WO2009115496A1

WO2009115496A1 - Furo [3, 2-d] pyrimidine derivatives as h4 receptor antagonists

Info

Publication number: WO2009115496A1
Application number: PCT/EP2009/053092
Authority: WO
Inventors: Elena CARCELLER GONZÁLEZ; Eva María MEDINA FUENTES; Marina VIRGILI BERNADÓ; Josep MARTÍ VIA
Original assignee: Palau Pharma, S. A.
Priority date: 2008-03-17
Filing date: 2009-03-16
Publication date: 2009-09-24
Also published as: PE20091958A1; TW200951136A; AR070928A1

Abstract

Furo[3,2-d]pyπnnidine derivatives of formula (I), wherein the meaning of the different substituents are those indicated in the description. These compounds are useful as histamine H₄ receptor antagonists.

Description

FURO [3 , 2-D] PYRIMIDINE DERIVATIVES AS H4 RECEPTOR ANTAGONISTS

Field of the invention

The present invention relates to a new series of furo[3,2-d]pyhmidine derivatives, processes to prepare them, pharmaceutical compositions comprising these compounds as well as their use in therapy.

Background of the invention

Histamine is one of the most potent mediators of immediate hypersensitivity reactions. While the effects of histamine on smooth muscle cell contraction, vascular permeability and gastric acid secretion are well known, its effects on the immune system are only now beginning to become unveiled. A few years ago, a novel histamine receptor, which was named H₄, was cloned by several research groups working independently (Oda T et al, J Biol Chem 2000, 275: 36781 -6; Nguyen T et al, MoI Pharmacol 2001 , 59: 427-33). As the other members of its family, it is a G-protein coupled receptor (GPCR) containing 7 transmembrane segments. However, the H₄ receptor has low homology with the three other histamine receptors (Oda T et al); it is remarkable that it shares only a 35% homology with the H₃ receptor. While the expression of the H₃ receptor is restricted to cells of the central nervous system, the expression of the H₄ receptor has been mainly observed in cells of the haematopoietic lineage, in particular eosinophils, mast cells, basophils, dendritic cells and T-cells (Oda T et al). The fact that the H₄ receptor is highly distributed in cells of the immune system suggests the involvement of this receptor in immuno-inflammatory responses. Moreover, this hypothesis is reinforced by the fact that its gene expression can be regulated by inflammatory stimuli such as interferon, TNFα and IL-6. Nevertheless, the H₄ receptor is also expressed in other types of cells such as human synovial cells obtained from patients suffering from rheumatoid arthritis (Wojtecka-Lukasik E et al, Ann Rheum Dis 2006, 65 (Suppl II): 129; Ikawa Y et al, Biol Pharm Bull 2005, 28: 2016-8) and osteoarthritis (Grzybowska-Kowalczyk A et al, European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, P-11 ), and in the human intestinal tract (Sander LE et al, Gut 2006, 55: 498- 504). An increase in the expression of the H₄ receptor has also been reported in nasal polyp tissue in comparison to nasal mucosa of healthy people (Jόkύti A et al, Cell Biol lnt 2007, 31 : 1367-70). Recent studies with specific ligands of the H₄ receptor have helped to delimit the pharmacological properties of this receptor. These studies have evidenced that several histamine-induced responses in eosinophils such as chemotaxis, conformational change and CD11 b and CD54 up-regulation are specifically mediated by the H₄ receptor (Ling P et al, Br J Pharmacol 2004, 142:161-71 ; Buckland KF et al, Br J Pharmacol 2003, 140:1117-27). In dendritic cells, the H₄ receptor has been shown to affect maturation, cytokine production and migration of these cells (Jelinek I et al, 1^st Joint Meeting of European National Societies of Immunology, Paris, France, 2006, PA-1255). Moreover, the role of the H₄ receptor in mast cells has been studied. Although H₄ receptor activation does not induce mast cell degranulation, histamine and other proinflammatory mediators are released; moreover, the H₄ receptor has been shown to mediate chemotaxis and calcium mobilization of mast cells (Hofstra CL et al, J Pharmacol Exp Ther 2003, 305: 1212-21 ). With regard to T-lymphocytes, it has been shown that H₄ receptor activation induces T-cell migration and preferentially attracts a T- lymphocyte population with suppressor/regulatory phenotype and function (Morgan RK et al, American Thoracic Society Conference, San Diego, USA, 2006, P-536), as well as regulating the activation of CD4+ T cells (Dunford PJ et al, J Immunol 2006, 176: 7062-70). As for the intestine, the distribution of the H₄ receptor suggests that it may have a role in the control of peristalsis and gastric acid secretion (Morini G et al, European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, 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.

Description of the invention

One aspect of the present invention relates to a compound of formula I

I wherein:

Ri represents H or NH₂;

R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group which 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 a 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 can 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 can be optionally substituted with one or more Ci_-4 alkyl groups; R₄ represents:

(1 ) Ci_-8 alkyl;

(2) C_3-8 cycloalkyl-Co-₆ alkyl;

(3) aryl-Co-6 alkyl; wherein in groups (1 ) to (3) any alkyl group can be optionally substituted with one or more halogen atoms and the C_3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen and aryl;

(4) a group of formula (i)

(i) ; or (5) a group of formula (ii):

(ϋ) ;

R₅ represents H, halogen, Ci_-8 alkyl or CN;

Re and R₇ are each independently selected from H and Ci_-4 alkyl, and additionally one of the Re or R₇ groups can represent aryl or C3-8 cycloalkyl-Co-6 alkyl, and additionally a Re group and a R₇ group on a same C atom can be bound forming together with said C atom a Cs-s cycloalkyl group;

R₈ represents a group selected from Ci_-8 alkyl, C_3-8 cycloalkyl-Co-e alkyl and aryl-

Co_-4 alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms and the C3_-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen and aryl;

Rg represents a 4- to 7-membered saturated monocyclic heterocyclic ring containing one heteroatom or group selected from O, S, SO and SO2 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 R₉ can be optionally substituted with one or more groups independently selected from Ci_-4 alkyl and halogen;

X represents O, S, SO or SO₂; n represents 1 , 2 or 3; p represents 0, 1 or 2; 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, CN and NH₂.

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

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

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

I wherein:

Ri represents H or NH₂;

R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group which 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 a 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 can be optionally substituted with one or more Ci_-4 alkyl groups; R₃ represents H or Ci_-4 alkyl; Rb represents H or Ci_-4 alkyl; or R₃ and Rb form, together with the N atom to which they are bound, an azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group that can be optionally substituted with one or more Ci_-4 alkyl groups; R₄ represents: (1 ) Ci-₈ alkyl;

(2) C_3-8 cycloalkyl-Co-₆ alkyl;

(3) aryl-Co-6 alkyl; wherein in groups (1 ) to (3) any alkyl group can be optionally substituted with one or more halogen atoms and the C3_-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen and aryl;

(4) a group of formula (i)

(i) ; or

(5) a group of formula (ii):

(U) ;

R₅ represents H, halogen, Ci_-8 alkyl or CN;

Re and R₇ are each independently selected from H and Ci_-4 alkyl, and additionally one of the Re or R₇ groups can represent aryl or C3_-8 cycloalkyl-Co-6 alkyl, and additionally a Re group and a R₇ group on a same C atom can be bound forming together with said C atom a C_3-8 cycloalkyl group;

R₈ represents a group selected from Ci_-8 alkyl, C_3-8 cycloalkyl-Co-e alkyl and aryl- Co_-4 alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms and the C3_-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen and aryl;

Rg represents a 4- to 7-membered saturated monocyclic heterocyclic ring containing one heteroatom or group selected from O, S, SO and SO2 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 R₉ can be optionally substituted with one or more groups independently selected from Ci_-4 alkyl and halogen; X represents O, S, SO or SO₂; n represents 1 , 2 or 3; p represents O, 1 or 2; 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, CN and NH₂; for use in therapy.

Another aspect of the invention relates to a pharmaceutical composition which comprises a compound of formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease mediated by the 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 manufacture of a medicament for the treatment or prevention of an allergic, immunological or inflammatory disease or pain.

Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of an allergic, immunological or inflammatory disease. More preferably, the allergic, immunological or inflammatory disease is selected from respiratory diseases, ocular diseases, skin diseases, inflammatory bowel diseases, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection. Still more preferably, the allergic, immunological or inflammatory disease is selected from asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataracts, dermatitis (e.g. atopic dermatitis), psoriasis, urticaria, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection.

Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of pain. More preferably, the pain is selected from inflammatory pain, inflammatory hyperalgesia, hyperalgesia, postsurgical pain, migraine, cancer pain, visceral pain, osteoarthritis pain and neuropathic pain.

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

Another aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of an allergic, immunological or inflammatory disease or pain. Another aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of an allergic, immunological or inflammatory disease. More preferably, the allergic, immunological or inflammatory disease is selected from respiratory diseases, ocular diseases, skin diseases, inflammatory bowel diseases, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection. Still more preferably, the allergic, immunological or inflammatory disease is selected from asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataracts, dermatitis (e.g. atopic dermatitis), psoriasis, urticaria, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection.

Another aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of pain. More preferably, the pain is selected from inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-surgical pain, migraine, cancer pain, visceral pain, osteoarthritis pain and neuropathic pain.

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

Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of an allergic, immunological or inflammatory disease or pain. Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of an allergic, immunological or inflammatory disease. More preferably, the allergic, immunological or inflammatory disease is selected from respiratory diseases, ocular diseases, skin diseases, inflammatory bowel diseases, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection. Still more preferably, the allergic, immunological or inflammatory disease is selected from asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataracts, dermatitis (e.g. atopic dermatitis), psoriasis, urticaria, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection.

Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of pain. More preferably, the pain is selected from inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-surgical pain, migraine, cancer pain, visceral pain, osteoarthritis pain and neuropathic pain.

Another aspect of the present invention relates to a method of treating or preventing a disease mediated by the histamine H₄ receptor in a subject in need thereof, preferably a human being, which comprises administering to said subject a compound of formula I or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention relates to a method of treating or preventing an allergic, immunological or inflammatory disease or pain in a subject in need thereof, preferably a human being, which comprises administering to said subject a compound of formula I or a pharmaceutically acceptable salt thereof. Another aspect of the present invention relates to a method of treating or preventing an allergic, immunological or inflammatory disease in a subject in need thereof, preferably a human being, which comprises administering to said subject a compound of formula I or a pharmaceutically acceptable salt thereof. More preferably, the allergic, immunological or inflammatory disease is selected from respiratory diseases, ocular diseases, skin diseases, inflammatory bowel diseases, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection. Still more preferably, the allergic, immunological or inflammatory disease is selected from asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataracts, dermatitis (e.g. atopic dermatitis), psoriasis, urticaria, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection.

Another aspect of the present invention relates to a method of treating or preventing pain in a subject in need thereof, preferably a human being, which comprises administering to said subject a compound of formula I or a pharmaceutically acceptable salt thereof. More preferably, the pain is selected from inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-surgical pain, migraine, cancer pain, visceral pain, osteoarthritis pain and neuropathic pain.

Another aspect of the present invention relates to a process for the preparation of a compound of formula I as 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, R3, R₄ and R₅ have the meaning described above, followed if necessary by the removal of any protecting 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)

wherein Ri₀ represents a leaving group and Ri, R2, R3, R₄ and R₅ have the meaning described above, followed if necessary by the removal of any protecting group that may be present; or

(c) when in a compound of formula I R₅ represents halogen, reacting a compound of formula I (or an amino-protected form thereof) wherein R₅ represents H with a halogenating agent, followed if necessary by the removal of any protecting group that may be present; or (d) when in a compound of formula I R₅ represents CN, reacting a compound of formula I (or an amino-protected form thereof) wherein R₅ represents halogen with a cyanating agent, followed if necessary by the removal of any protecting group that may be present; or (e) 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 linear or branched alkyl chain containing from x to y carbon atoms. Thus, a C1-8 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. fluoro, chloro, bromo or iodo) that can be the same or different. Examples include, amongst others, trifluoromethyl, fluoromethyl, 1 -chloroethyl, 2-chloroethyl, 1 - fluoroethyl, 2-fluoroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 4-fluorobutyl 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. fluoro, chloro, bromo or iodo) that can 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 can 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.

The term C_3-S cycloalkyl-Co-e alkyl includes C_3-S cycloalkyl and C_3-8 cycloalkyl-Ci-₆ alkyl.

A C_3-S 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 C_3-s cycloalkyl groups, and more preferably it is substituted with one C_3-8 cycloalkyl group. The C_3-8 cycloalkyl group may substitute either one H atom on a C atom or two H atoms on the same C atom of the alkyl group (in which case the C_3-8 cycloalkyl group shares one C atom with the alkyl group), such as in the groups shown as examples below:

2-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, 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. When in the definition of a compound of formula I it is indicated that a C3-8 cycloalkyl group can be optionally substituted with one or more groups independently selected from Ci_-4 alkyl, halogen and aryl, said substituents can be the same or different and can be located on any available carbon atom of the C3-8 cycloalkyl group, including the carbon binding the cycle to the rest of the molecule. The term aryl-Co_-yalkyl includes aryl and aryl-Ci_-y alkyl.

An aryl-Ci-y alkyl group means a group resulting from the substitution of a hydrogen atom of a Ci_-y alkyl group with an aryl group. When y is 4, examples of aryl-Ci_-4 alkyl include, amongst others, the groups benzyl, 1 -phenylethyl, 2- phenylethyl, 1-phenyl-1 -methylethyl, 3-phenylpropyl, 4-phenylbutyl and 2-phenyl- 1 -methylpropyl, wherein the phenyl groups can be optionally substituted as indicated above in the definition of aryl.

As indicated in the definition of R₄ regarding meanings (1 ) to (3) and in the definition of Rs, any alkyl group can be optionally substituted with one or more halogen groups. This refers to the Ci_-8 alkyl group and the Co-6 alkyl group that forms part of the C_3-S cycloalkyl-Co-e alkyl group both in R₄ and R₈, as well as to the Co-6 alkyl group that forms part of the aryl-Co-e alkyl group in R₄ and the C_0-4 alkyl group that forms part of the aryl-C_0-4 alkyl group in R₈.

As described above, R₉ represents a 4- to 7-membered saturated monocyclic heterocycle containing one heteroatom or group selected from O, S, SO and SO2 and not containing any other additional heteroatoms. Said heterocyclic ring can be bound to the rest of the molecule via any available C atom. Examples of Rg rings include, amongst others:

Any R₉ ring can be optionally substituted with one or more groups independently selected from Ci_-4 alkyl and halogen, as described above, and said substituents can be in any available position on the ring.

A halogen group or its abbreviation halo means fluoro, chloro, bromo or iodo. Preferred halogen atoms as substituents of alkyl, cycloalkyl or aryl groups are fluoro and chloro, and more preferably fluoro. Preferred halogen atoms in relation to R₅ are fluoro and chloro, and more preferably chloro.

The term "saturated" relates to groups that do not have any double or triple bonds. A "bridged bicyclic" group refers to a bicyclic system having two common atoms (bridgeheads) connecting three acyclic chains (bridges), so that the two bridges with the higher number of atoms form then the main ring and the bridge with the lower number of atoms is the "bridge". In the definition of NR2R3, R2 and R3 together with N atom to which they are bound can form a saturated 4- to 7-membered monocyclic heterocyclic ring containing up to two N atoms and not containing any other heteroatom. Examples include, among others, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and homopiperazinyl. In the definition of NR2R3, R2 and R3 together with the N atom to which they are bound can form a 7- to 8-membered bridged bicyclic group. Said bicyclic group can contain up to two N atoms and does not contain any other heteroatoms. 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 bicyclic group can contain up to two N atoms in any available position and does not contain any other heteroatoms. Examples include, among others, octahydropyrrolo[3,4-b]pyridinyl, 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 Re group and more than one R₇ group in said compound, each R₆ and each R₇ is independently selected from the list of possible meanings indicated above in the definition of a compound of formula I and therefore these groups can 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 1 , 2, 3 or 4, more preferably 1 , 2 or 3, and more preferably 1 or 2 substituents, provided that said group has enough positions available susceptible of being substituted. These substituents can be the same or different, and can be located at any available position. Throughout the present specification, by the term "treatment" is meant eliminating, reducing or ameliorating the cause or the effects of a disease. For purposes of this invention treatment includes, but is not limited to, alleviation, amelioration or elimination of one or more symptoms of the disease; diminishment of the extent of the disease; stabilized (i.e. not worsening) state of disease; delay or slowing of disease progression; amelioration or palliation of the disease state; and remission of the disease (whether partial or total).

As used herein, "prevention" refers to preventing the occurrence of a disease in a subject that is predisposed to or has risk factors but does not yet display symptoms of the disease. Prevention includes also preventing the recurrence of a disease in a subject that has previously suffered said disease.

The invention therefore relates to the compounds of formula I as defined above.

In another embodiment, the invention relates to compounds of formula I wherein Ri is NH₂. 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 which 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 a 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:

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

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

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

In another embodiment, the invention relates to 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), (b), (c), (d), (f), (g) and (h), and R₃ and Rb have the meaning described above for compounds of formula I, R₀ represents H or Ci_-4 alkyl, preferably H or methyl, more preferably H, and R_d represents H or Ci_-4 alkyl, preferably H or methyl. In another embodiment, the invention relates to 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), (b), (c), (d), (f), (g) and (h), and R_a, R_b, Rc and R_d independently represent H or Ci_-4 alkyl, preferably R₃, Rb, Rc and R_d independently represent H or methyl, and more preferably R_a, Rb and Rd independently represent H or methyl and R₀ represents H.

In another embodiment, the invention relates to 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), (b), (e) and (f), and R_a and Rb have the meaning described above for compounds of formula I, R₀ represents H or Ci_-4 alkyl, preferably H or methyl, more preferably H, and Rd represents H or Ci_-4 alkyl, preferably H or methyl.

In another embodiment, the invention relates to 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), (b), (e) and (f), and R₃, Rb, Rc and Rd independently represent H or Ci_-4 alkyl, preferably R₃, Rb, Rc and R_d independently represent H or methyl, and more preferably R_a, Rb and Rd independently represent H or methyl and R₀ represents H.

In another embodiment, the invention relates to 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 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) and (b), and R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ independently represent H or methyl, and more preferably R_a and Rb independently represent H or methyl and R₀ represents H.

In another embodiment, the invention relates to the compounds of formula I wherein 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 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), 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 selected from (a) and (b), R₃ represents H, R_b represents methyl and R₀ represents H.

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

In another embodiment, the invention relates to 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, 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 (a), R₃ represents H, R_b represents H or Ci_-4 alkyl and R₀ represents H.

In another embodiment, the invention relates to the compounds of formula I wherein 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 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), R₃ 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 R₃, 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 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 represent 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 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 represents H and R3 represents 1 -methyl-pyrrol id in-3-yl .

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

(1 ) Ci_-8 alkyl;

(2) Cs-s cycloalkyl-Co-e alkyl;

(3) aryl-Co-6 alkyl; wherein in groups (1 ) to (3) any alkyl group can be optionally substituted with one or more halogen atoms and the C_3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen and aryl; or

(4) a group of formula (i)

(i) In another embodiment, the invention relates to compounds of formula I wherein R₄ represents:

(1 ) Ci_-8 alkyl;

(2) Cs-s cycloalkyl-Co-e alkyl; wherein in groups (1 ) and (2) any alkyl group can be optionally substituted with one or more halogen atoms and the C3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen and aryl;

(3) a group of formula (i)

(i) ; or

(4) a group of formula (ii)

(ϋ) .

In another embodiment, the invention relates to compounds of formula I wherein R₄ represents: (1 ) d-s alkyl; (2) Cs-s cycloalkyl-Co-β alkyl; or (3) aryl-Co-6 alkyl; wherein in groups (1 ) to (3) any alkyl group can be optionally substituted with one or more halogen atoms and the C_3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen and aryl.

(1 ) Ci_-8 alkyl;

(2) C3-8 cycloalkyl-Co-6 alkyl; and (3) aryl-Ci.₆ alkyl; wherein in groups (1 ) to (3) any alkyl group can be optionally substituted with one or more halogen atoms and the C_3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen and aryl. In another embodiment, the invention relates to compounds of formula I wherein R₄ represents Ci-S alkyl or C3-8 cycloalkyl-Co-6 alkyl; wherein the alkyl groups can be optionally substituted with one or more halogen atoms (preferably fluoro) and the Cs-s cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl.

In another embodiment, the invention relates to compounds of formula I wherein R₄ represents Ci-S alkyl or Cs-s cycloalkyl-Co-β alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₄ represents C2-8 alkyl or C3-8 cycloalkyl-Co-1 alkyl; wherein the alkyl groups can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C3_-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl.

In another embodiment, the invention relates to compounds of formula I wherein R₄ represents C_2-S alkyl or C₃-8 cycloalkyl-C₀-i alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₄ represents C2-8 alkyl or C3-8 cycloalkyl, preferably C_2-4 alkyl or C3-6 cycloalkyl , and more preferably ethyl, isopropyl, te/t-butyl or cyclopropyl; wherein the alkyl groups can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl.

In another embodiment, the invention relates to compounds of formula I wherein R₄ represents C2-8 alkyl or C3-8 cycloalkyl, more preferably C_2-4 alkyl or C3-6 cycloalkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₄ represents ethyl, isopropyl, te/t-butyl or cyclopropyl.

In another embodiment, the invention relates to compounds of formula I wherein R₄ represents Ci_-8 alkyl, preferably C_2-8 alkyl, more preferably C_2-4 alkyl optionally substituted with one or more halogen atoms (preferably fluoro).

In another embodiment, the invention relates to compounds of formula I wherein R₄ represents Ci_-8 alkyl, preferably C_2-8 alkyl, more preferably C_2-4 alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₄ represents ethyl, isopropyl or te/t-butyl. In another embodiment, the invention relates to compounds of formula I wherein R₄ represents C3_-8 cycloalkyl-Co-6 alkyl, wherein the alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C3-S cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl. In another embodiment, the invention relates to compounds of formula I wherein R₄ represents C3_-8 cycloalkyl-Co-6 alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₄ represents C3_-8 cycloalkyl-Co-i alkyl, wherein the alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl.

In another embodiment, the invention relates to compounds of formula I wherein R₄ represents C₃-8 cycloalkyl-C₀-i alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₄ represents C3-8 cycloalkyl, preferably C3-6 cycloalkyl, and more preferably cyclopropyl, optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl. In another embodiment, the invention relates to compounds of formula I wherein R₄ represents C_3-S cycloalkyl, preferably C_3-6 cycloalkyl.

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

In another embodiment, the invention relates to compounds of formula I wherein R₄ represents aryl-Co-6 alkyl, wherein the alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro).

In another embodiment, the invention relates to compounds of formula I wherein R₄ represents aryl-Co-2 alkyl, wherein the alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro). In another embodiment, the invention relates to compounds of formula I wherein R₄ represents aryl-Ci-6 alkyl, wherein the alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro).

In another embodiment, the invention relates to compounds of formula I wherein R₄ represents aryl. In another embodiment, the invention relates to compounds of formula I wherein R₄ represents a group of formula (i).

In another embodiment, the invention relates to compounds of formula I wherein R₄ represents a group of formula (i) and X is O.

In another embodiment, the invention relates to compounds of formula I wherein R₄ represents a group of formula (ii).

In another embodiment, the invention relates to compounds of formula I wherein R₅ represents H, halogen or Ci-S alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₅ represents H, halogen or Ci-2 alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₅ represents H, halogen, Ci-2 alkyl or CN.

In another embodiment, the invention relates to compounds of formula I wherein R₅ represents H, halogen or CN, more preferably H, chloro or CN.

In another embodiment, the invention relates to compounds of formula I wherein R₅ represents H or halogen, more preferably H or chloro.

In another embodiment, the invention relates to compounds of formula I wherein R₅ represents halogen or CN, more preferably chloro or CN. In another embodiment, the invention relates to compounds of formula I wherein R₅ represents H.

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

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

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

In another embodiment, the invention relates to compounds of formula I wherein R₆ and R₇ are each independently selected from H and Ci_-4 alkyl, and additionally one of the R₆ or R₇ groups can represent aryl or C_3-S cycloalkyl-C_0-6 alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ and R₇ are each independently selected from H and Ci_-4 alkyl, and additionally a R₆ group and a R₇ group on a same C atom can be bound forming together with said C atom a C_3-S cycloalkyl group.

In another embodiment, the invention relates to compounds of formula I wherein R₆ and R₇ are each independently selected from H and Ci_-4 alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ and R₇ are each independently selected from H and methyl. In another embodiment, the invention relates to compounds of formula I wherein one of the R₆ or R₇ groups represents C_3-s cycloalkyl-Co_-6 alkyl.

In another embodiment, the invention relates to compounds of formula I wherein one of the R₆ or R₇ groups represents aryl. In another embodiment, the invention relates to compounds of formula I wherein a Re group and a R₇ group on a same C atom are bound forming together with said C atom a C_3-8 cycloalkyl group.

In another embodiment, the invention relates to compounds of formula I wherein X represents O.

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 p represents O or 1. In another embodiment, the invention relates to compounds of formula I wherein R₈ represents Ci_-8 alkyl optionally substituted with one or more halogen atoms (preferably fluoro).

In another embodiment, the invention relates to compounds of formula I wherein R₈ represents Ci_-8 alkyl. In another embodiment, the invention relates to compounds of formula I wherein R₈ represents C3_-8 cycloalkyl-Co-6 alkyl, wherein the alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C3-S cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl. In another embodiment, the invention relates to compounds of formula I wherein R₈ represents C_3-8 cycloalkyl-C_0-i alkyl, wherein the alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C_3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl. In another embodiment, the invention relates to compounds of formula I wherein R₈ represents C_3-8 CyClOaIkVl-Co-I alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₈ represents C_3-8 cycloalkyl optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl.

In another embodiment, the invention relates to compounds of formula I wherein R₈ represents C_3-8 cycloalkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₈ represents aryl-Co_-4 alkyl, wherein the alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro).

In another embodiment, the invention relates to compounds of formula I wherein R₈ represents aryl-C_0-i alkyl. In another embodiment, the invention relates to compounds of formula I wherein R₈ represents aryl.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents NH₂ and R₅ represents H, halogen or Ci_-8 alkyl.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents NH₂ and R₅ represents H, halogen or Ci_-2 alkyl.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents NH₂ and R₅ represents H, halogen or CN, more preferably H, chloro or CN.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents NH₂ and R₅ represents H or halogen, more preferably H or chloro.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents NH₂ and R₅ represents halogen or CN, more preferably chloro or CN. In another embodiment, the invention relates to compounds of formula I wherein Ri represents NH₂ and R₅ represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents NH₂ and R₅ represents halogen.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents NH₂ and R₅ represents chloro.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents NH₂ and R₅ represents CN.

In another embodiment, the invention relates to compounds of formula I wherein: Ri represents NH₂;

R₅ represents H, halogen or CN, preferably halogen or CN, and more preferably chloro or CN; and

R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group which 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 a NR₃Rb group, or contains 1 N atom and is substituted with one NR₃R_b group.

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

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

Ri represents NH₂;

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.

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 and Rb have the meaning described above for compounds of formula I, and R₀ and Rd independently represent H or Ci_-4 alkyl.

R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), and R_a, Rb, Rc and Rd independently represent H or Ci_-4 alkyl, preferably R_a, Rb, Rc and Rd independently represent H or methyl.

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

Ri represents NH₂; R₅ represents H, halogen or CN, preferably halogen or CN, and more preferably chloro or CN; and

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

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

Ri represents NH₂;

R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a), (b), (c), (d), (f), (g) and (h), and R_a, Rb, Rc and Rd independently represent H or Ci_-4 alkyl, preferably R_a, Rb, Rc and Rd independently represent H or methyl.

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), (b), (e) and (f), wherein R₃ and Rb have the meaning described above for compounds of formula I, and R₀ and Rd independently represent H or Ci_-4 alkyl.

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

Ri represents NH₂;

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

Ri represents NH₂;

R₅ represents H, halogen or CN, preferably halogen or CN, and more preferably chloro or CN; and 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 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:

Ri represents NH₂;

R₅ represents H, halogen or CN, more preferably halogen or CN, still more preferably chloro or CN; and 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, more preferably R_a and Rb independently represent H or methyl and R₀ represents H, 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:

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

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

Ri represents NH₂;

R₅ represents H, halogen or CN, more preferably halogen or CN, still more preferably chloro or CN; and

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

R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), wherein R_a 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.

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 independently represent H or Ci_-4 alkyl, and 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, 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 NH₂;

R₅ represents halogen, more preferably chloro; and

R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group which 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 a NR₃R_b 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 NH₂;

R₅ represents halogen, more preferably chloro; and 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 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.

R₅ represents halogen, more preferably chloro; and

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:

Ri represents NH₂;

R₅ represents halogen, more preferably chloro; 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 and Rb have the meaning described above for compounds of formula I, and R₀ and Rd independently represent H or Ci_-4 alkyl.

R₅ represents halogen, more preferably chloro; and

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, Rc and R_d independently represent H or Ci_-4 alkyl, preferably R₃, R_b, R_c and R_d independently represent H or methyl.

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

Ri represents NH₂; R₅ represents halogen, more preferably chloro; and

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

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

Ri represents NH₂;

R₅ represents halogen, more preferably chloro; and R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a), (b), (c), (d), (f), (g) and (h), and R₃, R_b, Rc and R_d independently represent H or Ci_-4 alkyl, preferably R₃, Rb, Rc and R_d independently represent H or methyl.

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

Ri represents NH₂;

R₅ represents halogen, more preferably chloro; and

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

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

Ri represents NH₂; R₅ represents halogen, more preferably chloro; and

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

Ri represents NH₂;

R₅ represents halogen, more preferably chloro; and 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 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:

Ri represents NH₂;

R₅ represents halogen, more preferably chloro; and

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, more preferably R_a and Rb independently represent H or methyl and R₀ represents H, 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 NH₂;

R₅ represents halogen, more preferably chloro; and

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 independently represent H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ independently represent H or methyl, and more preferably R₃ and R_b independently represent 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 NH₂;

R₅ represents halogen, more preferably chloro; and

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

R₅ represents halogen, more preferably chloro; and

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

R₄ represents Ci_-8 alkyl or C3-8 cycloalkyl-Co-e alkyl, preferably Ci_-8 alkyl or C_3-S cycloalkyl-Co-1 alkyl, more preferably C_2-8 alkyl or C_3-8 cycloalkyl, still more preferably C_2-4 alkyl or C3-6 cycloalkyl; wherein the alkyl groups can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C3_-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and even still more preferably R₄ represents ethyl, isopropyl, te/t-butyl or cyclopropyl;

R₅ represents H, halogen or CN, preferably halogen or CN, more preferably chloro or CN, and still more preferably chloro; and R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group which 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 a 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 NH₂;

R₄ represents Ci-S alkyl or C3-8 cycloalkyl-Co-6 alkyl, preferably Ci-S alkyl or C3-8 cycloalkyl-Co-1 alkyl, more preferably C2-8 alkyl or C3-8 cycloalkyl, still more preferably C_2-4 alkyl or C3-6 cycloalkyl; wherein the alkyl groups can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and even still more preferably R₄ represents ethyl, isopropyl, te/t-butyl or cyclopropyl; R₅ represents H, halogen or CN, preferably halogen or CN, more preferably chloro or CN, and still more preferably chloro; and

R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:

R₄ represents Ci-S alkyl or C3-8 cycloalkyl-Co-6 alkyl, preferably Ci-S alkyl or C3-8 cycloalkyl-Co-1 alkyl, more preferably C_2-s alkyl or C3-8 cycloalkyl, still more preferably C_2-4 alkyl or C3-6 cycloalkyl; wherein the alkyl groups can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and even still more preferably R₄ represents ethyl, isopropyl, te/t-butyl or cyclopropyl; R₅ represents H, halogen or CN, preferably halogen or CN, more preferably chloro or CN, and still more preferably chloro; and

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:

Ri represents NH₂;

R₄ represents Ci_-8 alkyl or C3-8 cycloalkyl-Co-e alkyl, preferably Ci_-8 alkyl or C3-8 cycloalkyl-Co-1 alkyl, more preferably C2-8 alkyl or C3-8 cycloalkyl, still more preferably C_2-4 alkyl or C3-6 cycloalkyl; wherein the alkyl groups can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and even still more preferably R₄ represents ethyl, isopropyl, te/t-butyl or cyclopropyl; R₅ represents H, halogen or CN, preferably halogen or CN, more preferably chloro or CN, and still more preferably chloro; and

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

Ri represents NH₂;

R₄ represents Ci_-8 alkyl or C_3-8 cycloalkyl-Co-e alkyl, preferably Ci_-8 alkyl or C_3-8 cycloalkyl-Co-1 alkyl, more preferably C_2-8 alkyl or C_3-8 cycloalkyl, still more preferably C_2-4 alkyl or C_3-6 cycloalkyl; wherein the alkyl groups can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C_3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and even still more preferably R₄ represents ethyl, isopropyl, te/t-butyl or cyclopropyl;

R₅ represents H, halogen or CN, preferably halogen or CN, more preferably chloro or CN, and still more preferably chloro; and R2 and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), and R_a, Rb, Rc and Rd independently represent H or Ci_-4 alkyl, preferably R_a, Rb, Rc and Rd independently represent H or methyl.

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

Ri represents NH₂;

R₄ represents Ci_-8 alkyl or C3-8 cycloalkyl-Co-e alkyl, preferably Ci_-8 alkyl or C_3-S cycloalkyl-Co-1 alkyl, more preferably C_2-S alkyl or C3-8 cycloalkyl, still more preferably C_2-4 alkyl or C3-6 cycloalkyl; wherein the alkyl groups can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and even still more preferably R₄ represents ethyl, isopropyl, te/t-butyl or cyclopropyl;

R₅ represents H, halogen or CN, preferably halogen or CN, more preferably chloro or CN, and still more preferably chloro; and

R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a), (b), (c), (d), (f), (g) and (h), wherein Ra and Rb have the meaning described above for compounds of formula I, and R₀ and R_d independently represent H or Ci_-4 alkyl. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents NH₂;

R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a), (b), (c), (d), (f), (g) and (h), and R₃, Rb, Rc and Rd independently represent H or Ci_-4 alkyl, preferably R_a, Rb, Rc and Rd independently represent H or methyl.

R₅ represents H, halogen or CN, preferably halogen or CN, more preferably chloro or CN, and still more preferably chloro; and R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a), (b), (e) and (f), wherein R₃ and R_b have the meaning described above for compounds of formula I, and R₀ and Rd independently represent H or Ci_-4 alkyl.

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

Ri represents NH₂;

R₄ represents Ci_-8 alkyl or C_3-8 cycloalkyl-Co-e alkyl, preferably Ci_-8 alkyl or C_3-8 cycloalkyl-Co-1 alkyl, more preferably C_2-8 alkyl or C_3-8 cycloalkyl, still more preferably C_2-4 alkyl or C_3-6 cycloalkyl; wherein the alkyl groups can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C_3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and even still more preferably R₄ represents ethyl, isopropyl, te/t-butyl or cyclopropyl; R₅ represents H, halogen or CN, preferably halogen or CN, more preferably chloro or CN, and still more preferably chloro; and

R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a), (b), (e) and (f), and R₃, Rb, Rc and Rd independently represent H or Ci_-4 alkyl, preferably R₃, Rb, Rc and R_d independently represent H or methyl.

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

Ri represents NH₂; R₄ represents Ci_-8 alkyl or C3-8 cycloalkyl-Co-e alkyl, preferably Ci_-8 alkyl or

C_3-S cycloalkyl-Co-1 alkyl, more preferably C_2-8 alkyl or C_3-8 cycloalkyl, still more preferably C_2-4 alkyl or C3-6 cycloalkyl; wherein the alkyl groups can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C3_-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and even still more preferably R₄ represents ethyl, isopropyl, te/t-butyl or cyclopropyl;

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 described above for compounds of formula I and R₀ represents H or Ci_-4 alkyl and preferably R₀ represents H.

R₄ represents Ci_-8 alkyl or C3_-8 cycloalkyl-Co-6 alkyl, preferably Ci_-8 alkyl or

C_3-8 cycloalkyl-Co-1 alkyl, more preferably C_2-8 alkyl or C_3-8 cycloalkyl, still more preferably C_2-4 alkyl or C_3-6 cycloalkyl; wherein the alkyl groups can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C_3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and even still more preferably R₄ represents ethyl, isopropyl, te/t-butyl or cyclopropyl;

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

R₅ represents H, halogen or CN, preferably halogen or CN, more preferably chloro or CN, and still more preferably chloro; and R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R₃ and Rb have the meaning described above for compounds of formula I and R₀ represents H or Ci_-4 alkyl, and preferably R₀ represents H.

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

Ri represents NH₂;

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 independently represent H or Ci_-4 alkyl, and 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, 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 NH₂;

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

Ri represents NH₂;

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 independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ independently represent H or methyl, and more preferably R_a and Rb independently represent H or methyl and R₀ represents H, 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 NH₂;

R₄ represents Ci_-8 alkyl, preferably C_2-8 alkyl, more preferably C_2-4 alkyl; which can be optionally substituted with one or more halogen atoms (preferably fluoro); and still more preferably R₄ represents ethyl, isopropyl or te/t-butyl;

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

Ri represents NH₂;

R₅ represents H, halogen or CN, preferably halogen or CN, more preferably chloro or CN, and still more preferably chloro; and R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:

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

Ri represents NH₂; R₄ represents Ci-S alkyl, preferably C_2-s alkyl, more preferably C_2-4 alkyl; which can be optionally substituted with one or more halogen atoms (preferably fluoro); and still more preferably R₄ represents ethyl, isopropyl or te/t-butyl;

R₅ represents H, halogen or CN, preferably halogen or CN, more preferably chloro or CN, and still more preferably chloro; and 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.

R₄ represents Ci-S alkyl, preferably C_2-s alkyl, more preferably C_2-4 alkyl; which can be optionally substituted with one or more halogen atoms (preferably fluoro); and still more preferably R₄ represents ethyl, isopropyl or te/t-butyl;

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

Ri represents NH₂; R₄ represents Ci_-8 alkyl, preferably C_2-S alkyl, more preferably C_2-4 alkyl; which can be optionally substituted with one or more halogen atoms (preferably fluoro); and still more preferably R₄ represents ethyl, isopropyl or te/t-butyl;

R₅ represents H, halogen or CN, preferably halogen or CN, more preferably chloro or CN, and still more preferably chloro; and 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, Rc and R_d independently represent H or Ci_-4 alkyl, preferably R₃, Rb, Rc and R_d independently represent H or methyl.

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

Ri represents NH₂;

R₄ represents Ci_-8 alkyl, preferably C_2-8 alkyl, more preferably C_2-4 alkyl; which can be optionally substituted with one or more halogen atoms (preferably fluoro); and still more preferably R₄ represents ethyl, isopropyl or te/t-butyl; R₅ represents H, halogen or CN, preferably halogen or CN, more preferably chloro or CN, and still more preferably chloro; and

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

Ri represents NH₂;

R₅ represents H, halogen or CN, preferably halogen or CN, more preferably chloro or CN, and still more preferably chloro; and R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a), (b), (c), (d), (f), (g) and (h), and R₃, R_b, Rc and R_d independently represent H or Ci_-4 alkyl, preferably R₃, Rb, Rc and R_d independently represent H or methyl. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents NH₂;

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

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

Ri represents NH₂; R₄ represents Ci_-8 alkyl, preferably C_2-8 alkyl, more preferably C_2-4 alkyl; which can be optionally substituted with one or more halogen atoms (preferably fluoro); and still more preferably R₄ represents ethyl, isopropyl or te/t-butyl;

R₅ represents H, halogen or CN, preferably halogen or CN, more preferably chloro or CN, and still more preferably chloro; and R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a), (b), (e) and (f), and R_a, Rb, Rc and Rd independently represent H or Ci_-4 alkyl, preferably R₃, Rb, Rc and R_d independently represent H or methyl.

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

Ri represents NH₂;

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 described above for compounds of formula I and R₀ represents H or Ci_-4 alkyl and preferably 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), and R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, preferably R₃, Rb and R₀ independently represent H or methyl, more preferably R_a and Rb independently represent H or methyl and R₀ represents H, 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:

R₅ represents H, halogen or CN, preferably halogen or CN, more preferably chloro or CN, and still more preferably chloro; and R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R₃ and Rb have the meaning described above for compounds of formula I and R₀ represents H or Ci_-4 alkyl, and preferably R₀ represents H. In another embodiment, the invention relates to compounds of formula I wherein:

Ri represents NH₂;

R₄ represents Ci_-8 alkyl, preferably C_2-S alkyl, more preferably C_2-4 alkyl; which can be optionally substituted with one or more halogen atoms (preferably fluoro); and still more preferably R₄ represents ethyl, isopropyl or te/t-butyl;

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 independently represent H or Ci_-4 alkyl, and 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, 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 NH₂;

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

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

Ri represents NH₂; R₄ represents Ci_-8 alkyl, preferably C_2-8 alkyl, more preferably C_2-4 alkyl; which can be optionally substituted with one or more halogen atoms (preferably fluoro); and still more preferably R₄ represents ethyl, isopropyl or te/t-butyl.

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 independently represent H or Ci_-4 alkyl, and 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, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H.

R₄ represents C_3-S cycloalkyl-Co-e alkyl, preferably C_3-S cycloalkyl-C_0-i alkyl, more preferably C_3-8 cycloalkyl, still more preferably C_3-6 cycloalkyl; wherein the alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C_3-s cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and even still more preferably R₄ represents cyclopropyl;

R₅ represents H, halogen or CN, preferably halogen or CN, more preferably chloro or CN, and still more preferably chloro; and R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group which 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 a NR₃Rb group, or contains 1 N atom and is substituted with one NR₃R_b group.

R₄ represents C_3-s cycloalkyl-Co-6 alkyl, preferably C_3-s cycloalkyl-Co-1 alkyl, more preferably C_3-s cycloalkyl, still more preferably C_3-6 cycloalkyl; wherein the alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and even still more preferably R₄ represents cyclopropyl; R₅ represents H, halogen or CN, preferably halogen or CN, more preferably chloro or CN, and still more preferably chloro; and

R₄ represents C3-8 cycloalkyl-Co-e alkyl, preferably C3-8 cycloalkyl-C_0-i alkyl, more preferably C3-8 cycloalkyl, still more preferably C3-6 cycloalkyl; wherein the alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and even still more preferably R₄ represents cyclopropyl;

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

Ri represents NH₂;

R₄ represents C_3-S cycloalkyl-Co-e alkyl, preferably C_3-S cycloalkyl-Co-i alkyl, more preferably C_3-8 cycloalkyl, still more preferably C_3-6 cycloalkyl; wherein the alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C_3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and even still more preferably R₄ represents cyclopropyl; R₅ represents H, halogen or CN, preferably halogen or CN, more preferably chloro or CN and still more preferably chloro; and

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

Ri represents NH₂;

R₄ represents C_3-8 cycloalkyl-Co-e alkyl, preferably C_3-8 cycloalkyl-C_0-i alkyl, more preferably C_3-8 cycloalkyl, still more preferably C_3-6 cycloalkyl; wherein the alkyl group can be optionally substituted with one or more halogen atoms

(preferably fluoro) and the C_3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen

(preferably fluoro) and aryl; and even still more preferably R₄ represents cyclopropyl;

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, Rc and R_d independently represent H or Ci_-4 alkyl, preferably R₃, Rb, Rc and R_d independently represent H or methyl.

R₄ represents C_3-S cycloalkyl-Co-e alkyl, preferably C_3-S cycloalkyl-Co-i alkyl, more preferably C_3-8 cycloalkyl, still more preferably C_3-6 cycloalkyl; wherein the alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C_3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and even still more preferably R₄ represents cyclopropyl;

Ri represents NH₂;

R₄ represents C_3-8 cycloalkyl-Co-e alkyl, preferably C_3-8 cycloalkyl-C_0-i alkyl, more preferably C_3-8 cycloalkyl, still more preferably C_3-6 cycloalkyl; wherein the alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C_3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and even still more preferably R₄ represents cyclopropyl; R₅ represents H, halogen or CN, preferably halogen or CN, more preferably chloro or CN and still more preferably chloro; and

R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a), (b), (c), (d), (f), (g) and (h), and R₃, R_b, Rc and R_d independently represent H or Ci_-4 alkyl, preferably R₃, Rb, Rc and R_d independently represent H or methyl.

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

Ri represents NH₂; R₄ represents C3-8 cycloalkyl-Co-6 alkyl, preferably C3-8 cycloalkyl-Co-i alkyl, more preferably C_3-S cycloalkyl, still more preferably C_3-6 cycloalkyl; wherein the alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C_3-S cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and even still more preferably R₄ represents cyclopropyl;

R₅ represents H, halogen or CN, preferably halogen or CN, more preferably chloro or CN, and still more preferably chloro; and R2 and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a), (b), (e) and (f), wherein R₃ and R_b have the meaning described above for compounds of formula I, and R₀ and Rd independently represent H or Ci_-4 alkyl.

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

Ri represents NH₂;

R₄ represents C_3-8 cycloalkyl-Co-6 alkyl, preferably C_3-8 cycloalkyl-Co-1 alkyl, more preferably C_3-8 cycloalkyl, still more preferably C_3-6 cycloalkyl; wherein the alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C_3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and even still more preferably R₄ represents cyclopropyl;

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

Ri represents NH₂;

R₄ represents C_3-8 cycloalkyl-Co-6 alkyl, preferably C_3-8 cycloalkyl-Co-1 alkyl, more preferably C3-8 cycloalkyl, still more preferably C3-6 cycloalkyl; wherein the alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C_3-S cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and even still more preferably R₄ represents cyclopropyl;

R₄ represents C_3-s cycloalkyl-Co-6 alkyl, preferably C_3-s cycloalkyl-Co-i alkyl, more preferably C_3-s cycloalkyl, still more preferably C_3-6 cycloalkyl; wherein the alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C_3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and even still more preferably R₄ represents cyclopropyl;

R₅ represents H, halogen or CN, preferably halogen or CN, more preferably chloro or CN, and still more preferably chloro; and R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), and R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, preferably R₃, Rb and R₀ independently represent H or methyl, more preferably R_a and Rb independently represent H or methyl and R₀ represents H, 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:

R₅ represents H, halogen or CN, preferably halogen or CN, more preferably chloro or CN, and still more preferably chloro; and R2 and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R₃ and Rb have the meaning described above for compounds of formula I and R₀ represents H or Ci_-4 alkyl, and preferably R₀ represents H.

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

Ri represents NH₂;

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 independently represent H or Ci_-4 alkyl, and 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, and still more preferably R₃ represents H, R_b represents methyl and R₀ represents H.

Ri represents NH₂;

R₄ represents C_3-8 cycloalkyl-Co-e alkyl, preferably C_3-8 cycloalkyl-C_0-i alkyl, more preferably C_3-8 cycloalkyl, still more preferably C_3-6 cycloalkyl; wherein the alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C_3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and even still more preferably R₄ represents cyclopropyl; R₅ represents H, halogen or CN, preferably halogen or CN, more preferably chloro or CN, and still more preferably chloro; and

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 independently represent H or Ci_-4 alkyl, and 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, 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 NH₂;

R₅ represents H or halogen, preferably H or chloro;

R₄ represents Ci_-8 alkyl or C_3-S cycloalkyl-Co-e alkyl, preferably C_2-S alkyl or C_3-S cycloalkyl-Co-1 alkyl, more preferably C_2-8 alkyl or C_3-8 cycloalkyl; wherein the alkyl groups can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C_3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group which 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 a NR₃Rb group, or contains 1 N atom and is substituted with one NR₃R_b group.

R₅ represents H or halogen, preferably H or chloro;

R₄ represents Ci_-8 alkyl or C_3-8 cycloalkyl-Co-e alkyl, preferably C_2-8 alkyl or C_3-8 cycloalkyl-Co-1 alkyl, more preferably C_2-8 alkyl or C_3-8 cycloalkyl; wherein the alkyl groups can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C_3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and

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.

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

Ri represents NH₂;

R₅ represents H or halogen, preferably H or chloro; R₄ represents Ci_-8 alkyl or C_3-S cycloalkyl-Co-e alkyl, preferably C_2-S alkyl or

C_3-S cycloalkyl-Co-1 alkyl, more preferably C_2-8 alkyl or C_3-8 cycloalkyl; wherein the alkyl groups can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C_3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and

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

Ri represents NH₂;

R₅ represents H or halogen, preferably H or chloro;

R₄ represents Ci_-8 alkyl or C_3-8 cycloalkyl-Co-6 alkyl, preferably C_2-8 alkyl or C_3-8 cycloalkyl-Co-1 alkyl, more preferably C_2-8 alkyl or C_3-8 cycloalkyl; wherein the alkyl groups can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C_3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and

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

Ri represents NH₂;

R₅ represents H or halogen, preferably H or chloro;

R₄ represents Ci_-8 alkyl or C_3-S cycloalkyl-Co-e alkyl, preferably C_2-S alkyl or C_3-S cycloalkyl-Co-1 alkyl, more preferably C_2-8 alkyl or C_3-8 cycloalkyl; wherein the alkyl groups can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C_3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and 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, Rc and R_d independently represent H or Ci_-4 alkyl, preferably R₃, Rb, Rc and R_d independently represent H or methyl.

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

Ri represents NH₂;

R₅ represents H or halogen, preferably H or chloro;

R₄ represents Ci_-8 alkyl or C_3-8 cycloalkyl-Co-6 alkyl, preferably C_2-8 alkyl or C_3-8 cycloalkyl-Co-1 alkyl, more preferably C_2-8 alkyl or C_3-8 cycloalkyl; wherein the alkyl groups can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C_3-S cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and R2 and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), and R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, preferably R_a, Rb and R₀ independently represent H or methyl, more preferably R_a and Rb independently represent H or methyl and R₀ represents H, 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 NH₂;

R₅ represents H or halogen, preferably H or chloro; R₄ represents Ci_-8 alkyl or C3_-8 cycloalkyl-Co-6 alkyl, preferably C2-8 alkyl or

C3-8 cycloalkyl-Co-1 alkyl, more preferably C2-8 alkyl or C3-8 cycloalkyl; wherein the alkyl groups can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and

R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R_a 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:

Ri represents NH₂;

R₅ represents H or halogen, preferably H or chloro;

R₄ represents Ci_-8 alkyl or C3-8 cycloalkyl-Co-e alkyl, preferably C_2-8 alkyl or C_3-S cycloalkyl-Co-1 alkyl, more preferably C_2-8 alkyl or C_3-8 cycloalkyl; wherein the alkyl groups can be optionally substituted with one or more halogen atoms

(preferably fluoro) and the C3_-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and

R₅ represents H or halogen, preferably H or chloro;

R₄ represents Ci_-8 alkyl or C3-8 cycloalkyl-Co-e alkyl, preferably C_2-8 alkyl or C_3-S cycloalkyl-Co-1 alkyl, more preferably C_2-8 alkyl or C_3-8 cycloalkyl; wherein the alkyl groups can be optionally substituted with one or more halogen atoms (preferably fluoro) and the C_3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen (preferably fluoro) and aryl; and

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

Ri represents NH₂; R₅ represents H or halogen, preferably H or chloro;

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 independently represent H or Ci_-4 alkyl, preferably R_a, Rb and R₀ independently represent H or methyl, more preferably R_a and Rb independently represent H or methyl and R₀ represents H, and still more preferably R_a represents H, R_b represents methyl and R₀ represents H. Moreover, the present invention includes all possible combinations of the particular and preferred embodiments described above.

In an additional embodiment, the invention relates to a compound of formula I selected from the list of examples 1 -46.

In an additional embodiment, the invention relates to compounds according to formula I which provide more than 50% inhibition of H₄ receptor activity at 10 μM, more preferably at 1 μM and even more preferably at 0.1 μM, in a H₄ receptor assay such as the one described in examples 47 or 48.

The compounds of the present invention contain one or more basic nitrogens and may, therefore, form salts with organic or inorganic acids. Examples of these salts include: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; and salts with organic acids such as methanesulfonic acid, thfluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, fumaric acid, oxalic acid, acetic acid, maleic acid, ascorbic acid, citric acid, lactic acid, tartaric acid, malonic acid, glycolic acid, succinic acid and propionic acid, among others.

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 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:

wherein Ri, R₂, R₃, R₄ and R₅ have the meaning described above with respect to a compound of formula I, and Rio represents a leaving group such as halogen, mesylate, tosylate or thflate.

The reaction between the compounds of formulae Il and III may be performed using a coupling agent such as for example PyBOP (benzotriazol-1-yl- oxytripyrrolidinophosphonium hexafluorophosphate) in a suitable solvent such as 1 ,4-dioxane, tetrahydrofuran, dichloromethane, Λ/,Λ/-dinnethylfornnannide, acetonitrile or mixtures thereof, preferably in acetonitrile or a mixture of acetonitrile/dioxane, in the presence of a base, such as N,N- diisopropylethylamine, dimethylaniline, diethylamide, triethylamine or 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU), preferably triethylamine. The reaction can be carried out at a temperature comprised between room temperature and the reflux temperature, preferably heating.

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 of formula Il into a leaving group such as a halogen, mesylate, tosylate or triflate.

The -OH group from a compound of formula Il may be transformed into a leaving group such as halogen, preferably chloro, by reaction with a halogenating agent such as POCI3, optionally in the presence of a suitable solvent, optionally in the presence of a base such as tetraethylammonium chloride, diisopropylethylamine or diethylaniline, among others; or with POCI3/PCI5 or N, N- dimethylformamide/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. The hydroxy group of a compound of formula Il can be transformed into a triflate group by reaction with thfluoromethanesulphonic anhydride in the presence of pyridine. The hydroxy group of a compound of formula Il can be transformed into a tosylate or mesylate group by reaction with p-toluenesulfonyl chloride or methanesulfonyl chloride in a suitable solvent such as dichloromethane in the presence of a base such as triethylamine or pyridine.

The reactive derivative of a compound of formula Il thus obtained (MB) is then allowed to react with a compound of formula III 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, acetonitrile or toluene, in the presence of a base, including organic amines such as triethylamine, Λ/,Λ/-diisopropylethylamine, dimethylaniline and diethylaniline among others, and heating, preferably at a temperature comprised between 50 and 140 °C. The heating may be thermal or by irradiating with microwaves at a wattage that allows to reach the temperature mentioned above.

In general, before conducting the reaction between the compounds of formula 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 (Ri) of the compounds of formula Il and MB can also be protected if necessary. Any suitable amino-protective group may be used, such as for example a te/f-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. When the protective group is Boc, the 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 procedures described in the literature.

The compounds of formula Il can be obtained by reacting a compound of formula IV with either cyanamide or formamide depending on the nature of the substituent Ri (NH₂ or H) as shown in the following scheme:

wherein Ri, R₄ and R₅ have the meaning described in formula I.

The reaction with cyanamide takes place in the presence of an acid such as HCI in a suitable solvent such as 1 ,4-dioxane or diethyl ether by heating at a suitable temperature usually comprised between room temperature and the reflux temperature, preferably under reflux. The reaction can be completed by subsequent addition of a base such as sodium hydroxide and heating at a suitable temperature, preferably under reflux.

The reaction with formamide is performed by heating a compound of formula IV in neat formamide at a suitable temperature usually comprised between 100 ⁰C and 200 ⁰C.

The compounds of formula IV can be obtained by reacting a compound of formula V with diethyl chloromalonate as shown in the following scheme:

VB wherein R₄ and R₅ have the meaning described in formula I, and M represents an alkali metal within group IA, such as lithium, sodium or potassium, preferably lithium.

The reaction can be carried out in a suitable solvent such as N, N- dimethylformamide followed by addition of a base such as 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU) or preferably 1 ,5-diazabicyclo[4.3.0]non-5- ene (DBN) in a suitable solvent such as ethanol.

Alternatively, the compounds of formula IV can be prepared by reacting a compound of formula VB with ethyl glycolate. The reaction is carried out using triphenylphosphine and diethyl azodicarboxylate (DEAD) in a suitable solvent such as tetrahydrofuran. The reaction can be carried out at a temperature comprised between 0 °C and reflux, preferably at room temperature. Generally it is necessary to add a base such as NaH to cause cyclization. The compounds of formula V and VB are commercially available or can be readily obtained from commercially available compounds by standard procedures. For example, enolate formation can be carried out under standard conditions such as lithium diisopropylamide (LDA)/tetrahydrofuran, sodium hydride/diethyl ether or potassium fe/t-butoxide/tetrahydrofuran, amongst others (see for example Journal of Medicinal Chemistry 2004, 47, 1448-1464 and Tetrahedron Letters 1982, 23, 47, 4977-4980).

Moreover, certain compounds of the present invention can also be obtained starting from other compounds of formula I by appropriate conversion reactions of functional groups, in one or several steps, using well-known reactions in organic chemistry under standard experimental conditions. These conversion reactions include, amongst others: the halogenation of a compound of formula I where R₅ represents H (Ia) by treatment with a halogenating agent to yield a compound of formula Ib:

Ia Ib wherein Ri, R₂, R3 and R₄ have the meaning described above with respect to a compound of formula I, and Y represents halogen, preferably chloro. For example, when Y represents Cl, the reaction can be carried out using a suitable chlorinating agent such as sulfuryl chloride, in a suitable solvent, such as chloroform, toluene or acetonitrile, preferably acetonithle, at a temperature comprised between - 50 ⁰C and room temperature, preferably at about -10 ⁰C; the cyanation of a compound of formula Ib by treatment with a cyanating agent to yield a compound of formula Ic:

wherein Ri, R₂, R3 and R₄ have the meaning described above with respect to a compound of formula I, and Y represents halogen, preferably chloro or bromo, more preferably chloro. The reaction can be performed by treating a compound of formula Ib with a cyanide source such as sodium, potassium, copper or zinc cyanide, in a suitable solvent such as dimethylsulfoxide, Λ/,Λ/-dimethylformamide or /V-methylpyrrolidinone, preferably dimethylsulfoxide, and heating, preferably at 110 ⁰C, or by treatment with copper or zinc cyanide and a palladium catalyst such as tetrakis(thphenylphosphine)palladium(0) or palladium acetate, in a suitable solvent, such as Λ/,Λ/-dimethylformamide and heating.

Before conducting the above mentioned interconversion reactions of compounds of formula I it is advisable to protect the amino groups present in NR2R3 with a suitable protecting group, preferably a te/t-butoxycarbonyl (Boc) group. If Boc is used, 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 thfluoroacetic acid in dichloromethane.

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 for the treatment or prevention of diseases mediated by the H₄ receptor in mammals, including human beings.

Diseases that can be treated or prevented with the compounds of the present invention include, among others, allergic, immunological or inflammatory diseases, or pain. Examples of allergic, immunological or inflammatory diseases that can be treated or prevented with the compounds of the invention include without limitation: respiratory diseases, such as asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD); ocular diseases, such as allergic rhinoconjunctivitis, dry eye and cataracts; skin diseases, such as dermatitis (e.g. atopic dermatitis), psoriasis, urticaria and pruritus; inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease; rheumatoid arthritis; multiple sclerosis; cutaneous lupus; systemic lupus erythematosus; and transplant rejection. Examples of pain conditions that can be treated or prevented with the compounds of the invention include, among others, inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-surgical pain, migraine, cancer pain, visceral pain, osteoarthritis pain and neuropathic pain.

In a preferred embodiment, the compounds of the invention are used for the treatment or prevention of an allergic, immunological or inflammatory disease. In a more preferred embodiment, the compounds of the invention are used for the treatment or prevention of an allergic, immunological or inflammatory disease selected from a respiratory disease, an ocular disease, a skin disease, an inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus, and transplant rejection. In a still more preferred embodiment, the allergic, immunological or inflammatory disease is selected from asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataracts, dermatitis (e.g. atopic dermatitis), psoriasis, urticaria, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection.

In another preferred embodiment, the compounds of the invention are used for the treatment or prevention of pain, preferably inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-surgical pain, migraine, cancer pain, visceral pain, osteoarthritis pain or neuropathic pain.

Assays to determine the ability of a compound to interact with the histamine H₄ receptor are well known in the art. For example, one can use a H₄ receptor binding assay such as the one explained in detail in example 47. 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 48; this assay is well know in the art (see for example the method disclosed in Buckland KF et al, 2003, cited above in the Background section, which is incorporated herein by reference). In vivo assays that can be used to test the activity of the compounds of the invention are also well known in the art (see for example the various literature references listed for in vivo animal models in the Background section, particularly those relating to in vivo models of peritonitis, pleurisy, allergic asthma, inflammatory bowel disease, atopic dermatitis, pruritus and pain, which are all incorportated herein by reference).

The selectivity profile of the compounds of the invention can be tested using standard histamine receptor binding assays using the various histamine receptors similarly to the one disclosed in example 47. In addition, to test the selectivity for other receptors or ion channels, displacement assays of the corresponding radioligands can be used following the standard procedures reported in the literature (see for example Cerep-Le Bois I'Eveque 2008 catalogue and the references cited therein). To test the selectivity for enzymes, determination of enzymatic activity by product formation from its substrate can be used.

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 47. 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 48; 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 which comprises a compound of the invention (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients. The excipients must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.

The compounds of the present invention can be administered in the form of any pharmaceutical formulation, the nature of which, as it is well known, will depend upon the nature of the active compound and its route of administration. Any route of administration may be used, for example oral, parenteral, nasal, ocular, topical and rectal administration. In a preferred embodiment, the compounds of the invention are administered orally. In another embodiment, the compounds of the invention are administered topically.

Solid compositions for oral administration include tablets, granulates and capsules. In any case the manufacturing method is based on a simple mixture, dry granulation or wet granulation of the active compound with excipients. These excipients can be, for example, diluents such as lactose, microcrystalline cellulose, mannitol or calcium hydrogenphosphate; binding agents such as for example starch, gelatin or povidone; disintegrants such as sodium carboxymethyl starch or sodium croscarmellose; and lubricating agents such as for example magnesium stearate, stearic acid or talc. Tablets can be additionally coated with suitable excipients by using known techniques with the purpose of delaying their disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period, or simply to improve their organoleptic properties or their stability. The active compound can also be incorporated by coating onto inert pellets using natural or synthetic film-coating agents. Soft gelatin capsules are also possible, in which the active compound is mixed with water or an oily medium, for example coconut oil, mineral oil or olive oil.

Powders and granulates for the preparation of oral suspensions by the additon of water can be obtained by mixing the active compound with dispersing or wetting agents; suspending agents and preservatives. Other excipients can also be added, for example sweetening, flavouring and colouring agents.

Liquid forms for oral administration include emulsions, solutions, suspensions, syrups and elixirs containing commonly-used inert diluents, such as purified water, 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 by the following examples. Examples

The following abreviations are used in the examples:

AcN: acetonitrile

DMF: Λ/,Λ/-dimethylformamide DMSO: dimethylsulfoxide EtOAc: ethyl acetate MeOH: methanol Min: minutes MS: mass spectrometry

PyBOP: (benzothazol-1 -yloxy)tripyrrolidinophosphonium hexafluorophosphate t_R: retention time

LC-MS: liquid chromatography-mass spectrometry

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

Method 1 : X-Terra MS C18 column 5 μm (100 mm x 2.1 mm), temperature: 30 °C, rate: 0.35 mL/min, eluent: 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 1 ,7 μm (2.1 x 50 mm) column, temperature: 40 °C, rate: 0.50 mL/min, eluent: 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 terf-Butyl methyl[(3R)-pyrrolidin-3-yl]carbamate

(a) tert-Butyl[(3R)-1-benzylpyrrolidin-3-yl] methylcarbamate

Di-te/t-butyl dicarbonate (11.6 g, 53.07 mmol) dissolved in 15 mL of CH₂CI₂ was added to a solution of (3R)-1 -benzyl-Λ/-methylpyrrolidin-3-amine (10 g, 52.55 mmol) in 115 mL of CH₂CI₂, cooled 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 was filtered through CeI ite^® 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 terf-Butyl azetidin-3-yl(methyl)carbamate (a) tert-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 terf-Butyl methyl(3-methylazetidin-3-yl)carbamate (a) terf-Butyl [1 -(diphenylmethyl)-3-methylazetidin-3-yl]methylcarbamate 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-Λ/-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. Next 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, which was further used as obtained.

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 4a 2-Cyclopropyl-3-hydroxyacrylonitrile lithium salt

To a solution of diisopropyl amine (18.3 ml_, 129.44 mmol) in tetrahydrofuran (220 ml_) at -78 ⁰C, n-butyllithium (1.6 M in hexanes, 81 ml_, 129.44 mmol) was added dropwise. The reaction was stirred at -78 ⁰C for 1 hour. A solution of cyclopropylacetonitrile (11.4 ml_, 123.27 mmol) in tetrahydrofuran (20 ml_) was added and then allowed to warm to -30 ⁰C (over 40 min). Ethyl formate (12.3 ml_, 147.93 mmol) was added and the reaction was stirred at -10 ⁰C for 1 hour, then allowed to warm to room temperature and stirred overnight. The precipitated solids were collected by vacuum filtration, washed with diethyl ether and air dried to give the desired compound as a white powder (7.8g, 55%). 1H NMR (300 MHz, DMSO) δ: 0.12 (m, 2H), 0.43 (m, 2H), 1.39 (m, 1 H), 8.16 (s, 1 H).

REFERENCE EXAMPLES 4b-4k

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

(I)¹H NMR (300 MHz, DMSO) δ: 0.86 (t, 3H, J 7.2 Hz), 1.93 (q, 2H, J 7.2 Hz), 8.04 (s, 1H).

(2)¹H NMR (300 MHz, DMSO) δ: 0.85 (t, 3H, J 7.2 Hz), 1.27 (m, 2H), 1.85 (q, 2H, J 9.6 Hz), 8.06

(s, 1H).

(3)¹H NMR (300 MHz, DMSO) δ: 0.86 (d, 6H, J 6.9 Hz), 2.7 (m, 1H), 7.98 (s, 1H).

(4)¹H NMR (300 MHz, DMSO) δ: 3.2 (s, 2H), 7-7.3 (m, 5H), 8.26 (s, 1H).

(5)¹H NMR (300 MHz, DMSO) δ: 1.5-1.9 (m, 6H), 3.28 (m, 1H), 7.99 (s, 1H).

(6)¹H NMR (300 MHz, DMSO) δ: 0.82 (d, 6H, J 6.6 Hz), 1.54 (hept, 1H, J 6.9 Hz), 1.78 (d, 2H, J

6.9Hz), 8.12 (s, 1H). (7)¹H NMR (300 MHz, DMSO) δ: 1.1-1.75 (m, 8H), 2.8 (m, 1H), 8.05 (s, 1H). (8)¹H NMR (300 MHz, DMSO) δ: 1.05 (s, 9H), 8.00 (s, 1H).

(9) ¹H NMR (300 MHz, DMSO) δ: 1.25-1.45 (m, 4H), 2.55 (m, 1H), 3.25 (m, 2H), 3.79 (m, 2H), 8.11 (s, 1H). (10) ¹H NMR (300 MHz, DMSO) δ: 0.35-0-50 (m, 4H), 3.11 (s, 2H), 3.32 (s, 3H), 8.06 (s, 1H).

REFERENCE EXAMPLE 5a Ethyl 3-amino-4-cyclopropylfuran-2-carboxylate

To a solution of compound obtained in reference example 4a (5 g, 43.47 mmol) in DMF (108 ml_) was added diethyl chloromalonate (8.4 ml_, 52.17 mmol). The reaction mixture was stirred overnight at room temperature. After diluting with water (500 ml_), the reaction mixture was extracted with ethyl acetate. The combined organic extracts were dried over Na2SO₄. After filtration, the filtrate was concentrated to dryness providing an orange syrup. The orange syrup was dissolved in ethanol (217 ml_) to which 1 ,5-diazabicyclo[4.3.0]non-5-ene (5.9 ml_, 47.8 mmol) was added, and the mixture was stirred at room temperature overnight. The solution was concentrated to dryness and the crude residue was purified by flash chromatography on silica gel using ethyl acetate and hexane mixtures of increasing polarity to afford 3 g of the title compound (yield: 65%) as a light brown oil. LC-MS (Method 2): t_R = 1.88 min; m/z 196 (MH⁺).

REFERENCE EXAMPLES 5b-5l The following compounds were obtained following a procedure similar to that described in reference example 5a, but using suitable starting materials instead of reference example 4a:

REFERENCE EXAMPLE 6a 2-Amino-7-cyclopropylfuro[3,2 d]pyτimidin-4-ol

To a solution of the compound obtained in reference example 5a (2.4 g, 12.17 mmol) in 1 ,4-dioxane (37 ml_), cyanamide (2.0 g, 48.66 mmol) was added and then, slowly, 4 M HCI in 1 ,4-dioxane solution (24 ml_). The resulting suspension was stirred at room temperature for 2 hours and then, at reflux overnight. The solvent was evaporated and 2M NaOH aqueous solution (60 ml_) was added, and the resulting mixture was heated at reflux for 6 hours. The reaction mixture was neutralized with 3M HCI aqueous solution. The resulting precipitate was collected by filtration, washed with H₂O and dried to afford 1.6 g of the title compound (yield:

69%).

LC-MS (Method 2): t_R = 1.03 min; m/z = 192 (MH⁺).

REFERENCE EXAMPLES 6b-6l

The following compounds were obtained following a procedure similar to that described in reference example 6a, but using suitable starting materials:

REFERENCE EXAMPLE 7a 7-cyclopropylfuro[3,2 c/]pyrimidin-4-ol

A mixture of the compound obtained in reference example 5a (1 g, 5.1 mmol) and formamide (20 ml_) was stirred at 130 ⁰C for 3 hours and 170 ⁰C overnight. The reaction mixture was poured over H₂O and extracted with ethyl acetate. The combined organic extracts were dried over Na₂SO₄. After filtration, the filtrate was concentrated to dryness providing a solid which was washed with a mixture of hexane/ethyl acetate (1/1 ) and dried, to afford 0.66 g of the desired compound (yield: 73%). LC-MS (Method 2): t_R = 1.03 min; m/z = 177 (MH⁺).

REFERENCE EXAMPLE 8a

(R)-tert-Butyl 1-(2-amino-7-isopropylfuro[3,2-c(]pyrimidin-4-yl)pyrrolidin-3- yl(methyl)carbamate

To a suspension of the compound obtained in reference example 6d (1.3 g, 6.7 mmol) in acetonitrile (26 mL), triethylamine (26 mL), PyBOP (3.85 g, 7.4 mmol) and reference example 1 (2.15 g, 10.8 mmol) were added. The resulting suspension was heated at 80 ⁰C overnight. The solvent was evaporated to dryness and the residue was diluted with dichloromethane and water. pH was adjusted to 9-10 with 1 N NaOH and the phases were separated. The aqueous phase was extracted again with dichloromethane, and the combined organic phases were dried over Na₂SO₄ and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using EtOAc as eluent, to afford 2.08 g of the desired compound (yield: 82%)

LC-MS (Method 2): t_R = 2.39 min; m/z 376 (MH⁺).

REFERENCE EXAMPLE 8b terf-Butyl 1 -(2-amino-7-cyclopropylfuro[3,2-c(]pyrimidin-4-yl) azetidin-3-yl(methyl)carbamate

Following a similar procedure to that described in reference example 8a but using reference examples 6a and 2 as starting materials, the title compound was obtained.

LC-MS (Method 2): t_R = 2.11 min; m/z 360 (MH⁺).

REFERENCE EXAMPLE 9a terf-Butyl 1-(2-amino-6-chloro-7-cyclopropylfuro[3,2-c(]pyrimidin-4- yl)azetidin-3-yl(methyl)carbamate

To a suspension of the compound obtained in reference example 8b (1.38 g, 3.84 mmol) in acetonitrile (38 ml_), cooled at -10 ⁰C, sulfuryl chloride (0.31 ml_, 3.84 mmol) was added. After 45 min, additional sulfuryl chloride (0.2 ml_) was added and the mixture stirred at -10 ⁰C for additional 30 min. Again, additional sulfuryl chloride (0.15 ml_) was added and the reaction mixture stirred at -10 ⁰C for another 30 min. Then, NaHCO3 saturated solution was added at -10 ⁰C to quench the reaction mixture and it was then diluted with ethyl acetate. Phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over Na2SO₄ and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using mixtures of hexane/EtOAc of increasing polarity as eluent, to afford 790 mg of the desired compound (yield: 52%)

LC-MS (Method 2): t_R = 2.49 min; m/z 394/396 (MH⁺).

REFERENCE EXAMPLE 9b

(R)-tert-Buty\ 1-(2-amino-6-chloro-7-isopropylfuro[3,2-cGpyrimidin-4- yl)pyrrolidin-3-yl(methyl)carbamate

Following a procedure similar to that described in reference example 9a but using reference example 8a as starting material and chloroform as the reaction solvent, the title compound was obtained.

LC-MS (Method 2): t_R = 2.83 min; m/z 410/412 (MH⁺). EXAMPLE 1 7-Cyclopropyl-4-(4-methylpiperazin-1-yl)furo[3,2-cy]pyrimidin-2-amine

To a suspension of the compound obtained in reference example 6a (0.15 g, 0.78 mmol) in a mixture of 1 ,4-dioxane (5 ml_) and acetonitrile (5 ml_), triethylamine (4.7 ml_), PyBOP (0.41 g, 0.78 mmol) and 1-methylpiperazine (0.12 ml_, 1.09 mmol) were added. The resulting suspension was heated at 80 ⁰C for 20 hours. The reaction mixture was partitioned between ethyl acetate and NaHCO3 saturated aqueous solution. The organic phase was dried over Na2SO₄ and concentrated to dryness. The crude product obtained was purified by preparative HPLC-MS (column X-Terra PREP MS C18 5 μm (100 mm x 19 mm), rate: 20 mL/min, eluent: A = AcN, B = NH₄HCO₃ 75 mM, gradient: 0 min A at 10%; 1 min A at 10%; 8 min A at 90%) and the fractions containing the product were evaporated to dryness, providing 67 mg of the title compound (yield: 31 %).

LC-MS (Method 2): t_R = 1.53 min; m/z 274 (MH⁺).

EXAMPLES 2-4

The following compounds were obtained following a procedure similar to that described in example 1 , but using suitable starting materials:

EXAMPLE 5 7-Cyclopropyl-4-(3-(methylamino)azetidin-1-yl)furo[3,2-c/]pyrimidin-2-amine (a) tert-Butyl 1 -^-amino-y-cyclopropylfuroIS^-cGpyrimidin^-ylJazetidin-S- yl(methyl)carbamate

To a suspension of the compound obtained in reference example 6a (0.15 g, 0.78 mmol) in a mixture of 1 ,4-dioxane (5 ml_) and acetonitrile (5ml_), triethylamine (4.7 ml_), PyBOP (0.41 g, 0.78 mmol) and reference example 2 (0.38 g, 1.09 mmol) were added. The resulting suspension was heated at 80 ⁰C for 20 hours. The reaction mixture was partitioned between ethyl acetate and NaHCO3 saturated aqueous solution. The organic phase was dried over Na2SO₄ and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using EtOAc/MeOH mixtures of increasing polarity as eluent, to afford 330 mg of the desired compound.

LC-MS (Method 2): t_R = 2.15 min; m/z 360 (MH⁺). b) Title compound

A mixture of the compound obtained in section a) (0.33g, 0.92 mmol) and 4 M HCI in 1 ,4-dioxane solution (7 ml_) was stirred at room temperature for 1 hour. MeOH was added and the reaction mixture was stirred 15 min more and then concentrated to dryness. The residue was dissolved in water and extracted once with ethyl acetate that was discarded, then 1 N NaOH solution was added to the aqueous phase until basic pH and it was extracted three times with ethyl acetate. The combined organic phases were dried over Na2SO₄ and concentrated to dryness. The crude product obtained was purified by chromatography on aluminum oxide using EtOAc/MeOH mixtures of increasing polarity as eluent, to afford 105 mg of the title compound (yield: 52% both steps). LC-MS (Method 2): t_R = 1.28 min; m/z 260 (MH⁺).

EXAMPLES 6-36

The following compounds were obtained following a procedure similar to that described in example 5, but using suitable starting materials:

(*) Reaction was performed in acetonitrile instead of a 1 ,4-dioxane-acetonitrile mixture.

EXAMPLE 37

6-Chloro-7-cyclobutyl-4-(3-(methylamino)azetidin-1-yl)furo[3,2-cy]pyrimidin-2- amine

A mixture of the compound obtained in example 26 (0.1 g, 0.36 mmol), 4 M HCI in 1 ,4-dioxane solution (0.5 ml_) and methanol (1 ml_) was stirred at room temperature for 2 hours, then concentrated to dryness. The salt was suspended in CHCI3 and sulfuryl chloride was added (0.44 mmol, 0.036 ml_). The reaction mixture was stirred for 2 hours and then more sulfuryl chloride was added (0.44 mmol, 0.036 ml_). After stirring 1 more hour, the residue was dissolved in water and extracted once with CHCI3 that was discarded, then 1 N NaOH solution was added to the aqueous phase until basic pH and it was extracted three times with CHCI3. The combined organic phases were dried over Na2SO₄ and concentrated to dryness. The crude product obtained was purified by preparative HPLC (column X-Terra PREP MS C18 5 μm (100 mm x 19 mm), rate: 19 mL/min, eluent: A = AcN, B = NH₄HCO₃ 75 mM, gradient: 0 min A at 20%; 3 min A at 20%; 6 min A at 80%) and the fractions containing the product were evaporated to dryness, providing 3.45 mg of the title compound (yield: 1 %). LC-MS (Method 2): t_R = 1.87 min; m/z 308 (MH⁺).

EXAMPLES 38-42

Method A

The following compounds were obtained following a procedure similar to that described in example 37, but using suitable starting materials:

Method B

Examples 37 to 42 can also be obtained following a similar chlorination procedure to that described in example 37 but using the corresponding starting material in Boc-protected form and acetonitrile as the solvent, followed by removal of the Boc- protecting group. Thus, for example, compound of example 38 was also obtained from reference example 8b (i.e. te/t-butyl 1 -(2-amino-7-cyclopropylfuro[3,2-c/]pyhmidin-4- yl)azetidin-3-yl(methyl)carbamate), which was chlorinated as disclosed in reference example 9a to render te/t-butyl 1-(2-amino-6-chloro-7- cyclopropylfuro[3,2-c/]pyhmidin-4-yl)azetidin-3-yl(methyl)carbamate. Compound of reference example 9a was then treated with trifluoroacetic acid following the procedure of example 44 section b) to give example 38 in 87% yield.

EXAMPLE 43 4-(3-(Methylamino)azetidin-1 -yl)-7-(tetrahydro-2H-pyran-4-yl) furo[3,2-c/]pyrimidin-2-amine

Following a similar procedure to that described in example 5, but using reference examples 6k and 2 as starting materials, the desired compound was obtained with a 52% yield. LC-MS (Method 2): t_R = 1.15 min; m/z = 304 (MH⁺).

EXAMPLE 44

2-Amino-7-isopropyl-4-((3/?)-3-(methylamino)pyrrolidin-1-yl)furo[3,2- d]pyrimidine-6-carbonitrile (a) (R)-tert-Buty\ 1-(2-amino-6-cyano-7-isopropylfuro[3,2-cflpyrimidin-4- yl)pyrrolidin-3-yl(methyl)carbamate

To a solution of reference example 9b (80 mg, 0.19 mmol) in DMSO (1.5 mL), sodium cyanide (110 mg, 2.25 mmol) was added and the mixture was heated at 100 ⁰C overnight. Additional sodium cyanide (50 mg, 0.98 mmol) was added and the mixture heated at 110 ⁰C for 3 days. The reaction mixture was allowed to cool down and then it was diluted with ethyl acetate and water. The phases were separated and the aqueous phase was back extracted three times with ethyl acetate. The combined organic phases were dried over Na2SO₄ and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using mixtures of hexane/EtOAc of increasing polarity as eluent, to afford 19 mg of the desired compound (yield: 24%)

LC-MS (Method 2): t_R = 2.54 min; m/z 401 (MH⁺). (b) Title compound To a solution of the compound obtained in section a) (19 mg, 0.05 mmol) in dichloromethane (0.6 ml_), thfluoroacetic acid (0.3 ml_) was added and the reaction mixture was stirred at room temperature for 2 hours and then concentrated to dryness. The residue was dissolved in water and extracted twice with ethyl acetate that was discarded. Then 1 N NaOH solution was added to the aqueous phase until basic pH and it was extracted three times with ethyl acetate. The combined organic phases were dried over Na2SO₄ and concentrated to dryness. The crude product obtained was purified by chromatography on aluminum oxide using EtOAc/MeOH mixtures of increasing polarity as eluent, to afford 9.7 mg of the title compound (yield: 68%). LC-MS (Method 2): t_R = 1.60 min; m/z 301 (MH⁺).

EXAMPLE 45

2-Amino-7-cyclopropyl-4-(3-(methylamino)azetidin-1-yl)furo[3,2- d]pyrimidine-6-carbonitrile

Following a similar procedure to that described in example 44, but using reference example 9a as starting material, the desired compound was obtained. LC-MS (Method 2): t_R = 1.47 min; m/z = 285 (MH⁺).

EXAMPLE 46

7-(1-(Methoxymethyl)cyclopropyl)-4-(3-(methylamino)azetidin-1-yl)furo[3,2- d]pyrimidin-2-amine

Following a similar procedure to that described in example 5, but using reference examples 61 and 2 as starting materials, the desired compound was obtained with a 73% yield.

LC-MS (Method 2): t_R = 1.22 min; m/z = 304 (MH⁺)

EXAMPLE 47 Binding competition assay of [³H]-histamine to human histamine H₄ receptor To perform the binding assay, membrane extracts prepared from a stable

CHO recombinant cell line expressing the human histamine H₄ receptor (Euroscreen/Perkin-Elmer) were used. Test compounds were incubated at the selected concentration in duplicate, with 10 nM [³H]-histamine and 15 μg membranes extract in a total volume of 250 μl_ of 50 mM Tris-HCI, pH 7.4, 1.25 mM EDTA for 60 minutes at 25 ⁰C. Nonspecific binding was defined in the presence of 100 μM unlabeled histamine. The reaction was stopped by filtration using a vacuum collector (Multiscreen Millipore) in 96-well plates (Multiscreen HTS Millipore) which had been previously soaked in a 0.5% polyethylenimine solution for 2 hours at 0 ⁰C. Subsequently, the plates were washed with 50 mM Tris (pH 7.4), 1.25 mM EDTA at 0 ⁰C and filters were dried during 1 hour at 50-60 ⁰C, before adding the scintillation liquid to determine bound radioactivity by using a betaplate scintillation counter.

The compounds of examples 1 to 44 and 46 were assayed in this test and showed an inhibition of more than 50% of binding to the human histamine H₄ receptor at 10 μM. In addition, the compounds of examples 1 to 14, 16 to 35, 37 to 44 and 46 exhibited more than 50% inhibition of binding to the human H₄ histamine receptor H₄ at 1 μM.

EXAMPLE 48

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 centhfugation 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 14, 16 to 35, 37 to 44 and 46 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 H or NH₂;

R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group which 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 a 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 can be optionally substituted with one or more Ci_-4 alkyl groups; R₃ represents H or Ci_-4 alkyl; Rb represents H or Ci_-4 alkyl; or R₃ and Rb form, together with the N atom to which they are bound, an azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group that can be optionally substituted with one or more Ci_-4 alkyl groups; R₄ represents: (1 ) Ci_-8 alkyl; (2) C₃-S cycloalkyl-Co-6 alkyl;

(4) a group of formula (i)

(5) a group of formula (ii):

(U) ;

R₅ represents H, halogen, Ci_-S alkyl or CN;

Re and R₇ are each independently selected from H and Ci_-4 alkyl, and additionally one of the R₆ or R₇ groups can represent aryl or C_3-S cycloalkyl-Co-e alkyl, and additionally a Re group and a R₇ group on a same C atom can be bound forming together with said C atom a C_3-8 cycloalkyl group;

Rs represents a group selected from Ci-S alkyl, C_3-s cycloalkyl-Co-6 alkyl and aryl- Co_-4 alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms and the C_3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen and aryl;

Rg represents a 4- to 7-membered saturated monocyclic heterocyclic ring containing one heteroatom or group selected from O, S, SO and SO2 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 R₉ can be optionally substituted with one or more groups independently selected from Ci_-4 alkyl and halogen; X represents O, S, SO or SO₂; n represents 1 , 2 or 3; p represents 0, 1 or 2; 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, CN and NH₂; or a salt thereof.

2.- A compound according to claim 1 wherein Ri is NH₂.

3.- A compound according to claim 1 or 2 wherein R₅ represents H, halogen, Ci_-2 alkyl or CN.

4.- A compound according to claim 3 wherein R₅ represents H, halogen or CN.

5.- A compound according to claim 4 wherein R₅ represents H.

6.- A compound according to claim 4 wherein R₅ represents halogen.

7.- A compound according to claim 6 wherein R₅ represents chloro.

8.- A compound according to claim 4 wherein R₅ represents CN.

9.- A compound according to any of claims 1 to 8 wherein R₄ represents Ci-S alkyl or C3-8 cycloalkyl-Co-6 alkyl; wherein the alkyl groups can be optionally substituted with one or more halogen atoms and the C3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen and aryl.

10.- A compound according to claim 9 wherein R₄ represents C_2-s alkyl or C3-8 cycloalkyl, wherein the alkyl group can be optionally substituted with one or more halogen atoms and the C3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen and aryl.

11.- A compound according to claim 10 wherein R₄ represents ethyl, isopropyl, te/t-butyl or cyclopropyl.

12.- A compound according to any of claims 1 to 8 wherein R₄ represents Ci-S alkyl optionally substituted with one or more halogen atoms.

13.- A compound according to claim 12 wherein R₄ represents ethyl, isopropyl or te/t-butyl.

14.- A compound according to any of claims 1 to 8 wherein R₄ represents C3-8 cycloalkyl-Co-6 alkyl, wherein the alkyl group can be optionally substituted with one or more halogen atoms and the C3-8 cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen and aryl.

15.- A compound according to claim 14 wherein R₄ represents C3-8 cycloalkyl, which can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, halogen and aryl.

16.- A compound according to claim 15 wherein R₄ represents C₃-₈ cycloalkyl.

17.- A compound according to claim 16 wherein R₄ represents cyclopropyl.

18.- A compound according to any of claims 1 to 8 wherein R₄ represents a group of formula (i).

19.- A compound according to any of claims 1 to 8 wherein R₄ represents a group of formula (ii).

20.- A compound according to any of claims 1 to 19 wherein R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group which 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 a NR₃Rb group, or contains 1 N atom and is substituted with one NR₃Rb group.

21.- A compound according to claim 20 wherein R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:

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

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

23.- A compound according to claim 21 or 22 wherein R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a), (b), (e) and (f).

24.- A compound according to claim 21 or 22 wherein R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b).

25.- A compound according to claim 21 or 22 wherein R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula

(a).

26.- A compound according to claim 21 or 22 wherein R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula

(b).

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

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

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

30.- A compound according to any of claims 1 to 19 wherein 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.

31.- A pharmaceutical composition which comprises a compound of formula I according to any of claims 1 to 30 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

32.- A compound of formula I according to any of claims 1 to 30 or a pharmaceutically acceptable salt thereof for use in therapy.

33.- A compound according to any of claims 1 to 30 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease mediated by the histamine H₄ receptor.

34.- A compound according to any of claims 1 to 30 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of an allergic, immunological or inflammatory disease, or pain.

35.- Use of a compound according to any of claims 1 to 30 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease mediated by the histamine H₄ receptor.

36.- Use according to claim 35, wherein the disease mediated by the histamine H₄ receptor is an allergic, immunological or inflammatory disease, or pain.

37.- 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, R3, R₄ and R₅ have the meaning described in claim 1 , followed if necessary by the removal of any protecting 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)

wherein R10 represents a leaving group and Ri, R₂, R3, R₄ and R₅ have the meaning described in claim 1 , followed if necessary by the removal of any protecting group that may be present; or

(c) when in a compound of formula I R₅ represents halogen, reacting a compound of formula I (or an amino-protected form thereof) wherein R₅ represents H with a halogenating agent, followed if necessary by the removal of any protecting group that may be present; or

(d) when in a compound of formula I R₅ represents CN, reacting a compound of formula I (or an amino-protected form thereof) wherein R₅ represents halogen with a cyanating agent, followed if necessary by the removal of any protecting group that may be present; or

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