WO2009056551A1

WO2009056551A1 - Furo[3,2-d]pyrimidine derivatives

Info

Publication number: WO2009056551A1
Application number: PCT/EP2008/064622
Authority: WO
Inventors: Elena CARCELLER GONZÁLEZ; Eva María MEDINA FUENTES; Josep MARTÍ VIA; Marina VIRGILI BERNADÓ
Original assignee: Palau Pharma, S. A.
Priority date: 2007-10-30
Filing date: 2008-10-28
Publication date: 2009-05-07
Also published as: TW200934783A; AR069113A1; PE20090978A1

Abstract

Furo[3,2-d]pyrimidine derivatives of formula I, wherein the meanings for the various substituents are as defined in the description. These compounds are useful as H4 receptor antagonists.

Description

Furo[3,2-d]pyrimidine derivatives

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 to 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 models of immunoinflammation. Moreover, compounds should reach the target tissue or organ when administered via the chosen route of administration and possess favourable pharmacokinetic properties. In addition, they should be non-toxic and demonstrate few side-effects.

Description of the invention

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

wherein: Ri represents H or NH₂;

R₂ and R3 form, together with the N atom to which they are bonded, 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 heteroatom, and can be optionally substituted with one or more substitutents independently selected from Ci_-4 alkyl and NR₃Rb, with the proviso that the heterocyclic group must contain 2 N atoms or contain 1 N atom and be substituted with one NR₃Rb 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 bonded, an azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group, which can be optionally substituted with one or more Ci_-4 alkyl groups;

R₄ represents one or more groups independently selected from H and Ci_-4 alkyl, and optionally two groups R₄ on the same carbon atom or on two different carbon atoms can be bonded together forming a -Ci-6 alkyl- group, wherein said R₄ group(s) can be placed on any available position in ring A; and n represents 0, 1 , 2 or 3.

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 exhibit high affinity for the H₄ receptor. Thus, another aspect of the invention relates to a compound of formula I

wherein:

Ri represents H or NH₂;

R₂ and R3 form, together with the N atom to which they are bonded, 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 heteroatom, and can be optionally substituted with one or more substitutents independently selected from Ci_-4 alkyl and NR₃Rb, with the proviso that the heterocyclic group must contain 2 N atoms or contain 1 N atom and be substituted with one NR₃Rb 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 bonded, an azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group, which can be optionally substituted with one or more Ci_-4 alkyl groups; R₄ represents one or more groups independently selected from H and Ci_-4 alkyl, and optionally two groups R₄ on the same carbon atom or on two different carbon atoms can be bonded together forming a -Ci-6 alkyl- group, wherein said R₄ group(s) can be placed on any available position in ring A; and n represents 0, 1 , 2 or 3; for use in therapy.

Another aspect of this invention relates to a pharmaceutical composition which comprises a compound of formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease mediated by the 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 of an allergic, immunological or inflammatory disease or pain.

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

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

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

Another aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of an allergic, immunological or inflammatory disease or pain.

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

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

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

Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of an allergic, immunological or inflammatory disease or pain.

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

More preferably, the pain is selected from inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-surgical pain, migraine, cancer pain, visceral pain, osteoarthritis pain and neuropathic pain.

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

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

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

Another aspect of the present invention relates to a process for the preparation of a compound of formula I as defined above, which comprises: (a) reacting a compound of formula Il with a compound of formula III

wherein Ri, R₂, R3, R₄ and n have the previously described meaning; or (b) reacting a compound of formula IV with a compound of formula III

IV III wherein R₅ represents a leaving group and Ri, R₂, R3, R₄ and n have the previously described meaning; or (c) converting, in one or a plurality of steps, a compound of formula I into another compound of formula I.

In the above definitions, the term Ci_-4 alkyl means a straight or branched alkyl chain which contains from 1 to 4 carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and te/t-butyl. A -Ci-6 alkyl- group, in relation to the group formed when two R₄ substitutents on ring A of a compound of formula I are bonded together, refers to a straight or branched alkylene chain which contains from 1 to 6 carbon atoms. In case the two R₄ substitutents that are bonded together are placed on the same carbon atom of ring A, said alkylene chain together with ring A give rise to a spirocyclic system; in case the two R₄ substitutents that are bonded together are placed on different carbon atoms of ring A, said alkylene chain together with ring A give rise to a bridged bicyclic system. The groups R₄ forming a -Ci_-6 alkyl- group can be placed on any available carbon atom of ring A of a compound of formula I, as long as the resulting cyclic system can be chemically obtained and is stable. Examples of -Ci-β alkyl- groups formed by two R₄ groups on the same carbon atom thus forming spirocycles include, among others:

Examples of -d-β alkyl- groups formed by two R₄ groups on different carbon atoms of ring A thus forming a bridge include, among others:

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

A "bridged bicyclic" group refers to a bicyclic system having two common atoms (bridgeheads) connecting three acyclic chains (bridges), so that the two bridges with the higher number of atoms form then the main ring and the bridge with the lower number of atoms is the "bridge". In the definition of NR2R3, R2 and R3 together with the N atom to which they are bonded can form a saturated 4- to 7-membered monocyclic heterocycle containing up to 2 N atoms and no other heteroatom. Examples include, among others, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and homopiperazinyl.

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

The term "fused bicyclic" group, in the definition of NR2R3, refers to a 8- to 12-membered bicyclic system consisting of two adjacent rings sharing two atoms in common. Said fused bicyclic group can contain up to two N atoms in any available position and does not contain any other heteroatom. Examples include, among others, octahydropyrrolo[3,4-b]pyhdinyl, octahydropyrrolo[3,2-c]pyridinyl, octahydro-pyrrolo[1 ,2-a]pyrazinyl and octahydropyrrolo[3,4-c]pyrrolinyl.

As indicated 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 if the ring contains only 1 N atom, then the ring must be substituted with one NR₃Rb 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.

The expression "optionally substituted with one or more" means that a group can be substituted with one or more, preferably with 1 , 2, 3 or 4 substituents, more preferably with 1 or 2 substituents, provided that said group has enough positions available susceptible of being substituted. These substituents can be the same or different, and can be placed on any available position.

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

The invention thus relates to the compounds of formula I as defined above. In another embodiment, the invention relates to the compounds of formula I wherein Ri is H.

In another embodiment, the invention relates to the compounds of formula I wherein Ri is NH₂. In another embodiment, the invention relates to the compounds of formula I wherein n represents 1 , 2 or 3.

In another embodiment, the invention relates to the compounds of formula I wherein n represents 0, 1 or 2. In another embodiment, the invention relates to the compounds of formula I wherein n represents 1 or 2.

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

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

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

In another embodiment, the invention relates to the compounds of formula I wherein n represents 2. In another embodiment, the invention relates to the compounds of formula I wherein R₄ represents one or more substitutents selected from H and Ci_-4 alkyl.

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

In another embodiment, the invention relates to the compounds of formula I wherein n represents 1 , 2 or 3 and R₄ represents one or more substitutents selected from H and Ci_-4 alkyl.

In another embodiment, the invention relates to the compounds of formula I wherein n represents 1 , 2 or 3 and R₄ represents H.

In another embodiment, the invention relates to the compounds of formula I wherein n represents 0, 1 or 2 and R₄ represents one or more substitutents selected from H and Ci_-4 alkyl.

In another embodiment, the invention relates to the compounds of formula I wherein n represents 0, 1 or 2 and R₄ represents H.

In another embodiment, the invention relates to the compounds of formula I wherein n represents 1 or 2 and R₄ represents one or more substitutents selected from H and Ci_-4 alkyl.

In another embodiment, the invention relates to the compounds of formula I wherein n represents 1 or 2 and R₄ represents H. In another embodiment, the invention relates to the compounds of formula I wherein n represents 0 or 1 and R₄ represents one or more substitutents selected from H and Ci_-4 alkyl.

In another embodiment, the invention relates to the compounds of formula I wherein n represents 0 or 1 and R₄ represents H.

In another embodiment, the invention relates to the compounds of formula I wherein n represents 0 and R₄ represents one or more substitutents selected from H and Ci_-4 alkyl.

In another embodiment, the invention relates to the compounds of formula I wherein n represents 0 and R₄ represents H.

In another embodiment, the invention relates to the compounds of formula I wherein n represents 1 and R₄ represents one or more substitutents selected from H and Ci_-4 alkyl.

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

In another embodiment, the invention relates to the compounds of formula I wherein n represents 2 and R₄ represents one or more substitutents selected from H and Ci_-4 alkyl.

In another embodiment, the invention relates to the compounds of formula I wherein n represents 2 and R₄ 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 bonded, 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 the compounds of formula I wherein R₂ and R3 form, together with the N atom to which they are bonded, 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 heteroatom, and can be optionally substituted with one or more substitutents independently selected from Ci_-4 alkyl and NR₃Rb, with the proviso that the heterocyclic group must contain 2 N atoms or contain 1 N atom and be substituted with one NR₃Rb 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 bonded, a saturated heterocyclic group selected from: (i) a heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said heterocyclic group can be optionally substituted with one or more Ci_-4 alkyl groups; and

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

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

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

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

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

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

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

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

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

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

(a) (b) (C) (d)

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 bonded, a saturated heterocyclic group selected from (a) to (h), and R₃, R_b 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 bonded, a saturated heterocyclic group selected from (a) to (e), 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 bonded, a saturated heterocyclic group selected from (a) to (e), and 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. 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 bonded, a saturated heterocyclic group selected from (a) to (d), 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 bonded, a saturated heterocyclic group selected from (a) to (d), and 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 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 bonded, 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 the compounds of formula I wherein R₂ and R₃ form, together with the N atom to which they are bonded, a saturated heterocyclic group selected from (a) and (b), and 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.

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 bonded, a saturated heterocyclic group selected from (a) and (b), R_a represents H, R_b represents H or Ci_-4 alkyl and R₀ represents H.

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

In another embodiment, the invention relates to the compounds of formula I wherein R₂ and R₃ together with the N atom to which they are bonded form a heterocycle 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 bonded, a heterocycle of formula (a), 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 bonded, a heterocycle of formula (a), R_a represents H, R_b represents H or Ci_-4 alkyl and R₀ represents H.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ and R3 form, together with the N atom to which they are bonded, a heterocycle 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 together with the N atom to which they are bonded form a heterocycle 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 bonded, a heterocycle of formula (b), and 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. 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 bonded, a heterocycle of formula (b), R_a represents H, R_b represents H or Ci_-4 alkyl and R₀ represents H.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ and R₃ form, together with the N atom to which they are bonded, a heterocycle 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 together with the N atom to which they are bonded form a heterocycle of formula (c)

(C) wherein R₃ and R₀ independently represent H or Ci_-4 alkyl, and preferably R_a and R₀ independently represent H or methyl, and more preferably R_a represents H or methyl and R₀ represents H.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ and R3 together with the N atom to which they are bonded form a heterocycle of formula (d) Ra

(d) wherein R₃ represents H or Ci_-4 alkyl, and preferably R_a represents H or methyl. In another embodiment, the invention relates to the 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, and preferably R₂ represents H and R₃ represents 1 -methyl- pyrrol id in-3-yl. In another embodiment, the invention relates to the compounds of formula I wherein n is 0, 1 or 2 and Ri is NH₂.

In another embodiment, the invention relates to the compounds of formula I wherein n is 0 or 1 and Ri is NH₂.

In another embodiment, the invention relates to the compounds of formula I wherein n is 1 or 2 and Ri is NH₂. In another embodiment, the invention relates to the compounds of formula I wherein n is 0 and Ri is NH₂.

In another embodiment, the invention relates to the compounds of formula I wherein n is 1 and Ri is NH₂. In another embodiment, the invention relates to the compounds of formula I wherein n is 2 and Ri is NH₂.

In another embodiment, the invention relates to the compounds of formula I wherein n is 0, 1 or 2 and Ri is H.

In another embodiment, the invention relates to the compounds of formula I wherein n is 0 or 1 and Ri is H.

In another embodiment, the invention relates to the compounds of formula I wherein n is 0 and Ri is H.

In another embodiment, the invention relates to the compounds of formula I wherein n is 1 and Ri is H. In another embodiment, the invention relates to the compounds of formula I wherein n is 2 and Ri is H.

In another embodiment, the invention relates to the compounds of formula I wherein: n is O, 1 or 2; Ri is H; and

R₂ and R₃ form, together with the N atom to which they are bonded, 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 heteroatom, and can be optionally substituted with one or more substitutents independently selected from Ci_-4 alkyl and NR₃Rb, with the proviso that the heterocyclic group must contain 2 N atoms or contain 1 N atom and be substituted with one NR₃Rb group.

In another embodiment, the invention relates to the compounds of formula I wherein: n is O, 1 or 2;

Ri is H; and

R₂ and R₃ form, together with the N atom to which they are bonded, 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 the compounds of formula I wherein: n is O, 1 or 2; Ri is H; and

R₂ and R3 form, together with the N atom to which they are bonded, a saturated heterocyclic group selected from (a) to (h), wherein R₃, Rb and R₀ have the previously described meaning, and preferably R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, and more preferably R_a, Rb and R₀ independently represent H or methyl, and still more preferably R_a and Rb independently represent H or methyl and R₀ represents H. In another embodiment, the invention relates to the compounds of formula I wherein: n is O, 1 or 2; Ri is H; and

R₂ and R3 form, together with the N atom to which they are bonded, a saturated heterocyclic group selected from (a) and (b), wherein R₃, Rb and R₀ have the previously described meaning, and preferably R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, and more preferably R₃, Rb and R₀ independently represent H or methyl, and still more preferably R_a and Rb independently represent H or methyl and R₀ represents H. In another embodiment, the invention relates to the compounds of formula I wherein: n is O, 1 or 2; Ri is H; and R₂ and R3 together with the N atom to which they are bonded form a heterocycle 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.

Ri is H; and R₂ and R3 together with the N atom to which they are bonded form a heterocycle 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. In another embodiment, the invention relates to the compounds of formula I wherein: n is O, 1 or 2;

Ri is H; 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, and preferably R₂ represents H and R₃ represents 1 -methyl- pyrrol id in-3-yl.

Ri is NH₂; and

In another embodiment, the invention relates to the compounds of formula I wherein: n is O, 1 or 2; Ri is NH₂; and

R₂ and R3 form, together with the N atom to which they are bonded, 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.

Ri is NH₂; and R₂ and R3 form, together with the N atom to which they are bonded, a saturated heterocyclic group selected from (a) to (h), wherein R₃, R_b and R₀ have the previously described meaning, and preferably R₃, R_b and R₀ independently represent H or Ci_-4 alkyl, and more preferably R₃, Rb and R₀ independently represent H or methyl, and still more preferably R₃ and R_b independently represent H or methyl and R₀ represents H.

Ri is NH₂; and R₂ and R3 form, together with the N atom to which they are bonded, a saturated heterocyclic group selected from (a) to (d), wherein R₃, R_b and R₀ have the previously described meaning, and preferably R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, and more preferably R₃, Rb and R₀ independently represent H or methyl, and still more preferably R_a and Rb independently represent H or methyl and R₀ represents H.

Ri is NH₂; and

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

In another embodiment, the invention relates to the compounds of formula I wherein: n is 0, 1 or 2;

Ri is NH₂; and

R₂ and R₃ together with the N atom to which they are bonded form a heterocycle 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.

R₂ and R₃ together with the N atom to which they are bonded form a heterocycle of formula (b), wherein R₃, Rb and R₀ independently represent H or Ci-

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

Ri is NH₂; and R₂ and R3 together with the N atom to which they are bonded form a heterocycle of formula (d), wherein R₃ independently represents H or Ci_-4 alkyl, and preferably R_a represents H or methyl.

Ri is NH₂; 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, and preferably R₂ represents H and R₃ represents 1-methyl- pyrrol id in-3-yl.

In another embodiment, the invention relates to the compounds of formula I wherein: n is 1 or 2;

Ri is NH₂; and R₂ and R3 form, together with the N atom to which they are bonded, 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 heteroatom, and can be optionally substituted with one or more substitutents independently selected from Ci_-4 alkyl and NR₃Rb, with the proviso that the heterocyclic group must contain 2 N atoms or contain 1 N atom and be substituted with one NR₃Rb group.

Ri is NH₂; and

R₂ and R3 form, together with the N atom to which they are bonded, a saturated heterocyclic group selected from (a) to (h), wherein R₃, Rb and R₀ have the previously described meaning, and preferably R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, and more preferably R_a, Rb and R₀ independently represent H or methyl, and still more preferably R_a and Rb independently represent H or methyl and R₀ represents H. In another embodiment, the invention relates to the compounds of formula I wherein: n is 1 or 2;

Ri is NH₂; and

R₂ and R₃ form, together with the N atom to which they are bonded, a saturated heterocyclic group selected from (a) to (e), wherein R₃, Rb and R₀ have the previously described meaning, and preferably R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, and more preferably R_a, Rb and R₀ independently represent H or methyl, and still more preferably R_a and R_b independently represent H or methyl and R₀ represents H. In another embodiment, the invention relates to the compounds of formula I wherein: n is 1 or 2;

Ri is NH₂; and

R₂ and R₃ form, together with the N atom to which they are bonded, a saturated heterocyclic group selected from (a) to (d), wherein R_a, R_b and R₀ have the previously described meaning, and preferably R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, and more preferably R_a, R_b and R₀ independently represent H or methyl, and still more preferably R_a and R_b independently represent H or methyl and R₀ represents H. In another embodiment, the invention relates to the compounds of formula I wherein: n is 1 or 2;

Ri is NH₂; and R₂ and R3 form, together with the N atom to which they are bonded, a saturated heterocyclic group selected from (a) and (b), wherein R₃, Rb and R₀ have the previously described meaning, and preferably R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, and more preferably R₃, Rb and R₀ independently represent H or methyl, and still more preferably R_a and Rb independently represent H or methyl and R₀ represents H.

In another embodiment, the invention relates to the compounds of formula I wherein: n is 1 or 2; R₁ is NH₂; and

R₂ and R₃ together with the N atom to which they are bonded form a heterocycle 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 Rb independently represent H or methyl and R₀ represents H.

Ri is NH₂; and R₂ and R3 together with the N atom to which they are bonded form a heterocycle of formula (b), wherein R₃, R_b and R₀ independently represent H or Ci- 4 alkyl, and preferably R₃, R_b and R₀ independently represent H or methyl, and more preferably R₃ and Rb independently represent H or methyl and R₀ represents H. In another embodiment, the invention relates to the compounds of formula I wherein: n is 1 or 2;

Ri is NH₂; and

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

Ri is NH₂; and

R₂ and R3 together with the N atom to which they are bonded form a heterocycle of formula (d), wherein R₃ represents H or Ci_-4 alkyl, and preferably R₃ represents H or methyl.

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, and preferably R₂ represents H and R₃ represents 1 -methyl- pyrrol id in-3-yl. In another embodiment, the invention relates to the compounds of formula I wherein: n is 0 or 1 ;

Ri is NH₂; and

R₂ and R₃ form, together with the N atom to which they are bonded, 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 heteroatom, and can be optionally substituted with one or more substitutents independently selected from Ci_-4 alkyl and NR₃Rb, with the proviso that the heterocyclic group must contain 2 N atoms or contain 1 N atom and be substituted with one NR₃R_b group.

In another embodiment, the invention relates to the compounds of formula I wherein: n is 0 or 1 ; Ri is NH₂; and

R₂ and R₃ form, together with the N atom to which they are bonded, 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 the compounds of formula I wherein: n is O oM ;

Ri is NH₂; and

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

Ri is NH₂; and

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

Ri is NH₂; and

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

Ri is NH₂; and

R₂ and R3 together with the N atom to which they are bonded form a heterocycle 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.

In another embodiment, the invention relates to the compounds of formula I wherein: n is 0 or 1 ;

Ri is NH₂; and

R₂ and R₃ together with the N atom to which they are bonded form a heterocycle 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.

Ri is NH₂; and

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

R₂ and R3 together with the N atom to which they are bonded form a heterocycle of formula (d), wherein R₃ independently represents H or Ci_-4 alkyl, and preferably R_a represents H or methyl. In another embodiment, the invention relates to the compounds of formula I wherein: n is 0 or 1 ; Ri is NH₂; and

In another embodiment, the invention relates to the compounds of formula I wherein: n is O;

Ri is NH₂; and

R₂ and R₃ form, together with the N atom to which they are bonded, 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 heteroatom, and can be optionally substituted with one or more substitutents independently selected from Ci_-4 alkyl and NR₃Rb, with the proviso that the heterocyclic group must contain 2 N atoms or contain 1 N atom and be substituted with one NR₃Rb group. In another embodiment, the invention relates to the compounds of formula I wherein: n is 0;

Ri is NH₂; and

(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 the compounds of formula I wherein: n is 0;

Ri is NH₂; and R₂ and R3 form, together with the N atom to which they are bonded, a saturated heterocyclic group selected from (a) to (h), wherein R₃, Rb and R₀ have the previously described meaning, and preferably R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, and more preferably R₃, R_b and R₀ independently represent H or methyl, and still more preferably R₃ and R_b independently represent H or methyl and R₀ represents H.

Ri is NH₂; and R₂ and R3 form, together with the N atom to which they are bonded, a saturated heterocyclic group selected from (a) to (d), wherein R₃, R_b and R₀ have the previously described meaning, and preferably R₃, R_b and R₀ independently represent H or Ci_-4 alkyl, and more preferably R₃, Rb and R₀ independently represent H or methyl, and still more preferably R₃ and R_b independently represent H or methyl and R₀ represents H.

Ri is NH₂; and R₂ and R3 form, together with the N atom to which they are bonded, a saturated heterocyclic group selected from (a) and (b), wherein R₃, R_b and R₀ have the previously described meaning, and preferably R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, and more preferably R₃, Rb and R₀ independently represent H or methyl, and still more preferably R_a and Rb independently represent H or methyl and R₀ represents H.

Ri is NH₂; and

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: n is 0; R₁ is NH₂; and

Ri is NH₂; and R₂ and R3 together with the N atom to which they are bonded form a heterocycle of formula (c), wherein R₃ and R₀ independently represent H or Ci_-4 alkyl, and preferably R_a and R₀ independently represent H or methyl, and still more preferably R_a represents H or methyl and R₀ represents H.

Ri is NH₂; and

R₂ and R₃ together with the N atom to which they are bonded form a heterocycle of formula (d), wherein R₃ independently represents H or Ci_-4 alkyl, and preferably R_a represents H or methyl.

Ri is NH₂; 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, and preferably R₂ represents H and R3 represents 1-methyl- pyrrol id in-3-yl.

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

Ri is NH₂; and

(ii) a heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one NR₃R_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic groups (i) and (ii) can be 4- to 7-membered monocyclic,

7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic.

Ri is NH₂; and

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

Ri is NH₂; and

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

Ri is NH₂; and

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

Ri is NH₂; and R₂ and R3 together with the N atom to which they are bonded form a heterocycle 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. In another embodiment, the invention relates to the compounds of formula I wherein: n is 1 ;

Ri is NH₂; and

H.

Ri is NH₂; and

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

In another embodiment, the invention relates to the compounds of formula I wherein: n is 1 ; Ri is NH₂; and

R₂ and R₃ together with the N atom to which they are bonded form a heterocycle of formula (d), wherein R_a independently represents H or Ci_-4 alkyl, and preferably R_a represents H or methyl. In another embodiment, the invention relates to the compounds of formula I wherein: n is 1 ;

Ri is NH₂; 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, and preferably R₂ represents H and R₃ represents 1 -methyl- pyrrol id in-3-yl.

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

Ri is NH₂; and

Ri is NH₂; and R₂ and R₃ form, together with the N atom to which they are bonded, a saturated heterocyclic group selected from:

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

In another embodiment, the invention relates to the compounds of formula I wherein: n is 2; Ri is NH₂; and

In another embodiment, the invention relates to the compounds of formula I wherein: n is 2; R₁ is NH₂; and

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

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

Ri is NH₂; and

R₂ and R3 together with the N atom to which they are bonded form a heterocycle 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.

Ri is NH₂; and

R₂ and R₃ together with the N atom to which they are bonded form a heterocycle 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.

R₂ and R₃ together with the N atom to which they are bonded form a heterocycle of formula (c), wherein R₃ and R₀ independently represent H or Ci_-4 alkyl, and preferably R_a and R₀ independently represent H or methyl, and still more preferably R_a represents H or methyl and R₀ represents H. In another embodiment, the invention relates to the compounds of formula I wherein: n is 2;

Ri is NH₂; and

R₂ represents H or Ci_-4 alkyl and R₃ represents azetidinyl, pyrrol id inyl, piperidinyl or azepanyl, which can be optionally substituted with one or more Ci_-4 alkyl groups, and preferably R₂ represents H and R₃ represents 1 -methyl- pyrrol id in-3-yl.

In another embodiment, the invention relates to the compounds of formula I wherein: n is O, 1 or 2; Ri is NH₂;

R₂ and R₃ form, together with the N atom to which they are bonded, 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 heteroatom, and can be optionally substituted with one or more substitutents independently selected from Ci_-4 alkyl and NR₃Rb, with the proviso that the heterocyclic group must contain 2 N atoms or contain 1 N atom and be substituted with one NR₃Rb group; and

R₄ represents one or more substituents selected from H and Ci_-4 alkyl, and preferably R₄ represents H.

In another embodiment, the invention relates to the compounds of formula I wherein: n is O, 1 or 2; Ri is NH₂; R₂ and R₃ form, together with the N atom to which they are bonded, a saturated heterocyclic group selected from:

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

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

In another embodiment, the invention relates to the compounds of formula I wherein: n is O, 1 or 2; Ri is NH₂; R₂ and R3 form, together with the N atom to which they are bonded, a saturated heterocyclic group selected from (a) to (d), wherein R₃, Rb and R₀ have the previously described meaning, and preferably R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, and more preferably R₃, Rb and R₀ independently represent H or methyl, and still more preferably R₃ and R_b independently represent H or methyl and R₀ represents H; and

Ri is NH₂;

R₂ and R₃ form, together with the N atom to which they are bonded, a saturated heterocyclic group selected from (a) and (b), wherein R₃, R_b and R₀ have the previously described meaning, and preferably R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, and more preferably R₃, Rb and R₀ independently represent H or methyl, and still more preferably R_a and Rb independently represent H or methyl and R₀ represents H; and R₄ represents one or more substituents selected from H and Ci_-4 alkyl, and preferably R₄ represents H.

In another embodiment, the invention relates to the compounds of formula I wherein: n is O, 1 or 2; R₁ is NH₂; and

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

Ri is NH₂;

H; and

Ri is NH₂;

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

In another embodiment, the invention relates to the compounds of formula I wherein: n is O, 1 or 2; Ri is NH₂; R₂ and R3 together with the N atom to which they are bonded form a heterocycle of formula (d), wherein R₃ independently represents H or Ci_-4 alkyl, and preferably R_a represents H or methyl; and

R₄ represents one or more substituents selected from H and Ci_-4 alkyl, and preferably R₄ represents H. In another embodiment, the invention relates to the compounds of formula I wherein: n is O, 1 or 2; Ri is 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, and preferably R₂ represents H and R₃ represents 1 -methyl- pyrrol id in-3-yl; and

R₄ represents one or more substituents selected from H and Ci_-4 alkyl, and preferably R₄ represents H. Furthermore, the present invention covers all possible combinations of the particular and preferred embodiments described hereinabove.

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

4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydrobenzofuro[3,2- c/]pyhmidin-2-amine;

4-[3-(Methylamino)azetidin-1 -yl]-6,7,8,9-tetrahydrobenzofuro[3,2- c/]pyhmidin-2-amine; 4-[(3R)-3-Aminopyrrolidin-1-yl]-6,7,8,9-tetrahydrobenzofuro[3,2-c/]pyπnnidin- 2-amine;

4-(3-Aminoazetidin-1 -yl)-6,7,8,9-tetrahydrobenzofuro[3,2-c/]pyπnnidin-2- amine; 4-[(4aR7af?)-Octahydro-6H-pyrrolo[3,4-ib]pyridin-6-yl]-6,7,8,9- tetrahydrobenzofuro[3,2-c/]pyrimidin-2-annine;

4-[3-Methyl-3-(Methylamino)azetidin-1-yl]-6,7,8,9-tetrahydrobenzofuro[3,2- c/]pyrinnidin-2-annine;

4-Piperazin-1 -yl-6,7,8,9-tetrahydrobenzofuro[3,2-c/]pyrinnidin-2-annine; 4-(1 ,4-Diazepan-1 -yl)-6,7,8,9-tetrahydrobenzofuro[3,2-c/]pyrinnidin-2-annine;

4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydrobenzofuro[3,2- c/]pyrimidine;

4-[3-(Methylamino)azetidin-1 -yl]-6,7,8,9-tetrahydrobenzofuro[3,2- c/]pyrimidine; 4-(1 ,4-Diazepan-1 -yl)-6,7,8,9-tetrahydrobenzofuro[3,2-c/]pyrinnidine;

4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-7,8,9,10-tetrahydro-6/-/- cyclohepta[4,5]furo[3,2-c/]pyrinnidin-2-annine;

4-[3-(Methylamino)azetidin-1 -yl]-7,8,9,10-tetrahydro-6H- cyclohepta[4,5]furo[3,2-c/]pyrinnidin-2-annine; 4-[(3R)-3-Aminopyrrolidin-1-yl]-7,8,9,10-tetrahydro-6H- cyclohepta[4,5]furo[3,2-c/]pyrinnidin-2-annine;

4-[3-Methyl-3-(methylamino)azetidin-1-yl]-7,8,9,10-tetrahydro-6H- cyclohepta[4,5]furo[3,2-c/]pyrinnidin-2-annine;

4-[3-(Methylamino)azetidin-1 -yl]-7,8-dihydro-6/-/-cyclopenta[4,5]furo[3,2- c/]pyrimidin-2-annine;

4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-7,8-dihydro-6/-/- cyclopenta[4,5]furo[3,2-c/]pyrinnidin-2-annine;

N⁴-[(3R)-1-(Methylpyrrolidin-3-yl]amino-6,7,8,9-tetrahydrobenzofuro[3,2- c/]pyrinnidine-2,4-diannine; 4-(4-Methylpiperazin-1 -yl)-6,7,8,9-tetrahydrobenzofuro[3,2-c/]pyrinnidin-2- amine;

(S)-4-(3-Methylpiperazin-1 -yl)-6,7,8,9-tetrahydrobenzofuro[3,2-c/]pyrinnidin- 2-amine; and 4-(4-Methylpiperazin-1 -yl)-6,7,8,9-tetrahydrobenzofuro[3,2-d]pyrimidine. In a further 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 still more preferably at 0.1 μM, in a H₄ receptor binding assay such as the one described in example 22.

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 of salts thereof), including hydrates, are included within the scope of the invention. The compounds of formula I may exist in different physical forms, i.e. amorphous and crystalline forms. Moreover, the compounds of the invention may have the ability to crystallize in more than one form, a characteristic which is known as polymorphism. Polymorphs can be distinguished by various physical properties well known in the art such as X-ray diffraction pattern, melting point or solubility. All physical forms of the compounds of formula I, including all polymorphic forms ("polymorphs") thereof, are included within the scope of the invention.

Some of the compounds of the present invention may exist as several optical isomers and/or several diastereoisomers. Diastereoisomers can be separated by conventional techniques such as chromatography or fractional crystallization. Optical isomers can be resolved by conventional techniques of optical resolution to give optically pure isomers. This resolution can be carried out on any chiral synthetic intermediate or on the products of formula I. Optically pure isomers can also be individually obtained using enantiospecific synthesis. The present invention covers all individual isomers as well as mixtures thereof (for example racemic mixtures or mixtures of diastereomers), whether obtained by synthesis or by physically mixing them.

The compounds of formula I can be obtained by following the processes described below. As it will be obvious to one skilled in the art, the exact method used to prepare a given compound may vary depending on its chemical structure. Moreover, in some of the processes described below it may be necessary or advisable to protect the reactive or labile groups with conventional protecting groups. Both the nature of these protecting groups and the procedures for their introduction or removal are well known in the art (see for example Greene T.W. and Wuts P. G. M, "Protective Groups in Organic Synthesis", John Wiley & Sons, 3^rd edition, 1999). Unless otherwise stated, in the methods described below the meanings of the different substituents are the meanings described above with regard to a compound of formula I. In general, the compounds of formula I can be obtained by reacting a compound of formula Il with a compound of formula III, as shown in the following scheme:

"V wherein Ri, R₂, R3, R₄ and n have the meaning previously described in relation to a compound of formula I, and R₅ represents a leaving group such as a halogen atom or triflate.

The reaction between the compounds of formula Il and III can be carried out 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/-dimethylformamide or acetonitrile, preferably in acetonitrile, in the presence of a base such as N, N- diisopropylethylamine, dimethylaniline, diethylamide or thethylamine, preferably triethylamine. The reaction can be carried out at a temperature comprised between room temperature and reflux, preferably at room temperature.

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 (IV) prepared by conversion of the hydroxy group present in a compound Il into a leaving group such as halogen or triflate, preferably chloro.

Thus, the -OH group of a compound of formula Il can be converted 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, or with POCI3/PCI5 or /V,/V-dimethylfornnannide/oxalyl chloride mixtures in a suitable solvent such as 1 ,4-dioxane or 1 ,2-dichloroethane. The reaction is carried out by heating, preferably at a temperature comprised between 100 °C and 140 °C. Moreover, the hydroxy group of a compound of formula Il can be converted into a triflate group by reaction with trifluoromethanesulfonic anhydride in the presence of pyridine.

Next, the reactive derivative of the compound of formula Il thus obtained (IV) is allowed to react with a compound of formula III to give a compound of formula I. The reaction is carried out in a suitable solvent such as ethanol, methanol, butanol, Λ/,Λ/-dimethylformamide, dimethylsulfoxide, tetrahydrofuran or toluene, preferably ethanol, in the presence of a base, including organic amines such as thethylamine, Λ/,Λ/-diisopropylethylamine, dimethylaniline and diethylamide among others, and heating, preferably at a temperature comprised between 50 and 100 °C. Heating can be carried out thermally or by microwave irradiation at a wattage that allows to reach the above mentioned temperatures.

In general, before performing the reaction between the compounds of formulae Il and III, or IV and III, the amino substitutents of the compounds of formula III are protected to avoid the formation of byproducts. Moreover, if required, the amino group (Ri) of the compounds of formulae Il and IV can also be protected. Any suitable protecting group can be used, such as for example tert- butoxycarbonyl (Boc). When the amino substitutents of the compounds of formula Il and/or III and/or IV are protected, a subsequent deprotection step may be required, which is carried out under standard conditions. Thus, when the protecting group used is Boc, deprotection can be carried out directly upon the crude product by the addition of a solution of a strong acid such as HCI in a suitable solvent such as 1 ,4-dioxane, diethyl ether or methanol, or by treatment with thfluoroacetic acid in dichloromethane. The compounds of formula III are commercially available or can be obtained by procedures disclosed in the literature.

The compounds of formula Il can be prepared from a compound of formula V, as shown in the following scheme, using different procedures depending on the nature of substituent Ri:

wherein n, Ri and R₄ have the meaning disclosed in formula I.

The compounds of formula Il wherein Ri is hydrogen can be obtained by allowing to react a compound of formula V with formamide. The reaction can be carried out by heating at a suitable temperature usually comprised between room temperature and reflux, preferably at reflux.

The compounds of formula Il wherein Ri is NH₂ can be obtained by allowing to react a compound of formula V with cyanamide, in an acidic medium, preferably HCI, in a suitable solvent, preferably dioxane. The reaction can be carried out by heating at a suitable temperature usually comprised between room temperature and reflux, preferably at reflux. Subsequent treatment of the resulting formamidine intermediate with NaOH leads to the cyclicized compound.

The compounds of formula V can be prepared following the scheme shown below:

wherein n and R₄ have the meaning previously disclosed.

The reaction between a compound of formula Vl and the compound of formula VII 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 Vl are commercially available or can be readily obtained from commercially available compounds by standard procedures (see for example F. Fleming et al, J Org Chem 2007, 72, 1431 and G. K. Chip and T.R. Lynch, Can J Chem 1974, 52, 2249).

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

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

Diseases that can be treated 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 with the compounds of the invention include without limitation: respiratory diseases, such as asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD); ocular diseases, such as allergic rhinoconjunctivitis, dry eye and cataracts; skin diseases, such as dermatitis (e.g. atopic dermatitis), psoriasis, urticaria and pruritus; inflammatory bowel diseases, such as ulcerative colitis and

Crohn's disease; rheumatoid arthritis; multiple sclerosis; cutaneous lupus; systemic lupus erythematosus; and transplant rejection.

Examples of pain conditions that can be treated with the compounds of the invention include, among others, inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-surgical pain, migraine, cancer pain, visceral pain, osteoarthritis pain and neuropathic pain. In a preferred embodiment, the compounds of the invention are used for the treatment of an allergic, immunological or inflammatory disease. In a more preferred embodiment, the compounds of the invention are used for the treatment of an allergic, immunological or inflammatory disease selected from a respiratory disease, an ocular disease, a skin disease, an inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus, and transplant rejection. In a still more preferred embodiment, the allergic, immunological or inflammatory disease is selected from asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataracts, dermatitis (e.g. atopic dermatitis), psoriasis, urticaria, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection.

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

Assays to determine the ability of a compound to interact with the histamine H₄ receptor are well known in the art. For example, one can use a H₄ receptor binding assay such as the one explained in detail in example 22. 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. Another useful functional assay that can be used is the Gated Autofluorescence Forward Scatter assay (GAFS) in eosinophils, for example human eosinophils, which is well know in the art (see for example the method disclosed in Buckland KF et al, 2003, cited above in the Background section, which is incorportated herein by reference). In vivo assays that can be used to test the activity of the compounds of the invention are also well known in the art (see for example the various literature references listed for in vivo animal models in the Background section, particularly those relating to in vivo models of peritonitis, pleurisy, allergic asthma, inflammatory bowel disease, atopic dermatitis and pruritus, which are all incorportated herein by reference). 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 22. More preferably, compounds should exhibit more than 50% inhibition at 1 μM and still more preferably at 0.1 μM. 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.

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 abbreviations have been used in the examples: AcN: acetonitrile

DMF: dimethylformamide EtOAc: ethyl acetate MeOH: methanol PyBOP: (benzotriazol-1 -yloxy)tripyrrolidinophosphonium hexafluorophosphate THF: tetrahydrofuran t_R: retention time

LC-MS: liquid chromatography-mass spectrometry

LC-MS spectra have been performed using one of the following methods: Method 1 : Column X-Terra, MS C18 5 μm (100 mm x 2.1 mm), temperature: 30 ⁰C, flow: 0.35 mL/min, eluent: A = AcN, B = 1O mM NH₄HCO₃, gradient: 0 min 10% A; 10 min 90% A; 15 min 90% A. Method 2: Column Acquity UPLC BEH C18 1.7 μm (2.1 x 50 mm), temperature: 40 ⁰C, flow: 0.50 mL/min, eluent: A = AcN, B = 1O mM NH₄HCO₃, gradient: 0 min 10% A; 0.25 min 10% A; 3.00 min 90% A; 3.75 min 90% A.

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

(a) tert-Butyl [(SRJ-i-benzylpyrrolidin-S-yllmethylcarbamate

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

A solution of the compound 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 a mixture of MeOH (390 mL) and water (45 mL) was heated at reflux for 5 hours. The reaction was filtered through CeI ite^® and the filtrate was washed with EtOAc and MeOH. The solvent was concentrated to dryness, to afford 10.6 g of the title compound as an oil (yield: 100%).

¹H NMR (300 MHz, CDCI₃) δ: 1.38 (s, 9H), 1.72 (m, 1 H), 1.96 (m, 1 H), 2.53 (s, NH), 2.80 (s, 3H), 2.87 (m, 1 H), 2.93 (m, 1 H), 3.11 (m, 2H), 4.58 (m, 1 H). REFERENCE EXAMPLE 2 terf-Butyl azetidin-3-yl(methyl)carbamate (a) terf-Butyl [1-(diphenylmethyl)azetidin-3-yl]methylcarbamate Following a similar procedure to the one 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 (yield: 73%). 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. Then Pd/C (10%, 50% in water) (929 mg) was added and the solution was purged again with argon and was stirred under H₂ atmosphere for 18 hours. The reaction was filtered through CeI ite^® and the filtrate was washed with EtOAc and MeOH. The solvent was concentrated to dryness, to afford 5.66 g of a mixture of the title compound together with one equivalent of diphenylmethane, which was further used as obtained. 1H NMR (300 MHz, CD₃OD) δ: 1.44 (s, 9H), 2.88 (s, 3H), 3.56 (m, 2H), 3.71 (m, 2H), 4.75 (m, 1 H).

REFERENCE EXAMPLE 3 terf-Butyl (4aR,7aR)-octahydro-1H-pyrrolo[3,4-b]pyridin-1-carboxylate (a) tert-Butyl (4aR,7aR)-6-benzyloctahydro-1H-pyrrolo[3,4-b]pyridin-1- carboxylate

To a solution of (R,R)-6-benzyloctahydropyrrolo[3,4-ιb]pyridine dihydrochlohde (0.9 g, 3.11 mmol) in 9 mL of CH₂CI₂, triethylamine (0.95 mL, 6.84 mmol) and di-te/t- butyl dicarbonate (0.75 g, 3.42 mmol) dissolved in 2 mL of CH₂CI₂ were added. The resulting solution was stirred at room temperature overnight. The solvent was evaporated and the crude product obtained was chromatographed on silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 0.79 g of the desired compound (yield: 72%). LC-MS (Method 2): t_R = 2.94 min; m/z = 317 (MH⁺). (b) Title compound

A solution of the compound obtained in section a) (0.79 g, 2.49 mmol) in 10 ml_ of MeOH was purged with argon. Next Pd/C (10%, 50% in water) (157 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 filtrate was washed with MeOH. The solvent was concentrated to dryness, to afford 0.61 g of the desired compound in quantitative yield. LC-MS (Method 2): t_R = 1.29 min; m/z = 227 (MH⁺).

REFERENCE EXAMPLE 4 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 filtrate 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 5

(3R)-1-Methylpyrrolidin-3-amine dihydrochloride (a) tert-Butyl (3/?)-1-methylpyrrolidin-3-ylcarbamate To a solution of te/t-butyl (3R)-pyrrolidin-3-ylcarbamate (1.0 g, 5.34 mmol) in 23 ml_ of MeOH, 37% aqueous formaldehyde solution (1.19 ml_, 14.6 mmol) was added and then sodium borohydride (0.61 g, 16.1 mmol) was slowly added. The resulting mixture was stirred at room temperature under argon overnight. The solvent was evaporated and the crude product was dissolved in CHCI3 and was washed with brine and then with saturated NaHCO3 solution. The oganic phase was dried over Na2SO₄ and concentrated to dryness, to afford 0.85 g of the desired compound (yield: 79%). 1H NMR (300 MHz, CDCI₃) δ: 1.43 (s, 9H), 1.58 (m, 1 H), 2.25 (m, 2H), 2.33 (s, 3H), 2.52 (m, 2H), 2.77 (m, 1 H), 4.16 (m, 1 H), 4.86 (m, NH). (b) Title compound

A mixture of the compound obtained in section a) (0.85 g, 4.25 mmol), 4 M HCI in 1 ,4-dioxane solution (40 ml_) and MeOH (1 ml_) was stirred at room temperature for 1 hour. The resulting mixture was concentrated to dryness. The crude product obtained was dissolved in MeOH and concentrated again to dryness to afford 0.77 g of the title compound in quantitative yield.

¹H NMR (300 MHz, CD₃OD) δ: 2.15 (m, 1 H), 2.55 (m, 1 H), 2.91 (s, 3H), 3.15 (m, 1 H), 3.3-3.85 (m, 3H), 4.10 (m, 1 H).

REFERENCE EXAMPLE 6

Ethyl 3-amino-4,5,6,7-tetrahydrobenzofuran-2-carboxylate

To a solution of triphenylphosphine (29.9 g, 114 mmol) in 500 ml_ of THF, cooled to 0 ⁰C, was slowly added a 40% solution of diethyl azodicarboxylate in toluene (52.2 ml_, 114 mmol), ethyl glycolate (10.8 ml_, 114 mmol) and 2- oxocyclohexanecarbonitrile (10 g, 81.3 mmol). The resulting solution was stirred at room temperature for 20 hours. Then 50% sodium hydride (11 g, 229 mmol) was added and the mixture was stirred at room temperature for 5 hours. The reaction mixture was cooled to 0 ⁰C and a pH 7.8 phosphate buffer (Na₂HPO₄/KH₂PO₄) solution (375 ml_) was added. THF was evaporated and the resulting aqueous solution was extracted with EtOAc. The organic phase was dried over Na₂SO₄ and concentrated to dryness. The resulting crude product was chromatographed on silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 8.5 g of the desired compound (yield: 50%). LC-MS (Method 2): t_R = 1.97 min; m/z = 210 (MH⁺).

REFERENCE EXAMPLE 7 2-Amino-6,7,8,9-tetrahydrobenzofuro[3,2-c/]pyrimidin-4-ol To a solution of the compound obtained in reference example 6 (3.6 g, 17.4 mmol) in 1 ,4-dioxane (52 ml_), cyanamide (2.9 g, 69.5 mmol) was added and then, slowly, a 4 M HCI in 1 ,4-dioxane solution (35 ml_). The resulting suspension was stirred at room temperature for 2 hours and, then, at reflux for 20 hours. The solvent was evaporated and 2M NaOH (87 ml_) was added, and the resulting mixture was heated at reflux for 6 hours. The reaction mixture was neutralized with 3M HCI. The resulting precipitate was collected by filtration, washed with H₂O and dried to afford 3.1 g of the title compound (yield: 88%). LC-MS (Method 2): t_R = 1.17 min; m/z = 206 (MH⁺).

REFERENCE EXAMPLE 8

6,7,8,9-Tetrahydrobenzofuro[3,2-cdpyrimidin-4-ol

A mixture of the compound obtained in reference example 6 (1.4 g, 6.7 mmol) and formamide (24 mL) was stirred at 170 ⁰C for 24 hours. The reaction mixture was poured over H₂O. The precipitate obtained was collected by filtration, washed with cold H₂O and dried, to afford 0.9 g of the desired compound (yield: 71 %). LC-MS (Method 2): t_R = 1.23 min; m/z = 191 (MH⁺).

REFERENCE EXAMPLE 9 2-Oxocycloheptanecarbonitrile To a suspension of potassium te/t-butoxide (6.17 g, 55.0 mmol) in THF (50 mL) heated at reflux, a solution of 1 ,6-dicyanohexane (5.0 g, 36.7 mmol) in THF (25 mL) was added dropwise. The reaction mixture was allowed to cool down to room temperature, 10% H₂SO₄ (50 mL) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with water and EtOAc, and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated to dryness. The crude product obtained was purified by vacuum distillation (aprox 5 mm Hg), and the product was collected at a vapor temperature between 110-115 ⁰C, to afford 1.22 g of the title compound (yield: 24%).

LC-MS (Method 2): t_R = 1.37 min; m/z = 138 (MH⁺).

REFERENCE EXAMPLE 10

Ethyl 3-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan-2-carboxylate

Following a similar procedure to the one described in reference example 6, but using reference example 9 instead of 2-oxocyclohexanecarbonithle, the title compound was obtained in 41 % yield. LC-MS (Method 2): t_R = 2.18 min; m/z = 224 (MH⁺).

REFERENCE EXAMPLE 11 2-Amino-7,8,9,10-tetrahydro-6H-cyclohepta[4,5]furo[3,2-c(]pyrimidin-4-ol

Following a similar procedure to the one described in reference example 7, but using reference examplel O as starting product, the title compound was obtained in quantitative yield. LC-MS (Method 2): t_R = 1.40 min; m/z = 220 (MH⁺).

REFERENCE EXAMPLE 12 Ethyl 3-amino-5,6-dihydro-4H-cyclopenta[b]furan-2-carboxylate

To a solution of diisopropyl amine (6.8 mL, 48.11 mmol) in tetrahydrofuran (80 mL) at -78 ⁰C, n-butyllithium (1.6 M in hexanes, 30 mL, 48.11 mmol) was added dropwise. The reaction was stirred at -78 ⁰C for 1 hour. A solution of 2- oxocyclopentanecarbonithle (5 g, 45.82 mmol) in tetrahydrofuran (10 mL) was added and 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 a white powder.

To a solution of this powder in DMF (184 mL) at 0 ⁰C, diethyl chloromalonate (8.9 mL, 54.98 mmol) was added dropwise. 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 (210 mL) to which 1 ,5- diazabicyclo[4.3.0]non-5-ene (6.2 ml_, 50.4 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 2.50 g of the title compound (yield: 28%) as a light brown oil. LC-MS (Method 2): t_R = 1.81 min; m/z 196 (MH⁺).

REFERENCE EXAMPLE 13 2-Amino-7,8-dihydro-6H-cyclopenta[4,5]furo[3,2-d]pyrimidin-4-ol Following a similar procedure to the one described in reference example 7, but using reference example 12 as starting product, the title compound was obtained in 54% yield. LC-MS (Method 2): t_R = 0.96 min; m/z = 192 (MH⁺).

EXAMPLE 1

4-[(3/?)-3-(Methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydrobenzofuro[3,2- d]pyrimidin-2-amine

(a) tert-Butyl (/?)-1-(2-amino-6,7,8,9-tetrahydrobenzofuro[3,2-c(]pyrimidin-4- yl)pyrrolidin-3-yl(methyl)carbamate To a suspension of the compound obtained in reference example 7 (1 g, 4.88 mmol) in 1 ,4-dioxane (50 mL), triethylamine (12.5 mL), PyBOP (2.54 g, 4.88 mmol) and reference example 1 (1.47 g, 7.34 mmol) were added. The resulting suspension was stirred at room temperature for 72 hours and was then concentrated to dryness. The crude product obtained was partitioned between dichloromethane and 0.5 N NaOH. 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 1.12 g of the desired compound (yield: 59%).

LC-MS (Method 2): t_R = 2.38 min; m/z 388 (MH⁺). b) Title compound

A mixture of the compound obtained in section a) (1.12 g, 2.88 mmol), 4 M HCI in 1 ,4-dioxane solution (49 mL) and MeOH (25 mL) was stirred at room temperature for 3 hours and then concentrated to dryness. The crude product obtained was partitioned between dichloromethane and 1 N NaOH. The organic phase was dried over Na2SO₄ and concentrated to dryness, to afford 0.62 g of the title compound (yield: 75%). LC-MS (Method 2): t_R = 1.40 min; m/z 288 (MH⁺).

EXAMPLES 2-17

Following a similar procedure to the one described in example 1 but using appropriate starting materials in each case, the following compounds were obtained:

(*) The reaction was carried out in a 1 :1 AcN-1 ,4-dioxane mixture. (**) The reaction was carried out in AcN. (***)The reaction was carried out at 80° C.

EXAMPLES 18-21

Following a similar procedure to the one described in example 1 , section a), but using appropriate starting materials and a 1 :1 AcN-1 ,4-dioxane mixture as solvent, the following compounds were obtained:

(**) The reaction was carried out in AcN.

EXAMPLE 22 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 21 were tested in this assay and all gave more than 50% inhibition of histamine binding to the human H₄ receptor when tested at a concentration of 1 μM.

Claims

1.- A compound of formula I

wherein:

Ri represents H or NH₂;

R₃ represents H or Ci_-4 alkyl;

R₄ represents one or more groups independently selected from H and Ci_-4 alkyl, and optionally two groups R₄ on the same carbon atom or on two different carbon atoms can be bonded together forming a -Ci-6 alkyl- group, wherein said R₄ group(s) can be placed on any available position in ring A; and n represents 0, 1 , 2 or 3; or a salt thereof.

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

3.- A compound according to claim 1 wherein Ri is H.

4.- A compound according to any of claims 1 to 3 wherein n represents 0, 1 or 2.

5.- A compound according to any of claims 1 to 3 wherein n represents 0 or 1.

6.- A compound according to any of claims 1 to 3 wherein n represents 0.

7.- A compound according to any of claims 1 to 3 wherein n represents 1.

8.- A compound according to any of claims 1 to 3 wherein n represents 2.

9.- A compound according to any of claims 1 to 8 wherein R₄ represents one or more substitutents selected from H and Ci_-4 alkyl.

10.- A compound according to claim 9 wherein R₄ represents H.

11.- A compound according to any of claims 1 to 10 wherein R₂ and R3 form, together with the N atom to which they are bonded, 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 heteroatom, and can be optionally substituted with one or more substitutents independently selected from Ci_-4 alkyl and NR₃Rb, with the proviso that the heterocyclic group must contain 2 N atoms or contain 1 N atom and be substituted with one NR₃Rb group.

12.- A compound according to any of claims 1 to 10 wherein R₂ and R₃ form, together with the N atom to which they are bonded, a saturated heterocyclic group selected from:

13.- A compound according to any of claims 1 to 10 wherein R₂ and R3 form, together with the N atom to which they are bonded, a saturated heterocyclic group selected from:

(a) (b) (C) (d)

wherein R₀ represents H or Ci_-4 alkyl.

14.- A compound according to claim 13 wherein R₀ is H.

15.- A compound according to claim 13 or 14 wherein R₂ and R₃ form, together with the N atom to which they are bonded, a saturated heterocyclic group selected from (a) to (e).

16.- A compound according to claim 13 or 14 wherein R₂ and R₃ form, together with the N atom to which they are bonded, a saturated heterocyclic group selected from (a) to (d).

17.-A compound according to claim 13 or 14 wherein R₂ and R₃ form, together with the N atom to which they are bonded, a saturated heterocyclic group selected from (a) and (b).

18.- A compound according to claim 13 or 14 wherein R₂ and R₃ form, together with the N atom to which they are bonded, a saturated heterocyclic group of formula (a).

19.- A compound according to claim 13 or 14 wherein R₂ and R₃ form, together with the N atom to which they are bonded, a saturated heterocyclic group of formula (b).

20.- A compound according to claim 13 or 14 wherein R₂ and R₃ form, together with the N atom to which they are bonded, a saturated heterocyclic group of formula (c).

21.- A compound according to claim 13 wherein R₂ and R₃ form, together with the N atom to which they are bonded, a saturated heterocyclic group of formula (d).

22.- A compound according to any of claims 1 to 19 wherein R₃ and Rb independently represent H or Ci_-4 alkyl.

23.- A compound according to claim 22 wherein R₃ and Rb independently represent H or methyl.

24.- A compound according to claim 23 wherein R₃ represents H and Rb represents H or methyl.

25.- A compound according to any of claims 1 to 10 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.

26.- A compound according to claim 25 wherein R₂ represents H and R3 represents 1 -methyl-pyrrol id in-3-yl.

27- A compound according to claim 1 selected from:

4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydrobenzofuro[3,2- c/]pyhmidin-2-amine; 4-[3-(Methylamino)azetidin-1 -yl]-6,7,8,9-tetrahydrobenzofuro[3,2- c/]pyhmidin-2-amine;

4-[(3R)-3-Aminopyrrolidin-1-yl]-6,7,8,9-tetrahydrobenzofuro[3,2-c/]pyhmidin- 2-amine;

4-(3-Aminoazetidin-1 -yl)-6,7,8,9-tetrahydrobenzofuro[3,2-c/]pyhmidin-2- amine;

4-[(4af?,7af?)-Octahydro-6/-/-pyrrolo[3,4-ib]pyridin-6-yl]-6,7,8,9- tetrahydrobenzofuro[3,2-c/]pyhmidin-2-amine;

4-[3-Methyl-3-(Methylamino)azetidin-1-yl]-6,7,8,9-tetrahydrobenzofuro[3,2- c/]pyhmidin-2-amine; 4-Piperazin-1 -yl-6,7,8,9-tetrahydrobenzofuro[3,2-c/]pyhmidin-2-amine;

4-(1 ,4-Diazepan-1 -yl)-6,7,8,9-tetrahydrobenzofuro[3,2-c/]pyhmidin-2-amine;

4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydrobenzofuro[3,2- c/]pyhmidine; 4-[3-(Methylamino)azetidin-1 -yl]-6,7,8,9-tetrahydrobenzofuro[3,2- c/]pyrimidine;

4-(1 ,4-Diazepan-1 -yl)-6,7,8,9-tetrahydrobenzofuro[3,2-c/]pyrinnidine; 4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-7,8,9,10-tetrahydro-6H- cycloheptaK.Slfuroβ^-c/lpyrimidin^-amine;

4-[3-(Methylamino)azetidin-1 -yl]-7,8,9,10-tetrahydro-6H- cyclohepta[4,5]furo[3,2-c/]pyrinnidin-2-annine;

4-[(3R)-3-Aminopyrrolidin-1-yl]-7,8,9,10-tetrahydro-6/-/- cyclohepta[4,5]furo[3,2-c/]pyrinnidin-2-annine; 4-[3-Methyl-3-(methylamino)azetidin-1 -yl]-7,8,9,10-tetrahydro-6H- cyclohepta[4,5]furo[3,2-c/]pyrinnidin-2-annine;

4-[3-(Methylamino)azetidin-1 -yl]-7,8-dihydro-6/-/-cyclopenta[4,5]furo[3,2- c/]pyrinnidin-2-annine;

4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-7,8-dihydro-6H- cyclopenta^SJfuroβ^-c/Jpyrimidin^-annine;

N⁴-[(3R)-1-(Methylpyrrolidin-3-yl]amino-6,7,8,9-tetrahydrobenzofuro[3,2- c/]pyrinnidine-2,4-diannine;

4-(4-Methylpiperazin-1 -yl)-6,7,8,9-tetrahydrobenzofuro[3,2-c/]pyrinnidin-2- amine; (S)-4-(3-methylpiperazin-1 -yl)-6,7,8,9-tetrahydrobenzofuro[3,2-c/]pyrimidin-

2-amine; and

4-(4-methylpiperazin-1 -yl)-6,7,8,9-tetrahydrobenzofuro[3,2-d]pyrinnidine; or a salt thereof.

28.- A pharmaceutical composition which comprises a compound of formula I according to any of claims 1 to 27 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

29.- Use of a compound of formula I according to any of claims 1 to 27 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease mediated by the histamine H₄ receptor.

30.- Use according to claim 29, wherein the disease mediated by the histamine H₄ receptor is an allergic, immunological or inflammatory disease, or pain.

31.- A compound of formula I according to any of claims 1 to 27 or a pharmaceutically acceptable salt thereof for use in therapy.

32.- A compound of formula I according to any of claims 1 to 27 or a pharmaceutically acceptable salt thereof for the treatment of a disease mediated by the histamine H₄ receptor.

33.- A compound of formula I according to any of claims 1 to 27 or a pharmaceutically acceptable salt thereof for the treatment of an allergic, immunological or inflammatory disease, or pain.

34.- 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

wherein Ri, R₂, R3, R₄ and n are as defined in claim 1 ; or (b) reacting a compound of formula IV with a compound of formula

IV III wherein R₅ represents a leaving group and Ri, R₂, R3, R₄ and n are as defined in claim 1 ; or

(c) converting, in one or a plurality of steps, a compound of formula I into another compound of formula I.