WO2010094721A1

WO2010094721A1 - Piperidin-pyrimidine derivatives as antagonists of histamine h4 receptor

Info

Publication number: WO2010094721A1
Application number: PCT/EP2010/052006
Authority: WO
Inventors: Elena CARCELLER GONZÁLEZ; Eva María MEDINA FUENTES; Ana MORATÓ GARCÍA; Carles Ferrer Costa
Original assignee: Palau Pharma, S. A.
Priority date: 2009-02-18
Filing date: 2010-02-17
Publication date: 2010-08-26
Also published as: TW201041867A; AR075514A1

Abstract

Piperidin-pyrimidine derivatives of formula (I), wherein the meaning of the different substituents are those indicated in the description. These compounds are useful as histamine H4 receptor antagonists.

Description

PIPERIDIN-PYRIMIDINE DERIVATIVES AS ANTAGONISTS OF HISTAMINE H4 RECEPTOR

Technical field of the invention

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.

Background of the invention

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. A few years ago, a novel histamine receptor, which was named H₄, 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. However, the H₄ 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 H₃ receptor. While the expression of the H₃ receptor is restricted to cells of the central nervous system, the expression of the H₄ 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 H₄ receptor is highly distributed in cells of the immune system suggests the involvement of this receptor in immuno-inflammatory responses. Moreover, this hypothesis is reinforced by the fact that its gene expression can be regulated by inflammatory stimuli such as interferon, TNFα and IL-6. Nevertheless, the H₄ 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). An increase in the expression of the H₄ receptor has also been reported in nasal polyp tissue in comparison to nasal mucosa of healthy people (Jόkύti A et al, Cell Biol lnt 2007, 31 : 1367-70). Recent studies with specific ligands of the H₄ 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 H₄ receptor (Ling P et al, Br J Pharmacol 2004, 142:161-71 ; Buckland KF et al, Br J Pharmacol 2003, 140:1117-27). In dendritic cells, the H₄ 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 H₄ receptor in mast cells has been studied. Although H₄ receptor activation does not induce mast cell degranulation, histamine and other proinflammatory mediators are released; moreover, the H₄ 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 ). With regard to T-lymphocytes, it has been shown that H₄ 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). As for the intestine, the distribution of the H₄ 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).

The various functions of the H₄ receptor observed in eosinophils, mast cells and T-cells suggest that this receptor can play an important role in the immuno- inflammatory response. In fact, H₄ 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). In addition, H₄ 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 Chem. 2008; 51 (20): 6547-57). It is therefore expected that H₄ receptor antagonists can be useful for the treatment or prevention of allergic, immunological and inflammatory diseases, and pain.

Accordingly, it would be desirable to provide novel compounds having H₄ receptor antagonist activity and which are good drug candidates. In particular, preferred compounds should bind potently to the histamine H₄ receptor whilst showing little affinity for other receptors. In addition to binding to H₄ receptors, compounds should further exhibit good pharmacological activity in in vivo disease models. Moreover, 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.

Description of the invention

One aspect of the present 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: (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

(ii) a heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR₃Rb 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 R₂ represents azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, wherein R₂ 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 R₃ 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;

R₃ represents -COR₄, -CONR₄R₄ , -CO₂R₄, -SO₂R₄ or -SO₂NR₄R₄';

R₄ represents Ci_-8 alkyl, R₅-Ci_-8 alkyl or R₆-C_0-8 alkyl, wherein in the Ci_-8 alkyl, R₅-

Ci_-8 alkyl and R₆-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-;

R₄' represents H or Ci_-8 alkyl; and optionally R₄ and R₄' are bound forming a -C3_-5 alkylene- group which is optionally substituted with one or more Ci_-8 alkyl groups;

R₅ represents -CONR₄ R₇, -NR₄COR₇, -NR₄CO₂R₇, -NR₄SO₂R₇, -SO₂NR₄ R₇, -

NR₄CONR₄ R₇, -CONHSO₂R₇, -CO₂R₇, -OCOR₇, -SO₂R₇, -NR₄ R₇, -OH or 1 H- tetrazol-5-yl;

Re represents C_3-8cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein R₆ 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, R₅-Co_-S alkyl and R₈-Co_-S alkyl;

R₇ 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 R₄' and R₇, in a R₅ group, are bound forming a -C_3-5 alkylene- group which is optionally substituted with one or more Ci_-8 alkyl groups; and

R₈ represents C_3-8cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein R₈ 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 H₄ histamine receptor. Thus, another aspect of the invention relates to a compound of formula I

wherein:

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 (ii) a heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR₃Rb 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 R₂ represents azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, wherein R₂ is optionally substituted with one or more Ci_-4 alkyl groups;

Ra represents H or Ci_-4 alkyl;

R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄, -SO₂R₄ or -SO₂NR₄R₄';

R₄ represents Ci_-8 alkyl, R₅-Ci_-8 alkyl or R₆-C_0-8 alkyl, wherein in the Ci_-8 alkyl, R₅- 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-;

R₆ represents C_3-8cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein R₆ 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, R₅-C_0-8 alkyl and R₈-C_0-8 alkyl;

R₇ 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 R₄' and R₇, in a R₅ group, are bound forming a -C3_-5 alkylene- group which is optionally substituted with one or more Ci_-8 alkyl groups; and R₈ represents C_3-8cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein R₈ 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; for use in therapy.

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 H₄ histamine receptor. More preferably, the disease mediated by the histamine H₄ 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. More preferably, 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. 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. More preferably, 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 H₄ receptor. More preferably, the disease mediated by the histamine H₄ 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.

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. More preferably, 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. 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 H₄ receptor. More preferably, the disease mediated by the histamine H₄ 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.

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. More preferably, 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. 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 a disease mediated by the histamine H₄ receptor 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 disease mediated by the histamine H₄ receptor is an allergic, immunological or inflammatory disease or pain. Another aspect of the present invention relates to a method of treating or preventing an allergic, immunological or inflammatory disease or 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. 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. More preferably, 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. 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 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)

NR₁ 1R^2

wherein Ri and R₂ have the meaning described for a compound of formula I, (a) when in a compound of formula I R3 represents -COR₄, reacting a compound of formula Il with an acid or acid chloride of formula R₄-COY, wherein Y is OH or Cl; or (b) when in a compound of formula I R3 represents -CONR₄R₄', reacting a compound of formula Il with an isocyanate of formula R₄-NCO or a carbamoyl chloride of formula R₄R₄-NCOW, wherein W is a leaving group; or

(c) when in a compound of formula I R3 represents -CONR₄R₄', reacting a compound of formula Il with triphosgene or phosgene and subsequently treating with an amine of formula NHR₄R₄'; or

(d) when in a compound of formula I R3 represents -CO₂R₄, reacting a compound of formula Il with a chloroformate of formula R₄-OCOCI; or

(e) when in a compound of formula I R3 represents -CO₂R₄, reacting a compound of formula Il with an alcohol of formula R₄-OH previously treated with a synthetic equivalent for the CO synthon; or

(f) when in a compound of formula I R3 represents -CO₂R₄, reacting a compound of formula Il with triphosgene or phosgene and subsequently reacting it with an alcohol of formula R₄-OH; or

(g) when in a compound of formula I R3 represents -SO₂R₄, reacting a compound of formula Il with a sulfonyl chloride of formula R₄-SO₂CI; or

(h) when in a compound of formula I R3 represents -SO₂NR₄R₄', reacting a compound of formula Il with a sulfamoyl chloride of formula R₄R₄-NSO₂CI; or (i) when in a compound of formula I R3 represents -SO₂NR₄R₄', reacting a compound of formula Il with sulfuryl chloride and subsequently treating with an amine NHR₄R₄ ; in any of cases (a) to (i), followed if necessary by the removal of any protecting group that may be present; or

2. reacting a compound of formula Vl with a compound of formula III (or an amino- protected form thereof)

wherein Ri, R₂ and R3 have the aforementioned meaning, followed if necessary by the removal of any protecting group that may be present; or 3. transforming a compound of formula I into another compound of formula I in one or in several steps.

In the previous definitions, the term 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. Thus, 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 C₀ 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. 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.

A 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. 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.

A 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. Preferably, 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.

As indicated in the definition of R₄ in relation to Ci_-S alkyl, Rs-Ci_-8 alkyl and

R₆-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 R₅-Ci_-8 alkyl group and to the Co_-8 alkyl group which forms part of the R₆-Co_-8 alkyl group.

Likewise, as has been indicated in the definition of R₄, one methylene group of the alkyl chain of the Ci_-8 alkyl, Rs-Ci_-8 alkyl and R₆-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 R₅-Ci_-8 alkyl group and of the C_0-S alkyl group which forms part of the Re-C_0-S alkyl group) is optionally replaced by one -O- group. Examples of alkyl wherein one methylene group has been replaced by one -O- 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.

The term R₅-Ci_-8 alkyl relates to a group resulting from the substitution of one hydrogen atom of a Ci_-8 alkyl group with a R₅ group. The term R₆-C_0-S alkyl includes the R₆ and R₆-Ci_-8 alkyl groups. The term

R₆-Ci-S alkyl relates to a group resulting from the substitution of one hydrogen atom of a Ci_-8 alkyl group with a R₆ group.

As previously defined, R₆ is C_3-S cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and therefore an R₆-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.

As indicated in the definition of a compound of formula I, R₆ 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, R₅-C_0-8 alkyl and R₈-C_0-8 alkyl. Said substituents may be the same or different. Preferably R₆ 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, R₅-C_0-8 alkyl and R₈-C_0-8 alkyl, with the condition that there is no more than one substituent selected from R₅-C_0-8 alkyl and R₈-C_0-8 alkyl. More preferably, R₆ 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, R₅-C_0-8 alkyl and R₈-C_0-8 alkyl. In the C_3- scycloalkyl and aryl groups 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.

The term 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. Preferably, 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:

2-cycioprøpylbutyi (1 -ethyi-cyclopropyi)methyl butyi where 1 atom of H on a C butyl where 2 atoms of H on the same C is replaced by a cyclopropyi group are replaced by a cyclopropyl group

Examples of 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 -cyclopropyl-1 -methylethyl, 1 - cyclopropylethyl, 1 -cyclobutylethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 3- cyclopropyl propyl, 3-cyclobutyl propyl, 3-cyclopentyl propyl, 3-cyclohexyl propyl, 1 - cyclopropyl-2-methylpropyl, 4-cyclopropylbutyl, 3-cyclopropylbutyl, 2- cyclopropylbutyl, 1 -cyclopropylbutyl, 4-cyclobutyl butyl, 4-cyclopentyl butyl, 4- cyclohexylbutyl, 5-cyclopropylpentyl, 6-cyclopropylhexyl, 7-cyclopropylheptyl and

8-cyclopropyloctyl groups.

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. The 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. Examples of 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- thiomorpholinyl, azepanyl, [1 ,4]diazepanyl, [1 ,4]oxazepanyl, 2-oxo-azepanyl, 1 ,1 - dioxo-[1 ,2]thiazepanyl, 2-oxo-[1 ,3]diazepanyl, 7-oxo-bicyclo[2.2.1]heptanyl, 1 ,3- diaza-bicyclo[2.2.2]octanyl, 2,3-dihydro-benzofuranyl, 2,3-dihydro- benzo[1 ,4]dioxinyl and 2-oxo-1 ,3-dihydro-indolyl.

The term 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. Preferably, the Ci-S alkyl group is substituted with one or two heterocycloalkyl groups, and more preferably, is substituted with one heterocycloalkyl group. Examples of 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-(pyrrolidin-1 -yl)-octyl. The term aryl, either as a group or as part of an aryl-Co-s alkyl group, relates to phenyl or naphthyl. Preferably, aryl represents phenyl.

The term 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. Preferably, the Ci-S alkyl group is substituted with one or two aryl groups, and more preferably, is substituted with one aryl group. Examples of 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.

The term 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). Examples of 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, isoquinolinyl, naphthyhdinyl, pyrazolopyrazinyl, pyrazolopyridinyl, pyrazolopyhmidinyl, purinyl, quinazolinyl, quinolinyl and quinoxalinyl. In the definition of heteroaryl when the examples specified refer to a bicycle in general terms, they include all possible arrangements of the atoms. For example, the term 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-ιb]pyridinyl; the term imidazopyrazinyl includes groups such as 1 /-/-imidazo[4,5-ιb]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/]pyhmidinyl, 1 /-/-pyrazolo[4,3-c/]pyrimidinyl, pyrazolo[1 ,5- a]pyrimidinyl and pyrazolo[1 ,5-c]pyhmidinyl.

The term 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. Preferably, the Ci_-8 alkyl group is substituted with one or two heteroaryl groups and, more preferably, is substituted with one heteroaryl group. Examples of heteroaryl-Ci_-8 alkyl 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-2-yl-octyl and 8-(3H-imidazol-4-yl)-octyl.

As has been indicated in the definition of R₇ in relation to the Ci-s alkyl, C3-8 cycloalkyl-Co-8 alkyl and aryl-C_0-8 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_-8 alkyl group and to the Co_-8 alkyl group which forms part of the C3_-8 cycloalkyl-Co-β alkyl and aryl-Co-s alkyl groups.

In the definition of R₇, 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.

In the definition of R₈, 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_3-8cycloalkyl 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 R₄ and R₄ , or to the group formed by R₄' and R₇, refers to a linear alkylene chain which contains from 3 to 5 carbon atoms, i.e. a group of formula -(CH₂)3-5-. As indicated in the definition of a compound of formula I, 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 R₅ donde R₄ and R₄' or R₄' and R₇ which together form a -C3_-5 alkylene- group include, among others:

The term "saturated" relates to groups that do not have any double or triple bonds.

A "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 NRiR₂, refers to a 8- to 12- atom bicyclic system consisting of two adjacent rings sharing two atoms in common. In the definition of NRiR₂ Ri and R₂ 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_-4alkyl 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 -NR₃Rb 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.

The expression "optionally substituted with one or more" means that 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.

Throughout the present specification, by the term "treatment" is meant eliminating, reducing or ameliorating the cause or the effects of a disease. For purposes of this invention 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).

As used herein, "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.

In another embodiment, 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:

(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

(ii) a heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR₃Rb 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.

In another embodiment, the invention relates to the compounds of formula I wherein R₃ and R_b independently represent H or Ci_-4 alkyl.

In another embodiment, the invention relates to the compounds of formula I wherein R₃ and R_b independently represent H, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula I wherein R₃ and R_b independently represent H or methyl.

In another embodiment, the invention relates to compounds of formula I wherein R₃ and R_b represent H. In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents H and Rb represents H or Ci_-4 alkyl.

In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents H and R_b represents H, methyl or ethyl.

In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents H and Rb represents H or methyl.

In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents H and Rb represents Ci_-4 alkyl.

In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents H and Rb represents methyl or ethyl. In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents H and Rb represents methyl.

In another embodiment, 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:

wherein R₃ and Rb have the meaning described above for compounds of formula I, R₀ 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.

In another embodiment, 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 R₃, Rb, Rc and R_d independently represent H or Ci_-4 alkyl, preferably R₃, Rb, Rc and R_d independently represent H or methyl, and more preferably R_a, Rb and Rd independently represent H or methyl and R₀ represents H.

In another embodiment, 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 R₃ and Rb have the meaning described above for compounds of formula I, R₀ represents H or

Ci_-4 alkyl, preferably H or methyl, more preferably H, and R_d represents H or Ci_-4 alkyl, preferably H or methyl.

In another embodiment, 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 R₃, Rb, Rc and Rd independently represent H or Ci_-4 alkyl, preferably R₃, Rb, Rc and R_d independently represent H or methyl, and more preferably R_a, Rb and Rd independently represent H or methyl and R₀ represents H.

In another embodiment, 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 R₃ and Rb have the meaning described above for compounds of formula I and R₀ represents H or Ci_-4 alkyl, preferably H.

In another embodiment, 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 R₀ independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ independently represent H or methyl, and more preferably R_a and Rb independently represent H or methyl and R₀ represents H.

In another embodiment, 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), R₃ represents H, R_b represents H or Ci_-4 alkyl and R₀ represents H.

In another embodiment, 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 R₀ represents H.

In another embodiment, 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), R₃ represents H, R_b represents methyl and R₀ represents H.

In another embodiment, 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 R₀ represent H.

In another embodiment, 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)

(a) wherein R₃ and Rb have the meaning described above for compounds of formula I and R₀ represents H or Ci_-4 alkyl, and preferably R₀ represents H.

In another embodiment, 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 R₀ independently represent H or Ci_-4 alkyl, preferably R_a, Rb and R₀ independently represent H or methyl, and more preferably R_a and Rb independently represent H or methyl and R₀ represents H.

In another embodiment, 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), R₃ represents H, R_b represents H or Ci_-4 alkyl and R₀ represents H.

In another embodiment, 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 R₀ represents H.

In another embodiment, 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), R₃ represents H, R_b represents methyl and R₀ represents H.

In another embodiment, 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 R₀ represents H.

In another embodiment, 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)

(b) wherein R₃ and Rb have the meaning described above for compounds of formula I and R₀ represents H or Ci_-4 alkyl, and preferably R₀ represents H.

In another embodiment, 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 R₀ independently represent H or Ci_-4 alkyl, preferably R_a, Rb and R₀ independently represent H or methyl, and more preferably R_a and Rb independently represent H or methyl and R₀ represents H.

In another embodiment, 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), R₃ represents H, R_b represents H or Ci_-4 alkyl and R₀ represents H.

In another embodiment, 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 R₀ represents H.

In another embodiment, 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), R₃ represents H, R_b represents methyl and R₀ represents H.

In another embodiment, 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 R₀ represent H.

In another embodiment, 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 R₂ is optionally substituted with one or more Ci_-4 alkyl groups, and preferably Ri represents H and R₂ represents 1 -methyl- pyrrol id in-3-yl.

In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄ or -SO₂R₄.

In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -COR₄.

In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -CONR₄R₄'.

In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -CO₂R₄. In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -SO₂R₄.

In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -SO₂NR₄R₄'.

In another embodiment, the invention relates to the compounds of formula I wherein R₄ represents Ci_-8 alkyl, R₅-Ci_-8 alkyl or R₆-C_0-8 alkyl, wherein in the Ci_-8 alkyl, R₅-Ci_-8 alkyl and R₆-C_0-8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups.

In another embodiment, the invention relates to the compounds of formula I wherein R₄ represents Ci_-8 alkyl, R₅-Ci_-8 alkyl or R₆- C_0-8 alkyl, wherein in the Ci_-8 alkyl, R₅-Ci_-8 alkyl and R₆-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-.

In another embodiment, the invention relates to the compounds of formula I wherein R₄ represents Ci_-8 alkyl or R₆-C_0-8 alkyl, preferably Ci_-8 alkyl or R₆-Ci_-8 alkyl, wherein in the Ci_-8 alkyl, R_6-C_0-8 alkyl and R₆-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-. In another embodiment, the invention relates to the compounds of formula I wherein R₄ represents Ci_-8 alkyl or R₆-C_0-S alkyl, preferably Ci_-8 alkyl or R₆-Ci_-8 alkyl, wherein in the Ci_-8 alkyl, R_6-C_0-8 alkyl and R₆-Ci_-8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups. In another embodiment, the invention relates to the compounds of formula I wherein R₄ represents Ci_-8 alkyl or R₆-C_0-8 alkyl, preferably Ci_-8 alkyl or R₆-Ci_-8 alkyl, wherein in the Ci_-8 alkyl, R_6-C_0-8 alkyl and R₆-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-. In another embodiment, the invention relates to the compounds of formula I wherein R₄ 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-.

In another embodiment, the invention relates to the compounds of formula I wherein R₄ represents Ci_-8 alkyl optionally substituted with one or more halogen groups.

In another embodiment, the invention relates to the compounds of formula I wherein R₄ 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-. In another embodiment, the invention relates to the compounds of formula I wherein R₄ 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-.

In another embodiment, the invention relates to the compounds of formula I wherein R₄ represents Rs-Ci_-8 alkyl, wherein the alkyl group is optionally substituted with one or more halogen groups.

In another embodiment, the invention relates to the compounds of formula I wherein R₄ 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-.

In another embodiment, the invention relates to the compounds of formula I wherein R₄ represents R₆-C_0-8 alkyl, preferably R₆-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-.

In another embodiment, the invention relates to the compounds of formula I wherein R₄ represents Re-C_0-S alkyl, preferably Re-Ci_-8 alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups.

In another embodiment, the invention relates to the compounds of formula I wherein R₄ represents Re-Co-8 alkyl, preferably R₆-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-. In another embodiment, the invention relates to the compounds of formula I wherein R₄' represents H or Ci_-8 alkyl.

In another embodiment, the invention relates to the compounds of formula I wherein R₄' represents H.

In another embodiment, the invention relates to the compounds of formula I wherein R₅ represents -OH, -NR₄ R₇, -CONR₄ R₇, -CO₂Rz or -SO₂Rz-

In another embodiment, the invention relates to the compounds of formula I wherein R₅ represents -NR₄ R₇.

In another embodiment, the invention relates to the compounds of formula I wherein R₆ represents C_3-8cycloalkyl (preferably monocyclic), aryl (preferably phenyl) or heteroaryl, wherein R₆ 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, R₅-C_0-8 alkyl and R₈-C_0-8 alkyl.

In another embodiment, the invention relates to the compounds of formula I wherein R₆ 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,

R₅-C_0-8 alkyl and R₈-C_0-8 alkyl.

In another embodiment, the invention relates to the compounds of formula I wherein R₆ 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.

In another embodiment, the invention relates to the compounds of formula I wherein R₆ represents C3_-8cycloalkyl, 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, R₅-C_0-8 alkyl and R₈-C_0-8 alkyl. In another embodiment, the invention relates to the compounds of formula I wherein R₆ represents C3_-8cycloalkyl, 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.

In another embodiment, the invention relates to the compounds of formula I wherein R₆ 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, R₅-C_0-8 alkyl and R₈-C_0-8 alkyl.

In another embodiment, the invention relates to the compounds of formula I wherein R₆ 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, R₅-C_0-8 alkyl and R₈-C_0-8 alkyl.

In another embodiment, the invention relates to the compounds of formula I wherein R₆ 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.

In another embodiment, the invention relates to the compounds of formula I wherein R₆ 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, R₅-C_0-8 alkyl and R₈- C_0-8 alkyl.

In another embodiment, the invention relates to the compounds of formula I wherein R₆ 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. In another embodiment, the invention relates to the compounds of formula I wherein R₄' represents H or Ci_-8 alkyl;

R₇ 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, C₂A alkynyl and hydroxyCi_-8 alkyl; and optionally R₄' and R₇, in R₅, are bound forming a -C3_-5 alkylene- group which is optionally substituted with one or more Ci_-8 alkyl groups.

In another embodiment, the invention relates to the compounds of formula I wherein R₇ represents H or Ci_-8 alkyl, wherein the alkyl group is optionally substituted with one or more halogen groups; and optionally R₄' and R₇, in R₅, are bound forming a -C3_-5 alkylene- group which is optionally substituted with one or more Ci_-8 alkyl groups.

In another embodiment, the invention relates to the compounds of formula I wherein R₇ 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.

In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄ or -SO₂R₄; and

R₄ represents Ci_-8 alkyl or R₆-C_0-8 alkyl, preferably Ci_-8 alkyl or R₆-Ci_-8 alkyl, wherein in the Ci_-8 alkyl, R_6-C_0-8 alkyl and R₆-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-.

In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄ or -SO₂R₄; and R₄ represents Ci_-8 alkyl or R₆-C_0-8 alkyl, preferably Ci_-8 alkyl or R₆-Ci_-8 alkyl, wherein in the Ci_-8 alkyl, R_6-C_0-8 alkyl and R₆-Ci_-8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups.

In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄ or -SO₂R₄; and R₄ represents Ci_-8 alkyl or R₆-C_0-8 alkyl, preferably Ci_-8 alkyl or R₆-Ci_-8 alkyl, wherein in the Ci_-8 alkyl, R_6-C_0-8 alkyl and R₆-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-. In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄ or -SO₂R₄; and

R₄ 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-.

R₄ represents Ci_-8 alkyl optionally substituted with one or more halogen groups. In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄ or -SO₂R₄; and

R₄ 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-. In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄ or -SO₂R₄; and

R₄ represents R₅-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-.

R₄ represents R₅-Ci_-8 alkyl, wherein the alkyl group is optionally substituted with one or more halogen groups.

In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄ or -SO₂R₄; and R₄ represents Re-Co_-8 alkyl, preferably Rε-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-.

In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄ or -SO₂R₄; and R₄ represents Re-C_0-S alkyl, preferably Re-Ci_-8 alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups.

In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄ or -SO₂R₄; and R₄ represents R₆-Co_-S alkyl, preferably R₆-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-.

In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -CO₂R₄; and

R₄ represents Ci-S alkyl or R₆-Co-S alkyl, preferably Ci-S alkyl or R₆-Ci-S alkyl, wherein in the Ci-S alkyl, R_6-Co-S alkyl and R₆-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-. In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -CO₂R₄; and

R₄ represents Ci_-8 alkyl or R₆-C_0-S alkyl, preferably Ci_-8 alkyl or R₆-Ci_-8 alkyl, wherein in the Ci_-8 alkyl, R_6-C_0-8 alkyl and R₆-Ci_-8 alkyl groups any alkyl group is optionally substituted with one or more halogen groups. In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -CO₂R₄; and

R₄ represents Ci_-8 alkyl or R₆-C_0-8 alkyl, preferably Ci_-8 alkyl or R₆-Ci_-8 alkyl, wherein in the Ci_-8 alkyl, R_6-C_0-8 alkyl and R₆-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-.

R₄ represents Ci_-8 alkyl optionally substituted with one or more halogen groups. In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -CO₂R₄; and

R₄ 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-. In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -CO₂R₄; and

R₄ represents R₅-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-.

R₄ represents R₅-Ci-S alkyl, wherein the alkyl group is optionally substituted with one or more halogen groups. In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -CO₂R₄; and

R₄ represents R₆-C_0-S alkyl, preferably R₆-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-. In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -CO₂R₄; and

R₄ represents R₆-Co-S alkyl, preferably R₆-Ci-S alkyl, wherein any alkyl group is optionally substituted with one or more halogen groups.

R₄ represents R₆-C_0-S alkyl, preferably R₆-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-.

In another embodiment, the invention relates to the compounds of formula I wherein R₄ represents R₅-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

R₅ represents -NR₄ R₇

In another embodiment, the invention relates to the compounds of formula I wherein R₄ represents R₅-Ci_-8 alkyl, wherein the alkyl group may be optionally substituted with one or more halogen groups; and

R₅ represents -NR₄ R₇ In another embodiment, the invention relates to the compounds of formula I wherein R₄ 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 R₆ represents C_3-8cycloalkyl (preferably monocyclic), aryl preferably phenyl) or heteroaryl, wherein R₆ 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, R₅-Co-S alkyl and R₈-Co-S alkyl.

In another embodiment, the invention relates to the compounds of formula I wherein R₄ 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

R₆ 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, R₅-Co-S alkyl and R₈-Co-_S alkyl.

In another embodiment, the invention relates to the compounds of formula I wherein R₄ represents Re-C₀-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

R₆ 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, R₅-Co-S alkyl and R₈-Co-S alkyl. In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -COR₄, -CONR₄R₄ , -CO₂R₄, -SO₂R₄ or -SO₂NR₄R₄ , preferably -COR₄, -CONR₄R₄ , -CO₂R₄ or -SO₂R₄, and more preferably -CO₂R₄;

R₄ represents Ci_-8 alkyl or R₆-C_0-8 alkyl, preferably Ci_-8 alkyl or R₆-Ci_-8 alkyl, wherein in the Ci_-8 alkyl, R_6-C_0-8 alkyl and R₆-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

R₆ 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, C₂.₄ alkynyl, R₅-Co-₈ alkyl and R₈-Co_-S alkyl.

In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄, -SO₂R₄ or -SO₂NR₄R₄', preferably -COR₄, -CONR₄R₄', -CO₂R₄ or SO₂R₄, and more preferably -CO₂R₄; R₄ 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

Rε 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, R₅-C_0-8 alkyl and R₈-C_0-8 alkyl.

In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄, -SO₂R₄ or -SO₂NR₄R₄', preferably -COR₄, -CONR₄R₄', -CO₂R₄ or SO₂R₄, and more preferably -CO₂R₄; R₄ 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

Rε 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, R₅-C_0-8 alkyl and R₈-C_0-8 alkyl.

Rε 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.

In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -CO₂R₄;

R₄ represents R₅-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 R₅ represents -NR₄ R₇.

R₄ represents R₅-Ci-S alkyl, wherein the alkyl group is optionally substituted with one or more halogen groups; and R₅ represents -NR₄ R₇; and

R₇ 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, -

CN, C_2-4 alkynyl and hydroxyCi_-8 alkyl;

R₄ represents Ci_-8 alkyl or R₆-Co_-8 alkyl, preferably Ci_-8 alkyl or R₆-Ci_-8 alkyl, wherein in the Ci_-8 alkyl, R_6-Co_-8 alkyl and R₆-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 R₆ represents C_3-8cycloalkyl (preferably monocyclic), aryl (preferably phenyl) or heteroaryl, wherein R₆ 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, R₅-Co_-8 alkyl and R₈-Co_-8 alkyl.

R₄ represents Ci_-8 alkyl or R₆-Co_-8 alkyl, preferably Ci_-8 alkyl or R₆-Ci_-8 alkyl, wherein in the Ci_-8 alkyl, R_6-C_0-8 alkyl and R₆-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 R₆ represents aryl (preferably phenyl) or heteroaryl, wherein R₆ 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, R₅-Co_-8 alkyl and R₈-Co_-8 alkyl. In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -CO₂R₄;

R₄ represents R₆-C_0-S alkyl, preferably R₆-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

R₆ represents C_3-8cycloalkyl, 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, R₅-Co-S alkyl and R₈-C_0-8 alkyl. In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -CO₂R₄;

R₄ represents R₆-C_0-S alkyl, preferably R₆-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 R₆ represents aryl (preferably phenyl) or heteroaryl, wherein R₆ 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, R₅-C₀-_S alkyl and R₈-C_0-8 alkyl.

R₄ represents R₆-C_0-8 alkyl, preferably R₆-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

R₆ 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, R₅-C_0-8 alkyl and R₈- C_0-8 alkyl.

In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -CO₂R₄; R₄ represents R₆-C_0-8 alkyl, preferably R₆-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

R₆ represents aryl, preferably phenyl, which is optionally substituted with one or more groups independently selected from Ci-β alkyl, haloCi_-8 alkyl, halogen, Ci_-8 alkoxy, haloCi_-8 alkoxy, Ci_-8 alkylthio, -CN and C_2-4 alkynyl.

In another embodiment, the invention relates to the compounds of formula I wherein R₃ represents -CO₂R₄; R₄ 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

Rε 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, R₅-C_0-8 alkyl and R₈-C_0-8 alkyl.

In another embodiment, the invention relates to the compounds of formula I wherein:

R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄ or -SO₂R₄, and more preferably - CO₂R₄; and 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 (ii) a heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR₃Rb 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. In another embodiment, the invention relates to the compounds of formula I wherein:

R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄ or -SO₂R₄, and more preferably - CO₂R₄; and

Ri represents H or Ci_-4 alkyl and R₂ represents azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, wherein R₂ is optionally substituted with one or more Ci_-4 alkyl groups, and preferably Ri represents H and R₂ represents 1 -methyl- pyrrol id in-3-yl.

Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), wherein R₃ and Rb have the meaning described above for compounds of formula I, and R₀ 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 R₀ represents H.

R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄ or -SO₂R₄, and more preferably - CO₂R₄; and 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 R₃ and Rb have the meaning described above for compounds of formula I, and R₀ and Rd independently represent H or Ci_-4 alkyl, preferably R₃, Rb, Rc and R_d independently represent H or Ci_-4 alkyl, more preferably R₃, 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 R₀ represents H.

R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄ or -SO₂R₄; and more preferably - CO₂R₄; 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 R₃ and R_b have the meaning described above for compounds of formula I and R₀ represents H or Ci_-4 alkyl, preferably R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, more preferably R₃, Rb and R₀ independently represent H or methyl, still more preferably R₃ and Rb independently represent H or methyl and R₀ represents H, even more preferably R₃ represents H, R_b represents H or methyl and R₀ represents H and particularly preferred R₃ represents H, R_b represents methyl and R₀ represents H. In another embodiment, the invention relates to the compounds of formula I wherein:

R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄ or -SO₂R₄, and more preferably - CO₂R₄; and Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R₃ and Rb have the meaning described above for compounds of formula I and R₀ represents H or Ci_-4 alkyl, preferably R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, more preferably R_a, Rb and R₀ independently represent H or methyl, still more preferably R_a and Rb independently represent H or methyl and R₀ represents H, even more preferably Ra represents H, R_b represents H or methyl and R₀ represents H and particularly preferred R₃ represents H, R_b represents methyl and R₀ represents H.

In another embodiment, the invention relates to the compounds of formula I wherein: R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄ or -SO₂R₄, and more preferably -

CO₂R₄; and

Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), wherein R₃ and Rb have the meaning described above for compounds of formula I and R₀ represents H or Ci_-4 alkyl, preferably R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, more preferably

R_a, Rb and R₀ independently represent H or methyl, still more preferably R_a and Rb independently represent H or methyl and R₀ represents H, even more preferably

Ra represents H, R_b represents H or methyl and R₀ represents H and particularly preferred R_a represents H, R_b represents methyl and R₀ represents H. In another embodiment, the invention relates to the compounds of formula I wherein:

R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄, -SO₂R₄ or -SO₂NR₄R₄', preferably -COR₄, -CONR₄R₄', -CO₂R₄ or -SO₂R₄, and more preferably -CO₂R₄;

R₄ represents Ci_-8 alkyl, R₅-Ci_-8 alkyl or R₆-C_0-8 alkyl, wherein in the Ci_-8 alkyl, R₅-Ci_-8 alkyl and R₆-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-; R₅ represents -NR₄ R₇; R₆ represents C_3-8cycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably

Cs-scycloalkyl, aryl or heteroaryl, wherein R₆ 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, R₅-C_0-8 alkyl and R₈-C_0-8 alkyl; and

R₃ represents -COR₄, -CONR₄R₄ , -CO₂R₄, -SO₂R₄ or -SO₂NR₄R₄ , preferably -COR₄, -CONR₄R₄ , -CO₂R₄ or -SO₂R₄, and more preferably -CO₂R₄; R₄ represents Ci_-8 alkyl, R₅-Ci_-8 alkyl or R₆-C_0-8 alkyl, wherein in the Ci_-8 alkyl, R₅-Ci_-8 alkyl and R₆-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-;

R₅ represents -NR₄ R₇; R₆ represents C_3-8cycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably

C_3-8cycloalkyl, aryl or heteroaryl, wherein R₆ 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, R₅-C_0-8 alkyl and R₈-C_0-8 alkyl; and Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), wherein R₃ and Rb have the meaning described above for compounds of formula I, and R₀ 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 R₀ represents H.

R₄ represents Ci_-8 alkyl, R₅-Ci_-8 alkyl or R₆-Co_-8 alkyl, wherein in the Ci_-8 alkyl, R₅-Ci_-S alkyl and R₆-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-; R₅ represents -NR₄ R₇;

R₆ represents C₃-scycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably

C₃-scycloalkyl, aryl or heteroaryl, wherein R₆ 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, R₅-Co-S alkyl and Rs-Co-s alkyl; 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 R₃ and R_b have the meaning described above for compounds of formula I and R₀ represents H or

Ci_-4 alkyl, preferably R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, more preferably R_a, Rb and R₀ independently represent H or methyl, still more preferably

Ra and Rb independently represent H or methyl and R₀ represents H, even more preferably R_a represents H, R_b represents H or methyl and R₀ represents H and particularly preferred R_a represents H, R_b represents methyl and R₀ represents H.

R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄, -SO₂R₄ or -SO₂NR₄R₄', preferably -COR₄, -CONR₄R₄', -CO₂R₄ Or -SO₂R₄, and more preferably -CO₂R₄; R₄ represents Ci_-8 alkyl, R₅-Ci_-8 alkyl or R₆-C_0-8 alkyl, wherein in the Ci_-8 alkyl, R₅-Ci_-8 alkyl and R₆-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-; R₅ represents -NR₄ R₇;

R₆ represents C_3-8cycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably

Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R₃ and Rb have the meaning described above for compounds of formula I and R₀ represents H or Ci_-4 alkyl, preferably R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, more preferably

R₃ represents -COR₄, -CONR₄R₄ , -CO₂R₄, -SO₂R₄ or -SO₂NR₄R₄ , preferably -COR₄, -CONR₄R₄ , -CO₂R₄ Or -SO₂R₄, and more preferably -CO₂R₄;

R₄ represents Ci_-8 alkyl, R₅-Ci_-8 alkyl or R₆-C_0-8 alkyl, wherein in the Ci_-8 alkyl, R₅-Ci_-8 alkyl and R₆-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-; R₅ represents -NR₄ R₇;

R₆ represents C_3-8cycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably C_3-8cycloalkyl, aryl or heteroaryl, wherein R₆ 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, R₅-C_0-8 alkyl and R₈-C_0-8 alkyl; and

Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), wherein R₃ and Rb have the meaning described above for compounds of formula I and R₀ represents H or Ci_-4 alkyl, preferably R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, more preferably

R_a, Rb and R₀ independently represent H or methyl, still more preferably R_a and Rb independently represent H or methyl and R₀ represents H, even more preferably Ra represents H, R_b represents H or methyl and R₀ represents H and particularly preferred R₃ represents H, R_b represents methyl and R₀ represents H.

R₄ represents Ci-β alkyl or R₆-Co-S alkyl, preferably Ci-β alkyl or R₆-Ci-S alkyl, wherein in the Ci-S alkyl, R_6-Co-S alkyl and R₆-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-;

C₃-scycloalkyl, aryl or heteroaryl and more preferably aryl or heteroaryl, wherein R₆ 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, R₅-Co_-S alkyl and R₈-Co_-S alkyl; and

R₄ represents Ci-S alkyl or R₆-Co-S alkyl, preferably Ci-S alkyl or R₆-Ci-S alkyl, wherein in the Ci-S alkyl, R_6-Co-S alkyl and R₆-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-;

C_3-8cycloalkyl, aryl or heteroaryl and more preferably aryl or heteroaryl, wherein R₆ 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, R₅-Co_-8 alkyl and R₈-Co_-8 alkyl; and

Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), wherein R₃ and Rb have the meaning described above for compounds of formula I, and R₀ and Rd independently represent H or Ci_-4 alkyl, preferably R₃, Rb, Rc and R_d independently represent H or Ci_-4 alkyl, more preferably R₃, 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 R₀ represents H.

R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄, -SO₂R₄ or -SO₂NR₄R₄ , preferably -COR₄, -CONR₄R₄ , -CO₂R₄ Or -SO₂R₄, and more preferably -CO₂R₄;

R₄ represents Ci_-8 alkyl or R₆-C_0-8 alkyl, preferably Ci_-8 alkyl or R₆-Ci_-8 alkyl, wherein in the Ci_-8 alkyl, R_6-C_0-8 alkyl and R₆-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-;

C_3-8cycloalkyl, aryl or heteroaryl and more preferably aryl or heteroaryl, wherein R₆ 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, R₅-C_0-8 alkyl and R₈-C_0-8 alkyl; 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 R₃ and R_b have the meaning described above for compounds of formula I and R₀ represents H or Ci_-4 alkyl, preferably R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, more preferably R₃, Rb and R₀ independently represent H or methyl, still more preferably R₃ and Rb independently represent H or methyl and R₀ represents H, even more preferably R₃ represents H, R_b represents H or methyl and R₀ represents H and particularly preferred R_a represents H, R_b represents methyl and R₀ represents H.

R₄ represents Ci-β alkyl or R₆-Co-S alkyl, preferably Ci-β alkyl or R₆-Ci-S alkyl, wherein in the Ci-S alkyl, R_6-Co-S alkyl and R₆-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-; R₆ represents C₃-scycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably

C₃-scycloalkyl, aryl or heteroaryl and more preferably aryl or heteroaryl, wherein R₆ 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, R₅-Co_-8 alkyl and R₈-Co_-8 alkyl; and Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R₃ and Rb have the meaning described above for compounds of formula I and R₀ represents H or Ci_-4 alkyl, preferably R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, more preferably R_a, Rb and R₀ independently represent H or methyl, still more preferably R_a and Rb independently represent H or methyl and R₀ represents H, even more preferably Ra represents H, R_b represents H or methyl and R₀ represents H and particularly preferred R₃ represents H, R_b represents methyl and R₀ represents H.

In another embodiment, the invention relates to the compounds of formula I wherein: R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄, -SO₂R₄ or -SO₂NR₄R₄', preferably -COR₄, -CONR₄R₄', -CO₂R₄ Or -SO₂R₄, and more preferably -CO₂R₄;

R₆ represents C_3-8cycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably C_3-8cycloalkyl, aryl or heteroaryl and more preferably aryl or heteroaryl, wherein R₆ 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, R₅-C_0-S alkyl and R₈-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 R₃ and Rb have the meaning described above for compounds of formula I and R₀ represents H or Ci_-4 alkyl, preferably R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, more preferably

Ra represents H, R_b represents H or methyl and R₀ represents H and particularly preferred R₃ represents H, R_b represents methyl and R₀ represents H.

R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄, -SO₂R₄ or -SO₂NR₄R₄ , preferably -COR₄, -CONR₄R₄ , -CO₂R₄ or -SO₂R₄, and more preferably -CO₂R₄; R₄ 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 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

In another embodiment, the invention relates to the compounds of formula I wherein: R₃ represents -COR₄, -CONR₄R₄ , -CO₂R₄, -SO₂R₄ or -SO₂NR₄R₄ , preferably -COR₄, -CONR₄R₄ , -CO₂R₄ or -SO₂R₄, and more preferably -CO₂R₄;

R₄ 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 R2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), wherein R₃ and Rb have the meaning described above for compounds of formula I, and R₀ and Rd independently represent H or Ci_-4 alkyl, preferably R₃, 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 R₀ represents H.

R₄ 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 R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R₃ and Rb have the meaning described above for compounds of formula I and R₀ represents H or Ci_-4 alkyl, preferably R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, more preferably R_a, Rb and R₀ independently represent H or methyl, still more preferably Ra and Rb independently represent H or methyl and R₀ represents H, even more preferably R_a represents H, R_b represents H or methyl and R₀ represents H and particularly preferred R_a represents H, R_b represents methyl and R₀ represents H.

Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R₃ and Rb have the meaning described above for compounds of formula I and R₀ represents H or Ci_-4 alkyl, preferably R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, more preferably R_a, Rb and R₀ independently represent H or methyl, still more preferably R_a and Rb independently represent H or methyl and R₀ represents H, even more preferably Ra represents H, R_b represents H or methyl and R₀ represents H and particularly preferred R₃ represents H, R_b represents methyl and R₀ represents H.

R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄, -SO₂R₄ or -SO₂NR₄R₄', preferably -COR₄, -CONR₄R₄', -CO₂R₄ Or -SO₂R₄, and more preferably -CO₂R₄; R₄ 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

R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄, -SO₂R₄ or -SO₂NR₄R₄', preferably -COR₄, -CONR₄R₄', -CO₂R₄ or -SO₂R₄, and more preferably -CO₂R₄; R₄ 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-;

R₅ represents -CONR₄ R₇, -NR₄COR₇, -NR₄CO₂R₇, -NR₄SO₂R₇, - SO₂NR₄ R₇, -NR₄CONR₄ R₇, -CONHSO₂R₇, -CO₂R₇, -OCOR₇, -SO₂R₇, -NR₄ R₇, - OH or 1 H-tetrazol-5-yl, preferably -NR₄ R₇; and

In another embodiment, the invention relates to the compounds of formula I wherein: R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄, -SO₂R₄ or -SO₂NR₄R₄ , preferably -COR₄, -CONR₄R₄ , -CO₂R₄ or -SO₂R₄, and more preferably -CO₂R₄;

R₄ represents R₅-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-; R₅ represents -CONR₄ R₇, -NR₄COR₇, -NR₄CO₂R₇, -NR₄SO₂R₇, -

SO₂NR₄ R₇, -NR₄CONR₄ R₇, -CONHSO₂R₇, -CO₂R₇, -OCOR₇, -SO₂R₇, -NR₄ R₇, - OH or 1 H-tetrazol-5-yl, preferably -NR₄ R₇; and

Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), wherein R₃ and Rb have the meaning described above for compounds of formula I, and R₀ and Rd independently represent H or Ci_-4 alkyl, preferably R₃, Rb, Rc and R_d independently represent H or Ci_-4 alkyl, more preferably R₃, R_b, R_c and R_d independently represent H or methyl and still more preferably R₃, Rb and Rd independently represent H or methyl and R₀ represents H. In another embodiment, the invention relates to the compounds of formula I wherein:

R₄ represents R₅-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-;

Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R₃ and R_b have the meaning described above for compounds of formula I and R₀ represents H or Ci_-4 alkyl, preferably R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, more preferably R_a, Rb and R₀ independently represent H or methyl, still more preferably

Ra and Rb independently represent H or methyl and R₀ represents H, even more preferably R_a represents H, R_b represents H or methyl and R₀ represents H and particularly preferred R_a represents H, R_b represents methyl and R₀ represents H. In another embodiment, the invention relates to the compounds of formula I wherein:

R₄ represents R₅-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-;

R₅ represents -CONR₄ R₇, -NR₄COR₇, -NR₄CO₂R₇, -NR₄SO₂R₇, - SO₂NR₄ R₇, -NR₄CONR₄ R₇, -CONHSO₂R₇, -CO₂R₇, -OCOR₇, -SO₂R₇, -NR₄ R₇, - OH or 1 H-tetrazol-5-yl, preferably -NR₄ R₇; and Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R₃ and Rb have the meaning described above for compounds of formula I and R₀ represents H or Ci_-4 alkyl, preferably R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, more preferably R_a, Rb and R₀ independently represent H or methyl, still more preferably R_a and Rb independently represent H or methyl and R₀ represents H, even more preferably Ra represents H, R_b represents H or methyl and R₀ represents H and particularly preferred R₃ represents H, R_b represents methyl and R₀ represents H.

R₅ represents -CONR₄ R₇, -NR₄COR₇, -NR₄CO₂R₇, -NR₄SO₂R₇, - SO₂NR₄ R₇, -NR₄CONR₄ R₇, -CONHSO₂R₇, -CO₂R₇, -OCOR₇, -SO₂R₇, -NR₄ R₇, - OH or 1 H-tetrazol-5-yl, preferably -NR₄ R₇; and Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), wherein R₃ and Rb have the meaning described above for compounds of formula I and R₀ represents H or Ci_-4 alkyl, preferably R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, more preferably R_a, Rb and R₀ independently represent H or methyl, still more preferably R_a and Rb independently represent H or methyl and R₀ represents H, even more preferably Ra represents H, R_b represents H or methyl and R₀ represents H and particularly preferred R₃ represents H, R_b represents methyl and R₀ represents H.

R₄ represents R₆-Co_-S alkyl, preferably R₆-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-; R₆ represents C_3-scycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably

C_3-scycloalkyl, aryl or heteroaryl and more preferably aryl or heteroaryl, wherein R₆ 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, R₅-Co_-S alkyl and R₈-Co_-S alkyl; and 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 (ii) a heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR₃Rb 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.

R₄ represents R₆-Co_-S alkyl, preferably R₆-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-;

R₆ represents C₃-scycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably C₃-scycloalkyl, aryl or heteroaryl and more preferably aryl or heteroaryl, wherein R₆ 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, R₅-C_0-8 alkyl and R₈-C_0-8 alkyl; and

Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), wherein R₃ and Rb have the meaning described above for compounds of formula I, and R₀ 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 R₃, 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 R₀ represents H.

R₃ represents -COR₄, -CONR₄R₄', -CO₂R₄, -SO₂R₄ or -SO₂NR₄R₄', preferably -COR₄, -CONR₄R₄', -CO₂R₄ Or -SO₂R₄, and more preferably -CO₂R₄; R₄ represents R₆-C_0-8 alkyl, preferably R₆-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-;

Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R₃ and Rb have the meaning described above for compounds of formula I and R₀ represents H or C1-4 alkyl, preferably R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, more preferably R_a, Rb and R₀ independently represent H or methyl, still more preferably Ra and Rb independently represent H or methyl and R₀ represents H, even more preferably R_a represents H, R_b represents H or methyl and R₀ represents H and particularly preferred R_a represents H, R_b represents methyl and R₀ represents H.

R₄ represents R₆-C_0-S alkyl, preferably R₆-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-; R₆ represents C_3-8cycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably

Cs-scycloalkyl, aryl or heteroaryl and more preferably aryl or heteroaryl, wherein R₆ 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, R₅-C_0-8 alkyl and R₈-C_0-8 alkyl; and Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R₃ and Rb have the meaning described above for compounds of formula I and R₀ represents H or Ci_-4 alkyl, preferably R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, more preferably R_a, Rb and R₀ independently represent H or methyl, still more preferably R_a and Rb independently represent H or methyl and R₀ represents H, even more preferably Ra represents H, R_b represents H or methyl and R₀ represents H and particularly preferred R₃ represents H, R_b represents methyl and R₀ represents H.

R₄ represents R₆-C_0-8 alkyl, preferably R₆-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-;

Ra represents H, R_b represents H or methyl and R₀ represents H and particularly preferred R_a represents H, R_b represents methyl and R₀ represents H. Moreover, the present invention includes all possible combinations of the particular and preferred embodiments described above.

In an additional embodiment, the invention relates to a compound of formula I selected from the list of examples 1 -771.

In an additional embodiment, the invention relates to compounds according to formula I that provide more than 50% inhibition of histamine H₄ receptor activity at 10 μM, more preferably at 1 μM and even more preferably at 0.1 μM, in an H₄ 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. Examples of 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. Examples of 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. There is no limitation on the type of salt that can be used, provided that these are pharmaceutically acceptable when used for therapeutic purposes. The term 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. As used herein, the term solvate refers to a complex of variable stoichiometry formed by a solute (a compound of formula I or a salt thereof) and a solvent. Examples of 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. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶CI, and ¹²⁵I, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with ¹⁴C), reaction kinetic studies (with, for example ²H or ³H), 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. In particular, an ¹⁸F or ¹¹C labeled compound may be particularly preferred for PET or SPECT studies. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) 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.

In general, 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.

wherein Ri and R2 have the meaning described in formula I and X represents CO or SO₂.

In general, these reactions can be carried out in one or several steps, using well-known reactions in organic chemistry under standard experimental conditions.

For example, the compounds of formula I wherein R₃ represents -COR₄ can conveniently be prepared by a reaction of a compound of formula Il with an acid or acyl chloride of formula R₄-COY, wherein Y is OH or Cl.

The compounds of formula I wherein R₃ represents -CONR₄R₄' can be prepared by reaction of a compound of formula Il with an isocyanate (R₄-NCO) or a carbamoyl chloride (R₄R₄-NCOW, wherein W is a leaving group, such as, for example Cl or para-NO2-phenoxyl). Alternatively, the compounds of formula I wherein R₃ is a -CONR₄R₄' group can be prepared by treatment of a compound of formula Il with triphosgene or phosgene to give MB (X = CO) and subsequent reaction with an amine of formula NHR₄R₄'. The compounds of formula I wherein R₃ represents -CO2R₄ can be prepared by reaction of a compound of formula Il with a chloroformate (R₄- OCOCI).

Alternatively, the compounds of formula I wherein R₃ represents -CO2R₄ can be prepared by reacting a compound of formula Il with an alcohol R₄-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. Tetrahedron Lett 42, 2001 , 5227); phosgene or its derivatives (diphosgene, triphosgene) 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. Alternatively, the compounds of formula I wherein R₃ represents -CO2R₄ can be produced by treatment of Il with triphosgene or phosgene to give MB (X = CO) and subsequent reaction with an alcohol R₄-OH.

The compounds of formula I wherein R₃ represents -SO2R₄ can be prepared by reaction of a compound of formula Il with a sulfonyl chloride (R₄- SO₂CI).

The compounds of formula I wherein R₃ represents -SO₂NR₄R₄' can be prepared by reaction of a compound of formula Il with a sulfamoyl chloride (R₄R₄- NSO₂CI). Alternatively the compounds of formula I wherein R₃ is a -SO₂NR₄R₄' group can be obtained by treatment of a compound of formula Il with sulfuryl chloride to give MB (X = SO2) and subsequent reaction with an amine R₄R₄ NH.

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:

wherein 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.

Alternatively, 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. Thus, 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. The reaction is carried out by heating, preferably at a temperature between 70 °C and 140 °C. Likewise, 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. Next, 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, Λ/,Λ/-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.

In general, before conducting the reaction between the compounds of formula IV and III, or IVB and III, 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.

Likewise, 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). When the amino substituents of the compounds of formula IV and/or III and/or IVB are protected, 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. Thus, when the protecting group is a Boc, 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.

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:

wherein P relates to a protecting group.

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. 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.

Alternatively, 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, R₂ 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.

Moreover, certain compounds of the present invention can also be obtained starting from other compounds of formula I by appropriate conversion reactions of functional groups, in one or several steps, using well-known reactions in organic chemistry under standard experimental conditions.

As previously mentioned, the compounds of the present invention show potent histamine H₄ receptor antagonist activity. Therefore, the compounds of the invention are expected to be useful to treat diseases mediated by the H₄ receptor in mammals, including human beings.

Diseases mediated by the H₄ receptor that can be treated or prevented with the compounds of the present invention include, among others, allergic, immunological or inflammatory diseases, or pain.

Examples of allergic, immunological or inflammatory diseases that can be treated or prevented with the compounds of the invention 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. 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. In a preferred embodiment, the compounds of the invention are used for the treatment or prevention of an allergic, immunological or inflammatory disease. In a more preferred embodiment, 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. In a still more preferred embodiment, 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.

In another preferred embodiment, 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.

Assays to determine the ability of a compound to interact with the histamine H₄ receptor are well known in the art. For example, one can use a H₄ receptor binding assay such as the one explained in detail in example 78. Another useful assay is a GTP [γ-³⁵S] binding assay to membranes that express the H₄ receptor. Functional assays with H₄ 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 H₄ receptor such as intracellular cAMP levels or Ca²⁺ mobilization. In this regard, a very useful functional assay that can be used to determine anti-H₄ 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). 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. In addition, to test the selectivity for other receptors or ion channels, 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).

For selecting active compounds, testing at 10 μM must result in an activity of more than 50% inhibition of H₄ receptor activity in the test provided in example

78. More preferably, compounds should exhibit more than 50% inhibition at 1 μM and still more preferably at 0.1 μM 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 μM, more preferably at 1 μM and still more preferably at 0.1 μM in this assay.

Preferred compounds should exhibit selective affinity for the H₄ receptor over other receptors, particularly the H₃ 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. In a preferred embodiment, the compounds of the invention are administered orally. In another embodiment, the compounds of the invention are administered topically.

Solid compositions for oral administration include tablets, granulates and capsules. In any case the manufacturing method is based on a simple mixture, dry granulation or wet granulation of the active compound with excipients. These 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, according to the present invention, 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. 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.

For the nasal administration or for inhalation, the compound can be formulated as an aerosol, from which it can be conveniently released using suitable propellants.

The dosage and frequency of doses will depend upon the nature and severity of the disease to be treated, the age, the general condition and body weight of the patient, as well as the particular compound administered and the route of administration, among other factors. As an example, 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.

The invention is illustrated by the following examples.

Examples

The following abbreviations have been used in the examples:

AcN: acetonitrile

EtOAc : ethyl acetate

Cone: concentrate DIEA: Λ/,Λ/-diisopropylethylamine

EtOH: etanol

H: hours

HBTU: O-benzotriazol-1 -yl-/V,/V,/V',/V'-tetramethyluronium hexafluorophosphate

MeOH: methanol Min: minutes

MS: mass spectrometry

PyBOP: (benzotriazole-1 -yl-oxythpyrrolidinophosphonium hexafluorophosphate)

TEA: triethylamine THF: tetrahydrofurane t_R: retention time LC-MS: liquid chromatography-mass spectrometry

One of the following methods has been used to determine the LC-MS spectrums:

Method 1 : Column: X-Terra , MS C18 5 μm (100 mm x 2.1 mm), temperature: 30 °C, rate: 0.35 mL/min, eluent: A = AcN, B = 10 mM NH₄HCO₃, gradient: 0 min A at 10%; 10 min A at 90%; 15 min A at 90%. Method 2: Column: Acquity UPLC BEH C18 1.7 μm (2.1 x 50 mm), temperature: 40 °C, rate: 0.50 mL/min, eluent: A = AcN, B = 10 mM NH₄HCO₃, gradient: 0 min A at 10%; 0.25 min A at 10%; 3.00 min A at 90%; 3.75 min A at 90%.

REFERENCE EXAMPLE 1 terf-Butyl methyl[(3/?)-pyrrolidin-3-yl]carbamate

(a) terf-Butyl [(3/?)-1-benzylpyrrolidin-3-yl]methylcarbamate

Di-te/t-butyl carbonate (11.6 g, 53.07 mmol) dissolved in 15 mL of CH₂CI₂ was added to a solution of (3R)-1 -benzyl-Λ/-methylpyrrolidin-3-amine (10 g, 52.55 mmol) in 115 mL of CH₂CI₂, cooled to 0 °C. The resulting solution was stirred at room temperature for 18 hours. The solvent was evaporated and the crude was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, providing 14.5 g of the desired compound (yield: 95%). LC-MS (Method 1 ): t_R = 9.55 min; m/z = 291 (MH⁺).

(b) Title compound A solution of the compound previously obtained (14.5 g, 50.14 mmol), Pd/C (10%, 50% in water) (3 g) and ammonium formate (12.7 g, 200.5 mmol) in MeOH (390 mL) and water (45 mL) was heated under reflux for 5 hours. The reaction was filtered through Celite^® and the filtrate was washed with EtOAc and MeOH. The solvent was concentrated to dryness, providing 10.6 g of the title compound as an oil (yield: 100%).

¹H NMR (300 MHz, CDCI₃) δ: 1.38 (s, 9H), 1.72 (m, 1 H), 1.96 (m, 1 H), 2.53 (s, NH), 2.80 (s, 3H), 2.87 (m, 1 H), 2.93 (m, 1 H), 3.11 (m, 2H), 4.58 (m, 1 H). REFERENCE EXAMPLE 2 tert-Butyl azetidin-3-yl(methyl)carbamate

(a) terf-Butyl [1-(diphenylmethyl)azetidin-3-yl]methylcarbamate Following a similar process to that described in section a of reference example 1 , but using 1 -(diphenylmethyl)-Λ/-methylazetidin-3-amine instead of (3R)-1-benzyl- /V-methylpyrrolidin-3-amine, the desired compound was obtained with a 73% yield. LC-MS (Method 1 ): t_R = 10.14 min; m/z = 353 (MH⁺).

(b) Title compound A solution of the compound previously obtained (6.18 g, 17.53 mmol) in 60 mL of MeOH and 15 mL of EtOAc was purged with argon. Pd/C (10%, 50% in water) (929 mg) was added and then the solution was purged again with argon and it was stirred in an H₂ atmosphere for 18 hours. The reaction was filtered through Celite^® and the filtrate was washed with EtOAc and MeOH. The solvent was concentrated to dryness, providing 5.66 g of a mixture of the title compound together with an equivalent of diphenylmethane, which was used as such in the following steps.

¹H NMR (300 MHz, CD₃OD) δ: 1.44 (s, 9H), 2.88 (s, 3H), 3.56 (m, 2H), 3.71 (m, 2H), 4.75 (m, 1 H).

REFERENCE EXAMPLE 3

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 suspension was stirred at temperature for 2 hours. The precipitated solids were filtered, they were washed with abundant water and then with diethyl ether and they were dried in a vacuum, providing 4.13 g of the title compound (yield: 84%) LC-MS (Method 2): t_R = 1.51 min; m/z = 329 (MH⁺). REFERENCE EXAMPLE 4a

Benzyl 4-(2-amino-6-((3/?)-3-(fert-butoxycarbonyl(methyl)amino)pyrrolidin-1- yl)pyrimidin-4-yl)piperidin-1-carboxylate

A mixture of the compound obtained in reference example 3 (2.0 g, 6.09 mmol), the amine obtained in reference example 1 (1.95 g, 9.7 mmol), PyBOP (4.1 g, 7.9 mmol), TEA (0,9 ml_) and acetonitrile (61 ml_) was heated at reflux overnight, and then further amount of compound obtained in reference example 1 (0.61 g) and PyBOP (1.6 g) were added and it was stirred at reflux for 2 further hours. The reaction mixture was concentrated to dryness and the residue was diluted with water and ethyl acetate and 2 N NaOH aqueous solution was added until basic pH. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with a saturated solution of NaCI, they were dried over anhydrous Na2SO₄ and concentrated to dryness. The crude obtained was purified by chromatography over silica gel using EtOAc as eluent, providing 2.46 g of the desired compound (yield: 79%) LC-MS (Method 2): t_R = 2.43 min; m/z 511 (MH⁺)

REFERENCE EXAMPLES 4b-4d

Following a process similar to that described in reference example 4a but using the corresponding amine instead of reference example 1 , the following compounds were obtained:

REFERENCE EXAMPLE 5a tert-Butyl (R)-1-(2-amino-6-(piperidin-4-yl)pyrimidin-4-yl)pyrrolidin-3- yl(methyl)carbamate

A solution of reference example 4a (2.46 g, 4,8 mmol) in MeOH (96 ml_) was hydrogenated in an H-Cube™ apparatus using a 10% Pd/C cartridge (70x4 mm) at 35 ⁰C and 1 bar of hydrogen at a rate of 1 mL/min, providing after 2 cycles of hydrogenation the desired compound with quantitative yield. LC-MS (Method 2): t_R = 1.47 min; m/z 377 (MH⁺)

REFERENCE EXAMPLE 5b tert-Butyl 1 -(2-amino-6-(piperidin-4-yl)pyrimidin-4-yl)azetidin-3- yl(methyl)carbamate

The title compound was obtained following a process similar to that described in reference example 5a but using reference example 4b as starting material. LC-MS (Method 2): t_R = 1.35 min; m/z 363 (MH⁺)

REFERENCE EXAMPLE 5c tert-Butil (R)-1-(2-amino-6-(piperidin-4-yl)pyrimidin-4-yl)pyrrolidin-3- ylcarbamate A solution of reference example 4c (353 mg, 0,71 mmol) in 2 mL of MeOH was treated with active C (18 mg) and was stirred for 1 hour at room temperature. The reaction was filtered through Celite^® and the filtrate was concentrated to dryness. The residue was dissolved in MeOH (2 mL) and was purged with argon. Pd/C (10%) was added (35,3 mg), and the solution was purged with argon again and it was stirred in an H₂ atmosphere overnigth. 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 Na₂SO₄ and were concentrated to dryness, providing the desired compound with quantitative yield.

LC-MS (Method 2): t_R = 1 ,30 min; m/z 363 (MH⁺)

REFERENCE EXAMPLE 6 Benzyl 4-(2-amino-6-chloropyrimidin-4-yl)piperidin-1-carboxylate

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 ⁰C 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. The combined organic phases were washed with an aqueous solution of nitric acid 5% and then with a saturated solution of NaHCO3. They were dried over anhydrous Na2SO₄ and concentrated to dryness, providing the title compound with quantitative yield. LC-MS (Method 2): t_R = 2.22 min; m/z 347/349 (MH⁺)

REFERENCE EXAMPLE 7 (R)-1-Methylpyrrolidin-3-amine dichlorohydrate

(a) tert-Butyl (/?)-1-methylpyrrolidin-3-ylcarbamate

To a solution of te/t-butyl (R)-pyrrolidin-3-ylcarbamate (1.0 g, 5.34 mmol) in MeOH (23 mL) was added an aqueous solution of formaldehyde 37% (1.19 mL, 14.6 mmol) and, then slowly sodium borohydhde (0.61 g, 16.1 mmol). The mixture was then stirred at room temperature under argon atmosphere overnigth. It was concentrated to dryness and the residue was dissolved in CHCI3 and washed with brine and then with saturated solution of NaHCO3. The organic pase was dried over Na2SO₄ and was concentrated to dryness, providing 0.85 g of the title compound (yield: 79%). 1H NMR (300 MHz, CDCI₃) δ: 1.43 (s, 9H), 1.58 (m, 1 H), 2.25 (m, 2H), 2.33 (s, 3H), 2.52 (m, 2H), 2.77 (m, 1 H), 4.16 (m, 1 H), 4.86 (m, NH).

(b) Title compound

To a mixture of the compound previously obtained in section a) (0.85 g, 4.25 mmol), a HCI (4 M solution in 1 ,4-dioxane, 40 mL) and MeOH (1 mL) was added and it was stirred at room temperature for 1 hour. It was concentrated to dryness. The crude product was dissolved in MeOH and and it was concentrated to dryness again providing 0.77 g of the title compound with quantitative yield. ¹H NMR (300 MHz, CD₃OD) 2.15 (m, 1 H), 2.55 (m, 1 H), 2.91 (s, 3H), 3.15 (m, 1 H), 3.3-3.85 (m, 3H), 4.10 (m, 1 H).

EXAMPLE 1 Benzyl 4-(2-amino-6-(1,4-diazepan-1-yl)pyrimidin-4-yl)piperidin-1-carboxylate

The title compound was obtained following a process similar to that described in reference example 4a but using reference example 3 and 1 ,4-diazepan as starting materials.

LC-MS (Method 2): t_R = 1.59 min; m/z 411 (MH⁺)

EXAMPLE 2

Benzyl 4-(2-amino-6-(3-(methylamino)azetidin-1 -yl)pyrimidin-4-yl)piperidin-1 - carboxylate

HCI (4 M solution 1 ,4-dioxane, 7 mL) was added to the reference example 4b (200 mg, 0.4 mmol) and the mixture was stirred at room temperature for 3 hours. The solvent was concentrated to dryness. The residue was dissolved in methanol and was passed through the sulfonic resin Bond elut SCX-Varian previously compacted with methanol. It was then eluted with methanol, which was discarded, and the product was recovered eluting with 2 N NH₃ in MeOH, which was collected and concentrated to dryness. The crude product thus obtained was purified by chromatography over silica gel using mixtures of chloroform/MeOH/NH_{3 COnc} of increasing polarity as eluent, providing 30.4 mg of the title compound (yield: 19%). LC-MS (Method 2): t_R = 1.65 min; m/z 397 (MH⁺).

EXAMPLES 3-5

The following compounds were obtained following a process similar to that described in the example 2 but using the corresponding starting materials:

EXAMPLE 6

1-(4-(2-Amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidin-

1 -yl)-3-phenylpropan-1 -one A mixture of 3-phenylpropanoic acid (40 mg, 0.27 mmol), HBTU (101 mg, 0.27 mmol) and DIEA (52 mg, 0,4 mmol) in DMF (2 ml_) was stirred at room temperature for one hour. Reference example 5a (100 mg, 0.27 mmol) was then added and it was stirred at room temperature overnight. It was concentrated to dryness and the residue was diluted in chloroform. The organic phase was washed with 0.5 N NaOH aqueous solution and then with saturated solution of sodium chloride, it was dried over Na2SO₄ and it was concentrated to dryness, obtaining the Boc-protected precursor. This crude was treated with HCI (4 M solution in 1 ,4-dioxane, 5 ml_) and the mixture was stirred at room temperature for 4 h, and then concentrated to dryness. The residue was purified by preparative HPLC (Column: X-Bridge Prep C18 5 μm (19 x 100 mm), rate: 20 mL/min, eluent: A = AcN, B = NH₄HCO₃ 75 mM, gradient: 0 min A at 10%; 1.0 min A at 10%; 2.0 min A at 25%; 7.0 min A at 30%;8.0 min A at 90%) and the fractions containing the product were concentrated to dryness, providing 8.8 mg of the title compound (yield: 8%). LC-MS (Method 2): t_R = 1 ,50 min; m/z 409 (MH⁺).

EXAMPLES 7-8

The following compounds were obtained following a process similar to that described in the example 6 but using suitable starting materials:

EXAMPLE 9 lsobutyl 4-(2-amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4- yl)piperidin-1 -carboxylate DIEA (26 mg, 0.2 mmol) and then isobutyl chloroformate (18.1 mg, 0.13 mmol) were added to a solution of reference example 5a (50 mg, 0.13 mmol) in dichloromethane (2 ml_). The mixture was stirred at room temperature for 3 hours and then was washed with a saturated solution of NaHCO3. The organic phase was dried over Na2SO₄ and was concentrated to dryness, obtaining the Boc- protected precursor compound. This crude product was treated with HCI (4 M solution in 1 ,4-dioxane, 5 ml_) and the mixture was stirred at room temperature for 3 h and then it was concentrated to dryness. The residue was dissolved in methanol and it was passed through a sulfonic resin Bond elut SCX-Varian previously compacted with methanol. It was then eluted with methanol, which was discarded, and the eluted product was recovered with 2 N NH₃ in MeOH, which was collected and it was concentrated to dryness. The crude product thus obtained was purified by chromatography over silica gel using mixtures of chloroform/MeOH/NH_{3 ∞}nc of increasing polarity as eluent, providing 16.9 mg of the title compound (yield: 34%). LC-MS (Method 2): t_R = 1.59 min; m/z 377 (MH⁺).

EXAMPLES 10-13

The following compounds were obtained following a process similar to that described in the example 9 but using suitable starting materials:

EXAMPLE 14

4-(Benzyloxy)butyl 4-(2-amino-6-((3R)-3-(methylamino)pyrrolidin-1- yl)pyrimidin-4-yl)piperidin-1-carboxylate To a carbonyldiimidazole solution (51.7 mg, 0.32 mmol) in anhydrous dichloromethane (1.3 ml_), previously cooled with an ice bath, a solution of 4- (benzyloxy)butan-i -ol (57.4 mg, 0.32 mmol) was added in anhydrous dichloromethane (0.5 ml_). The ice bath was removed and the mixture was stirred at room temperature for 1 hour. A solution of reference example 5a (100 mg, 0.27 mmol) in anhydrous dichloromethane (0.8 ml_) was then added and the mixture was stirred at room temperature overnight. It was concentrated to dryness, obtaining the Boc-protected precursor compound. This crude product was dissolved in dichloromethane (10 ml_), it was cooled with an ice bath, and trifluoroacetic acid (0.51 ml_, 6,7 mmol) was added. It was stirred at room temperature for 4 hours and it was concentrated to dryness. The residue was purified by preparative HPLC (Column: X-Bridge Prep C18 5 μm (19 x 100 mm), rate: 20 mL/min, eluent: A = AcN, B = NH₄HCO₃ 75 mM, gradient: 0 min A at 5%; 2.0 min A at 5%; 3.0 min A at 35%; 8.0 min A at 40%; 9.0 min A at 80%; 10.0 min A at 80%) and the fractions containing the product were concentrated to dryness, providing 68.6 mg of the title compound (yield: 53%). LC-MS (Method 2): t_R = 1.89 min; m/z 483 (MH⁺). EXAMPLES 15-37

The following compounds were obtained following a process similar to that described in the example 14 but using suitable starting materials:

(1 ) The deprotection of the Boc group was carried out with HCI (4 M solution in 1 ,4-dioxane) instead of trifluoroacetic acid.

EXAMPLE 38

4-(2-Amino-6-((3/?)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)-Λ/- benzylpiperidin-1 -carboxamide

DIEA (72 mg, 0.56 mmol) and then benzyl isocyanate were added (70.1 mg, 0.53 mmol) to a solution of reference example 5a (100 mg, 0.27 mmol) in dichloromethane (3 ml_). The mixture was stirred at room temperature for 5 hours and then it was concentrated to dryness, obtaining the Boc-protected precursor compound. This crude product was dissolved in dichloromethane (10 ml_), it was cooled with an ice bath, and trifluoroacetic acid was added (1.4 ml_, 18.5 mmol). It was stirred at room temperature for 4 hours and it was concentrated to dryness. The residue was purified with preparative HPLC (Column: X-Bridge Prep C18 5 μm (19 x 100 mm), rate: 20 mL/min, eluent: A = AcN, B = NH₄HCO₃ 75 mM, gradient: 0 min A at 5%; 2.0 min A at 5%; 3.0 min A at 20%; 8.0 min A at 50%; 9.0 min A at 80%; 10.0 min A at 80%) and the fractions containing the product were concentrated to dryness, providing 42 mg of the title compound (yield: 39%). LC-MS (Method 2): t_R = 1.36 min; m/z 410 (MH⁺).

EXAMPLE 39 4-(2-Amino-6-((3/?)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)-Λ/- butylpiperidin-1 -carboxamide

The title compound was obtained following a process similar to that described in the example 38 but using butyl isocyanate instead of benzyl isocyanate. LC-MS (Method 2): t_R = 1.27 min; m/z 376 (MH⁺)

EXAMPLE 40 4-(1-(Butylsulfonyl)piperidin-4-yl)-6-((3/?)-3-(methylamino)pyrrolidin-1- yl)pyrimidin-2-amine DIEA (26 mg, 0.2 mmol) and then 1 -butanesulfonyl chloride (20.7 mg, 0.13 mmol) were added to a solution of reference example 5a (50 mg, 0.13 mmol) in dichloromethane (2 ml_). The mixture was stirred at room temperature overnight and then it was washed with saturated solution of NaHCO3. The organic phase was dried over Na2SO₄ and it was concentrated to dryness, obtaining the Boc- protected precursor compound. This crude product was dissolved in dichloromethane (5 ml_), it was cooled with an ice bath, and thfluoroacetic acid (0.26 ml_, 3.3 mmol) was added. It was stirred at room temperature for 4 hours and it was concentrated to dryness. The residue was diluted with water and ethyl acetate, the pH was adjusted to basic and the phases were separated. The aqueous phase was again extracted with ethyl acetate. The combined organic phases were dried over anhydrous Na2SO₄ and it was concentrated to dryness, providing 22.6 mg of the title compound (yield: 43%). LC-MS (Method 2): t_R = 1.46 min; m/z 397 (MH⁺).

EXAMPLES 41-43 The following compounds were obtained following a process similar to that described in the example 40 but using suitable starting materials:

EXAMPLE 44

4-(2-Amino-6-((3/?)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)-Λ/-butyl-Λ/- methylpiperidin-1 -carboxamide To a solution of /V-methylbutylamine (23.2 mg, 0.27 mmol) in anydrous dichloromethane (2 ml_) TEA (0.1 ml_) was added and then a solution of triphosgene (31 mg, 0.11 mmol) in anydrous dichloromethane (2 ml_). The mixture was stirred in a nitrogen atmosphere at room temperature for one hour and then a solution of reference example 5a (100 mg, 0.27 mmol) and TEA (0.1 ml_) in anydrous dichloromethane (2 ml_) were added, and the mixture was stirred at room temperature overnigth. The crude product was washed with a solution of HCI (0.5 N aqueous solution). The acidic aqueous phase was re-extacted with dichlorometane. The combined organic phases were dried over Na2SO₄ and were concentrated to dryness, to afford the Boc-protected precursor. This crude was dissolved in dichlorometane (0.6 ml_) and then trifluoroacetic acid (0.3 ml_, 4 mmol) was added. It was stirred at room temperature for 2 horas and it was concentrated to dryness. The residue was was purified by preparative HPLC (method: XBridge Prep C18 (5μm) OBD 19x100 mm column, rate: 20 mL/min, eluent: A = AcN, B = NH₄HCO₃ 75 mM, gradient: 0 min A at 5%; 2.0 min A at 5%; 3.0 min A at 25%; 8.0 min A at 35%; 9.0 min A at 80%; 10.0 min A at 80%) and the fractions containing the product were concentrated to dryness, providing 18.4 mg of the title compound (yield: 18%). LC-MS (Method 2): t_R = 1.50 min; m/z 390 (MH⁺).

EXAMPLE 45

4-Hydroxybutyl 4-(2-amino-6-((3/?)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-

4-yl)piperidin-1 -carboxylate A solution of example 14 (64 mg, 0.13 mmol) in MeOH (3 ml_) was hydrogenated in an H-Cube™ apparatus using a 10% Pd/C cartridge (70x4 mm) at 50 ⁰C and 20 bar of hydrogen at a flow of 1 mL/min. The crude product obtained after concentrating to dryness was purified by preparative HPLC (method: XBridge Prep C18 (5μm) OBD 19x100 mm column, rate: 20 mL/min, eluent: A = AcN, B = NH₄HCO₃ 75 mM, gradient: 0 min A at 5%; 3.0 min A at 15%; 8.0 min A at 25%; 9.0 min A at 80%; 10.0 min A at 80%) and the fractions containing the product were concentrated to dryness, providing 3.7 mg of the title compound (yield: 7%). LC-MS (Method 2): t_R = 1.15 min; m/z 393 (MH⁺)

EXAMPLE 46

Butyl 4-(2-amino-6-((3/?)-3-aminopyrrolidin-1-yl)pyrimidin-4-yl) piperidin-1-carboxylate

Following a procedure similar to that described in example 9, but using the referente example 5c and butyl chloroformate as starting materials, the title compound was obtained. LC-MS (Method 2): t_R = 1.55 min; m/z = 363 (MH⁺).

EXAMPLES 47-48 Following a procedure similar to that described in example 40 but using suitable starting materials, the desired compounds were obtained:

EJEMPLOS 49-73 The following compounds were obtained following a procedure similar to that described in example 14, but using suitable starting materials:

(1 ) The use of methanol during the synthesis of example 54 caused the transesterification rendering a mixture of ethyl ester and methyl ester, that were separated by preparative HPLC to afford examples 54 and 55, respectively.

(2) Boc deprotection in acidic media caused the hydrolisys of tert-butyl ester, and the use of methanol during the synthesis caused the esterification rendering the methyl ester.

EXAMPLE 74

6-Hydroxyhexyl 4-(2-amino-6-((3R)-3-(methylamino)pyrrolidin-1-il)pyrimidin-

4-yl) piperidin-1-carboxilate A solution of example 55 (11.8 mg, 0.03 mmol) in THF (0.53 ml_) was cooled with an ice bath. Then LiAIH₄ (solution 1 M in THF, 0.08 mL, 0.08 mmol) was added and was stirred at 0 ⁰C for 2 hours. The reaction was stopped by adding an aqueous solution of sodium tartrate 1 M (2 mL). It was diluted with water and chloroform, and the phases were separated. The aqueous phase was re-extracted with chloroform, and the combined organic phases were concentrated to dryness. The residue was purified by preparative HPLC (method: X-Bridge Prep C18 (5 μm) OBD (19 x 100 mm) column, rate: 20 mL/min, eluent: A = AcN, B = NH₄HCO₃ 75 mM, gradient: 0 min A at 5%; 2.0 min A at 5%; 3.0 min A at 30%; 8.0 min A at 40%; 9.0 min A at 80%; 10.0 min A at 80%) and the fractions containing the product were concentrated to dryness, providing 1.84 mg of the title compound (yield: 16%). LC-MS (Method 2): t_R = 1.31 min; m/z = 421 (MH⁺) EXAMPLE 75

4-(Hydroxymethyl)benzyl 4-(2-amino-6-((3/?)-3-(methylamino)pyrrolidin-1- yl)pyrimidin-4-yl) piperidin-1 -carboxylate

Following a similar procedure to the one described in example 74, but using the example 49 as starting material, the title compound was obtained. LC-MS (Method 2): t_R = 1.33 min; m/z = 441 (MH⁺).

EXAMPLE 76 (1-Methyl-1H-benzo[cφmidazol-2-yl)methyl 4-(2-amino-6-((3R)-3- (methylamino)pyrrolidin-i -yl)pyrimidin-4-yl) piperidin-1 -carboxylate a) (1H-Benzo[c/]imidazol-2-yl)methyl 4-(2-amino-6-((3/?)-3-(tert- butoxycarbonyl(methyl)amino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidin-1- carboxylate To a mixture of carbonyldiimidazole (240 mg, 1.46 mmol) in anydrous dichlorometane (12 mL) was added (1 H-benzo[d]imidazol-2-yl)methanol (216 mg, 1.46 mmol) and the mixture was stirred at 35 ⁰C for 90 min. Reference example 5a (500 mg, 0.27 mmol) was then added and the mixture was stirred at 40 ⁰C for 2 days. It was diluted with dichlorometane and washed with aqueous solution of citric acid 5%. The aqueous phase was re-extracted with dichlorometane. The combined organic phases were dried over Na2SO₄ and then were concentrated to dryness. The crude product was purified by chromatography over silica gel using mixtures of AcOEt/MeOH of increasing polarity as eluent, providing 615 mg of the title compound (yield: 84%). LC-MS (Method 2): t_R = 2.03 min; m/z = 551 (MH⁺). b) Title compound

To a solution of the compound obtained in secction a) (100 mg, 0.18 mmol) in DMF (1.8 mL) anhydrous potassium carbonate (25 mg. 0.18 mmol) was added and then methyl iodide(0.01 mL, 0.18 mmol) and the mixture was heated at 70 ⁰C overnigth. It was concentrated to dryness and the residue was purified by preparative HPLC (method: X-Bridge Prep C18 (5 μm) OBD (19 x 100 mm) column, rate: 20 mL/min, eluent: A = AcN, B = NH₄HCOs 75 mM, gradient: 0 min A at 5%; 2.0 min A at 5%; 3.0 min A at 35%; 8.0 min A at 45%; 9.0 min A at 90%; 10.0 min A at 90%) and the fractions containing the product were concentrated to dryness, providing 45 mg of the Boc protected precursor compound. This product was dissolved in dichlorometane (0.4 ml_) and trifluoroacetic acid(0.2 ml_) was added. It was stirred at room temperature for 2 hours and it was concentrated to dryness. The residue was diluted in water with some HCI and ethyl acetate and the phases were separated. The acidic aqueous phase was adjusted to pH 10-11 with 1 N NaOH aqueous solution and was extracted with AcOEt several times. The combined organic phases were dried over Na2SO₄ and then were concentrated to dryness, providing 9.3 mg of the title compound (yield: 11 %). LC-MS (Method 2): t_R = 1.43 min; m/z = 465 (MH⁺).

EXAMPLE 77 Benzyl 4-(2-amino-6-(1-methylpyrrolidin-(3/?)-3-ylamino)pyrimidin-4- yl)piperidin-1 -carboxylate A solution of the reference example 6 (0.96 g of crude product, equivalents to 0.73 mmol) and DIEA (4.8 ml_) in EtOH (3 ml_) was heated at reflux for 3 hours and then the solution was concentrated to dryness. The residue was diluted in EtOH (3 ml_) and DIEA (4.8 ml_) and reference example 7 (622 mg, 3.6 mmol) were added and the mixture was heated at 90 ⁰C overnigth. It was concentrated to dryness and the residue was diluted with HCI (0.5 N aqueous solution) and AcOEt. The phases were separated and the acidic aqueous phase was washed again with AcOEt, that was discarded. The pH of the aqueous phase was adjusted to 11 with 0.5 N NaOH aqueous solution and was extracted several times with AcOEt. The combined organic phases were dried over Na2SO₄ and were concentrated to dryness. The crude product thus obtained was purified by preparative HPLC (method: X-Bridge Prep C18 (5 μm) OBD (19 x 100 mm) column, rate: 20 mL/min, eluent: A = AcN, B = NH₄HCO₃ 75 mM, gradient: 0 min A at 5%; 2.0 min A at 5%; 3.0 min A at 30%; 8.0 min A at 40%; 9.0 min A at 80%; 10.0 min A at 80%) and the fractions containing the product were concentrated to dryness, providing 63.9 mg of the title compound (yield: 21 %). LC-MS (Method 2): t_R = 1.69 min; m/z = 411 (MH⁺).

EXAMPLES 77b-77k The following compounds were obtained following a similar procedure to that described in example 14 but the mixture of carbonyldiimidazole and the corresponding alcohol in dichloromethane was heated at 35⁰C for 2 hours, instead of at room temperature for 1 hour, and the mixture resulting after reference example 5a addition was heated at 4O⁰C overnight, instead of at room temperature. Overnight. The corresponding starting materials are used in each case:

EXAMPLE 77I

2-(4-Fluorophenylamino)ethyl 4-(2-amino-6-((3R)-3-(methylamino)pyrrolidin- 1 -yl)pyrimidin-4-yl)piperidine-1 -carboxylate a) 2-Bromoethyl 4-(2-amino-6-((3R)-3-(tert- butoxycarbonyl(methyl)amino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidine-1- carboxylate

The title compound was obtained reacting reference compound 5a with 2- bromoethylchloroformate following the procedure described in example 14. A mixture of desired bromo derivative and the chloro derivative obtained from chlorine anion substitution were isolated. LC-MS (Method 2): t_R 2.21 = min; m/z 485 (MH⁺) and t_R 2.27= min; m/z 527 (MH⁺) b) Title compound A solution of the mixture obtained above (100 mg, 0.19 mmol), A- fluoroaniline (63.2 mg, 0.569 mmol), potassium carbonate (79 mg, 0.569 mmol) and potassium iodide (12.59 mg, 0.076 mmol) in 1.9 mL of DMF was stirred at 5O⁰C for 18 hours and at 8O⁰C for additional 18 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was dried over Na2SO₄ and the solvent was concentrated to dryness and purified by preparative HPLC (method: X-Bridge Prep C18 (5 μm) (19 x 100 mm) column, rate: 19 mL/min at column dilution of 1 mL/min, eluent: A =MeOH, B = NH₄HCOs 30 mM, gradient: 0 min A at 25%; 3,0 min A at 65%; 8,0 min A at 80%; 9,0 min A at 95%; 10,0 min A at 95%).

After BOC group hydrolysis with TFA as described in example 14 , 6.6 mg of the title compound were obtained (yield: 7.6% for two steps). LC-MS (Method 2): t_R = 1.66 min; m/z 458 (MH⁺)

EXAMPLE 78 Binding competition assay of [³H]-histamine to human histamine H₄ receptor

To perform the binding assay, membrane extracts prepared from a stable CHO recombinant cell line expressing the human histamine H₄ receptor (Euroscreen/Perkin-Elmer) were used.

Test compounds were incubated at the selected concentration in duplicate, with 10 nM [³H]-histamine and 15 μg membranes extract in a total volume of 250 μl_ of 50 mM Tris-HCI, pH 7.4, 1.25 mM EDTA for 60 minutes at 25 ⁰C. Non- specific binding was defined in the presence of 100 μM 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 ⁰C. Subsequently, the plates were washed with 50 mM Tris (pH 7.4), 1.25 mM EDTA at 0 ⁰C and filters were dried during 1 hour at 50-60 ⁰C, before adding the scintillation liquid to determine bound radioactivity by using a betaplate scintillation counter.

The compounds of examples 1 to 77I were assayed in this test and showed an inhibition of more than 50% of binding to human histamine receptor H₄ at 1 μM.

EXAMPLE 79

Histamine-induced shape change assay (gated autofluorescence forward scatter assay, GAFS) in human eosinophils

In this assay 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).

Polymorphonuclear leucocytes (PMNL, fraction containing neutrophils and eosinophils) were prepared from whole blood of human healthy volunteers. Briefly, 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 1.1x10⁶ cells/ml/tube and were pretreated with different concentrations of test compounds (dissolved in PBS) for 30 min at 37⁰C and then stimulated with 300 nM histamine (Fluka) for 5 min. Then, paraformaldehyde (1 % final concentration in PBS) was added to terminate the reaction and maintain cell shape. Cell shape change was analyzed by flow cytometry (FACS Calibur, BD Biosystems). Eosinophils in PMNL were gated based on their higher autofluorescence relative to that of neutrophils (fluorescence channel FL2). Cell shape change was monitored in forward scatter signals (FSC). Results are expressed as percentage inhibition of shape change induced by histamine for each concentration of test compound.

The compounds of examples 1 to 5, 7 to 11 , 13 to 15, 17, 21 to 23, 25, 27, 28, 31 , 32, 35, 37, 38, 41 , 43, 46, 48 to 58, 64 to 67 and 76 to 77I were assayed in this test and produced more than 50% inhibition of histamine-induced human eosinophil shape change at 1 μM.

Claims

1.- A compound of formula I

wherein:

Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:

(ii) a heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR₃Rb 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 R2 represents azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, wherein R₂ 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 R₃ 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; R₃ represents -COR₄, -CONR₄R₄ , -CO₂R₄, -SO₂R₄ or -SO₂NR₄R₄'; R₄ represents Ci-β alkyl, R₅-Ci-S alkyl or R₆-Co-S alkyl, wherein in the Ci-s alkyl, R₅- C1-8 alkyl and R₆-C_0-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-; R₄' represents H or Ci_-8 alkyl; and optionally R₄ and R₄' are bound forming a -C3_-5 alkylene- group which is optionally substituted with one or more Ci-S alkyl groups;

R₅ represents -CONR₄ R₇, -NR₄COR₇, -NR₄CO₂Rz, -NR₄SO₂Rz, -SO₂NR₄ R₇, - NR₄CONR₄ R₇, -CONHSO₂R₇, -CO₂R₇, -OCOR₇, -SO₂R₇, -NR₄ R₇, -OH or 1 H- tetrazol-5-yl;

R₆ represents C_3-scycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein R₆ 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, R₅-Co_-8 alkyl and R₈-Co_-8 alkyl; R₇ represents H, Ci_-8 alkyl, C3_-8 cycloalkyl-Co-s alkyl or aryl-Co_-8 alkyl, wherein in the Ci_-8 alkyl, C3_-8 cycloalkyl-Co-s 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 R₄' and R₇, in a R₅ group, are bound forming a -C_3-5 alkylene- group which is optionally substituted with one or more Ci_-8 alkyl groups; and R₈ represents C_3-8cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein R₈ 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; or a salt thereof.

2.- A compound according to claim 1 , wherein R₃ represents -COR₄, -CONR₄R₄', - CO₂R₄ or -SO₂R₄.

3.- A compound according to claim 2, wherein R₃ represents -CO₂R₄.

4.- A compound according to claim 2, wherein R₃ represents -SO₂R₄.

5.- A compound according to any of claims 1 to 4, wherein R₄ represents Ci_-8 alkyl or R₆-Co_-8 alkyl, wherein in the Ci_-8 alkyl and R₆-Co_-8 alkyl groups 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-.

6.- A compound according to any of claims 1 to 4, wherein R₄ represents Ci_-8 alkyl optionally substituted with one or more halogen groups and wherein one methylene group of the alkyl chain is optionally replaced by -O-.

7.- A compound according to any of claims 1 to 4, wherein R₄ represents R₅-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-.

8.- A compound according to any of claims 1 to 4, wherein R₄ represents R₆-Co_-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-.

9.- A compound according to claim 8, wherein R₄ represents R₆-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-.

10.- A compound according to any of claims 1 to 4 or 7, wherein R₅ represents -

NR₄ R₇.

11.- A compound according to claim 10 wherein R₇ 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.

12.- A compound according to claim 11 wherein R₇ represents aryl-Ci_-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.

13.- A compound according to any of claims 1 to 5 and 8 to 9, wherein R₆ represents C_3-8cycloalkyl, aryl or heteroaryl, wherein R₆ 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, R₅-Co_-8 alkyl and R₈-Co_-8 alkyl.

14.- A compound according to claim 13, wherein R₆ represents C_3-8cycloalkyl, 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, R₅-C_0-8 alkyl and R₈-C_0-8 alkyl.

15.- A compound according to claim 14, wherein R₆ represents monocyclic Cs- scycloalkyl, 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, R₅-C_0-8 alkyl and R₈-C_0-8 alkyl.

16.- A compound according to claim 13, wherein R₆ represents aryl 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, R₅-C_0-8 alkyl and R₈-C_0-8 alkyl.

17.- A compound according to claim 16, wherein R₆ represents aryl 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, R₅-C_0-8 alkyl and R₈-C_0-8 alkyl.

18.- A compound according to claim 17, wherein R₆ represents phenyl 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, R₅-C_0-8 alkyl and R₈-C_0-8 alkyl.

19.- A compound according to claim 16, wherein R₆ 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, R₅-C_0-8 alkyl and R₈-C_0-8 alkyl.

20.- A compound according to any of claims 1 to 19 wherein Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:

21.- A compound according to claim 20, wherein Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:

wherein R₀ and R_d independently represent H or Ci_-4 alkyl.

22.- A compound according to claim 21 wherein R₀ represents H.

23.- A compound according to claims 21 or 22, 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).

24.- A compound according to claims 21 or 22, wherein Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b).

25.- A compound according to claim 24 wherein Ri and R₂ form, together with the

N atom to which they are bound, a saturated heterocyclic group of formula (a).

26.- A compound according to claim 24 wherein Ri and R₂ form, together with the

N atom to which they are bound, a saturated heterocyclic group of formula (b).

27.- A compound according to any of claims 1 to 26 wherein R₃ and Rb independently represent H or Ci_-4 alkyl.

28.- A compound according to claim 27, wherein R₃ and Rb independently represent H or methyl.

29.- A compound according to claim 28 wherein R₃ represents H and Rb represents methyl.

30.- A compound according to claim 28 wherein R₃ and Rb represent H.

31.- A compound according to any of claims 1 to 19, wherein Ri represents H or

Ci_-4 alkyl, and R₂ represents azetidinyl, pyrrolidinyl, pipehdinyl or azepanyl, wherein R₂ is optionally substituted with one or more Ci_-4 alkyl groups.

32.- A pharmaceutical composition which comprises a compound of formula I according to any of claims 1 to 31 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

33.- A compound of formula I according to any of claims 1 to 31 or a pharmaceutically acceptable salt thereof for use in therapy.

34.- A compound according to any of claims 1 to 31 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease mediated by the histamine H₄ receptor.

35.- A compound according to claim 34, or a pharmaceutically acceptable salt thereof, wherein the disease mediated by the histamine H₄ receptor is an allergic, immunological or inflammatory disease, or pain.

36.- Use of a compound according to any of claims 1 to 31 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease mediated by the histamine H₄ receptor.

37.- Use according to claim 36, wherein the disease mediated by the histamine H₄ receptor is an allergic, immunological or inflammatory disease, or pain.

38.- A process for the preparation of a compound of formula I according to claim 1 , which comprises:

1. starting from a compound of formula Il (or an amino-protected form thereof)

wherein Ri and R₂ have the meaning described in claim 1 ,

(a) when in a compound of formula I R3 represents -COR₄, reacting a compound of formula Il with an acid or acid chloride of formula R₄-COY, wherein Y is OH or Cl; or

(b) when in a compound of formula I R3 represents -CONR₄R₄', reacting a compound of formula Il with an isocyanate of formula R₄-NCO or a carbamoyl chloride of formula R₄R₄-NCOW, wherein W is a leaving group; or

(c) when in a compound of formula I R3 represents -CONR₄R₄', reacting a compound of formula Il with thphosgene or phosgene and subsequently treating with an amine of formula NHR₄R₄'; or

(f) when in a compound of formula I R3 represents -CO₂R₄, reacting a compound of formula Il with thphosgene or phosgene and subsequently reacting it with an alcohol of formula R₄-OH; or (g) when in a compound of formula I R3 represents -SO₂R₄, reacting a compound of formula Il with a sulfonyl chloride of formula R₄-SO₂CI; or (h) when in a compound of formula I R3 represents -SO₂NR₄R₄', reacting a compound of formula Il with a sulfamoyl chloride of formula R₄R₄-NSO₂CI; or (i) when in a compound of formula I R3 represents -SO₂NR₄R₄', reacting a compound of formula Il with sulfuryl chloride and subsequently treating with an amine NHR₄R₄ ; in any of cases (a) to (i), followed if necessary by the removal of any protecting group that may be present; or

wherein Ri, R₂ and R3 have the meaning described in claim 1 , followed if necessary by the removal of any protecting group that may be present; or 3. transforming a compound of formula I into another compound of formula I in one or in several steps.