WO2009077608A1

WO2009077608A1 - 2 -aminopyrimidine derivatives as histamine h4 antagonists

Info

Publication number: WO2009077608A1
Application number: PCT/EP2008/067949
Authority: WO
Inventors: Elena CARCELLER GONZÁLEZ; Marina VIRGILI BERNADÓ; Josep MARTÍ VIA; Eva María MEDINA FUENTES
Original assignee: Palau Pharma, S. A.
Priority date: 2007-12-19
Filing date: 2008-12-18
Publication date: 2009-06-25
Also published as: TW200940529A; PE20091524A1; AR069813A1

Abstract

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

Description

2 -AMINOPYRIMIDINE DERIVATIVES AS HISTAMINE H4 ANTAGONISTS Technical field of the invention

The present invention relates to a new series of 2-amino-pyhmidine derivatives, procedures to prepare them, pharmaceutical compositions comprising these compounds as well as their use in therapy.

State of the art 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, OR-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 neuropathic 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. Additionally, when used for peripheral therapeutic applications, compounds should exhibit reduced CNS penetration.

Description of the invention

One aspect of the present invention relates to compounds of formula I

wherein: Ri represents a group selected from (i) and (ii):

R2 and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl and NR₃Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃Rb group, or contains 1 N atom and is substituted with one NR₃R_b group; or R₂ represents H or Ci_-4 alkyl, and R3 represents azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, which may be optionally substituted with one or more Ci_-4 alkyl groups;

R₃ represents H or Ci_-4 alkyl;

R_b 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 may be optionally substituted with one or more Ci_-4 alkyl groups;

R₄ and R₅ are each independently selected from H and Ci_-4 alkyl, and additionally one of the R₄ or R₅ groups may represent aryl or C3-s cycloalkyl-Co-6 alkyl, and additionally two R₄ and R₅ groups on a same C atom may be bound forming a C3-s cycloalkyl group together with said C atom; R₆ represents a group selected from Ci_-8 alkyl, C3-8 cycloalkyl-Co-e alkyl and An- Co_-4 alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups atom and the C_3-S cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen and aryl; R₇ represents a saturated monocyclic 4- to 7-membered heterocyclic ring containing one O atom and not containing any other additional heteroatoms, wherein said ring may be bound to the rest of the molecule through any available

C atom, and wherein R₇ may be optionally substituted with one or more groups independently selected from Ci_-4 alkyl and halogen; n represents 1 , 2 or 3; p represents 0, 1 or 2;

An represents phenyl optionally substituted with one or more groups independently selected from Ci_-4 alkyl, halogen, Ci_-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, cyano, hydroxy-Co-6 alkyl, R₈CO2-Co-6 alkyl, R₈SO2NHCO-Co-6 alkyl, (1 H-tetrazol-5-yl)-C₀-6 alkyl, -CONR₈R₈, -SO₂NR₈R₈, -SO₂R₈', -NR₈SO₂R₈'

-NR₈CONR₈R₈, -NR₈COR₈ and -NR₈R₈;

R₈ represents H, Ci_-6 alkyl, C_3-8 cycloalkyl-Co-e alkyl or aryl-C_0-4 alkyl;

R₈' represents Ci_-6 alkyl, C_3-8 cycloalkyl-Co-e alkyl or aryl-C_0-4 alkyl; and additionally two R₈ or a R₈ and a R₈' can be bonded together to form a -C_2-5 alkylene- group; and aryl represents phenyl optionally substituted with one or more groups independently selected from Ci_-4 alkyl, halogen, Ci_-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, cyano and amino.

The present invention also relates to the salts and solvates of the compounds of formula I.

Some compounds of formula I may have chiral centres that can give rise to various stereoisomers. The present invention relates to each of these stereoisomers and also to mixtures thereof.

The compounds of formula I show a high affinity for the H₄ histamine receptor. Thus, another aspect of the invention relates to a compound of formula I

wherein: Ri represents a group selected from (i) and (ii):

R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl and NR₃Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃Rb group, or contains 1 N atom and is substituted with one NR₃R_b group; or R₂ represents H or Ci_-4 alkyl, and R₃ represents azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, which may be optionally substituted with one or more Ci_-4 alkyl groups; R₃ represents H or Ci_-4 alkyl; R_b 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 may be optionally substituted with one or more Ci_-4 alkyl groups; R₄ and R₅ are each independently selected from H and Ci_-4 alkyl, and additionally one of the R₄ or R₅ groups may represent aryl or C_3-S cycloalkyl-Co-6 alkyl, and additionally two R₄ and R₅ groups on a same C atom may be bound forming a C_3-s cycloalkyl group together with said C atom; Re represents a group selected from Ci-S alkyl, C_3-s cycloalkyl-Co-6 alkyl and An- Co_-4 alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups atom and the C_3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen and aryl; R₇ represents a saturated monocyclic 4- to 7-membered heterocyclic ring containing one O atom and not containing any other additional heteroatoms, wherein said ring may be bound to the rest of the molecule through any available C atom, and wherein R₇ may be optionally substituted with one or more groups independently selected from Ci_-4 alkyl and halogen; n represents 1 , 2 or 3; p represents 0, 1 or 2;

An represents phenyl optionally substituted with one or more groups independently selected from Ci_-4 alkyl, halogen, Ci_-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, cyano, hydroxy-Co-6 alkyl, R₈CO2-Co-6 alkyl, R₈SO2NHCO-Co-6 alkyl, (1 H-tetrazol-5-yl)-C₀-6 alkyl, -CONR₈R₈, -SO₂NR₈R₈, -SO₂R₈', -NR₈SO₂R₈' -NR₈CONR₈R₈, -NR₈COR₈ and -NR₈R₈;

R₈' represents Ci_-6 alkyl, C_3-8 cycloalkyl-Co-e alkyl or aryl-C_0-4 alkyl; and additionally two R₈ or a R₈ and a R₈' can be bonded together to form a -C_2-5 alkylene- group; and aryl represents phenyl optionally substituted with one or more groups independently selected from Ci_-4 alkyl, halogen, Ci_-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, cyano and amino; 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 of a disease mediated by the H₄ histamine receptor. 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 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 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 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 compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of a disease mediated by the H₄ histamine receptor.

Another aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment 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 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 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 of a disease mediated by the histamine H₄ receptor.

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 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 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 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 a disease mediated by the histamine H₄ receptor in a subject in need thereof, specially 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 an allergic, immunological or inflammatory disease or pain in a subject in need thereof, specially 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 an allergic, immunological or inflammatory disease in a subject in need thereof, specially 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 pain in a subject in need thereof, specially 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 defined above, comprising: (a) reacting a compound of formula Il with a compound of formula III (or an amino- protected form thereof)

wherein Ri, R₂ and R3 have the meaning described above, followed if necessary by the removal of any protective group that may be present; or (b) reacting a compound of formula MB with a compound of formula (or an amino-protected form thereof)

MB

wherein L represents a leaving group and Ri, R2 and R3 have the meaning described above, followed if necessary by the removal of any protective group that may be present; or (c) 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 refers to a saturated linear or branched alkyl chain containing from x to y carbon atoms. Thus, a Ci_-S alkyl group refers to a linear or branched alkyl chain containing from 1 to 8 C atoms. A Ci_-4 alkyl group refers to a linear or branched alkyl chain containing from 1 to 4 C atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and te/t-butyl. The term Co alkyl indicates that the alkyl group is absent.

A Ci_-4 haloalkyl group means a group resulting from the substitution of one or more hydrogen atoms of a Ci_-4 alkyl group with one or more halogen atoms (i.e. fluorine, chlorine, bromine or iodine) that may be the same or different. Examples include, amongst others, thfluoromethyl, fluoromethyl, 1 -chloroethyl, 2-chloroethyl, 1 -fluoroethyl, 2-fluoroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2-trifluoroethyl, pentafluoropropyl, 3-chloropropyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3- pentafluoropropyl, heptafluoropropyl, 4-fluorobutyl and nonafluorobutyl.

A Ci_-4 alkoxy group means a group of formula Ci_-4 alkyl-O-, wherein the alkyl moiety has the same meaning as defined above. This term includes thus methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert- butoxy. A Ci_-4 haloalkoxy group means a group resulting from the substitution of one or more hydrogen atoms of a Ci_-4 alkoxy group with one or more halogen atoms (i.e. fluorine, chlorine, bromine or iodine) that may be the same or different. Examples include, amongst others, trifluoromethoxy, fluoromethoxy, 1 - chloroethoxy, 2-chloroethoxy, 1 -fluoroethoxy, 2-fluoroethoxy, 2-bromoethoxy, 2- iodoethoxy, 2,2,2-thfluoroethoxy, pentafluoroethoxy, 3-fluoropropoxy, 3- chloropropoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, heptafluoropropoxy, 4-fluorobutoxy and nonafluorobutoxy.

A C3-8 cycloalkyl group, either as a group or as part of a C3-8 cycloalkyl-Co-6 alkyl group, relates to a saturated carbocyclic ring having from 3 to 8 carbon atoms that may be a monocyclic or a bridged bicyclic group. Examples include, amongst others, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptanyl and bicyclo[2.2.2]octanyl. Preferred C_3-S cycloalkyl groups are monocyclic C3-6 cycloalkyl groups. The term C3-8 cycloalkyl-Co-6 alkyl includes C3-8 cycloalkyl and C3-8 cycloalkyl-Ci-₆ alkyl.

A C3-8 cycloalkyl-Ci-6 alkyl group means a group resulting from the substitution of one or more hydrogen atoms of a Ci-6 alkyl group with one or more C_3-S cycloalkyl groups, which may be the same or different. Preferably, the Ci_-6 alkyl group is substituted with one or two C3-8 cycloalkyl groups, and more preferably it is substituted with one C3-8 cycloalkyl group. The C3-8 cycloalkyl groups may substitute either one H atom on a C atom of the alkyl group, or two H atoms on a same C atom of the alkyl group (in which case the C3-8 cycloalkyl group shares one C atom with the alkyl group), such as in the groups shown as examples below:

2-cyclopropybutyl (i-ethyl-cyclopropyl)methyl butyl group where 1 H atom on a C atom butyl group where 2 H atoms on a same C atom is substituted with a cyclopropyl group are substituted with a cyclopropyl group Examples of C3-8 cycloalkyl-Ci-6 alkyl groups include, amongst others, the groups cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, 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- cyclopropylpropyl, 3-cyclobutylpropyl, 3-cyclopentylpropyl, 3-cyclohexylpropyl, 1 - cyclopropyl-2-methylpropyl, 4-cyclopropylbutyl, 3-cyclopropylbutyl, 2- cyclopropylbutyl, 1 -cyclopropylbutyl, 4-cyclobutylbutyl, 4-cyclopentylbutyl, 4- cyclohexylbutyl, 5-cyclopropylpentyl, and 6-cyclopropylhexyl.

As described above in the definition of R₆, C_3-8 cycloalkyl groups, either as a group or as part of a C3-8 cycloalkyl-Ci-6 alkyl group, may be optionally substituted with one or more groups independently selected from Ci_-4 alkyl, halogen and aryl. Said substituents may be the same or different and may be located on any available carbon atom of the C3-8 cycloalkyl group, including the carbon binding the ring to the rest of the molecule.

The term An-Co_-4 alkyl in the definition of Re includes An and An-Ci_-4 alkyl. An An-Ci_-4 alkyl group means a group resulting from the substitution of a hydrogen atom of a Ci_-4 alkyl group with an An group. Examples of An-Ci_-4 alkyl include, amongst others, the groups benzyl, 1-phenylethyl, 2-phenylethyl, 1- phenyl-1-methylethyl, 3-phenylpropyl and 2-phenyl-1-methylpropyl, wherein the phenyl groups may be optionally substituted as indicated above in the definition of An. Likewise the term aryl-Co_-4 alkyl in the definition of Rs includes aryl and aryl-Ci- ₄ alkyl. An aryl-Ci_-4 alkyl group means a group resulting from the substitution of a hydrogen atom of a Ci_-4 alkyl group with an aryl group.

In the definition of An, two R₈ groups or a R₈ group and R₈' group, either placed on the same atom or on different atoms, can be bonded together to form a -C_2-5 alkylene- group. Said -C_2-5 alkylene- group refers to a linear alkylene chain which contains from 2 to 5 carbon atoms, i.e. a group of formula -(CH₂)_2-5-. Examples of two R₈ groups or a R₈ and a R₈' group forming together a -C_2-5 alkylene- group include, among others:

The term hydroxy-C_0-6 alkyl includes hydroxy and hydroxy-Ci_-6 alkyl.

A hydroxy-Ci_-6 alkyl group means a group resulting from the replacement of one or more hydrogen atoms of a Chalky! group with one or more hydroxy groups. Preferably, the Ci_-6 alkyl group is substituted with one hydroxy group.

Examples include, among others, the groups hydroxymethyl, 1 -hydroxyethyl, 2- hydroxyethyl, 1 ,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1 - hydroxy propyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 2- hydroxybutyl and 1-hydroxybutyl.

The term R₈CO₂-C_0-B alkyl includes -CO₂Rs and R₈CO₂-Ci_-6 alkyl.

A R₈CO₂-Ci_-6 alkyl group means a group resulting from the replacement of one or more hydrogen atoms of a Ci_-6alkyl group with one or more -CO₂R₈ groups. Preferably, the Ci_-6 alkyl group is substituted with one -CO₂R₈ group. The term R₈SO₂NHCO-C_0-6 alkyl includes -CONHSO₂R₈ and R₈SO₂NHCO-

Ci_-6 alkyl.

A R₈SO₂NHCO-Ci_-6 alkyl group means a group resulting from the replacement of one or more hydrogen atoms of a Ci_-6alkyl group with one or more -CONHSO₂R₈ groups. Preferably, the Ci_-6 alkyl group is substituted with one - CONHSO₂R₈ group.

The term (1 H-tetrazol-5-yl)-C_0-6 alkyl includes (1 H-tetrazol-5-yl)- and (1 H- tetrazol-5-yl)-Ci_-6 alkyl.

A (1 H-tetrazol-5-yl)-Ci_-6 alkyl group means a group resulting from the replacement of one or more hydrogen atoms of a Ci_-6alkyl group with one or more (1 /-/-tetrazol-5-yl)- groups. Preferably, the Ci-6 alkyl group is substituted with one (1 H-tetrazol-5-yl)- group.

As indicated in the definition of Re, any alkyl group may be optionally substituted with one or more halogen groups. This refers to the Ci-S alkyl group, the Co-6 alkyl group that forms part of the C_3-S cycloalkyl-Co-e alkyl group and the Co_-4 alkyl group that forms part of the An-Co_-4 alkyl group.

As described above, R₇ represents a saturated monocyclic heterocyclic ring having from 4 to 7 ring atoms and containing one O atom and no other heteroatom. Said heterocyclic ring may be bound to the rest of the molecule via any available C atom. Examples of R₇ rings include, amongst others:

Any R₇ ring may be optionally substituted with one or more groups independently selected from Ci_-4 alkyl and halogen, as described above, and said substituents may be placed in any available position on the ring.

A halogen group or its abbreviation halo means fluorine, chlorine, bromine or iodine. Preferred halogen groups are fluorine and chlorine, and more preferably fluorine.

An amino group in the definition of aryl means NH₂.

The term "saturated" refers to groups that do not contain any double or triple bond.

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".

In the definition of NR₂R₃, R₂ and R₃ together with the N atom to which they are bound can form a saturated 4- to 7-membered monocyclic heterocycle containing up to 2 N atoms and no other heteroatom. Examples include, among others, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and homopiperazinyl.

In the definition of NR2R3, R2 and R3 together with N atom to which they are bound can form a bridged bicyclic group having from 7 to 8 atoms. Said bridged bicyclic group can contain up to two N atoms and does not contain any other heteroatom. Examples include, among others, 2,5-diaza-bicyclo[2.2.1]heptanyl and 2,5-diaza-bicyclo[2.2.2]octanyl.

The term "fused bicyclic" group, in the definition of NR2R3, refers to a 8- to 12-membered bicyclic system consisting of two adjacent rings sharing two atoms in common. Said fused bicyclic group can contain up to two N atoms in any available position and does not contain any other heteroatom. Examples include, among others, octahydropyrrolo[3,4-b]pyhdinyl, octahydropyrrolo[3,2-c]pyhdinyl, octahydro-pyrrolo[1 ,2-a]pyrazinyl and octahydropyrrolo[3,4-c]pyrrolinyl. As indicated above for the term NR2R3 in the definition of a compound of formula I, the above three types of saturated heterocyclic rings (monocyclic, bridged bicyclic and fused bicyclic) can be optionally substituted with one or more groups independently selected from Ci_-4 alkyl and NR₃Rb, with the proviso that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃Rb group, or contains 1 N atom and is substituted with one NR₃R_b group. Thus, if the heterocyclic ring contains 1 N atom, then the ring must be substituted with one NR₃Rb group and can additionally be optionally substituted with one or more Ci_-4 alkyl groups. If the ring contains 2 N atoms, it can be optionally substituted with one or more Ci_-4 alkyl groups while it cannot be substituted with any NR₃R_b group. The substituents, if present, can be placed on any available position of the ring, including on a N atom in the case of Ci_-4 alkyl groups.

When in a compound of formula I n represents 2 or 3 or p represents 2 and therefore there is more than one R₄ group and more than one R₅ group in said compound, each R₄ and each R₅ is independently selected from the list of possible meanings for said substitutents indicated above in the definition of a compound of formula I and therefore these groups may be the same or different.

The expression "optionally substituted with one or more" means that a group can be substituted with one or more, preferably with 1 , 2, 3 or 4 substituents, more preferably with 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 placed on any available position. Throughout the present specification, the expressions "treatment" of a disease, "treating" a disease and the like refer both to curative treatment as well as palliative treatment or prophylactic treatment of said disease. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total). Those in need of treatment include those already with the disease or disorder as well as those prone to have the disease or disorder or those in which the disease or disorder is to be prevented.

The expression "amino-protected form" in relation to a compound of formula HNR2R3 (III) means any form of a compound III where an amino-type N atom is protected with a protecting group. The invention thus relates to the compounds of formula I as defined above.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents (i).

In another embodiment, the invention relates to compounds of formula I wherein Ri represents (ii). In another embodiment, the invention relates to compounds of formula I wherein R₄ and R₅ are each independently selected from H and Ci_-4 alkyl, and additionally one of the R₄ or R₅ groups may represent aryl or C_3-S cycloalkyl-Co-e alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₄ and R₅ are each independently selected from H and Ci_-4 alkyl, and additionally one of the R₄ or R₅ groups may represent aryl.

In another embodiment, the invention relates to compounds of formula I wherein R₄ and R₅ are each independently selected from H and Ci_-4 alkyl. In another embodiment, the invention relates to compounds of formula I wherein R₄ and R₅ are each independently selected from H and methyl.

In another embodiment, the invention relates to compounds of formula I wherein R₄ and R₅ represent H. In another embodiment, the invention relates to compounds of formula I wherein n represents 1 or 2.

In another embodiment, the invention relates to compounds of formula I wherein n is 1.

In another embodiment, the invention relates to compounds of formula I wherein n is 2.

In another embodiment, the invention relates to compounds of formula I wherein p represents 0 or 1.

In another embodiment, the invention relates to compounds of formula I wherein p is 0. In another embodiment, the invention relates to compounds of formula I wherein p is 1.

In another embodiment, the invention relates to compounds of formula I wherein in a group (i) n represents 1 or 2 and in a group (ii) p represents 0 or 1.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents (i) and n represents 1.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents (i), n represents 1 and R₄ and R₅ are each independently selected from H and Ci_-4 alkyl.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents (i), n represents 1 and R₄ and R₅ are each independently selected from H and methyl.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents (i), n represents 1 and R₄ and R₅ represent H.

In another embodiment, the invention relates to compounds of formula I wherein An represents phenyl optionally substituted with one or more groups independently selected from Ci_-4 alkyl, halogen, Ci_-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, cyano and amino.

In another embodiment, the invention relates to compounds of formula I wherein An represents phenyl substituted with one group selected from hydroxy- Co-6 alkyl, R₈CO₂-C_0-6 alkyl, R₈SO₂NHCO-C_0-6 alkyl, (1 H-tetrazol-5-yl)-C_0-6 alkyl, - CONR₈R₈, -SO₂NR₈R₈, -SO₂R₈', -NR₈SO₂R₈', -NR₈CONR₈R₈, -NR₈COR₈ and - NR₈R₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy.

In another embodiment, the invention relates to compounds of formula I wherein An represents phenyl substituted with one group selected from hydroxy- C_0-6 alkyl, -CONR₈R₈, -SO₂R₈' and -NR₈COR₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy. In another embodiment, the invention relates to compounds of formula I wherein An represents phenyl substituted at the meta position with one group selected from hydroxy-C_0-6 alkyl, R₈CO₂-C_0-6 alkyl, R₈SO₂NHCO-C_0-6 alkyl, (1 H- tetrazol-5-yl)-C_0-6 alkyl, -CONR₈R₈, -SO₂NR₈R₈, -SO₂R₈', -NR₈SO₂R₈', - NR₈CONR₈R₈, -NR₈COR₈ and -NR₈R₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy.

In another embodiment, the invention relates to compounds of formula I wherein An represents represents phenyl substituted at the meta position with one group selected from hydroxy-C_0-6 alkyl, -CONR₈R₈, -SO₂R₈' and -NR₈COR₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy.

In another embodiment, the invention relates to compounds of formula I wherein An represents represents phenyl substituted at the meta position with one group selected from hydroxy-C_0-6 alkyl, -CONR₈R₈, -SO₂R₈' and -NR₈COR₈.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents a group selected from C_4-8 alkyl, C3_-8 cycloalkyl-C_0-6 alkyl and An-C_0-4 alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine) and the C_3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl. In another embodiment, the invention relates to compounds of formula I wherein R₆ represents a group selected from Ci_-8 alkyl, C_3-8 cycloalkyl-C_0-i alkyl and An-C_0-2 alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine) and the C_3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents a group selected from Ci_-8 alkyl, C_3-S cycloalkyl-C_0-i alkyl and An -Co-₂ alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents a group selected from C_4-5 alkyl, C_3-6 cycloalkyl-Co-i alkyl and An -Co-₂ alkyl

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents a group selected from Ci_-5 alkyl, C_3-8 cycloalkyl-C_0-i alkyl and An-Co-1 alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine) and the C_3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl. In another embodiment, the invention relates to compounds of formula I wherein R₆ represents a group selected from Ci_-5 alkyl, C_3-8 cycloalkyl-Co-i alkyl and An-Co-1 alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents a group selected from Ci_-8 alkyl and C_3-8 cycloalkyl-C_0-6 alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine) and the C_3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents a group selected from Ci_-5 alkyl and C_3-8 cycloalkyl-Co-i alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and the C_3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl. In another embodiment, the invention relates to compounds of formula I wherein R₆ represents a group selected from Ci_-5 alkyl and C_3-8 cycloalkyl-Co-i alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents a group selected from C_4-5 alkyl and C3-8 cycloalkyl-Co-i alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents a group selected from Ci_-8 alkyl and C_3-6 cycloalkyl-C_0-i alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and the C_3-6 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents a group selected from Ci_-8 alkyl and C_3-6 cycloalkyl-C_0-i alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents a group selected from C_4-5 alkyl and C_3-6 cycloalkyl-C_0-i alkyl. In another embodiment, the invention relates to compounds of formula I wherein R₆ represents a group selected from Ci_-8 alkyl and C_3-6 cycloalkyl-Ci alkyl. In another embodiment, the invention relates to compounds of formula I wherein R₆ represents a group selected from C_4-5 alkyl and C_3-6 cycloalkyl-Ci alkyl. In another embodiment, the invention relates to compounds of formula I wherein R₆ represents isobutyl or cyclopropylmethyl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents a group selected from C_3-8 cycloalkyl-C_0-6 alkyl and An-C_0-4 alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine) and the C_3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents a group selected from C_3-8 cycloalkyl-C_0-i alkyl and AιvCo-2 alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine) and the C_3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents a group selected from Cs-s cycloalkyl-Co-i alkyl and An-Co-2 alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents a group selected from C₃-8 cycloalkyl-C₀-i alkyl and An-C_0-I alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents a group selected from C3-8 cycloalkyl-Ci_-6 alkyl and An-Co_-4 alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine) and the C3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents a group selected from C_3-S cycloalkyl-Ci_-6 alkyl and An-C_0-2 alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine) and the C_3-S cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents a group selected from C_3-8 cycloalkyl-Ci alkyl and An-Ci alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine) and the C_3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents a group selected from C_3-8 cycloalkyl-Ci alkyl and An-Ci alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents a group selected from C_3-6 cycloalkyl-Ci alkyl and An-Ci alkyl. In another embodiment, the invention relates to compounds of formula I wherein R₆ represents Ci_-8 alkyl optionally substituted with one or more halogen groups (preferably fluorine).

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents Ci_-5 alkyl optionally substituted with one or more halogen groups (preferably fluorine).

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents Ci_-5 alkyl. In another embodiment, the invention relates to compounds of formula I wherein R₆ represents C_4-5 alkyl optionally substituted with one or more halogen groups (preferably fluorine).

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents C_4-5 alkyl. In another embodiment, the invention relates to compounds of formula I wherein R₆ represents isobutyl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents C_3-S cycloalkyl-C_0-6 alkyl, wherein the alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine) and the C_3-S cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents C_3-S cycloalkyl-C_0-i alkyl, wherein the alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine) and the C_3-S cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents C_3-s cycloalkyl-Co-i alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents C_3-6 cycloalkyl-C_0-i alkyl, wherein the alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine) and the C_3-S cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents C_3-6 CyClOaIkVl-Co-I alkyl. In another embodiment, the invention relates to compounds of formula I wherein R₆ represents C_3-S cycloalkyl-Ci_-6 alkyl, wherein the alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine) and the C_3-S cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents C3-8 cycloalkyl-Ci alkyl, wherein the alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine) and the C3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents Cs-s cycloalkyl-Ci alkyl. In another embodiment, the invention relates to compounds of formula I wherein R₆ represents C3_-6 cycloalkyl-Ci alkyl.

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

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents An-Co_-4 alkyl, wherein the alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine).

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents An-Co-2 alkyl, wherein the alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine). In another embodiment, the invention relates to compounds of formula I wherein R₆ represents An -C0-2 alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents An-Co-1 alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents An-Ci alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents An-Co-2 alkyl, wherein An represents phenyl substituted with one group selected from hydroxy-Co_-6 alkyl, R₈CO2-Co_-6 alkyl, R₈SO2NHCO- Co-6 alkyl, (1 H-tetrazol-5-yl)-C_0-6 alkyl, -CONR₈Rs, -SO₂NR₈Rs, -SO₂R₈', - NR₈SO₂R₈', -NR₈CONR₈R₈, -NR₈COR₈ and -NR₈R₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy; and preferably An represents phenyl substituted with one group selected from hydroxy-Co-6 alkyl, -CONR₈R₈, -SO₂R₈' and -NR₈COR₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents An-Co_-2 alkyl, wherein An represents phenyl substituted at the meta position with one group selected from hydroxy-C_0-6 alkyl, R₈CO₂-C_0-B alkyl, R₈SO₂NHCO-C_0-6 alkyl, (1 H-tetrazol-5-yl)-C_0-6 alkyl, - CONR₈R₈, -SO₂NR₈R₈, -SO₂R₈', -NR₈SO₂R₈', -NR₈CONR₈R₈, -NR₈COR₈ and -NR₈R₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy; and preferably An represents phenyl substituted at the meta position with one group selected from hydroxy-C_0-6 alkyl, -CONR₈R₈, -SO₂R₈' and - NR₈COR₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents An-Ci alkyl, wherein An represents phenyl substituted with one group selected from hydroxy-C_0-6 alkyl, R₈CO₂-C_0-6 alkyl, R₈SO₂NHCO-C_0-6 alkyl, (1 H-tetrazol-5-yl)-C_0-6 alkyl, - CONR₈R₈, -SO₂NR₈R₈, -SO₂R₈', -NR₈SO₂R₈', - NR₈CONR₈R₈, -NR₈COR₈ and -NR₈R₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy; and preferably An represents phenyl substituted with one group selected from hydroxy-C_0-6 alkyl, -CONR₈R₈, -SO₂R₈' and -NR₈COR₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents An-Ci alkyl, wherein An represents phenyl substituted at the meta position with one group selected from hydroxy-C_0-6 alkyl, R₈CO₂-C_0-6 alkyl, R₈SO₂NHCO-C_0-6 alkyl, (1 H-tetrazol-5-yl)-C_0-6 alkyl, - CONR₈R₈, -SO₂NR₈R₈, -SO₂R₈', -NR₈SO₂R₈', -NR₈CONR₈R₈, -NR₈COR₈ and -NR₈R₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy; and preferably An represents phenyl substituted at the meta position with one group selected from hydroxy-C_0-6 alkyl, -CONR₈Rs, -SO₂Rs' and - NR₈CORs, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy. In another embodiment, the invention relates to compounds of formula I wherein R₆ represents An .

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

Ri represents (i); n represents 1 ;

R₄ and R₅ represent H; and

R₆ represents a group selected from Ci_-8 alkyl, C₃-₈ cycloalkyl-C₀-i alkyl and

An-Co-2 alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine) and the C3_-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from

Ci_-4 alkyl, halogen (preferably fluorine) and aryl.

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

Ri represents (i); n represents 1 ;

R₄ and R₅ represent H; and

R₆ represents a group selected from Ci_-8 alkyl, C_3-8 cycloalkyl-C_0-i alkyl and An -Co-₂ alkyl.

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

Ri represents (i); n represents 1 ;

R₄ and R₅ represent H; and

R₆ represents a group selected from C_4-5 alkyl, C_3-6 cycloalkyl-C_0-i alkyl and An -Co-₂ alkyl.

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

Ri represents (i); n represents 1 ;

R₄ and R₅ represent H; and

R₆ represents a group selected from Ci_-8 alkyl and C_3-6 CyClOaIkVl-C_0-I alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and the C_3-6 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl.

In another embodiment, the invention relates to compounds of formula I wherein: Ri represents (i); n represents 1 ;

R₄ and R₅ represent H; and

R₆ represents a group selected from Ci_-8 alkyl and C₃-6 cycloalkyl-C₀-i alkyl.

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

Ri represents (i); n represents 1 ;

R₄ and R₅ represent H; and

R₆ represents a group selected from C_4-5 alkyl and C₃-₆ cycloalkyl-C₀-i alkyl. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents (i); n represents 1 ;

R₄ and R₅ represent H; and R₆ represents isobutyl or cyclopropylmethyl.

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

Ri represents (i); n represents 1 ; R₄ and R₅ represent H; and

R₆ represents a group selected from C_3-8 cycloalkyl-Co_-6 alkyl and An-Co_-4 alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine) and the C_3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl.

R₄ and R₅ represent H; and

Re represents a group selected from C3-8 cycloalkyl-Co-i alkyl and ArrCo-2 alkyl. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents (i); n represents 1 ;

R₄ and R₅ represent H; and Re represents a group selected from C3-8 cycloalkyl-Ci-6 alkyl and An-Co_-4 alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine) and the C3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents (i); n represents 1 ;

R₄ and R₅ represent H; and Re represents a group selected from C3-6 cycloalkyl-Ci alkyl and An-Ci alkyl.

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

Ri represents (i); n represents 1 ; R₄ and R₅ represent H; and

Re represents Ci-S alkyl optionally substituted with one or more halogen groups (preferably fluorine).

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

Ri represents (i); n represents 1 ;

R₄ and R₅ represent H; and R₆ represents Ci_-5 alkyl, preferably C_4-5 alkyl.

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

Ri represents (i); n represents 1 ; R₄ and R₅ represent H; and

R₆ represents isobutyl.

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

Ri represents (i); n represents 1 ;

R₄ and R₅ represent H; and

R₆ represents C3-8 cycloalkyl-Co-i alkyl, wherein the alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine) and the C3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl.

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

Ri represents (i); n represents 1 ;

R₄ and R₅ represent H; and

R₆ represents C₃-₆ cycloalkyl-C₀-i alkyl.

R₄ and R₅ represent H; and

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

Ri represents (i); n represents 1 ; R₄ and R₅ represent H; and

Re represents C3-8 cycloalkyl-Ci-6 alkyl, wherein the alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine) and the C3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl.

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

Ri represents (i); n represents 1 ; R₄ and R₅ represent H; and

Re represents C3_-8 cycloalkyl-Ci alkyl.

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

Ri represents (i); n represents 1 ;

R₄ and R₅ represent H; and

R₆ represents An -C0-2 alkyl.

R₄ and R₅ represent H; and

Re represents An -C0-2 alkyl, wherein An represents phenyl substituted with one group selected from hydroxy-Co-e alkyl, R₈CO₂-C_0-B alkyl, R₈SO₂NHCO-Co-B alkyl, (1 H-tetrazol-5-yl)-C₀-₆ alkyl, -CONR₈R₈, -SO₂NR₈R₈, -SO₂R₈', -NR₈SO₂R₈' -NR₈CONR₈R₈, -NR₈COR₈ and -NR₈R₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy; and preferably An represents phenyl substituted with one group selected from hydroxy-Co-6 alkyl, -CONR₈Rs, -SO₂R₈'and -NR₈COR₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy.

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

Ri represents (i); n represents 1 ; R₄ and R₅ represent H; and

Re represents An -C0-2 alkyl, wherein An represents phenyl substituted at the meta position with one group selected from hydroxy-C_0-6 alkyl, R₈CO₂-C_0-B alkyl, R₈SO₂NHCO-C_0-6 alkyl, (1 H-tetrazol-5-yl)-C_0-6 alkyl, -CONR₈R₈, -SO₂NR₈R₈,

-SO₂R₈', -NR₈SO₂R₈', -NR₈CONR₈R₈, -NR₈COR₈ and -NR₈R₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and

Ci_-4 alkoxy; and preferably An represents phenyl substituted at the meta position with one group selected from hydroxy-C_0-6 alkyl, -CONR₈R₈, -SO₂R₈' and -

NR₈COR₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy.

In another embodiment, the invention relates to compounds of formula I wherein: Ri represents (i); n represents 1 ; R₄ and R₅ represent H; and Re represents An-Ci alkyl.

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

Ri represents (i); n represents 1 ; R₄ and R₅ represent H; and

Re represents An-Ci alkyl, wherein An represents phenyl substituted with one group selected from hydroxy-C_0-6 alkyl, R₈CO₂-C_0-6 alkyl, R₈SO₂NHCO-C_0-6 alkyl, (1 H-tetrazol-5-yl)-C_0-6 alkyl, -CONR₈R₈, -SO₂NR₈R₈, -SO₂R₈', -NR₈SO₂R₈'

-NR₈CONR₈R₈, -NR₈COR₈ and -NR₈R₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy; and preferably An represents phenyl substituted with one group selected from hydroxy-Co-6 alkyl, -CONR₈R₈, -SO₂R₈' and -NR₈COR₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy; In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents (i); n represents 1 ;

R₄ and R₅ represent H; and Re represents An-Ci alkyl, wherein An represents phenyl substituted at the meta position with one group selected from hydroxy-Co-e alkyl, R₈CO₂-C_0-B alkyl, R₈SO₂NHCO-C_0-6 alkyl, (1 H-tetrazol-5-yl)-C₀-₆ alkyl, -CONR₈R₈, -SO₂NR₈R₈, - SO₂R₈', -NR₈SO₂R₈', -NR₈CONR₈R₈, -NR₈COR₈ and -NR₈R₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy; and preferably An represents phenyl substituted at the meta position with one group selected from hydroxy-Co-6 alkyl, -CONR₈R₈, -SO₂R₈' and - NR₈COR₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ and R₃ 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 can be 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 can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic groups (i) and (ii) can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; or R₂ represents H or Ci_-4 alkyl, and R₃ represents azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, which can be optionally substituted with one or more Ci_-4 alkyl groups.

In another embodiment, the invention relates to compounds of formula I wherein R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7-membered monocyclic, 7- to 8- membered bridged bicyclic or 8- to 12-membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl and NR₃Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃Rb group, or contains 1 N atom and is substituted with one NR₃R_b group.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ and R3 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 can be 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 NR₃R_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic groups (i) and (ii) can be 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 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 compounds of formula I wherein R₃ and R_b independently represent H or methyl.

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 Rb 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 R₃ and Rb represent H.

In another embodiment, the invention relates to compounds of formula I wherein R₂ and R3 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 and R₀ represents H or Ci_-4 alkyl, and preferably R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), and R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, preferably R₃, 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 compounds of formula I wherein R₂ and R3 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 previously described for the compounds of formula I and R₀ represents H or C1-4 alkyl, and preferably R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein R₂ and R3 form together with the N atom to which they are bound a saturated heterocyclic group selected from (a) and (b), and R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, preferably R₃, 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 R₂ and R₃ 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 Ci_-4 alkyl and R₀ represents H.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ and R₃ 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 methyl and R₀ represents H.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ and R₃ 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 methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein R₂ and R₃ 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 previously described for the 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 R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), and R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ independently represent H or methyl.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ and R3 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 Ci_-4 alkyl and R₀ represents H.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ and R₃ 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 methyl and R₀ represents H.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ and R₃ 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 methyl and R₀ represents H or methyl.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ and R₃ 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 methyl. In another embodiment, the invention relates to the compounds of formula I wherein R₂ and R₃ 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 methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein R₂ and R3 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 previously described for the 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 R₂ and R3 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 R₂ and R₃ 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 R₂ and R₃ 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 R₂ and R₃ 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 compounds of formula I wherein R₂ represents H or Ci_-4 alkyl and R₃ represents azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, which may be optionally substituted with one or more Ci_-4 alkyl groups, and preferably R₂ represents H and R₃ represents 1 -methyl- pyrrol id in-3-yl.

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

Ri represents a group selected from (i) and (ii);

R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7-membered monocyclic, 7- to 8- membered bridged bicyclic or 8- to 12-membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl and NR₃Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃Rb group, or contains 1 N atom and is substituted with one NR₃R_b group; and Re represents a group selected from Ci-S alkyl and C_3-s cycloalkyl-Co-6 alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and the C_3-s cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents a group selected from (i) and (ii);

R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7-membered monocyclic, 7- to 8- membered bridged bicyclic or 8- to 12-membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl and NR₃R_b, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃R_b group, or contains 1 N atom and is substituted with one NR₃R_b group;

Re represents a group selected from Ci-S alkyl and C_3-s cycloalkyl- Co-6 alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and the C_3-s cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl; n represents 1 or 2; and p represents 0 or 1. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents a group selected from (i) and (ii);

R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7-membered monocyclic, 7- to 8- membered bridged bicyclic or 8- to 12-membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl and NR₃Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃Rb group, or contains 1 N atom and is substituted with one NR₃R_b group;

Re represents a group selected from Ci-S alkyl and Cs-s cycloalkyl- Co-6 alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and the C3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl;

R₄ and R₅ are each independently selected from H and Ci_-4 alkyl; n represents 1 or 2; and p represents 0 or 1.

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

R 1 represents a group selected from (i) and (ii);

R₂ and R3 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 can be 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 NR₃R_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic groups (i) and (ii) can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; and R₆ represents a group selected from Ci_-8 alkyl and C_3-S cycloalkyl-Co-e alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and the C_3-S cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents a group selected from (i) and (ii);

R₂ and R₃ 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 can be 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 can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic groups (i) and (ii) can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic;

Re represents a group selected from Ci-S alkyl and C_3-8 cycloalkyl-Co-6 alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and the C_3-s cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl; n represents 1 or 2; and p represents 0 or 1.

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

Ri represents a group selected from (i) and (ii); R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:

R₆ represents a group selected from Ci_-8 alkyl and C₃-₈ cycloalkyl-C₀-₆ alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and the C3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl;

R₄ and R₅ are each independently selected from H and Ci_-4 alkyl; n represents 1 or 2; and p represents 0 or 1. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents a group selected from (i) and (ii);

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

R₆ represents a group selected from Ci_-8 alkyl and C_3-8 cycloalkyl-C_0-6 alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and the C_3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents a group selected from (i) and (ii);

R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), wherein R₃, Rb and R₀ have the meaning described above, preferably R_a, Rb and R₀ represent independently H or Ci_-4 alkyl, more preferably R_a, Rb and R₀ represent independently H or methyl, and still more preferably R_a and Rb independently represent H or methyl and R₀ represents H; R₆ represents a group selected from Ci_-8 alkyl and C3-8 cycloalkyl-Co-e alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and the C3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl; n represents 1 or 2; and p represents 0 or 1.

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

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

Re represents a group selected from Ci-S alkyl and Cs-s cycloalkyl-Co-β alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and the C3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl;

Ri represents a group selected from (i) and (ii);

R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R₃, Rb and R₀ have the meaning described above, and preferably R_a, Rb and R₀ represent independently H or Ci_-4 alkyl, and more preferably R_a, Rb and R₀ represent independently H or methyl, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H; and R₆ represents a group selected from Ci_-8 alkyl and C3-8 cycloalkyl-Co-e alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and the C3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents a group selected from (i) and (ii);

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

Re represents a group selected from Ci-S alkyl and Cs-s cycloalkyl-Co-β alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and the C3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl; n represents 1 or 2; and p represents 0 or 1.

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

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

Ri represents a group selected from (i) and (ii);

R₂ and R3 together with the N atom to which they are bound form a saturated heterocyclic group of formula (a), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ represent independently H or methyl, and still more preferably R₃ represents H, R_b represents methyl and R₀ represents H; and

Re represents a group selected from Ci-S alkyl and Cs-s cycloalkyl-Co-β alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and the C3-s cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl.

In another embodiment, the invention relates to compounds of formula I wherein: Ri represents a group selected from (i) and (ii);

R₂ and R₃ together with the N atom to which they are bound form a saturated heterocyclic group of formula (a), wherein R₃, R_b and R₀ represent independently H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ represent independently H or methyl, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H;

R₆ represents a group selected from Ci_-8 alkyl and C_3-8 cycloalkyl-Co-e alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and the C_3-S cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl; n represents 1 or 2; and p represents 0 or 1. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents a group selected from (i) and (ii);

R₂ and R₃ together with the N atom to which they are bound form a saturated heterocyclic group of formula (a), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ represent independently H or methyl, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H;

R₆ represents a group selected from Ci_-8 alkyl and C_3-8 cycloalkyl-Co-e alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and the C_3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl;

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

Ri represents a group selected from (i) and (ii);

R₂ and R₃ together with the N atom to which they are bound form a saturated heterocyclic group of formula (b), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ represent independently H or methyl, and more preferably R_a and Rb represent independently H or methyl and R₀ represents H, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H; and

R₆ represents a group selected from Ci_-8 alkyl and C_3-8 cycloalkyl-Co-e alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and the C_3-S cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl.

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

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

R₂ and R₃ together with the N atom to which they are bound form a saturated heterocyclic group of formula (b), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ represent independently H or methyl, and more preferably R_a and Rb represent independently H or methyl and R₀ represents H, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H;

Re represents a group selected from Ci-S alkyl and C_3-8 cycloalkyl-Co-6 alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and the C3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl;

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

Ri represents (i); and R2 and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7-membered monocyclic, 7- to 8- membered bridged bicyclic or 8- to 12-membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl and NR₃Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃Rb group, or contains 1 N atom and is substituted with one NR₃R_b group.

In another embodiment, the invention relates to compounds of formula I wherein: Ri represents (i); 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 NR₃R_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic groups (i) and (ii) can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic.

R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), wherein R₃, Rb and R₀ have the meaning described above, preferably R₃, Rb and R₀ represent independently H or C1-4 alkyl, more preferably R₃, Rb and R₀ represent independently H or methyl, and still more preferably R_a and Rb independently represent H or methyl and R₀ represents H.

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

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

Ri represents (i); and R₂ and R3 together with the N atom to which they are bound form a saturated heterocyclic group of formula (a), wherein R₃, R_b and R₀ represent independently H or Ci_-4 alkyl, and preferably R₃, R_b and R₀ represent independently H or methyl, and still more preferably R₃ represents H, R_b represents methyl and R₀ represents H. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents (i); and

R₂ and R₃ together with the N atom to which they are bound form a saturated heterocyclic group of formula (b), wherein R₃, R_b and R₀ represent independently H or Ci_-4 alkyl, and preferably R₃, R_b and R₀ represent independently H or methyl, and more preferably R₃ and Rb represent independently H or methyl and R₀ represents H, and still more preferably R₃ represents H, R_b represents methyl and R₀ represents H. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents (i);

R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7-membered monocyclic, 7- to 8- membered bridged bicyclic or 8- to 12-membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl and NR₃Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃Rb group, or contains 1 N atom and is substituted with one NR₃R_b group; and

R₆ represents a group selected from Ci_-8 alkyl and C₃-₈ cycloalkyl-C₀-₆ alkyl, preferably from Ci_-8 alkyl and C_3-6 cycloalkyl-C_0-i alkyl, more preferably from Ci_-8 alkyl and C3-6 cycloalkyl-Ci alkyl, and still more preferably from C_4-5 alkyl and C3-6 cycloalkyl-Ci alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and any cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl.

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

Ri represents (i);

Re represents a group selected from Ci_-8 alkyl and C3_-8 cycloalkyl-Co-6 alkyl, preferably from Ci_-8 alkyl and C3-6 cycloalkyl-Co-i alkyl, more preferably from Ci_-8 alkyl and C_3-6 cycloalkyl-Ci alkyl, and still more preferably from C_4-5 alkyl and C_3-6 cycloalkyl-Ci alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and any cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl.

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

Ri represents (i); R2 and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7-membered monocyclic, 7- to 8- membered bridged bicyclic or 8- to 12-membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl and NR₃Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃Rb group, or contains 1 N atom and is substituted with one NR₃R_b group;

R₆ represents a group selected from Ci_-8 alkyl and C₃-₈ cycloalkyl-C₀-₆ alkyl, preferably from Ci_-8 alkyl and C3-6 cycloalkyl-C_0-i alkyl, more preferably from Ci_-8 alkyl and C3-6 cycloalkyl-Ci alkyl, and still more preferably from C_4-5 alkyl and C3-6 cycloalkyl-Ci alkyl, wherein any alkyl group may be optionally substituted by one or more halogen groups (preferably fluorine), and any cycloalkyl group may be optionally substituted by one or more substituents independently selected from Ci- 4 alkyl, halogen (preferably fluorine) and aryl; and n represents 1 or 2, and preferably n is 1.

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

Ri represents (i);

(i) a heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said heterocyclic group can be 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 can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic groups (i) and (ii) can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic;

Re represents a group selected from Ci_-8 alkyl and C3_-8 cycloalkyl-Co-6 alkyl, preferably from Ci_-8 alkyl and C3-6 cycloalkyl-Co-i alkyl, more preferably from Ci_-8 alkyl and C3-6 cycloalkyl-Ci alkyl, and still more preferably from C_4-5 alkyl and C3-6 cycloalkyl-Ci alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and any cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl; and n represents 1 or 2, and preferably n is 1. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents (i);

R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7-membered monocyclic, 7- to 8- membered bridged bicyclic or 8- to 12-membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl and NR₃Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃R_b group, or contains 1 N atom and is substituted with one NR₃R_b group;

Re represents a group selected from Ci_-8 alkyl and C3_-8 cycloalkyl-Co-6 alkyl, preferably from Ci_-8 alkyl and C3-6 cycloalkyl-C_0-i alkyl, more preferably from Ci_-8 alkyl and C3-6 cycloalkyl-Ci alkyl, and still more preferably from C_4-5 alkyl and C3-6 cycloalkyl-Ci alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and any cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl;

R₄ and R₅ are each independently selected from H and Ci_-4 alkyl, and preferably R₄ and R₅ represent H; and n represents 1 or 2, and preferably n is 1.

In another embodiment, the invention relates to compounds of formula I wherein: Ri represents (i);

Re represents a group selected from Ci_-8 alkyl and C3_-8 cycloalkyl-Co-6 alkyl, preferably from Ci_-8 alkyl and C_3-6 cycloalkyl-C_0-i alkyl, more preferably from Ci_-8 alkyl and C_3-6 cycloalkyl-Ci alkyl, and still more preferably from C_4-5 alkyl and C3-6 cycloalkyl-Ci alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and any cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl;

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

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

R₆ represents a group selected from Ci_-8 alkyl and C_3-8 cycloalkyl-C_0-6 alkyl, preferably from Ci_-8 alkyl and C_3-6 cycloalkyl-C_0-i alkyl, more preferably from Ci_-8 alkyl and C_3-6 cycloalkyl-Ci alkyl, and still more preferably from C_4-5 alkyl and C_3-6 cycloalkyl-Ci alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and any cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents (i);

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

R₆ represents a group selected from Ci_-8 alkyl and C_3-8 cycloalkyl-Co-e alkyl, preferably from Ci_-8 alkyl and C_3-6 cycloalkyl-C_0-i alkyl, more preferably from Ci_-8 alkyl and C_3-6 cycloalkyl-Ci alkyl, and still more preferably from C_4-5 alkyl and C_3-6 cycloalkyl-Ci alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and any cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl; and n represents 1 or 2, and preferably n is 1.

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

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

R₆ represents a group selected from Ci_-8 alkyl and C_3-8 cycloalkyl-Co-e alkyl, preferably from Ci_-8 alkyl and C_3-6 cycloalkyl-C_0-i alkyl, more preferably from Ci_-8 alkyl and C_3-6 cycloalkyl-Ci alkyl, and still more preferably from C_4-5 alkyl and C_3-6 cycloalkyl-Ci alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and any cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl; R₄ and R₅ are each independently selected from H and Ci_-4 alkyl, and preferably R₄ and R₅ represent H; and n represents 1 or 2, and preferably n is 1.

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

R₆ represents a group selected from Ci_-8 alkyl and C_3-8 cycloalkyl-Co-e alkyl, preferably from Ci_-8 alkyl and C_3-6 cycloalkyl-Co-i alkyl, more preferably from Ci_-8 alkyl and C_3-6 cycloalkyl-Ci alkyl, and still more preferably from C_4-5 alkyl and C_3-6 cycloalkyl-Ci alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and any cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl.

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

Ri represents (i);

R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R₃, Rb and R₀ have the meaning described above, and preferably R_a, Rb and R₀ represent independently H or Ci_-4 alkyl, and more preferably R₃, Rb and R₀ represent independently H or methyl and still more preferably R_a represents H, R_b represents methyl and R₀ represents H; R₆ represents a group selected from Ci_-8 alkyl and C_3-S cycloalkyl-Co-e alkyl, preferably from Ci-S alkyl and C3-6 cycloalkyl-Co-i alkyl, more preferably from Ci-S alkyl and C3-6 cycloalkyl-Ci alkyl, and still more preferably from C_4-5 alkyl and C3-6 cycloalkyl-Ci alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and any cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl; and n represents 1 or 2, and preferably n is 1.

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

R₆ represents a group selected from Ci_-8 alkyl and C₃-₈ cycloalkyl-C₀-₆ alkyl, preferably from Ci-S alkyl and Cs_-6 cycloalkyl-Co-1 alkyl, more preferably from Ci-S alkyl and Cs_-6 cycloalkyl-Ci alkyl, and still more preferably from C_4-5 alkyl and Cs_-6 cycloalkyl-Ci alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and any cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl;

R₄ and R₅ are each independently selected from H and Ci_-4 alkyl, preferably R₄ and R₅ represent H; and n represents 1 or 2, and preferably n is 1.

R₂ and R3 together with the N atom to which they are bound form a saturated heterocyclic group of formula (a), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ represent independently H or methyl and still more preferably R_a represents H, R_b represents methyl and R₀ represents H; and

Re represents a group selected from Ci_-8 alkyl and C3_-8 cycloalkyl-Co-6 alkyl, preferably from Ci_-8 alkyl and C3-6 cycloalkyl-Co-1 alkyl, more preferably from Ci_-8 alkyl and C3-6 cycloalkyl-Ci alkyl, and still more preferably from C_4-5 alkyl and C3-6 cycloalkyl-Ci alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and any cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl.

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

Ri represents (i);

R₂ and R3 together with the N atom to which they are bound form a heterocycle of formula (a), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ represent independently H or methyl and still more preferably R_a represents H, R_b represents methyl and R₀ represents H;

R₆ represents a group selected from Ci_-8 alkyl and C₃-₈ cycloalkyl-C₀-₆ alkyl, preferably from Ci_-8 alkyl and C3-6 cycloalkyl-Co-1 alkyl, more preferably from Ci_-8 alkyl and C3-6 cycloalkyl-Ci alkyl, and still more preferably from C_4-5 alkyl and C3-6 cycloalkyl-Ci alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and any cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl; and n represents 1 or 2, and preferably n is 1.

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

Ri represents (i);

R₂ and R₃ together with the N atom to which they are bound form a saturated heterocyclic group of formula (a), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ represent independently H or methyl and still more preferably R_a represents H, R_b represents methyl and R₀ represents H;

R₆ represents a group selected from Ci_-8 alkyl and C_3-S cycloalkyl-Co-e alkyl, preferably from Ci_-8 alkyl and C_3-6 cycloalkyl-C_0-i alkyl, more preferably from Ci_-8 alkyl and C3-6 cycloalkyl-Ci alkyl, and still more preferably from C_4-5 alkyl and C3-6 cycloalkyl-Ci alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and any cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl;

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

Ri represents (i);

R₂ and R3 together with the N atom to which they are bound form a saturated heterocyclic group of formula (b), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ represent independently H or methyl, and more preferably R_a and Rb represent independently H or methyl and R₀ represents H, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H; and

Re represents a group selected from Ci_-8 alkyl and C3_-8 cycloalkyl-Co-6 alkyl, preferably from Ci_-8 alkyl and C3-6 cycloalkyl-Co-i alkyl, more preferably from Ci_-8 alkyl and C3-6 cycloalkyl-Ci alkyl, and still more preferably from C_4-5 alkyl and C3-6 cycloalkyl-Ci alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and any cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents (i);

R₂ and R3 together with the N atom to which they are bound form a saturated heterocyclic group of formula (b), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ represent independently H or methyl, and more preferably R_a and Rb represent independently H or methyl and R₀ represents H, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H;

Re represents a group selected from Ci-S alkyl and Cs-s cycloalkyl-Co-β alkyl, preferably from Ci-S alkyl and C3-6 cycloalkyl-Co-i alkyl, more preferably from Ci-S alkyl and C3-6 cycloalkyl-Ci alkyl, and still more preferably from C_4-5 alkyl and C3-6 cycloalkyl-Ci alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and any cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl; and n represents 1 or 2, and preferably n is 1.

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

Ri represents (i);

Re represents a group selected from Ci-S alkyl and Cs-s cycloalkyl-Co-β alkyl, preferably from Ci-S alkyl and C3-6 cycloalkyl-Co-1 alkyl, more preferably from Ci-S alkyl and C3-6 cycloalkyl-Ci alkyl, and still more preferably from C_4-5 alkyl and C3-6 cycloalkyl-Ci alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups (preferably fluorine), and any cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluorine) and aryl; R₄ and R₅ are each independently selected from H and Ci_-4 alkyl, preferably

R₄ and R₅ represent H; and n represents 1 or 2, and preferably n is 1.

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

Ri represents (i);

R₆ represents isobutyl or cyclopropylmethyl;

R₄ and R₅ are each independently selected from H and Ci_-4 alkyl, preferably R₄ and R₅ represent H; and n represents 1 or 2, and preferably n is 1. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents (i);

R₂ and R3 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 can be 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 NR₃R_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic groups (i) and (ii) can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic;

R₆ represents isobutyl or cyclopropylmethyl; R₄ and R₅ are each independently selected from H and Ci_-4 alkyl, preferably

R₄ and R₅ represent H; and n represents 1 or 2, and preferably n is 1.

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

Ri represents (i);

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

Re represents isobutyl or cyclopropylmethyl; R₄ and R₅ are each independently selected from H and Ci_-4 alkyl, preferably

R₄ and R₅ represent H; and n represents 1 or 2, and preferably n is 1.

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

R₆ represents isobutyl or cyclopropylmethyl;

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

Ri represents (i);

R₂ and R₃ together with the N atom to which they are bound form a saturated heterocyclic group of formula (a), wherein R₃, R_b and R₀ represent independently H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ represent independently H or methyl, and still more preferably R₃ represents H, R_b represents methyl and R₀ represents H; Re represents isobutyl or cyclopropylmethyl;

Ri represents (i);

R₄ and R₅ represent H; and n represents 1 or 2, and preferably n is 1.

R₆ represents Ci_-8 alkyl, preferably Ci_-5 alkyl, more preferably C_4-5 alkyl and still more preferably isobutyl;

Ri represents (i);

(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 can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic groups (i) and (ii) can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; Re represents Ci-S alkyl, preferably Ci_-5 alkyl, more preferably C_4-5 alkyl and still more preferably isobutyl;

Ri represents (i);

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

Ri represents (i);

R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R₃, Rb and R₀ have the meaning described above, and preferably R_a, Rb and R₀ represent independently H or Ci_-4 alkyl, and more preferably R_a, Rb and R₀ represent independently H or methyl, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H; R₆ represents Ci_-8 alkyl, preferably Ci_-5 alkyl, more preferably C_4-5 alkyl and still more preferably isobutyl;

Ri represents (i);

R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ represent independently H or methyl, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H;

Re represents C1-8 alkyl, preferably Ci_-5 alkyl, more preferably C_4-5 alkyl and still more preferably isobutyl; R₄ and R₅ are each independently selected from H and Ci_-4 alkyl, preferably

R₄ and R₅ represent H; and n represents 1 or 2, and preferably n is 1.

R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ represent independently H or methyl, and more preferably R_a and Rb represent independently H or methyl and R₀ represents H, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H;

R₆ represents Ci_-8 alkyl, preferably C1-5 alkyl, more preferably C_4-5 alkyl and still more preferably isobutyl;

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

Ri represents (i);

R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7-membered monocyclic, 7- to 8- membered bridged bicyclic or 8- to 12-membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl and NR₃Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃Rb group, or contains 1 N atom and is substituted with one NR₃R_b group; R₆ represents C3-8 cycloalkyl-C_0-6 alkyl, preferably C_3-6 cycloalkyl-C_0-i alkyl, more preferably C_3-6cycloalkyl-Ci alkyl and still more preferably cyclopropylmethyl; R₄ and R₅ are each independently selected from H and Ci_-4 alkyl, preferably R₄ and R₅ represent H; and n represents 1 or 2, and preferably n is 1. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents (i);

R₂ and R₃ 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 can be 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 can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic groups (i) and (ii) can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic;

Re represents C3-8 cycloalkyl-Co-6 alkyl, preferably C3-6 cycloalkyl-Co-i alkyl, more preferably C3-6cycloalkyl-Ci alkyl and still more preferably cyclopropylmethyl; R₄ and R₅ are each independently selected from H and Ci_-4 alkyl, preferably R₄ and R₅ represent H; and n represents 1 or 2, and preferably n is 1.

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

Ri represents (i);

R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), wherein R₃, Rb and R₀ have the meaning described above, preferably R_a, Rb and R₀ represent independently H or Ci_-4 alkyl, more preferably R_a, Rb and R₀ represent independently H or methyl, and still more preferably R_a and Rb independently represent H or methyl and R₀ represents H; R₆ represents C_3-S cycloalkyl-Co-e alkyl, preferably C3-6 cycloalkyl-C_0-i alkyl, more preferably C_3-6cycloalkyl-Ci alkyl and still more preferably cyclopropylmethyl; R₄ and R₅ are each independently selected from H and Ci_-4 alkyl, preferably R₄ and R₅ represent H; and n represents 1 or 2, and preferably n is 1. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents (i);

R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R₃, Rb and R₀ have the meaning described above, and preferably R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, and more preferably R_a, Rb and R₀ represent independently H or methyl, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H; Re represents C3-8 cycloalkyl-Co-6 alkyl, preferably C3-6 cycloalkyl-Co-i alkyl, more preferably C_3-6cycloalkyl-Ci alkyl and still more preferably cyclopropylmethyl; R₄ and R₅ are each independently selected from H and Ci_-4 alkyl, preferably R₄ and R₅ represent H; and n represents 1 or 2, and preferably n is 1.

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

Ri represents (i);

R₂ and R3 together with the N atom to which they are bound form a saturated heterocyclic group of formula (a), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ represent independently H or methyl, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H;

Re represents C3-8 cycloalkyl-Co-6 alkyl, preferably C3-6 cycloalkyl-Co-i alkyl, more preferably Cs-βcycloalkyl-Ci alkyl and still more preferably cyclopropylmethyl; R₄ and R₅ are each independently selected from H and Ci_-4 alkyl, preferably R₄ and R₅ represent H; and n represents 1 or 2, and preferably n is 1.

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

Ri represents (i);

R₂ and R3 together with the N atom to which they are bound form a saturated heterocyclic group of formula (b), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ represent independently H or methyl, and more preferably R_a and Rb represent independently H or methyl and R₀ represents H, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H;

R₆ represents C3-8 cycloalkyl-Co-e alkyl, preferably C3-6 cycloalkyl-C_0-i alkyl, more preferably C_3-6cycloalkyl-Ci alkyl and still more preferably cyclopropylmethyl; R₄ and R₅ are each independently selected from H and Ci_-4 alkyl, preferably

R₄ and R₅ represent H; and n represents 1 or 2, and preferably n is 1.

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

Ri represents (i);

Re represents An-Co_-4 alkyl, wherein the alkyl group may be optionally substituted by one or more halogen groups (preferably fluorine), and preferably represents An-C_0-2 alkyl and more preferably An-Ci alkyl,.

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

Ri represents (i);

R₂ and R₃ 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 NR₃R_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic groups (i) and (ii) can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; and

Re represents An-Co_-4 alkyl, wherein the alkyl group may be optionally substituted by one or more halogen groups (preferably fluorine), and preferably represents An-C_0-2 alkyl and more preferably An-Ci alkyl.

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

Ri represents (i); R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7-membered monocyclic, 7- to 8- membered bridged bicyclic or 8- to 12-membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl and NR₃Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃Rb group, or contains 1 N atom and is substituted with one NR₃R_b group;

Re represents An-Co_-4 alkyl, wherein the alkyl group may be optionally substituted by one or more halogen groups (preferably fluorine), and preferably represents An-C_0-2 alkyl and more preferably An-Ci alkyl; and n represents 1 or 2, preferably n is 1.

Re represents An-Co_-4 alkyl, wherein the alkyl group may be optionally substituted by one or more halogen groups (preferably fluorine), and preferably represents An-C_0-2 alkyl and more preferably An-Ci alkyl;and n represents 1 or 2, preferably n is 1.

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

Re represents An-Co_-4 alkyl, wherein the alkyl group may be optionally substituted by one or more halogen groups (preferably fluorine), and preferably represents An-C_0-2 alkyl and more preferably An-Ci alkyl;

R₄ and R₅ are each independently selected from H and Ci_-4 alkyl, preferably R₄ and R₅ represent H; and n represents 1 or 2, preferably n is 1. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents (i);

Re represents An-Co_-4 alkyl, wherein the alkyl group may be optionally substituted by one or more halogen groups (preferably fluorine), and preferably represents An-Co_-2 alkyl and more preferably An-Ci alkyl;

R₄ and R₅ are each independently selected from H and Ci_-4 alkyl, preferably R₄ and R₅ represent H; and n represents 1 or 2, preferably n is 1.

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

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

Re represents An-Co_-4 alkyl, wherein the alkyl group may be optionally substituted by one or more halogen groups (preferably fluorine), and preferably represents An-Co-2 alkyl and more preferably An-Ci alkyl.

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

Ri represents (i);

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

Re represents An-Co_-4 alkyl, wherein the alkyl group may be optionally substituted by one or more halogen groups (preferably fluorine), and preferably represents An-Co-2 alkyl and more preferably An-Ci alkyl; and n represents 1 or 2, preferably n is 1.

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

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

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

Ri represents (i);

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

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

Ri represents (i);

R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R₃, Rb and R₀ have the meaning described above, and preferably R_a, Rb and R₀ represent independently H or Ci_-4 alkyl, and more preferably R₃, Rb and R₀ represent independently H or methyl, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H; R₆ represents An-C_0-4 alkyl, wherein the alkyl group may be optionally substituted by one or more halogen groups (preferably fluorine), and preferably represents An-C_0-2 alkyl and more preferably An-Ci alkyl;and n represents 1 or 2, preferably n is 1. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents (i);

R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R₃, Rb and R₀ have the meaning described above, and preferably R_a, Rb and R₀ represent independently H or Ci_-4 alkyl, and more preferably R_a, Rb and R₀ represent independently H or methyl, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H; Re represents An-Co_-4 alkyl, wherein the alkyl group may be optionally substituted by one or more halogen groups (preferably fluorine), and preferably represents An-C_0-2 alkyl and more preferably An-Ci alkyl;

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

Ri represents (i);

R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ represent independently H or methyl, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H; and

Re represents An-Co_-4 alkyl, wherein the alkyl group may be optionally substituted by one or more halogen groups (preferably fluorine), and preferably represents An-Co_-2 alkyl and more preferably An-Ci alkyl.

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

Ri represents (i); R₂ and R3 form, together with the N atom to which they are bound, a heterocycle of formula (a), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ represent independently H or methyl, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H I; Rβ represents An-Co_-4 alkyl, wherein the alkyl group may be optionally substituted by one or more halogen groups (preferably fluorine), and preferably represents An-C_0-2 alkyl and more preferably An-Ci alkyl; and n represents 1 or 2, preferably n is 1. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents (i);

Re represents An-Co_-4 alkyl, wherein the alkyl group may be optionally substituted by one or more halogen groups (preferably fluorine), and preferably represents An-Co-2 alkyl and more preferably An-Ci alkyl;

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

Ri represents (i);

R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ represent independently H or methyl, and more preferably R_a and Rb represent independently H or methyl and R₀ represents H, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H; and

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

Ri represents (i); R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ represent independently H or methyl, and more preferably R_a and Rb represent independently H or methyl and R₀ represents H, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H;

Re represents An-Co_-4 alkyl, wherein the alkyl group may be optionally substituted by one or more halogen groups (preferably fluorine), and preferably represents An-Co_-2 alkyl and more preferably An-Ci alkyl; and n represents 1 or 2, preferably n is 1.

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

Ri represents (i);

R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ represent independently H or methyl, and more preferably R_a and Rb represent independently H or methyl and R₀ represents H, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H; Re represents An-Co_-4 alkyl, wherein the alkyl group may be optionally substituted by one or more halogen groups (preferably fluorine), and preferably represents An-C_0-2 alkyl and more preferably An-Ci alkyl;

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

Ri represents (i);

R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7-membered monocyclic, 7- to 8- membered bridged bicyclic or 8- to 12-membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl and NR₃Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃Rb group, or contains 1 N atom and is substituted with one NR₃R_b group;

R₆ represents An -Co-₂ alkyl and preferably An-Ci alkyl; An represents phenyl substituted with one group selected from hydroxy-C_0-6 alkyl, R₈CO₂-C_0-B alkyl, R₈SO₂NHCO-Co-B alkyl, (1 H-tetrazol-5-yl)-C_0-6 alkyl, - CONR₈R₈, -SO₂NR₈R₈, -SO₂R₈', -NR₈SO₂R₈', -NR₈CONR₈R₈, -NR₈COR₈ and - NR₈R₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy; and preferably An represents phenyl substituted with one group selected from hydroxy-C_0-6 alkyl, -CONR₈R₈, -SO₂R₈' and -NR₈COR₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy;

R₄ and R₅ are each independently selected from H and Ci_-4 alkyl, preferably R₄ and R₅ represent H; and n is 1.

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

Ri represents (i);

(ii) a heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one NR₃R_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic groups (i) and (ii) can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; R₆ represents An-C_0-2 alkyl and preferably An-Ci alkyl; and

An represents phenyl substituted with one group selected from hydroxy-Co-6 alkyl, R₈CO₂-C_0-B alkyl, R₈SO₂NHCO-C_0-6 alkyl, (1 H-tetrazol-5-yl)-C_0-6 alkyl, - CONR₈R₈, -SO₂NR₈R₈, -SO₂R₈', -NR₈SO₂R₈', -NR₈CONR₈R₈, -NR₈COR₈ and - NR₈Re, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy; and preferably An represents phenyl substituted with one group selected from hydroxy-C_0-6 alkyl, -CONR₈Rs, -SO₂Rs' and -NR₈CORs, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy;

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

Ri represents (i);

R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7-membered monocyclic, 7- to 8- membered bridged bicyclic or 8- to 12-membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl and NR₃Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃Rb group, or contains 1 N atom and is substituted with one NR₃R_b group; R₆ represents An-C_0-2 alkyl and preferably An-Ci alkyl;

An represents phenyl substituted at the meta position with one group selected from hydroxy-C_0-6 alkyl, R₈CO₂-C_0-6 alkyl, R₈SO₂NHCO-C_0-6 alkyl, (1 H- tetrazol -5-yl)-C_0-6 alkyl, -CONR₈R₈, -SO₂NR₈R₈, -SO₂R₈', -NR₈SO₂R₈', - NR₈CONR₈R₈, -NR₈COR₈ and -NR₈R₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy; preferably An represents phenyl substituted at the meta position with one group selected from hydroxy-C_0-6 alkyl, -CONR₈R₈, -SO₂R₈' and -NR₈COR₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy; R₄ and R₅ are each independently selected from H and Ci_-4 alkyl, preferably

R₄ and R₅ represent H; and n is 1.

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

Ri represents (i);

Re represents An -Co-₂ alkyl and preferably An-Ci alkyl; An represents phenyl substituted at the meta position with one group selected from hydroxy-Co-e alkyl, R₈CO₂-C_0-B alkyl, R₈SO₂NHCO-Co-B alkyl, (1 H- tetrazol-5-yl)-C₀-6 alkyl, -CONR₈R₈, -SO₂NR₈R₈, -SO₂R₈', -NR₈SO₂R₈' , - NR₈CONR₈R₈, -NR₈COR₈ and -NR₈R₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy; preferably An represents phenyl substituted at the meta position with one group selected from hydroxy-Co-e alkyl, -CONR₈R₈, -SO₂R₈' and -NR₈COR₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy;

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

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

R₆ represents An -C₀-₂ alkyl and preferably An-Ci alkyl;

An represents phenyl substituted with one group selected from hydroxy-C_0-6 alkyl, R₈CO₂-C_0-6 alkyl, R₈SO₂NHCO-C_0-6 alkyl, (1 H-tetrazol-5-yl)-C_0-6 alkyl, -

CONR₈R₈, -SO₂NR₈R₈, -SO₂R₈', -NR₈SO₂R₈', -NR₈CONR₈R₈, -NR₈COR₈ and -

NR₈R₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy; preferably An represents phenyl substituted with one group selected from hydroxy-C_0-6 alkyl, -CONR₈R₈, -SO₂R₈' and -NR₈COR₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy;

R₄ and R₅ are each independently selected from H and Ci_-4 alkyl, preferably R₄ and R₅ represent H; and n is 1. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents (i);

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

R₆ represents An-C_0-2 alkyl and preferably An-Ci alkyl; An represents phenyl substituted at the meta position with one group selected from hydroxy-C_0-6 alkyl, R₈CO₂-C_0-6 alkyl, R₈SO₂NHCO-C_0-6 alkyl, (1 H- tetrazol -5-yl)-C_0-6 alkyl, -CONR₈R₈, -SO₂NR₈R₈, -SO₂R₈', -NR₈SO₂R₈', - NR₈CONR₈R₈, -NR₈COR₈ and -NR₈R₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy; preferably An represents phenyl substituted at the meta position with one group selected from hydroxy-C_0-6 alkyl, -CONR₈R₈, -SO₂R₈' and -NR₈COR₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy; R₄ and R₅ are each independently selected from H and Ci_-4 alkyl, preferably R₄ and R₅ represent H; and n is 1.

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

Ri represents (i);

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

R₆ represents An -Co-₂ alkyl and preferably An-Ci alkyl;

An represents phenyl substituted with one group selected from hydroxy-Co-6 alkyl, R₈CO₂-C_0-6 alkyl, R₈SO₂NHCO-C_0-6 alkyl, (1 H-tetrazol-5-yl)-C_0-6 alkyl, -

Ri represents (i);

R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R₃, Rb and R₀ have the meaning described above, and preferably R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, and more preferably R_a, Rb and R₀ represent independently H or methyl, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H; R₆ represents An-C_0-2 alkyl and preferably An-Ci alkyl;

An represents phenyl substituted at the meta position with one group selected from hydroxy-C₀-₆ alkyl, R₈CO₂-C_0-6 alkyl, R₈SO₂NHCO-C_0-6 alkyl, (1 H- tetrazol-5-yl)-C_0-6 alkyl, -CONR₈R₈, -SO₂NR₈R₈, -SO₂R₈', -NR₈SO₂R₈', - NR₈CONR₈R₈, -NR₈COR₈ and -NR₈R₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy; preferably An represents phenyl substituted at the meta position with one group selected from hydroxy-C_0-6 alkyl, -CONR₈R₈, -SO₂R₈' and -NR₈COR₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy;

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

Ri represents (i);

R₂ and R₃ together with the N atom to which they are bound form a saturated heterocyclic group of formula (a), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ represent independently H or methyl, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H;

R₆ represents An-C_0-2 alkyl and preferably An-Ci alkyl;

An represents phenyl substituted with one group selected from hydroxy-C_0-6 alkyl, R₈CO₂-C_0-6 alkyl, R₈SO₂NHCO-C_0-6 alkyl, (1 H-tetrazol-5-yl)-C_0-6 alkyl, - CONR₈R₈, -SO₂NR₈R₈, -SO₂R₈', -NR₈SO₂R₈', -NR₈CONR₈R₈, -NR₈COR₈ and -

Ri represents (i);

R₂ and R3 together with the N atom to which they are bound form a saturated heterocyclic group of formula (a), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ represent independently H or methyl, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H;

Re represents An -Co-₂ alkyl and preferably An-Ci alkyl; An represents phenyl substituted at the meta position with one group selected from hydroxy-C_0-6 alkyl, R₈CO₂-C_0-6 alkyl, R₈SO₂NHCO-C_0-6 alkyl, (1 H- tetrazol -5-yl)-C_0-6 alkyl, -CONR₈R₈, -SO₂NR₈R₈, -SO₂R₈', -NR₈SO₂R₈', - NR₈CONR₈R₈, -NR₈COR₈ and -NR₈R₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy; preferably An represents phenyl substituted at the meta position with one group selected from hydroxy-C_0-6 alkyl, -CONR₈R₈, -SO₂R₈' and -NR₈COR₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy;

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

Ri represents (i); R₂ and R3 together with the N atom to which they are bound form a saturated heterocyclic group of formula (b), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ represent independently H or methyl, and more preferably R_a and Rb represent independently H or methyl and R₀ represents H, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H;

R₆ represents An-C_0-2 alkyl and preferably An-Ci alkyl; An represents phenyl substituted with one group selected from hydroxy-C_0-6 alkyl, R₈CO₂-C_0-6 alkyl, R₈SO₂NHCO-C_0-6 alkyl, (1 H-tetrazol-5-yl)-C_0-6 alkyl, - CONR₈R₈, -SO₂NR₈R₈, -SO₂R₈', -NR₈SO₂R₈', -NR₈CONR₈R₈, -NR₈COR₈ and - NR₈R₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy; preferably An represents phenyl substituted with one group selected from hydroxy-C_0-6 alkyl, -CONR₈R₈, -SO₂R₈' and -NR₈COR₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy;

Ri represents (i);

R₂ and R₃ together with the N atom to which they are bound form a saturated heterocyclic group of formula (b), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ represent independently H or methyl, and more preferably R_a and Rb represent independently H or methyl and R₀ represents H, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H;

R₆ represents An-C_0-2 alkyl and preferably An-Ci alkyl; An represents phenyl substituted at the meta position with one group selected from hydroxy-C_0-6 alkyl, R₈CO₂-C_0-6 alkyl, R₈SO₂NHCO-C_0-6 alkyl, (1 H- tetrazol -5-yl)-C_0-6 alkyl, -CONR₈R₈, -SO₂NR₈R₈, -SO₂R₈', -NR₈SO₂R₈', - NR₈CONR₈R₈, -NR₈COR₈ and -NR₈R₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy; and preferably An represents phenyl substituted at the meta position with one group selected from hydroxy-C_0-6 alkyl, -CONR₈R₈, -SO₂R₈' and -NR₈COR₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy;

In another embodiment, the invention relates to compounds of formula I wherein: Ri represents (ii) and p represents 0 or 1.

In another embodiment, the invention relates to compounds of formula I wherein: Ri represents (ii) and

R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7-membered monocyclic, 7- to 8- membered bridged bicyclic or 8- to 12-membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl and NR₃Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃Rb group, or contains 1 N atom and is substituted with one NR₃R_b group.

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

Ri represents (ii);

R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7-membered monocyclic, 7- to 8- membered bridged bicyclic or 8- to 12-membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl and NR₃R_b, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃R_b group, or contains 1 N atom and is substituted with one NR₃R_b group; and p represents 0 or 1.

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

Ri represents (ii);

R₄ and R₅ are each independently selected from H and Ci_-4 alkyl; and p represents 0 or 1.

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

Ri represents (ii) and

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

Ri represents (ii);

R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), wherein R₃, R_b and R₀ have the meaning described above, preferably R₃, R_b and R₀ represent independently H or Ci_-4 alkyl, more preferably R₃, R_b and R₀ represent independently H or methyl, and still more preferably R₃ and Rb independently represent H or methyl and R₀ represents H; and p represents 0 or 1. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents (ii);

R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), wherein R₃, R_b and R₀ have the meaning described above, preferably R₃, R_b and R₀ represent independently H or Ci_-4 alkyl, more preferably R₃, Rb and R₀ represent independently H or methyl, and still more preferably R₃ and Rb independently represent H or methyl and R₀ represents H; R₄ and R₅ are each independently selected from H and Ci_-4 alkyl; and p represents 0 or 1.

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

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

Ri represents (ii); R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R₃, Rb and R₀ have the meaning described above, and preferably R_a, Rb and R₀ represent independently H or Ci_-4 alkyl, more preferably R₃, Rb and R₀ represent independently H or methyl, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H; and p represents 0 or 1.

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

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

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

Ri represents (ii) and

R₂ and R3 together with the N atom to which they are bound form a saturated heterocyclic group of formula (a), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, preferably R₃, Rb and R₀ represent independently H or methyl, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein: Ri represents (ii);

R₂ and R3 together with the N atom to which they are bound form a saturated heterocyclic group of formula (a), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, preferably R₃, Rb and R₀ represent independently H or methyl, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H; and p represents 0 or 1.

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

Ri represents (ii); R₂ and R3 together with the N atom to which they are bound form a saturated heterocyclic group of formula (a), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, preferably R₃, Rb and R₀ represent independently H or methyl, and still more preferably R₃ represents H, R_b represents methyl and R₀ represents H; R₄ and R₅ are each independently selected from H and Ci_-4 alkyl; and p represents 0 or 1.

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

Ri represents (ii) and R₂ and R3 together with the N atom to which they are bound form a saturated heterocyclic group of formula (b), wherein R₃, R_b and R₀ represent independently H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ represent independently H or methyl, and more preferably R₃ and Rb represent independently H or methyl and R₀ represents H, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H.

R₂ and R3 together with the N atom to which they are bound form a saturated heterocyclic group of formula (b), wherein R₃, Rb and R₀ represent independently H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ represent independently H or methyl, and more preferably R_a and Rb represent independently H or methyl and R₀ represents H, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H; and p represents 0 or 1.

Moreover, the present invention includes all possible combinations of the particular and preferred embodiments described above for the compounds of formula I.

In an additional embodiment, the invention relates to a compound of formula I selected from:

4-Cyclohexyloxymethyl-6-(3-(methylamino)azetidin-1 -yl)pyrimidin-2-amine; 4-Cyclohexyloxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyhmidin-2-amine; 4-(Cyclopropylmethoxymethyl)-6-(3-(methylamino)azetidin-1-yl)pyhmidin-2-amine; 4-(Cyclopropylmethoxymethyl)-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyrimidin-2- amine; 4-Cyclobutoxymethyl-6-(3-(methylamino)azetidin-1 -yl)pyπmidin-2-amine;

4-Cyclobutoxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyπmidin-2-amine;

4-Cyclopentoxymethyl-6-(3-(nnethylannino)azetidin-1 -yl)pynnnidin-2-annine;

4-Cyclopentoxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyπmidin-2-amine; 4-lsopropoxymethyl-6-(3-(nnethylannino)azetidin-1 -yl)pyπnnidin-2-annine;

4-lsopropoxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyπmidin-2-amine;

4-lsobutoxymethyl-6-(3-(nnethylannino)azetidin-1 -yl)pyπnnidin-2-annine;

4-lsobutoxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyπmidin-2-amine;

4-(2,2-Dimethylpropoxymethyl)-6-(3-(methylamino)azetidin-1-yl)pyπmidin-2-amine; 4-(2,2-Dimethylpropoxynnethyl)-6-((3R)-3-(nnethylannino)pyrrolidin-1 -yl)pyrinnidin-2- amine;

4-fert-Butoxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyπmidin-2-amine;

4-(Cyclopentylmethoxymethyl)-6-(3-(methylamino)azetidin-1-yl)pyπmidin-2-amine;

4-(Cyclopentylmethoxymethyl)-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyπmidin-2- amine;

4-(((1 S,2R,4R)-Bicyclo[2.2.1]heptan-2-yloxy) methyl)-6-(3-(methylamino)azetidin-

1 -yl) pyrinnidin-2-annine;

4-(((1 S,2R,4R)-Bicyclo[2.2.1]heptan-2-yloxy) methyl)-6-((3R)-3-(methylamino) pyrrol idin-1 -il)pyrimidine-2-amine; 4-Benzyloxymethyl-6-(3-(methylamino)azetidin-1 -yl)pyrimidin-2-amine;

4-Benzyloxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyrimidin-2-amine;

6-Methoxymethyl-4-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyrimidin-2-amine;

6-Methoxymethyl-4-(3-(methylamino)azetidin-1 -yl)pyrimidin-2-amine;

4-(3-(Methylamino)azetidin-1 -yl)-6-phenoxymethylpyrimidin-2-amine; 6-(2-Methoxyethyl)4-(3-(methylamino)azetidin-1 -yl)pyrimidin-2-amine;

4-(4-Fluorophenoxymethyl)-6-(3-(methylamino)azetidin-1 -yl)pyrimidin-2-amine;

4-(2,4-Difluorophenoxymethyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;

4-(3,4-Difluorophenoxymethyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine;

4-(2,4-Difluorophenoxymethyl)-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyrimidin-2- amine;

4-(3,4-Difluorophenoxymethyl)-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyrimidin-2- amine;

4-(3-Aminoazetidin-1 -yl)-6-isopropoxymethylpyhmidin-2-amine; 4-((3R)-3-Anninopyrrolidin-1 -yl)-6-isopropoxynnethylpyπnnidin-2-annine;

4-(3-(Methylamino)azetidin-1 -yl)-6-(tetrahydropyran-4-yl)pyπmidin-2-amine;

4-(3-(Methylamino)azetidin-1 -yl)-6-((S)-tetrahydrofuran-2-yl) pyrinnidin-2-annine;

4-((3R)-3-(Methylamino)pyrrolidin-1 -il)-6-((S)-tetrahydrofuran-2-yl) pyrimidin-2- amine;

4-(3-(Methylamino)azetidin-1 -yl)-6-((R)-tetrahydrofuran-2-yl)pyπmidin-2-amine;

4-((3R)-3-(Methylamino)pyrrolidin-1 -yl)-6-((R)-tetrahydrofuran-2-yl)pyrinriidin-2- amine;

4-(2-(4-Chlorophenoxy)propan-2-yl)-6-(3-(methylamino)azetidin-1 -yl)pyhmidin-2- amine;

4-(2-(4-Chlorophenoxy)propan-2-yl)-6-((3R)-3-(methylamino)pyrrolidin-1- yl)pyrimidin-2-amine;

6-((R)-1 -Methoxyethyl)-4-(3-(methylamino)azetidin-1 -yl)pyhmidin-2-amine;

4-(3-(Methylamino)azetidin-1 -yl)-6-((R)-phenyl(methoxy)methyl)pyrimidin-2-amine; 4-((3R)-3-(Methylamino)pyrrolidin-1 -yl)-6-((R)-phenyl(methoxy)methyl)pyrimidin-2- amine;

4-(3-(Methylamino)azetidin-1 -yl)-6-((S)-phenyl(methoxy)methyl)pyrimidin-2-amine;

4-Cyclohexyloxymethyl-6-[3-methyl-3-(methylamino)azetidin-1-yl]pyhmidin-2- amine; 4-lsobutoxymethyl-6-[3-methyl-3-(methylamino)azetidin-1 -yl]pyhmidin-2-amine;

4-lsopropoxymethyl-6-[3-methyl-3-(methylamino)azetidin-1 -yl]pyhmidin-2-amine;

4-(1 ,1-Dimethyl-2-methoxyethyl)-6-(3-(methylamino)azetidin-1-yl)pyhmidin-2- amine;

4-(2-lsopropoxyethyl)-6-(3-(methylamino)azetidin-1 -yl)pyhmidin-2-amine; 4-(1 -(Methoxymethyl)cyclopentyl)-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyhmidin-

2-amine;

4-[3-Methyl-3-(methylamino)azetidin-1-yl]-6-[(2S)-tetrahydrofuran-2-yl]pyrimidin-2- amine;

4-[(Dicyclopropylmethoxy)methyl]-6-(3-(methylamino)azetidin-1-yl)pyhmidin-2- amine;

4-(1 -(Methoxymethyl)cyclopentyl)-6-(3-(methylamino)azetidin-1-yl)pyhmidin-2- amine; Methyl 3-(((2-amino-6-(3-(methylamino)azetidin-1 -yl)pyrimidin-4- yl)methoxy)nnethyl)benzoate;

Methyl 4-(((2-amino-6-(3-(methylamino)azetidin-1 -yl)pyrimidin-4- yl)methoxy)nnethyl)benzoate; Methyl 2-(((2-amino-6-(3-(methylamino)azetidin-1 -yl )pyrim id in-4- yl)methoxy)nnethyl)benzoate;

4-(3-(Methylamino)azetidin-1 -yl)-6-((4-(nnethylsulfonyl)benzyloxy)nnethyl)pyπnnidin-

2-amine;

4-(3-(Methylamino)azetidin-1 -yl)-6-((3-(nnethylsulfonyl)benzyloxy)nnethyl)pyπnnidin- 2-amine;

2-[3-(((2-Amino-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4- yl)methoxy)nnethyl)phenyl]propan-2-ol;

[3-(((2-Amino-6-(3-(methylamino)azetidin-1 -yl)pyrimidin-4- yl)methoxy)nnethyl)phenyl]nnethanol; [4-(((2-Amino-6-(3-(methylamino)azetidin-1 -yl)pyrimidin-4- yl)methoxy)nnethyl)phenyl]nnethanol;

[2-(((2-Amino-6-(3-(methylamino)azetidin-1 -yl)pyrimidin-4- yl)methoxy)methyl)phenyl]methanol;

3-[((2-Amino-6-(3-(methylamino)azetidin-1 -yl)pyrimidin-4- yl)methoxy)nnethyl]benzoic acid;

3-[((2-Amino-6-(3-(methylamino)azetidin-1 -yl)pyrimidin-4- yl)methoxy)nnetil]benzannide; and

3-[((2-Amino-6-(3-(methylamino)azetidin-1 -yl)pyhmidin-4-yl)methoxy)methyl]-Λ/- butylbenzamide, or a salt thereof.

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 65 or 66. 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, trifluoromethanesulfonic 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.

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, ethanol and the like. A complex with water is known as a hydrate. Solvates of compounds of the invention (or of 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.

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 reacting a compound of formula Il with a compound of formula III, as shown in the following scheme:

MB

wherein Ri, R₂ and R3 have the meaning described above for a compound of formula I, and L represents a leaving group such as halogen, triflate or tosylate.

The reaction between the compounds of formula Il and III may be performed using a coupling agent such as for example PyBOP (benzotriazol-1-yl- oxythpyrrolidinophosphonium hexafluorophosphate) in a suitable solvent such as 1 ,4-dioxane, tetrahydrofuran, dichloromethane, Λ/,Λ/-dimethylformamide or acetonithle, preferably in acetonitrile, in the presence of a base, such as N, N- diisopropylethylamine, dimethylaniline, diethylamide or triethylamine, preferably triethylamine. The reaction can be carried out at a temperature comprised between room temperature and the reflux temperature, preferably under reflux.

Alternatively the compounds of formula I can be obtained by reacting a compound of formula III with a reactive derivative of a compound of formula Il (MB) obtained by conversion of the hydroxy group present in a compound Il into a leaving group such as halogen, triflate or tosylate, preferably chlorine.

Thus, the -OH group from a compound of formula Il may be transformed into a leaving group such as halogen, preferably chlorine, by reaction with a halogenating agent such as POCI3, optionally in the presence of a suitable solvent, or POCI3/PCI5 or /V,/V-dimethylfornnannide/oxalyl chloride mixtures in the presence of a suitable solvent such as 1 ,4-dioxane or 1 ,2-dichloroethane. The reaction is performed by heating, preferably at a temperature comprised between 100 °C and 140 °C. Similarly, the hydroxy group of the compound of formula Il can be transformed into a triflate group by reaction with thfluoromethane sulphonic anhydride in the presence of pyridine, or into a tosylate group by reaction with p- toluenesulfonyl chloride in the presence of a solvent such as dichloromethane and a base such as triethylamine. The reactive derivative from the compound of formula Il thus obtained (MB) is then allowed to react with a compound of formula III in order to give a compound of formula I. The reaction is performed in a suitable solvent such as ethanol, methanol, butanol, Λ/,Λ/-dimethylformamide, dimethylsulphoxide, tetrahydrofuran, toluene or acetonitrile, preferably ethanol, in the presence of a base, including organic amines such as triethylamine, Λ/,Λ/-diisopropylethylamine, dimethylaniline and diethylamide among others, and heating, preferably at a temperature comprised between 50 and 100 °C. The heating may be thermal or by irradiating with microwaves at a wattage that allows reaching the temperature mentioned above. In general, before conducting the reaction between the compounds of formula Il and III, or MB and III, the amino substituents of the compounds of formula III are protected in order to prevent the formation of side products. Similarly, the amino group of the compounds of formula Il and MB can also be protected if necessary. Any suitable protective group may be used, such as for example a te/t-butoxycarbonyl (Boc) group. A subsequent deprotection step may be necessary when the amino substituents of the compounds of formula Il and/or III and/or MB are protected, which is carried out under standard conditions. Therefore, when the protective group is Boc, deprotection can be conducted directly upon the crude product obtained by adding a solution of a strong acid such as HCI in a suitable solvent such as 1 ,4-dioxane, diethyl ether or methanol, or trifluoroacetic acid in dichloromethane.

The compounds of formula III are commercial or can be obtained by means of procedures described in the literature. The compounds of formula Il can be obtained by reacting a compound of formula IV with a guanidine salt, preferably the hydrochloride, as shown in the following scheme:

IV „ wherein Ri has the meaning described in formula I and Rg represents Ci_-4 alkyl.

The reaction takes place in the presence of a base such as potassium carbonate, sodium te/t-butoxide or sodium ethoxide and preferably sodium methoxide, in a suitable solvent, preferably ethanol. The reaction can be performed by heating at a suitable temperature usually comprised between room temperature and the reflux temperature, preferably under reflux.

The compounds of formula IV are commercial or can be easily obtained from commercial compounds by known methods. For example, they can be prepared from carboxylic acids V, after having transformed the carboxylic acid into its corresponding acid chloride, by means of conventional procedures such as by reaction with a Ci_-4 alkyl monomalonate such as ethyl monomalonate in the presence of butyl-lithium (see Journal of Organic Chemistry 2000, 65, 24, 8402) or by reaction with a Ci_-4 alkyl acetate such as ethyl acetate in the presence of lithium diisopropylamide (see Tetrahedron Letters 1991 , 32, 52, 7731 ), as shown in the following scheme:

V IV

wherein Ri has the meaning described in formula I and Rg represents Ci_-4 alkyl.

The compounds of formula IV wherein Ri represents a group (i) wherein R₄ and R₅ represent H and n represents 1 , can be easily obtained by reaction of an alcohol Vl with a Ci_-4 alkyl 4-chloro-3-oxobutanoate, such as ethyl 4-chloro-3- oxobutanoate as described in Monatsh Chem 1989, 120, 891 and shown in the following scheme:

Vl IV wherein R₆ has the meaning described in formula I and Rg represents Ci_-4 alkyl.

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 more steps, using well-known reactions in organic chemistry under standard experimental conditions. Examples of such transformation reactions include the reduction of an alkyl ester to obtain a primary alcohol, the hydrolysis of an ester to obtain a carboxylic acid, the reaction of an ester with an amine to obtain the corresponding amide, the addition of Grignard reagents to an ester to obtain a tertiary alcohol, and debenzylation of a benzyloxymethyl group to yield a hydroxymethyl group that can be alkylated. In some of the conversions it may be necessary or advisable to protect the reactive or unstable groups by means of conventional protective groups.

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 that can be treated with the compounds of formula I 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 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 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 of an allergic, immunological or inflammatory disease. In a more preferred embodiment, the compounds of the invention are used for the treatment 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 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 65. 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 66; 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 incorportated 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 65. 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 therein). To test the selectivity for enzymes, determination of enzymatic activity by product formation from its substrate can be used.

CNS distribution can be studied by determination of brain to plasma concentrations after administration by any route in different species (for example, mouse, rat or monkey).

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 65. 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 66; 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, muscarinic, adrenergic, dopamine and serotonine receptors.

The present invention also relates to a pharmaceutical composition comprising a compound of formula I (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.

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, ethanol, 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 with the following examples.

Examples

The following abbreviations are used in the examples: AcN: acetonitrile

EtOAc: ethyl acetate cone: concentrate

DMF: Λ/,Λ/-dimethylformamide

DMSO: dimethyl sulphoxide EtOH: ethanol g: gas

MeOH: methanol

Min: minutes PyBOP: (benzotriazol-1 -yloxy)tripyrrolidinophosphonium hexafluorophosphate TEA: triethylamine THF: tetrahydrofurane t_R: holding time LC-MS: liquid chromatography-mass spectrometry

One of the following methods was used to determine the LC-MS spectrums: Method 1 : X-Terra MS C18 column 5 μm (100 mm x 2.1 mm), temperature: 30 °C, rate: 0.35 mL/min, eluant: A = AcN, B = NH₄HCO₃ 10 mM, gradient: 0 min A at 10%; 10 min A at 90%; 15 min A at 90%.

Method 2: Acquity UPLC BEH C18 column 1.7 μm (2.1 x 50 mm), temperature: 40 °C, rate: 0.50 mL/min, eluant: A = AcN, B = NH₄HCO₃ 10 mM, 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 tert-Butyl methyl[(3R)-pyrrolidin-3-yl]carbamate

(a) te/?-Butyl[(3R)-1 Φenzylpyrrolidin-3-yl]methylcarbamate

Di-te/t-butyl dicarbonate (11.6 g, 53.07 mmol) dissolved in 15 mL of CH₂CI₂ is added to a solution of (3R)-1 -benzyl-Λ/-methylpyrrolidin-3-amine (10 g, 52.55 mmol) in 115 mL of CH₂CI₂, cooled at 0 °C. The resulting solution was stirred at room temperature for 18 hours. The solvent was evaporated and the crude product 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 mixture of the compound obtained above (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 mixture was filtered through Celite^® and the filter was washed with EtOAc and MeOH. The solvent was evaporated to dryness, providing 10.6 g of the title compound as an oil (yield: 100%). ¹H RMN (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 procedure similar to that described in section a) of reference example 1 , but using 1 -(diphenylmethyl)-Λ/-methylazetidin-3-amine instead of (3R)-1 - benzyl-Λ/-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 obtained above (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 the solution was then purged again with argon and stirred in a H₂ atmosphere for 18 hours. The reaction was filtered through Celite^® and the filter was washed with EtOAc and MeOH. The solvent was evaporated to dryness, providing 5.66 g of a mixture of the title compound together with one equivalent of diphenylmethane, that was used as such in the following steps. 1H RMN (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 Ethyl 4-cyclohexyloxy-3-oxobutanoate Cyclohexanol (2.43 g, 24.3 mmol) was added over a suspension of NaH (2.12 g 55% in mineral oil, 48.6 mmol) in anhydrous diethyl ether (16 mL) and the resulting mixture was stirred at room temperature for 75 minutes. Ethyl 4-chloro-3- oxobutanoate (1.64 mL, 12.1 mmol) was then slowly added and it was stirred at room temperature overnight. After adding a few drops of water, the solvent was evaporated to dryness and the residue was diluted with water. The pH was adjusted to 4 with 1 N HCI and it was extracted three times with diethyl ether. The combined organic phases were dried over Na₂SO₄ and it was concentrated to dryness, thus obtaining the title compound with quantitative yield as a crude product that was used as such in the following step.

¹H RMN (300 MHz, CDCI₃) δ: 1.28 (t, 3H), 1.52 (m, 2H), 1.74 (m, 4H), 1.88 (m, 4H), 3.31 (m, 1 H), 3.55 (s, 2H), 4.11 (s, 2H), 4.22 (q, 2H)

REFERENCE EXAMPLES 4-14

The following compounds were obtained following a procedure similar to that described in reference example 3, but using suitable starting materials instead of cyclohexanol:

REFERENCE EXAMPLE 15 Ethyl 4-(4-fluorophenoxy)-3-oxobutanoate

A solution of 4-fluorophenol (1.36 g, 12.1 mmol) in DMSO (2 ml_) was slowly added to a suspension of powdered KOH (1.36 g, 24.3 mmol) in DMSO (25 ml_) and the resulting mixture was stirred at room temperature for 15 minutes. Ethyl 4- chloro-3-oxobutanoate (1.64 ml_, 12.1 mmol) was then slowly added and it was stirred at room temperature overnight. The reaction mixture was diluted with water and 1 N HCI and extracted three times with diethyl ether. The combined organic phases were washed with brine, dried over Na2SO₄ and concentrated to dryness. The residue was purified by chromatography over silica gel using mixtures of hexane/EtOAc of increasing polarity as eluent, providing 0.60 g of the title compound (yield: 21 %) LC-MS ( Method 2): t_R = 2.13 min; m/z 239 (MH^").

REFERENCE EXAMPLES 16-17

The following compounds were obtained following a similar procedure to that described in reference example 15 but using suitable starting materials instead of 4-fluorophenol:

REFERENCE EXAMPLE 18 2-Amino-6-(cyclohexyloxymethyl)pyrimidin-4-ol

Guanidine hydrochloride (2.23 g, 23.4 mmol) and sodium methoxide (1.26 g, 23.4 mmol) were added to a solution of the compound obtained in reference example 3 (2.78 g, 12.2 mmol) in absolute ethanol (195 ml_) and the mixture was heated under reflux overnight. The solvent was evaporated to dryness and the residue was purified by chromatography over silica gel using mixtures of hexane/EtOAc of increasing polarity as eluent, providing the title compound with quantitative yield. LC-MS ( Method 2): t_R = 1.38 min; m/z 224 (MH⁺).

REFERENCE EXAMPLES 19-36

The following compounds were obtained following a procedure similar to that described in reference example 18, but using the corresponding starting material:

REFERENCE EXAMPLE 37 Ethyl 3-oxo-3-((2/?)-tetrahydrofuran-2-yl)propionate (a) (R)-Tetrahydro-2-furanoyl chloride

Oxalyl chloride (3.9 ml_, 44.7 mmol) was slowly added to a suspension of (R)- tetrahydro-2-furoic acid (4.72 g, 40.6 mmol) in anhydrous dichloromethane (16.5 ml_), cooled at 0 ⁰C, and finally a drop of DMF was added. The mixture was stirred overnight at room temperature. The solvent was evaporated to dryness, anhydrous dichloromethane was added and it was evaporated to dryness again, providing 5.43 g of the intended compound (yield: 99%), which was used as such in the following step of the synthesis. (b) Title compound

Butyl-lithium (87.5 ml_ of a 1.6 M solution in hexanes, 141.4 mmol) was slowly added to a solution of ethyl monomalonate (9.34 g, 70.7 mmol) in anhydrous THF (185 ml_), cooled at -78 ⁰C by means of an acetone-CO2 bath under an argon atmosphere. The bath was withdrawn and the internal temperature was allowed to rise to -5 ⁰C. The reaction mixture was then cooled again to -65 ⁰C and a solution of the compound obtained in the previous section (5.43 g, 40.4 mmol) in THF (10 ml_) was added, after what it was stirred for one hour at -65 ⁰C. The temperature was allowed to rise a little and the reaction crude was diluted with water. THF was evaporated to dryness, the residue was diluted with 1 N HCI and extracted three times with diethyl ether. The combined organic phases were dried over Na2SO₄ and concentrated to dryness, obtaining the title compound with quantitative yield in the form of a crude product that was used as such in the following step of the synthesis. LC-MS ( Method 2): t_R = 1.39 min; m/z = 185 (MH^").

REFERENCE EXAMPLE 38

Ethyl 3-oxo-3-((2S)-tetrahydrofuran-2-yl) propionate

The intended compound was obtained with quantitative yield following a procedure similar to that described in reference example 37, but using the (S) isomer. LC-MS ( Method 2): t_R = 1.39 min; m/z = 185 (MH^").

REFERENCE EXAMPLES 39-40 The following compounds were obtained following a procedure similar to that described in reference example 18, but using the corresponding starting material:

REFERENCE EXAMPLES 41-46

The following compounds were obtained following a similar procedure to that described in reference example 37 but using suitable starting materials instead of (R)-tetrahydro-2-furoic acid:

(i) ¹H NMR (300 MHz, CDCI₃) δ: 1.28 (m, 6H), 3.36 (s, 5H), 3.82 (q, 1 H), 4.12 (q, 2H).

(ii) ¹H NMR (300 MHz, CDCI₃) δ: 1.23 (t, 3H), 3.41 (s, 5H), 4.15 (q, 2H), 4.80 (s, 1 H), 7.39 (m, 5H). (iii) ¹H NMR (300 MHz, CDCI₃) δ: 1.23 (t, 3H), 3.41 (s, 5H), 4.15 (q, 2H), 4.80 (s, 1 H), 7.39

(m, 5H). (iv) ¹H NMR (300 MHz, CDCI₃) δ: 1.24 (s, 6H), 1.32 (t, 3H), 3.3-3.4 (complex signal,

2H+2H+3H), 4.24 (q, 2H),

REFERENCE EXAMPLES 47-53

REFERENCE EXAMPLE 54 Ethyl 5-isopropoxy-3-oxopentanoate

A solution of ethyl acetoacetate (2.7 g, 20.9 mmol) in THF (6.7 mL) was slowly added to an ice-cooled suspension of sodium hydride (0.97 g of a 55% dispersion in mineral oil, 22.2 mmol; washed with hexanes under argon to remove the oil before use) in anhydrous THF (25 mL). The mixture was stirred at 0 ⁰C for 45 min and then cooled to -25 ⁰C. Butyl-lithium (14.4 mL of a 1.6 M solution in hexanes, 23.0 mmol) was then slowly added and the mixture stirred at -25 ⁰C for 45 min. Then, a solution of chloromethyl isopropyl ether (2.5 g, 23.0 mmol) in THF (6.7 ml_) was added and the mixture stirred at -25 ⁰C for further 60 min. The reaction was quenched by the addition of ice-cooled 1 N HCI (22 ml_) and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over Na2SO₄ and concentrated to dryness, thus obtaining the title compound with quantitative yield as a crude product that was used as such in the following step.

LC-MS (Method 2): t_R = 1.79 min; m/z = 201 (MH^").

REFERENCE EXAMPLE 55 Methyl 3-methoxy-2,2-dimethylpropanoate

Methyl 2,2-dimethyl-3-hydroxypropanoate (5.0 g, 37.8 mmol) was slowly added to an ice-cooled suspension of sodium hydride (1.8g of a 55% dispersion in mineral oil, 41.6 mmol) in anhydrous THF (40 ml_). The slurry was then stirred at room temperature for 1 hour. Then, methyl iodide (8.0 g, 56.7 mmol) was added dropwise and the mixture stirred at room temperature overnight. Water was slowly added and the mixture further diluted with ethyl ether and ammonium chloride saturated solution. Phases were separated and the aqueous phase was again extracted with ethyl ether. The combined organic phases were dried over Na2SO₄ and concentrated to dryness, thus obtaining the title compound with quantitative yield as a crude product that was used as such in the following step. 1H RMN (300 MHz, CDCI₃) δ: 1.18 (s, 6H), 3.31 (s 3H), 3.34 (s, 2H), 3.67 (s, 3H) REFERENCE EXAMPLE 56

3-Methoxy-2,2-dimethylpropanoic acid

The compound obtained in reference example 55 (37.8 mmol) was heated at 60 ⁰C in a methanol (29 ml_), THF (29 ml_) and 1 N NaOH (39 ml_) mixture overnight. Volatiles were distilled off and the residue diluted with water. The basic phase was washed three times with hexanes that were discarded. pH was then adjusted to acid with 3N HCI and the aqueous phase was extracted three times with chloroform. The combined organic phases were dried over Na2SO₄ and concentrated to dryness, yielding 2.88 g of the title compound (yield 58%). ¹H RMN (300 MHz, CDCI₃) δ: 1.18 (s, 6H), 3.31 (s 3H), 3.37 (s, 2H), 11.9 (broad s, 1 H)

REFERENCE EXAMPLE 57 Methyl 1-(methoxymethyl)cyclopentanecarboxylate

Butyl-lithium (25 ml_ of a 1.6 M solution in hexanes, 40.1 mmol) was slowly added to a solution of diisopropylamine (4.1 g, 40.1 mmol) in anhydrous THF (48 ml_), cooled at -78 ⁰C by means of an acetone-CO2 bath under an argon atmosphere, and the solution stirred at -78 ⁰C for 30 min. Then, a solution of methyl cyclopentanecarboxylate (5.0 g, 39.0 mmol) in THF (25 ml_) was slowly added at - 78 ⁰C and the mixture allowed to warm to -40 ⁰C and stirred at that temperature for 30 min. Then, a solution of chloromethyl methyl ether (3.26 g, 39.0 mmol) in THF (12.5 ml_) was slowly added and the mixture allowed to reach room temperature and stirred overnight. THF was evaporated and the residue diluted with water and ethyl acetate. Phases were separated and the aqueous phase was extracted again with ethyl acetate. The combined organic phases were dried over Na2SO₄ and concentrated to dryness, thus obtaining 6.8 g of the title compound with quantitative yield as a crude product that was used as such in the following step. ¹H RMN (300 MHz, CDCI₃) δ: 1.55-1.75 (m, 6H), 2-2.15 (m, 2H), 3.33 (s, 3H), 3.45 (s, 2H), 3.72 (s, 3H).

REFERENCE EXAMPLE 58

1 -(Methoxymethyl)cyclopentanecarboxylic acid

The title compound was obtained following a procedure similar to that described in reference example 56 but using reference example 57 as starting material.

¹H RMN (300 MHz, CDCI₃) δ: 1.6-1.8 (m, 6H), 2-2.2 (m, 2H), 3.4 (s, 3H), 3.46 (s,

2H).

REFERENCE EXAMPLE 59 terf-Butyl methyl(3-methylazetidin-3-yl)carbamate (a) tert-Butyl [1 -(diphenylmethylJ-S-methylazetidin-S-yllmethylcarbamate

Following a similar procedure to the one described in section a) of reference example 1 but using 1 -(diphenylmethyl)-Λ/,3-dimethylazetidin-3-amine instead of (3R)-1-benzyl-/V-methylpyrrolidin-3-amine, the desired compound was obtained in quantitative yield.

¹H NMR (300 MHz, CDCI₃) δ: 1.53 (s, 12H), 2.59 (s, 3H), 2.89 (m, 2H), 3.16 (m, 2H), 4.30 (s, 1 H), 7.17 (m, 1 H), 7.26 (m, 2H), 7.42 (m, 1 H). (b) Title compound

A solution of the compound obtained in section a) (6.06 g, 16.5 mmol) in 60 ml_ of MeOH and 15 ml_ of EtOAc was purged with argon. Then, Pd/C (10%) (814 mg) was added and the solution was purged again with argon and was stirred under H₂ overnight. The reaction was filtered through Celite^® and the filter was washed with EtOAc and MeOH. The solvent was concentrated to dryness, to afford 4.55 g of a mixture of the title compound together with one equivalent of diphenylmethane, that was used as such.

¹H NMR (300 MHz, CDCI₃) δ: 1.45 (s, 12H), 2.67 (s, 3H), 3.28 (m, 1 H), 3.61 (m, 1 H), 3.87 (m, 1 H), 4.00 (m, 1 H)

REFERENCE EXAMPLE 60 terf-Butyl 1-(2-amino-6-(hydroxymethyl)pyrimidin-4-yl)azetidin-3- yl(methyl)carbamate

a) terf-Butyl 1-(2-amino-6-(benzyloxymethyl)pyrimidin-4-yl)azetidin-3- yl(methyl)carbamate

A mixture of the compound obtained in reference example 28 (10 g, 43.2 mmol), the amine obtained in reference example 2 (25.7 g of a 1 :1 mixture with diphenylmethane, equivalent to 12.9 g of amine, 69.1 mmol) and PyBOP (29.2 g, 56.2 mmol) in a mixture of TEA (250 ml_) and acetonitrile (420 ml_) was stirred overnight at 80 ⁰C. The reaction mixture was evaporated to dryness and the residue diluted with water and ethyl acetate. Phases were separated and the aqueous phase was extracted again with ethyl acetate. The combined organic phases were dried over Na₂SO₄ and concentrated to dryness. The crude product thus obtained was purified by chromatography over silica gel using mixtures of hexane/EtOAc/MeOH of increasing polarity as eluent, providing the intermediate precursor. This material was further purified by slurrying it in EtOAc (40 ml_), thus obtaining 14.1 g of the title compound (yield: 81 %) LC-MS ( Method 2): t_R = 2.19 min; m/z 400 (MH⁺). b) Title compound

A mixture of the compound obtained in section a) (5.2 g, 13.2 mmol), Pd/C (10%, 50% in water) (0.5 g) and ammonium formate (1.67 g, 26.4 mmol) in EtOH (57 ml_) and water (6.9 ml_) was heated under reflux for 3 hours. The reaction mixture was filtered through CeI ite^® and the filter aid was washed with EtOAc and MeOH. The solvent was evaporated to dryness, and the crude obtained was submitted to a second hydrogenation cycle, providing 3.97 g of the title compound (yield: 97%). LC-MS ( Method 2): t_R = 1.38 min; m/z 310 (MH⁺).

EXAMPLE 1

4-Cyclohexyloxymethyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine

A mixture of the compound obtained in reference example 18 (4.5 g, 20.1 mmol), the amine obtained in reference example 2 (12.0 g of a 1 :1 mixture with diphenylmethane, equivalent to 6.1 g of amine, 32.2 mmol) and PyBOP (13.6 g, 26.2 mmol) in a mixture of TEA (99 mL) and acetonitrile (170 mL) was stirred overnight at 80 ⁰C. The reaction mixture was evaporated to dryness and the residue was purified by chromatography over silica gel using mixtures of hexane/EtOAc of increasing polarity as eluent, providing the intermediate precursor with quantitative yield. HCI (4 M solution in 1.4-dioxane, 125 mL) was added to this intermediate and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated to dryness. The residue was dissolved in water and washed twice with EtOAc, that was discarded. 1 N NaOH solution was added to the acidic aqueous phase until basic pH and it was extracted three times with EtOAc. The combined organic phases were dried over anhydrous Na2SO₄ and it was concentrated to dryness. The crude product obtained was purified by chromatography over silica gel using mixtures of chloroform/MeOH/NH_{3 ∞}nc of increasing polarity as eluent, providing 2.6 g of the title compound (yield: 44%). LC-MS ( Method 2): t_R = 1.60 min; m/z 292 (MH⁺).

EXAMPLES 2-52 The following compounds were obtained following a procedure similar to that described in Example 1 , but using the corresponding starting materials in each case:

(*) The acidic treatment after reaction is not performed.

EXAMPLE 53

Methyl 3-(((2-amino-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4- yl)methoxy)methyl)benzoate

Reference example 60 (300 mg, 0.97 mmol) was slowly added to an ice-cooled suspension of sodium hydride (46.5 mg of a 55% dispersion in mineral oil, 1.07 mmol) in dry DMF (7 ml_). The slurry was stirred at room temperature for 30 min. Then, a solution of methyl 3-bromonnethylbenzoate (289 mg, 1.26 mmol) in DMF (1 ml_) was slowly added and the mixture stirred at room temperature overnight. Some drops of ammonium chloride saturated aqueous solution were slowly added and the solvent evaporated to dryness. The residue was partitioned between EtOAc and ammonium chloride saturated solution. Phases were separated and the aqueous phase was again extracted with EtOAc. The combined organic phases were dried over Na2SO₄ and concentrated to dryness, thus obtaining the Boc-protected precursor as a crude product. HCI (4 M solution in 1 ,4-dioxane, 15 ml_) and MeOH (20 ml_) were added to this intermediate and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated to dryness. The residue was dissolved in water and washed twice with EtOAc, that was discarded. 1 N NaOH solution was carefully added to the acidic aqueous phase until pH was around 8 and it was extracted three times with chloroform. The combined organic phases were washed with brine, dried over anhydrous Na2SO₄ and concentrated to dryness, providing 227 mg of the title compound, (yield: 65%) LC-MS ( Method 2): t_R = 1.47 min; m/z 358 (MH⁺).

EXAMPLES 54-57

The following compounds were obtained following a procedure similar to that described in example 53, but using the corresponding starting material in each case instead of methyl 3-bromomethylbenzoate:

(*) The Boc-precursor was treated with HCI-MeOH at room temperature for one week, in order to perform Boc-deprotection and esterification.

EXAMPLE 58 2-[3-(((2-Amino-6-(3-(methylamino)azetidin-1 -yl)pyrimidin-4- yl)methoxy)methyl)phenyl]propan-2-ol

Methylmagnesium bromide (0.12 ml_ of a 3 M solution in ethyl ether, 0.35 mmol) was slowly added under nitrogen to a solution of example 53 (25 mg, 0.07 mmol) in THF (1 ml_) cooled at 0 ⁰C. The ice bath was removed and it was allowed to warm, stirring at room temperature overnight. It was then cooled again to 0 ⁰C and additional methylmagnesium bromide (0.12 ml_ of a 3 M solution in ethyl ether, 0.35 mmol) was dropwise added. The mixture was again allowed to reach room temperature and stirred at that temperature overnight. The reaction mixture was diluted with ammonium chloride saturated solution and EtOAc. Phases were separated and the aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with water, dried over anhydrous Na2SO₄ and concentrated to dryness, providing 11.6 mg of the title compound, (yield: 46%) LC-MS ( Method 2): t_R = 1.32 min; m/z 358 (MH⁺).

EXAMPLE 59

[3-(((2-Amino-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4- yl)methoxy)methyl)phenyl]methanol

Lithium aluminum hydride (0.56 mL of a 1 N solution in THF, 0.56 mmol) was slowly added under argon to a solution of example 53 (50 mg, 0.14 mmol) in THF (0.25 mL) cooled at 0 ⁰C. The ice bath was removed and it was allowed to warm, stirring at room temperature overnight. It was then cooled again to 0 ⁰C and water (0.34 mL) and 1 N NaOH (0.5 mL) were sequentially added. The precipitated aluminates were removed by filtration and the filtrate was concentrated to dryness. The residue was diluted with water and chloroform, phases were separated and the aqueous phase was extracted twice with chloroform. The combined organic phases were dried over anhydrous Na2SO₄ and concentrated to dryness, providing 32.2 mg of the title compound, (yield: 70%) LC-MS ( Method 2): t_R = 1.14 min; m/z 330 (MH⁺).

EXAMPLES 60-61

The following compounds were obtained following a procedure similar to that described in example 59, but using the corresponding starting material in each case:

EXAMPLE 62

3-[((2-Amino-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4- yl)methoxy)methyl]benzoic acid

Lithium hydroxide monohydrate (0.92 mg, 0.02 mmol) was added to a solution of example 53 (3.57 mg, 0.01 mmol) in a mixture of THF (0.2 mL) and water (0.2 mL), and the reaction mixture was stirred at 50 ⁰C overnight. It was then concentrated to dryness providing the title compound in quantitative yield as its lithium salt. LC-MS ( Method 2): t_R = 0.75 min; m/z 344 (MH⁺).

EXAMPLE 63

3-[((2-Amino-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4- yl)methoxy)metil]benzamide

A solution of example 53 (25 mg, 0.07 mmol) in ammonia (1.5 mL of a 7N solution in MeOH) was stirred at 70 ⁰C for 5 days. It was then concentrated to dryness providing the title compound in quantitative yield. LC-MS ( Method 2): t_R = 1.01 min; m/z 343 (MH⁺).

EXAMPLE 64

3-[((2-Amino-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-yl) methoxy)methyl]-/V-butylbenzamide

A solution of example 53 (25 mg, 0.07 mmol) in butylamine (1 ml_) was stirred at

70 ⁰C for 3 days. It was then concentrated to dryness providing the title compound in quantitative yield.

LC-MS ( Method 2): t_R = 1.48 min; m/z 399 (MH⁺).

EXAMPLE 65

Competitive binding assay for [³H]-histamine to the human histamine H₄ receptor

Membrane extracts were used to perform the test that were prepared from a stable recombinant CHO cell line expressing the human histamine H₄ receptor

(Euroscreen/Perkin-Elmer).

The compounds to be tested were incubated at the desired concentration in duplicate with 10 nM [³H]-histamine and 15 μg of membrane 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 of unlabelled histamine. The reaction was interrupted by filtration by means of a vacuum manifold (Multiscreen Millipore) in 96 well plates (Multiscreen HTS Millipore) that were previously treated with 0.5% polyethylenimine for 2 hours at 0 ⁰C. The plates were subsequently washed with 50 mM Tris (pH 7.4), 1.25 mM EDTA at 0 ⁰C, and the filters were dried for 1 hour at 50-60 ⁰C before adding the scintillation liquid in order to determine bound radioactivity by means of a beta scintillation counter.

The compounds from examples 1 to 56, 58, 59 and 62 were assayed in this test and exhibited an inhibition of more than 50% of binding to human histamine receptor H₄ at a 1 μM concentration.

EXAMPLE 66

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. Finally, 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 16, 18 to 54, 56, 58 and 59 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

I wherein:

Ri represents a group selected from (i) and (ii):

(i) (ϋ) ; R2 and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl and NR₃Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃Rb group, or contains 1 N atom and is substituted with one NR₃R_b group; or R₂ represents H or Ci_-4 alkyl, and R₃ represents azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, which may be optionally substituted with one or more Ci_-4 alkyl groups;

R₃ represents H or Ci_-4 alkyl;

R₄ and R₅ are each independently selected from H and Ci_-4 alkyl, and additionally one of the R₄ or R₅ groups may represent aryl or C_3-S cycloalkyl-C_0-6 alkyl, and additionally two R₄ and R₅ groups on a same C atom may be bound forming a C_3-S cycloalkyl group together with said C atom;

Re represents a group selected from Ci_-8 alkyl, C_3-8 cycloalkyl-Co-6 alkyl and An- Co_-4 alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups atom and the C_3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen and aryl;

R₇ represents a saturated monocyclic 4- to 7-membered heterocyclic ring containing one O atom and not containing any other additional heteroatoms, wherein said ring may be bound to the rest of the molecule through any available C atom, and wherein R₇ may be optionally substituted with one or more groups independently selected from Ci_-4 alkyl and halogen; n represents 1 , 2 or 3; p represents 0, 1 or 2;

An represents phenyl optionally substituted with one or more groups independently selected from Ci_-4 alkyl, halogen, Ci_-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, cyano, hydroxy-C_0-6 alkyl, R₈CO₂-C_0-6 alkyl, R₈SO₂NHCO-C_0-6 alkyl, (1 H-tetrazol -5-yl)-C_0-6 alkyl, -CONR₈R₈, -SO₂NR₈R₈, -SO₂R₈', -NR₈SO₂R₈' -NR₈CONR₈R₈, -NR₈COR₈ and -NR₈R₈;

R₈ represents H, Ci_-6 alkyl, C_3-8 cycloalkyl-C_0-6 alkyl or aryl-C_0-4 alkyl; R₈' represents Ci_-6 alkyl, C_3-8 cycloalkyl-C_0-6 alkyl or aryl-C_0-4 alkyl; and additionally two R₈ or a R₈ and a R₈' can be bonded together to form a -C_2-5 alkylene- group; and aryl represents phenyl optionally substituted with one or more groups independently selected from Ci_-4 alkyl, halogen, Ci_-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, cyano and amino; or a salt thereof.

2.- A compound according to claim 1 wherein R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7- membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl and NR₃Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃Rb group, or contains 1 N atom and is substituted with one NR₃Rb group.

3.- A compound according to claim 2 wherein R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:

wherein R₀ represents H or Ci_-4 alkyl.

4.- A compound according to claim 3 wherein R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b).

5.- A compound according to claim 3 wherein R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a).

6.- A compound according to claim 3 wherein R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b).

7.- A compound according to any of claims 3 to 6 wherein R₀ represents H.

8.- A compound according to any of claims 1 to 7 wherein R₃ and Rb independently represent H or Ci_-4 alkyl.

9.- A compound according to claim 8 wherein R₃ and R_b independently represent

H or methyl.

10.- A compound according to claim 9 wherein R₃ represents H and Rb represents methyl.

11.- A compound according to any of claims 1 to 10 wherein R₄ and R₅ are each independently selected from H and Ci_-4 alkyl.

12.- A compound according to claim 11 wherein R₄ and R₅ represent H.

13.- A compound according to any of claims 1 to 12 wherein Ri represents (i).

14.- A compound according to any of claims 1 to 13 wherein n represents 1 or 2.

15.- A compound according to claim 14 wherein n represents 1.

16.- A compound according to any of claims 1 to 15 wherein R₆ represents a group selected from Ci-S alkyl, C_3-8 cycloalkyl-Co-i alkyl and An -C0-2 alkyl.

17.- A compound according to claim 16 wherein R₆ represents a group selected from C_4-5 alkyl, C₃-₆ cycloalkyl-C₀-i alkyl and An -C0-2 alkyl.

18.- A compound according to any of claims 1 to 15 wherein R₆ represents a group selected from Ci_-8 alkyl and C3-8 cycloalkyl-C_0-6 alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups, and the C_3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen and aryl.

19.- A compound according to claim 18 wherein R₆ represents a group selected from Ci-S alkyl and C3_-6 cycloalkyl-Co-i alkyl.

20.- A compound according to claim 19 wherein R₆ represents a group selected from C-1-8 alkyl and C_3-6 cycloalkyl-Ci alkyl.

21.- A compound according to claim 20 wherein R₆ represents a group selected from C_4-5 alkyl and C_3-6 cycloalkyl-Ci alkyl.

22.- A compound according to claim 21 wherein R₆ represents isobutyl or cyclopropylmethyl.

23.- A compound according to any of claims 1 to 15 wherein R₆ represents a group selected from C_3-S cycloalkyl-Co_-6 alkyl and An-Co_-4 alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups and the C3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen and aryl.

24.- A compound according to claim 23 wherein R₆ represents a group selected from C3-8 cycloalkyl-C₀-i alkyl and An -C0-2 alkyl.

25.- A compound according to any of claims 1 to 15 wherein R₆ represents a group selected from C3-8 cycloalkyl-Ci_-6 alkyl and An -C0-2 alkyl, wherein any alkyl group may be optionally substituted with one or more halogen groups and the C3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen and aryl.

26.- A compound according to claim 25 wherein R₆ represents a group selected from C3-8 cycloalkyl-Ci alkyl and An-Ci alkyl.

27.- A compound according to any of claims 1 to 15 wherein R₆ represents Ci-S alkyl optionally substituted with one or more halogen groups.

28.- A compound according to claim 27 wherein R₆ represents Ci_-5 alkyl.

29.- A compound according to claim 28 wherein R₆ represents isobutyl.

30.- A compound according to any of claims 1 to 15 wherein R₆ represents C3-8 cycloalkyl-Co_-6 alkyl, wherein the alkyl group may be optionally substituted with one or more halogen groups and the C3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen and aryl.

31.- A compound according to claim 30 wherein R₆ represents C3-8 cycloalkyl-C_0-i alkyl.

32.- A compound according to claim 31 wherein R₆ represents C3_-6 cycloalkyl-Ci alkyl.

33.- A compound according to claim 32 wherein R₆ represents cyclopropylmethyl.

34.- A compound according any of claims 1 to 15 wherein R₆ represents An-Co_-4 alkyl, wherein the alkyl group may be optionally substituted with one or more halogen groups.

35.- A compound according to claim 34 wherein R₆ represents An-Co-2 alkyl, wherein the alkyl group may be optionally substituted with one or more halogen groups.

36.- A compound according to claim 35 wherein R₆ represents An-Ci alkyl.

37.- A compound according to any of claims 1 to 17, 23 to 26 or 34 to 36 wherein An represents phenyl substituted with one group selected from hydroxy-C_0-6 alkyl, R₈CO₂-C_0-6 alkyl, R₈SO₂NHCO-C_0-6 alkyl, (1 H-tetrazol-5-yl)-C_0-6 alkyl, -CONR₈R₈, - SO₂NR₈R₈, -SO₂R₈', -NR₈SO₂R₈', -NR₈CONR₈R₈, -NR₈COR₈ and -NR₈R₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy.

38.- A compound according to claim 37 wherein An represents phenyl substituted in the meta position with one group selected from hydroxy-Co_-6 alkyl, R₈CO₂-Co_-6 alkyl, R₈SO₂NHCO-C_0-6 alkyl, (1 H-tetrazol-5-yl)-C_0-6 alkyl, -CONR₈R₈, -SO₂NR₈R₈, -SO₂R₈', -NR₈SO₂R₈', -NR₈CONR₈R₈, -NR₈COR₈ and -NR₈R₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy.

39.- A compound according to claim 37 wherein An represents phenyl substituted with one group selected from hydroxy-Co_-6 alkyl, -CONR₈R₈, -SO₂R₈' and - NR₈COR₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy.

40.- A compound according to claim 39 wherein An represents represents phenyl substituted at the meta position with one group selected from hydroxy-Co_-6 alkyl, - CONR₈R₈, -SO₂R₈' and -NR₈COR₈, and which can be further optionally substituted with one group selected from Ci_-4 alkyl, halogen and Ci_-4 alkoxy.

41.- A compound according to any of claims 1 to 12 wherein Ri represents (ii).

42.- A compound according to claim 41 wherein p is O

43.- A compound according to claim 41 wherein p is 1.

44.- A compound according to any of claims 1 to 17, 23 to 26 or 34 to 36 wherein An represents phenyl optionally substituted with one or more groups independently selected from Ci_-4 alkyl, halogen, Ci_-4 alkoxy, Ci_-4 haloalkyl, Ci_-4 haloalkoxy, cyano and amino.

45.- A compound according to claim 1 selected from: 4-Cyclohexyloxymethyl-6-(3-(methylamino)azetidin-1 -yl)pyrimidin-2-amine; 4-Cyclohexyloxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyhmidin-2-amine; 4-(Cyclopropylmethoxymethyl)-6-(3-(methylamino)azetidin-1-yl)pyhmidin-2-amine; 4-(Cyclopropylmethoxymethyl)-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyrimidin-2- amine; 4-Cyclobutoxymethyl-6-(3-(methylamino)azetidin-1 -yl)pyπmidin-2-amine;

4-Cyclobutoxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyπmidin-2-amine;

4-Cyclopentoxymethyl-6-(3-(nnethylannino)azetidin-1 -yl)pynnnidin-2-annine;

4-lsopropoxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyπmidin-2-amine;

4-lsobutoxymethyl-6-(3-(nnethylannino)azetidin-1 -yl)pyπnnidin-2-annine;

4-lsobutoxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyπmidin-2-amine;

4-fert-Butoxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyπmidin-2-amine;

4-(Cyclopentylmethoxymethyl)-6-(3-(methylamino)azetidin-1-yl)pyπmidin-2-amine;

1 -yl) pyrinnidin-2-annine;

4-Benzyloxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyrimidin-2-amine;

6-Methoxymethyl-4-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyrimidin-2-amine;

6-Methoxymethyl-4-(3-(methylamino)azetidin-1 -yl)pyrimidin-2-amine;

4-(4-Fluorophenoxymethyl)-6-(3-(methylamino)azetidin-1 -yl)pyrimidin-2-amine;

4-(3-Aminoazetidin-1 -yl)-6-isopropoxymethylpyhmidin-2-amine; 4-((3f?)-3-Aπninopyrrolidin-1 -yl)-6-isopropoxymethylpyrinnidin-2-annine;

4-(3-(Methylamino)azetidin-1 -yl)-6-(tetrahydropyran-4-yl)pyπmidin-2-amine;

6-((R)-1 -Methoxyethyl)-4-(3-(methylamino)azetidin-1 -yl)pyhmidin-2-amine;

4-lsopropoxymethyl-6-[3-methyl-3-(methylamino)azetidin-1 -yl]pyhmidin-2-amine;

2-amine;

4-[3-Methyl-3-(methylamino)azetidin-1-yl]-6-[(2S)-tetrahydrofuran-2-yl]pyhmidin-2- amine;

2-amine;

46.- A pharmaceutical composition which comprises a compound of formula I according to any of claims 1 to 45 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

47.- A compound of formula I according to any of claims 1 to 45 or a pharmaceutically acceptable salt thereof for use in therapy.

48.- A compound of formula I according to any of claims 1 to 45 or a pharmaceutically acceptable salt thereof for use in the treatment of a disease mediated by the histamine H₄ receptor.

49.- A compound of formula I according to any of claims 1 to 45 or a pharmaceutically acceptable salt thereof for use in the treatment of an allergic, immunological or inflammatory disease, or pain.

50.- Use of a compound of formula I according to any of claims 1 to 45 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease mediated by histamine H₄ receptor.

51.- Use according to claim 50, wherein the disease mediated by the histamine H₄ receptor is an allergic, immunological or inflammatory disease, or pain.

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

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

wherein Ri, R₂ and R3 have the meaning described in claim 1 , followed if necessary by the removal of any protective group that may be present; or (b) reacting a compound of formula MB with a compound of formula III (or an amino-protected form thereof)

MB

wherein L represents a leaving group and Ri, R₂ and R3 have the meaning described in claim 1 , followed if necessary by the removal of any protective group that may be present; or

(c) transforming a compound of formula I into another compound of formula I in one or in several steps.