminium, zinc, etc; and salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxylalkylamines, lysine, arginine, /V-methylglucamine, procaine and the like.
  • pharmaceutically acceptable salt refers to those salts which are, according to medical judgement, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like. Pharmaceutically acceptable salts are well known in the art.
  • the salts of a compound of formula I can be obtained during the final isolation and purification of the compounds of the invention or can be prepared by treating a compound of formula I with a sufficient amount of the desired acid to give the salt in a conventional manner.
  • the salts of the compounds of formula I can be converted into other salts of the compounds of formula I by ion exchange using ion exchange resins.
  • the compounds of formula I and their salts may differ in some physical properties but they are equivalent for the purposes of the present invention. All salts of the compounds of formula I are included within the scope of the invention.
  • the compounds of the present invention may form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as solvates.
  • solvate refers to a complex of variable stoichiometry formed by a solute (a compound of formula I or a salt thereof) and a solvent.
  • solvents include pharmaceutically acceptable solvents such as water, etanol and the like.
  • a complex with water is known as a hydrate.
  • Solvates of compounds of the invention (or salts thereof), including hydrates, are included within the scope of the invention.
  • the compounds of formula I may exist in different physical forms, i.e. amorphous and crystalline forms. Moreover, the compounds of the invention may have the ability to crystallize in more than one form, a characteristic which is known as polymorphism. Polymorphs can be distinguished by various physical properties well known in the art such as X-ray diffraction pattern, melting point or solubility. All physical forms of the compounds of formula I, including all polymorphic forms (“polymorphs”) thereof, are included within the scope of the invention.
  • Some of the compounds of the present invention may exist as several optical isomers and/or several diastereoisomers.
  • Diastereoisomers can be separated by conventional techniques such as chromatography or fractional crystallization.
  • Optical isomers can be resolved by conventional techniques of optical resolution to give optically pure isomers. This resolution can be carried out on any chiral synthetic intermediate or on the products of formula I.
  • Optically pure isomers can also be individually obtained using enantiospecific synthesis.
  • the present invention covers all individual isomers as well as mixtures thereof (for example racemic mixtures or mixtures of diastereomers), whether obtained by synthesis or by physically mixing them.
  • any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds, lsotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 36 CI, and 125 I, respectively.
  • Such isotopically labelled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single- photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single- photon emission computed tomography
  • an 18 F or 11 C labeled compound may be particularly preferred for PET or SPECT studies.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • Isotopically labeled compounds of this invention can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent. In addition to the unlabeled form, all isotopically labeled forms of the compounds of formula I are included within the scope of the invention.
  • the compounds of formula I can be obtained by following the processes described below. As it will be obvious to one skilled in the art, the exact method used to prepare a given compound may vary depending on its chemical structure. Moreover, in some of the processes described below it may be necessary or advisable to protect the reactive or labile groups with conventional protecting groups. Both the nature of these protecting groups and the procedures for their introduction or removal are well known in the art (see for example Greene T.W. and Wuts P. G. M, "Protective Groups in Organic Synthesis", John Wiley & Sons, 3 rd edition, 1999). Unless otherwise stated, in the methods described below the meanings of the different substituents are the meanings described above with regard to a compound of formula I.
  • the compounds of formula I can be obtained by the incorporation of R3 in the last step of synthesis from a compound of formula Il or of a reactive derivative of the compound of formula II, MB.
  • Ri and R2 have the meaning described in formula I and X represents CO or SO 2 .
  • these reactions can be carried out in one or several steps, using well-known reactions in organic chemistry under standard experimental conditions.
  • the compounds of formula I wherein R 3 represents -COR 4 can conveniently be prepared by a reaction of a compound of formula Il with an acid or acyl chloride of formula R 4 -COY, wherein Y is OH or Cl.
  • the compounds of formula I wherein R 3 represents -CONR 4 R 4 ' can be prepared by reaction of a compound of formula Il with an isocyanate (R 4 -NCO) or a carbamoyl chloride (R 4 R 4 -NCOW, wherein W is a leaving group, such as, for example Cl or para-NO2-phenoxyl).
  • R 4 -NCO isocyanate
  • R 4 R 4 -NCOW carbamoyl chloride
  • W is a leaving group, such as, for example Cl or para-NO2-phenoxyl
  • the compounds of formula I wherein R 3 represents -CO2R 4 can be prepared by reaction of a compound of formula Il with a chloroformate (R 4
  • the compounds of formula I wherein R 3 represents -CO2R 4 can be prepared by reacting a compound of formula Il with an alcohol R 4 -OH previously treated with a synthetic equivalent for the CO synthon in a suitable solvent.
  • Preferred conditions are: carbonyldiimidazole (CDI) in a suitable solvent such as dichloromethane (see, for example C. G. Bochet et al.
  • phosgene or its derivatives in a suitable solvent such as dichloromethane, chloroform or dioxane, in the presence of a base such as thethylamine or diisopropylethylamine, optionally in the presence of catalysis of 4-dimethylaminopyridine; bis-(2-pyhdyl) carbonate (DPC) in a suitable solvent such as dichloromethane, in the presence of a base such as triethylamine; and disuccinimidyl carbonate in a suitable solvent such as dichloromethane, in the presence of a base such as triethylamine, among others.
  • R 3 represents -SO2R 4
  • R 4 - SO 2 CI a sulfonyl chloride
  • the compounds of formula I wherein R 3 represents -SO 2 NR 4 R 4 ' can be prepared by reaction of a compound of formula Il with a sulfamoyl chloride (R 4 R 4 - NSO 2 CI).
  • R 4 R 4 - NSO 2 CI a sulfamoyl chloride
  • the compounds of formula Il can be produced by reaction of a hydroxyderivative of formula IV with an amine of formula III as shown in the following diagram:
  • Ri and R2 have the previously described meaning in relation to a compound of formula I
  • P represents a protecting group
  • Rg represents a leaving group such as a halogen atom, triflate or tosilate.
  • the reaction between the compounds of formula IV and III can be carried out using a coupling agent such as, for example PyBOP (benzotriazole-1 -yl- oxythpyrrolidinophosphonium hexafluorophosphate), in a suitable solvent, preferably in acetonitrile or in mixtures of acetonitrile and 1 ,4-dioxane, in the presence of a base, preferably thethylamine and a temperature between room temperature and reflux.
  • a coupling agent such as, for example PyBOP (benzotriazole-1 -yl- oxythpyrrolidinophosphonium hexafluorophosphate)
  • a suitable solvent preferably in acetonitrile or in mixtures of acetonit
  • the compounds of formula Il can be obtained by reaction of a compound of formula III with a reactive derivative of the compound of formula IV (IVB) obtained by conversion of the hydroxy group present in a compound IV in a leaving group such as halogen, triflate or tosilate, preferably chlorine.
  • IVB reactive derivative of the compound of formula IV
  • the -OH group of the compound of formula IV can be transformed into a leaving group such as halogen, preferably chlorine, by reaction with a halogenating agent such as POCI3 (see Journal of Medicinal Chemistry 1998, 41 , 3793), optionally in the presence of a suitable solvent, or POCI3/PCI5 or N, N- dimethylformamide/oxalyl chloride mixtures in the presence of a suitable solvent such as 1 ,4-dioxane, 1 ,2-dichloroeethane or propionitrile.
  • a suitable solvent such as 1 ,4-dioxane, 1 ,2-dichloroeethane or propionitrile.
  • the reaction is carried out by heating, preferably at a temperature between 70 °C and 140 °C.
  • the hydroxy group of the compound of formula IV can be transformed into a triflate group by reaction with thfluoromethanesulfonic anhydride in the presence of pyridine.
  • the reactive derivative of the compound of formula IV obtained (IVB) is reacted with a compound of formula III to give a compound of formula II.
  • the reaction is carried out in a suitable solvent such as etanol, methanol, butanol, N, N- dimethylformamide, dimethyl sulfoxide, tetrahydrofurane or toluene, preferably methanol or etanol, in the presence of a base, including organic amines such as triethylamine, ⁇ /, ⁇ /-diisopropylethylamine, dimethylaniline and diethylamide among others, and heating, preferably at 100 °C or at reflux.
  • the heating may be thermal or by irradiating with microwaves at a wattage that allows to reach the temperature mentioned above.
  • the piperidine group of the compounds of formula IV or IVB is protected (by a P group) in order to prevent the formation of side- products, in which case a subsequent deprotection step is necessary to obtain the compounds of formula II.
  • Any suitable protective group may be used, such as for example, a benzyloxycarbonyl group.
  • the subsequent deprotection step is carried out under standard conditions, such as, for example, by hydrogenation on Pd/C in a suitable solvent such as methanol or etanol.
  • the amino substituents of the compounds of formula III can also be protected to prevent the formation of side-products. If necessary, it is also possible to protect the amino group of the compounds of formula IV and IVB. Any suitable protective group may be used, such as for example, te/t-butoxycarbonyl (Boc).
  • Boc te/t-butoxycarbonyl
  • the amino substituents of the compounds of formula IV and/or III and/or IVB it may be necessary to carry out a subsequent deprotection step, which is carried out under standard conditions. Generally, when the amino substituents of the compounds of formula III are protected, the deprotection is usually carried out after the transformation of Il into I, i.e. on the compound of formula I.
  • the deprotection can be carried out by treatment with a strong acid such as HCI in a suitable solvent such as 1 ,4-dioxane, diethyl ether or methanol, and preferably trifluoroacetic acid in dichloromethane.
  • a strong acid such as HCI
  • a suitable solvent such as 1 ,4-dioxane, diethyl ether or methanol, and preferably trifluoroacetic acid in dichloromethane.
  • the compounds of formula III are commercially available or can be easily obtained from commercial compounds by known methods.
  • the compounds of formula IV can be obtained by reacting a compound of formula V with a guanidine salt, preferably hydrochloride, as shown in the following diagram:
  • the reaction takes place in the presence of a base such as potassium carbonate, sodium te/t-butoxide or sodium methoxide and preferably sodium ethoxide, in a suitable solvent, preferably etanol.
  • a base such as potassium carbonate, sodium te/t-butoxide or sodium methoxide and preferably sodium ethoxide
  • a suitable solvent preferably etanol.
  • the reaction can be carried out by heating at a suitable temperature generally between room temperature and reflux, preferably at reflux.
  • the compounds of formula V are commercially available or can be easily obtained from commercial compounds by known methods.
  • the compounds of formula I can be obtained from a derivative of formula Vl by reaction with a compound of formula III under similar conditions to that described for the transformation of IV into II, as shown in the following scheme: wherein Ri, R 2 and R3 have the previously described meaning in relation to a compound of formula I.
  • the compounds of formula Vl can be prepared by similar processes to those described to obtain a compound of formula IV.
  • the incorporation of R3 can be carried out by similar processes to those described to obtain the compounds of formula I from Il or MB.
  • the compounds of the present invention show potent histamine H 4 receptor antagonist activity. Therefore, the compounds of the invention are expected to be useful to treat diseases mediated by the H 4 receptor in mammals, including human beings.
  • H 4 receptor Diseases mediated by the H 4 receptor that can be treated or prevented with the compounds of the present invention include, among others, allergic, immunological or inflammatory diseases, or pain.
  • allergic, immunological or inflammatory diseases examples include without limitation: respiratory diseases, such as asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD); ocular diseases, such as allergic rhinoconjunctivitis, dry eye and cataracts; skin diseases, such as dermatitis (e.g. atopic dermatitis), psoriasis, urticaria and pruritus; inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease; rheumatoid arthritis; multiple sclerosis; cutaneous lupus; systemic lupus erythematosus; and transplant rejection.
  • respiratory diseases such as asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD); ocular diseases, such as allergic rhinoconjunctivitis, dry eye and cataracts
  • skin diseases such as dermatitis (e.g. atopic dermatitis), psoriasis, urticaria and pruritus
  • Examples of pain conditions that can be treated or prevented with the compounds of the invention include, among others, inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-surgical pain, migraine, cancer pain, visceral pain, osteoarthritis pain and neuropathic pain.
  • the compounds of the invention are used for the treatment or prevention of an allergic, immunological or inflammatory disease.
  • the compounds of the invention are used for the treatment or prevention of an allergic, immunological or inflammatory disease selected from a respiratory disease, an ocular disease, a skin disease, an inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus, and transplant rejection.
  • the allergic, immunological or inflammatory disease is selected from asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataracts, dermatitis (e.g. atopic dermatitis), psoriasis, urticaria, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection.
  • COPD chronic obstructive pulmonary disease
  • the compounds of the invention are used for the treatment or prevention of pain, preferably inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-surgical pain, migraine, cancer pain, visceral pain, osteoarthritis pain or neuropathic pain.
  • H 4 receptor binding assay such as the one explained in detail in example 78.
  • Another useful assay is a GTP [ ⁇ - 35 S] binding assay to membranes that express the H 4 receptor.
  • Functional assays with H 4 receptor-expressing cells can also be used, for example in a system measuring any kind of cellular activity mediated by a second messenger associated with the H 4 receptor such as intracellular cAMP levels or Ca 2+ mobilization.
  • a very useful functional assay that can be used to determine anti-H 4 receptor activity is the Gated Autofluorescence Forward Scatter assay (GAFS) in eosinophils, for example human eosinophils, as disclosed in detail in example 79; this assay is well know in the art (see for example the method disclosed in Buckland KF et al, 2003, cited above in the Background section, which is incorporated herein by reference).
  • GAFS Gated Autofluorescence Forward Scatter assay
  • In vivo assays that can be used to test the activity of the compounds of the invention are also well known in the art (see for example the various literature references listed for in vivo animal models in the Background section, particularly those relating to in vivo models of peritonitis, pleurisy, allergic asthma, inflammatory bowel disease, atopic dermatitis, pruritus and pain, which are all incorportated herein by reference).
  • the selectivity profile of the compounds of the invention can be tested using standard histamine receptor binding assays using the various histamine receptors similarly to the one disclosed in example 78.
  • displacement assays of the corresponding radioligands can be used following the standard procedures reported in the literature (see for example Cerep-Le Bois I'Eveque 2008 catalogue and the references cited therein).
  • testing at 10 ⁇ M must result in an activity of more than 50% inhibition of H 4 receptor activity in the test provided in example
  • compounds should exhibit more than 50% inhibition at 1 ⁇ M and still more preferably at 0.1 ⁇ M in this assay.
  • Preferred compounds should also exhibit potent activity in the GAFS assay of example 79; preferably, compounds should exhibit more than 50% inhibition at 10 ⁇ M, more preferably at 1 ⁇ M and still more preferably at 0.1 ⁇ M in this assay.
  • Preferred compounds should exhibit selective affinity for the H 4 receptor over other receptors, particularly the H 3 receptor.
  • the present invention also relates to a pharmaceutical composition which comprises a compound of the invention (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients.
  • the excipients must be "acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
  • the compounds of the present invention can be administered in the form of any pharmaceutical formulation, the nature of which, as it is well known, will depend upon the nature of the active compound and its route of administration.
  • any route of administration may be used, for example oral, parenteral, nasal, ocular, topical and rectal administration.
  • the compounds of the invention are administered orally.
  • the compounds of the invention are administered topically.
  • Solid compositions for oral administration include tablets, granulates and capsules.
  • the manufacturing method is based on a simple mixture, dry granulation or wet granulation of the active compound with excipients.
  • excipients can be, for example, diluents such as lactose, microcrystalline cellulose, mannitol or calcium hydrogenphosphate; binding agents such as for example starch, gelatin or povidone; disintegrants such as sodium carboxymethyl starch or sodium croscarmellose; and lubricating agents such as for example magnesium stearate, stearic acid or talc.
  • Tablets can be additionally coated with suitable excipients by using known techniques with the purpose of delaying their disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period, or simply to improve their organoleptic properties or their stability.
  • the active compound can also be incorporated by coating onto inert pellets using natural or synthetic film-coating agents.
  • Soft gelatin capsules are also possible, in which the active compound is mixed with water or an oily medium, for example coconut oil, mineral oil or olive oil.
  • Powders and granulates for the preparation of oral suspensions by the additon of water can be obtained by mixing the active compound with dispersing or wetting agents; suspending agents and preservatives.
  • Other excipients can also be added, for example sweetening, flavouring and colouring agents.
  • Liquid forms for oral administration include emulsions, solutions, suspensions, syrups and elixirs containing commonly-used inert diluents, such as purified water, etanol, sorbitol, glycerol, polyethylene glycols (macrogols) and propylene glycol.
  • Said compositions can also contain coadjuvants such as wetting, suspending, sweetening, flavouring agents, preservatives and buffers.
  • Injectable preparations for parenteral administration, comprise sterile solutions, suspensions or emulsions, in an aqueous or non-aqueous solvent such as propylene glycol, polyethylene glycol or vegetable oils.
  • aqueous or non-aqueous solvent such as propylene glycol, polyethylene glycol or vegetable oils.
  • These compositions can also contain coadjuvants, such as wetting, emulsifying, dispersing agents and preservatives. They may be sterilized by any known method or prepared as sterile solid compositions which will be dissolved in water or any other sterile injectable medium immediately before use. It is also possible to start from sterile materials and keep them under these conditions throughout all the manufacturing process.
  • the compounds of the invention can also be formulated for their topical application for the treatment of pathologies occurring in zones or organs accessible through this route, such as eyes, skin and the intestinal tract.
  • Formulations include creams, lotions, gels, powders, solutions and patches wherein the compound is dispersed or dissolved in suitable excipients.
  • the compound for the nasal administration or for inhalation, can be formulated as an aerosol, from which it can be conveniently released using suitable propellants.
  • a suitable dosage range is from about 0.01 mg/Kg to about 100 mg/Kg per day, which can be administered as a single or divided doses.
  • HBTU O-benzotriazol-1 -yl-/V,/V,/V',/V'-tetramethyluronium hexafluorophosphate
  • TEA triethylamine
  • THF tetrahydrofurane
  • t R retention time
  • LC-MS liquid chromatography-mass spectrometry
  • Benzyl 4-(2-amino-6-hydroxypyrimidin-4-yl)piperidin-1-carboxylate Guanidine hydrochloride (2.15 g, 22.5 mmol) and sodium ethoxide (7.3 g of a 21 % solution in etanol, 22.5 mmol) were added to a solution of benzyl 4-(3-ethoxy-3- oxopropanoyl)piperidin-1 -carboxylate (5.0 g, 15 mmol) in absolute etanol (150 mL) and the mixture was heated at reflux overnight. The solvent was concentrated to dryness, the residue was diluted with water and the pH was adjusted to 6-7 with 1 N HCI.
  • the reaction was filtered through Celite ® and the filtrate was concentrated to dryness.
  • the residue was diluted with a solution of 5% citric acid and it was washed twice with ethyl acetate.
  • the pH of the aqueous phase was adjusted to pH 11 with 1 N NaOH aqueous solution and was extracted three times with ethyl acetate.
  • the combined organic phases were dried over anhydrous Na 2 SO 4 and were concentrated to dryness, providing the desired compound with quantitative yield.
  • Phosphorus oxychloride (2.1 mL, 22.9 mmol) was added to a mixture of the reference example 3 (500 mg, 1.52 mmol) and tetraethylammonium chloride (757 mg, 4.57 mmol), in acetonitrile (8 mL) and the mixture was heated at 80 0 C for 3 h and then it was concentrated to dryness. The residue was diluted with ethyl acetate and cooled with an ice bath. The pH was adjusted to 9 with cone, ammonia. The phases were separated and the aqueous phase was re-extracted twice with ethyl acetate.
  • reaction mixture was diluted with water and extracted with EtOAc.
  • membrane extracts prepared from a stable CHO recombinant cell line expressing the human histamine H 4 receptor were used.
  • Test compounds were incubated at the selected concentration in duplicate, with 10 nM [ 3 H]-histamine and 15 ⁇ g membranes extract in a total volume of 250 ⁇ l_ of 50 mM Tris-HCI, pH 7.4, 1.25 mM EDTA for 60 minutes at 25 0 C.
  • Non-specific binding was defined in the presence of 100 ⁇ M unlabeled histamine.
  • the reaction was stopped by filtration using a vacuum collector (Multiscreen Millipore) in 96-well plates (Multiscreen HTS Millipore) which had been previously soaked in a 0.5% polyethylenimine solution for 2 hours at 0 0 C.
  • the plates were washed with 50 mM Tris (pH 7.4), 1.25 mM EDTA at 0 0 C and filters were dried during 1 hour at 50-60 0 C, before adding the scintillation liquid to determine bound radioactivity by using a betaplate scintillation counter.
  • Histamine-induced shape change assay (gated autofluorescence forward scatter assay, GAFS) in human eosinophils
  • the shape change induced by histamine in human eosinophils is determined by flow cytometry, detected as an increase in the size of the cells (forward scatter, FSC).
  • PMNL Polymorphonuclear leucocytes
  • erythrocytes were separated by sedimentation in 1.2% Dextran (SIGMA), and the leucocyte-rich fraction (PMNL) was isolated from the top layer by centrifugation at 45Og for 20 min in the presence of Ficoll-Paque ® (Biochrom).
  • PMNLs were resuspended in PBS buffer at a concentration of 1.1x10 6 cells/ml/tube and were pretreated with different concentrations of test compounds (dissolved in PBS) for 30 min at 37 0 C and then stimulated with 300 nM histamine (Fluka) for 5 min.

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Abstract

La présente invention concerne des dérivés de pipéridine-pyrimidine de formule (I), la signification des différents substituants étant indiquée dans la description. Ces composés sont utiles comme antagonistes des récepteurs histaminiques H4.
PCT/EP2010/052006 2009-02-18 2010-02-17 Dérivés de pipéridine-pyrimidine comme antagonistes des récepteurs histaminiques h4 WO2010094721A1 (fr)

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