AU2013204997A1 - Aminoalkylpyrimidine derivatives as histamine H4 receptor antagonists - Google Patents

Abstract

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

Description

Aminoalkylpyrimidine derivatives as histamine H4 receptor antagonists Field of the invention The present invention relates to a new series of aminoalkylpyrimidine derivatives, processes to prepare 5 them, pharmaceutical compositions comprising these compounds as well as their use in therapy. Background of the invention Histamine is one of the most potent mediators of immediate hypersensitivity reactions, While the effects of histamine on smooth muscle cell contraction, vascular permeability and gastric acid secretion are well known, its effects on the immune system are only now beginning to become unveiled. 10 A few years ago, a novel histamine receptor, which was named H 4 , was cloned by several research groups working independently (Oda T et al, J Biol Chem 2000, 275: 36781-6; Nguyen T at al, Mol 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 a); it is remarkable that it shares only a 35% homology with the H3 receptor. While the expression of the H3 receptor is 15 restricted to cells of the central nervous system, the expression of the H4 receptor has been mainly observed in cells of the haematopoletic lineage, in particular eosinophils, mast cells, basophils, dendritic cells and T-cells (Oda T at 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, TNFo. and IL-6. Nevertheless, the H4 20 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 1l): 129; Ikawa Y et at, Biol Pharm Bull 2005, 28: 2016-8) and osteoarthritis (Grzybowska-Kowalczyk A at 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 25 comparison to nasal mucosa of healthy people (J6k~ti A et al, Cell Biol nt 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 H 4 receptor (Ling P et al, Br J Pharmacol 2004, 142:161-71; Buckland KF et al, Br J Pharmacol 2003, 140:1117-27). In dendritic 30 cells, the H4 receptor has been shown to affect maturation, cytokine production and migration of these cells (Jelinek I et al, 1It Joint Meeting of European National Societies of Immunology, Paris, France, 2006, PA-1255). Moreover, the role of the H 4 receptor in mast cells has been studied. Although H 4 receptor activation does not induce mast cell degranulation, histamine and other proinflammatory mediators are released; moreover, the H4 receptor has been shown to mediate chemotaxis and calcium mobilization of mast cells (Hofstra CL et at, J Pharmacol Exp Ther 2003, 35 305: 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 at al, American Thoracic Society Conference, San Diego, USA, 2006, P-536), as well as regulating the activation of 2 CD4+ T cells (Dunford PJ et at, J Immunol 2006, 176: 7062-70). As for the intestine, the distribution of the H 4 receptor suggests that it may have a role in the control of peristalsis and gastric acid secretion (Morini G et al, European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, 0-10). The various functions of the H 4 receptor observed in eosinophils, nast cells and T-cells suggest that this 5 receptor can play an Important role in the immuno-Inflammatory response (see e.g. Zampeli E and Tiligada E, Br J Phannacol, 2009, 157, 24-33). In fact, H 4 receptor antagonists have shown in vivo activity in murine models of peritonitis (Thurmond RL at 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 at al, Br J Phannacol 2004,142 :374-80). In addition, H 4 receptor antagonists have demonstrated in vivo activity in experimental models of allergic asthma (Dunford PJ et al, 10 2006), inflammatory bowel disease (Varga C et al, Eur J Pharmacol 2005, 522:130-8), pruritus (Dunford PJ at al, J Allergy Clin Immunol 2007, 119: 176-83), atopic dermatitis (Cowden JM et a], 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 at at, European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, 0-36), edema and hyperalgesia (Coruzzi G et a, Eur J Pharmacol 2007, 563: 240-4), and 15 neuropathic pain (Cowart MD at a]., J Med Chem. 2008; 51 (20): 6547-57). Histamine H 4 receptor antagonists may also be useful in cancer (see e.g. Cianchi F et al, Clinical Cancer Research, 2005,11(19), 6807-6815). It is therefore expected that H 4 receptor antagonists can be useful among others for the treatment or prevention of allergic, immunological and inflammatory diseases, pain and cancer, Accordingly, it would be desirable to provide novel compounds having H 4 receptor antagonist activity and 20 which are good drug candidates. In particular, preferred compounds should bind potently to the histamine H 4 receptor whilst showing little affinity for other receptors and ion channels. In addition to binding to H 4 receptors, compounds should further exhibit good pharmacological activity in in vivo disease models. Moreover, compounds should reach the target tissue or organ when administered via the chosen route of administration and possess favourable pharmacokinetic properties. In addition, they should be non-toxic and demonstrate few side-effects. 25 Description of the invention One aspect of the present invention relates to the compounds of formula I

NH

2 R3 N N R4 n

NR

1

R

2

R

5

R

5 wherein: 30 R 1 and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from: 3 (i) a heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said heterocyclic group is optionally substituted with one or more C4 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 -NRaRb group and is optionally substituted with one or more C1.4 alkyl 5 groups; wherein said heterocyclic groups (i) and (ii) are 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; or R 1 represents H or C.4 alkyl, and R 2 represents azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, which are optionally substituted with one or more C4 alkyl groups; 10 R, represents H or C4 alkyl; Rb represents H or C14 alkyl; or Ra and Rb form, together with the N atom to which they are bound, an azetidinyl, pyrrolidiny, piperidinyl or azepanyl group that is optionally substituted with one or more C14 alkyl groups; R3 represents H or C,- alkyl; 15 R 4 represents Cis alkyl optionally substituted with one or more halogen, C 3 -io cycloaikyl-Co.4 alkyl, heterocycloalkyl Co.

4 alkyl, aryl-C.4 alkyl or heteroaryl-Co 4 alkyl, wherein in the C3.1o cycloalkyl-Co alkyl, heterocycloalkyl-C 4 alkyl, aryl-Co.4 alkyl and heteroaryl-Co- alkyl groups any alkyl group is optionally substituted with one or more R groups, any of the cycloalkyl and heterocycloalkyl groups are optionally substituted with one or more substituents independently selected from C1.8 alkyl and halogen, and any of the aryl and heteroaryl groups are optionally 20 substituted with one or more R7 groups; each R 5 independently represents H or C1.8 alkyl; each R 6 independently represents C,- alkyl, halogen, hydroxyCo.salkyl, C.io cycloalkyl optionally sustituted with one or more C,.8 alkyl groups, or phenyl optionally sustituted with one or more Ra; and optionally two R6 groups on the same carbon atom are bonded together to form a -C2 alkylene- group which is optionally substituted with one or 25 more C1 alkyl groups; each R 7 independently represents C,- alkyl, haloC, 4 alkyl, halogen, C alkoxy, haloC. alkoxy, -CN, C1 alkylthio, C24 alkynyl, hydroxyCm alkyl, C0 2 R-Co.5 alkyl, -CONRR, -SO 2 NRR, -SOrC.

6 alkyl, -NR 9 S0 2

-C

6 alkyl, NR 9 C0NRqRs, -NR 9 COR, -NR 9

R

9 , C3.0 cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein any of the C1o cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups in R 7 are optionally sustituted with one ore more C.8 alkyl 30 groups; each R 8 independently represents Ci.e alkyl, haloC, alkyl, halogen, C. alkoxy, haloC,.

6 alkoxy or -CN; each R9 independently represents H or C1.s alkyl; and optionally two R9 groups are bonded together to form a -C3.5 alkylene- group which is optionally substituted with one or more C1.8 alkyl groups; and n represents 1 or 2. 35 The compounds of formula I show high affinity for the H 4 histamine receptor and thus can be useful for the treatment or prevention of any disease mediated by this receptor. Thus, another aspect of the invention relates to a compound of formula I 4

NH

2 R3 N N N R4< n NR 1

R

2

R

5

R

5 wherein:

R

1 and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from: (i) a heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said 5 heterocyclic group is optionally substituted with one or more C4 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 -NRaRb group and is optionally substituted with one or more C 1

.

4 alkyl groups; wherein said heterocyclic groups (i) and (ii) are 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 10 8- to 12-membered fused bicyclic; or R 1 represents H or C alkyl, and R2 represents azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, which are optionally substituted with one or more C1 alkyl groups; Ra represents H or C14 alkyl; Rb represents H or C 1 4 alkyl; 15 or Ra and Rb form, together with the N atom to which they are bound, an azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group that is optionally substituted with one or more C- alkyl groups; R3 represents H or C,- alkyl;

R

4 represents C-B alkyl optionally substituted with one or more halogen, C31ai cycloalkyl-Co 4 alkyl, heterocycloalkyl Co4 alkyl, aryl-Co4 alkyl or heteroaryl-Co-4 alkyl, wherein in the Cs 1 o cycloalkyl-Co alkyl, heterocycloalkyl-Coi alkyl, 20 aryl-Co.4 alkyl and heteroaryl-Co. alkyl groups any alkyl group is optionally substituted with one or more R 6 groups, any of the cycloalkyl and heterocycloalkyl groups are optionally substituted with one or more substituents independently selected from CIe alkyl and halogen, and any of the aryl and heteroaryl groups are optionally substituted with one or more R 7 groups; each R 5 independently represents H or Ci-8alkyl; 25 each Re independently represents C,-8 alkyl, halogen, hydroxyCo.

6 alkyl, C340 cycloalky optionally sustituted with one or more C 1

.

5 alkyl groups, or phenyl optionally sustituted with one or more R; and optionally two R 6 groups on the same carbon atom are bonded together to form a -C 2 .5 alkylene- group which is optionally substituted with one or more Ci- alkyl groups; each R 7 independently represents C 1

.

8 alkyl, haloC 16 alkyl, halogen, Ct.6 alkoxy, haloC.e alkoxy, -CN, Ci- alkylthio, 30 C 2

.

4 alkynyl, hydroxyCo.6 alkyl, CO 2

R

9 -Co- alkyl, -CONR 9 Rs, -SO 2 NRqR 9 , -S0 2 -Cj-6 alkyl, -NRsS0 2

-C.

6 alkyl, - 5 NRCONRR, -NR 9 COR, -NRsR, CaIo cycloalkyl, heterocycloalkyl, aryl or heteroaryl: wherein any of the cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups in R? are optionally sustituted with one ore more C1.8 alkyl groups; each Rs independently represents Ci-salkyl, haloCi.salkyl, halogen, CIs alkoxy, haloCi- alkoxy or -CN; each R 9 independently represents H or C1.8 alkyl; and optionally two R 9 groups are bonded together to form a -C35 5 alkylene- group which is optionally substituted with one or more Ci. alkyl groups; and n represents 1 or 2; for use in therapy. Another aspect of the invention relates to a pharmaceutical composition which comprises a compound of formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. 10 Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease mediated by the histamine H 4 receptor. More preferably, the disease mediated by the histamine H 4 receptor is an allergic, immunological or inflammatory disease, pain or cancer. Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically 15 acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of an allergic, immunological or inflammatory disease, pain or cancer. Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of an allergic, immunological or inflammatory disease. More preferably, the allergic, immunological or inflammatory disease is 20 selected from respiratory diseases, ocular diseases, skin diseases, inflammatory bowel diseases, autoimmune diseases, 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, eczema, dermatitis (e.g. atopic dermatitis), psoriasis, urticaria, pemphigus, dermatitis herpetiformis, cutaneous vasculitis, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous 25 lupus, systemic lupus erythematosus, systemic vasculitis and transplant rejection. Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of pain. More preferably, the pain is selected from inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-surgical pain, migraine, cancer pain, visceral pain, osteoarthritis pain and neuropathic pain. 30 Another aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease mediated by the histamine H 4 receptor. More preferably, the disease mediated by the histamine H& receptor is an allergic, immunological or inflammatory disease, pain or cancer. Another aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable 35 salt thereof for use in the treatment or prevention of an allergic, immunological or inflammatory disease, pain or cancer. Another aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable 6 salt thereof for use in the treatment or prevention of an allergic, immunological or inflammatory disease. More preferably, the allergic, immunological or inflammatory disease is selected from respiratory diseases, ocular diseases, skin diseases, inflammatory bowel diseases, autoimmune diseases, and transplant rejection. Still more preferably, the allergic, immunological or inflammatory disease is selected from asthma, allergic rhinitis, chronic 5 obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataracts, eczema, dermatitis (e.g. atopic dermatitis), psoriasis, urticaria, pemphigus, dermatitis herpetiformis, cutaneous vasculitis, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus, systemic vasculitis and transplant rejection. Another aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable 10 salt thereof for use in the treatment or prevention of pain. More preferably, the pain is selected from inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-surgical pain, migraine, cancer pain, visceral pain, osteoarthrtis pain and neuropathic pain. Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of a disease mediated by the histamine H 4 receptor. More 15 preferably, the disease mediated by the histamine H 4 receptor is an allergic, immunological or inflammatory disease, pain or cancer. Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of an allergic, immunological or inflammatory disease, pain or cancer. 20 Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of an allergic, immunological or inflammatory disease. More preferably, the allergic, immunological or inflammatory disease is selected from respiratory diseases, ocular diseases, skin diseases, inflammatory bowel diseases, autoimmune diseases, and transplant rejection. Still more preferably, the allergic, immunological or inflammatory disease is selected from asthma, allergic rhinitis, chronic 25 obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataracts, eczema, dermatitis (e.g. atopic dermatitis), psoriasis, urticaria, pemphigus, dermatitis herpetiformis, cutaneous vasculitis, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus, systemic vasculitis and transplant rejection. Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically 30 acceptable salt thereof for the treatment or prevention of pain. More preferably, the pain is selected from inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-surgical pain, migraine, cancer pain, visceral pain, osteoarthritis pain and neuropathic pain. Another aspect of the present invention relates to a method of treating or preventing a disease mediated by the histamine H 4 receptor in a subject in need thereof, preferably a human being, which comprises administering to 35 said subject an amount of compound of formula I or a pharmaceutically acceptable salt thereof effective to treat or prevent said disease. More preferably, the disease mediated by the histamine H 4 receptor is an allergic, immunological or inflammatory disease, pain or cancer.

7 Another aspect of the present invention relates to a method of treating or preventing an allergic, immunological or inflammatory disease, pain or cancer in a subject in need thereof, preferably a human being, which comprises administering to said subject an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective to treat or prevent said allergic, immunological or inflammatory disease, pain or cancer. 5 Another aspect of the present invention relates to a method of treating or preventing an allergic, immunological or inflammatory disease in a subject in need thereof, preferably a human being, which comprises administering to said subject an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective to treat or prevent said disease. More preferably, the allergic, immunological or inflammatory disease is selected from respiratory diseases, ocular diseases, skin diseases, inflammatory bowel diseases, autoimmune 10 diseases, 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, eczema, dermatitis (e.g. atopic dermatitis), psoriasis, urticaria, pemphigus, dermatitis herpetiformis, cutaneous vasculitis, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus, systemic vasculitis and transplant rejection. 15 Another aspect of the present invention relates to a method of treating or preventing pain in a subject in need thereof, preferably a human being, which comprises administering to said subject an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective to treat or prevent said 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. 20 Another aspect of the present invention relates to a process for the preparation of a compound of formula I as defined above, comprising: (a) When in a compound of formula I n is 1, reacting a compound of formula I with a compound of formula Ill (or an amino-protected form thereof) in the presence of a reducing agent

NH

2 N N N-ZN HNR 3

R

4

R

5

NR

1

R

2 0 25 wherein Ri, R 2 , R 3 , R 4 and R 5 have the meaning described above, followed if necessary by the removal of any protecting group that may be present; or (b) When in a compound of formula I n is 1 and R 5 represents hydrogen, reacting a compound of formula IV with a compound of formula V (or an amino-protected form thereof) 8

NH

2 N N I HNRjR 2

R

4

R

3 N OH IV V wherein Ri, RZ R 3 and R 4 have the meaning described above, followed if necessary by the removal of any protecting group that may be present; or (c) When in a compound of formula I n is 1 and R5 represents hydrogen, reacting a compound of formula iVb with a 5 compound of formula V (or an amino-protected form thereof)

NH

2 N N

R

4

R

3 N Rje HNR.R2 IVb V wherein Rio represents a leaving group and Ri, R, R 3 and R 4 have the meaning described above, followed if necessary by the removal of any protecting group that may be present; or 10 -(d) When in a compound of formula I n is 1, reacting a compound of formula XX with a compound of formula III (or an amino-protected from thereof)

NH

2 N )N NR1R 2NRR 2

HNR

3

R

4

R

5 R.5 xxIII wherein R 1 2 represents a leaving group and R 1 , R 2 , R 3

R

4 and R 5 have the meaning described above, followed if necessary by the removal of any protecting group that may be present; or 15 (e) When in a compound of formula I n=1 and R 5 represents H or n=2 and (CRsRs) 2 represents -(CH 2 )-(CRsR 5

)-,

9 treating a compound of formula XIV with a reducing agent

NH

2 O NI N

R

4

R

3 N m NR 1

R

2

R

5

R

5 XIV wherein Ri, R 2 , R 3

R

4 and Rs have the meaning described above and m is 0 or 1; or (f) transforming a compound of formula I into another compound of formula I in one or in several steps. 5 In the previous definitions, the term Ci-y alkyl refers to a linear or branched alkyl chain containing from 1 to y carbon atoms. For example, a CA alkyl group refers to a linear or branched alkyl chain containing from I to 4 C atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. The term Co alkyl indicates that the alkyl group is absent. A haloCI.

6 alkyl group means a group resulting from the substitution of one or more hydrogen atoms of a C 1 . 10 6 alkyl group with one or more halogen atoms (i.e. fluoro, chloro, bromo or iodo) that can be the same or different. Examples include, amongst others, trifluoromethyl, fluoromethyl, 1-chloroethyl, 2-chloroethyl, 1-fluoroethyl, 2 fluoroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 2,2,3,3 tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 4-fluorobutyl, nonafluorobutyl, 5,5,5-trifluompentyl and 6,6,6-trifluorohexyl. 15 Likewise, the term C 1 .a alkyl optionally substituted with one or more halogen means a group resulting from the substitution of one or more hydrogen atoms of a Ci- alkyl group with one or more halogen atoms (i.e. fluoro, chloro, bromo or iodo) that can be the same or different. Preferably the halogen atom(s) islare fluoro. A C. alkoxy group relates to a group of formula Ci.

6 alkyl-O-, wherein the alkyl moiety has the same meaning as defined above. Examples include, amongst others, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 20 isobutoxy, sec-butoxy, terd-butoxy, pentyloxy and hexyloxy. A haloC 1

.

6 alkoxy group means a group resulting from the substitution of one or more hydrogen atoms of a Ci.6 alkoxy group with one or more halogen atoms (i.e. fluoro, chloro, bromo or lodo) that can be the same or different. Examples include, amongst others, trifluoromethoxy, fluoromethoxy, 1-chloroethoxy, 2-chloroethoxy, 1 fluoroethoxy, 2-fluoroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 3-fluoropropoxy, 25 3-chloropropoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, heptafluoropropoxy, 4-fluorobutoxy, nonafluorobutoxy, 2-chloropentyloxy and 3-chlorohexyloxy. A C6 alkylthio group means a group of formula C6 alkyl-S-, wherein the alkyl residue has the same meaning as that previously defined. Examples include methylthio, etylthio, propylthio, isopropylthio, butylthio, 10 isobutylthic, sec-butylthio, tert-butylthio, pentylthio and hexylthio. A C 2 .4 alkynyl group means a linear or branched alkyi chain which contains from 2 to 4 carbon atoms and which further contains one or two tiple bonds. Examples include, among others, the ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and 1,3-butadyinyl groups. 5 The term hydroxyCo.

6 alkyl includes hydroxy and hydroxyCl.

6 alkyl. A hydroxyC, 6 alkyl group means a group resulting from the replacement of one or more hydrogen atoms of a Ci.salkyl group with one or more hydroxy groups. Preferably, the C 1

.

6 alkyl group is substituted with one hydroxy group. Examples include, among others, the groups hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2 dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 3 10 hydroxybutyl, 2-hydroxybutyll-hydroxybutyl, 5-hydroxypentyl and 6-hydroxyhexyl. The term C02R-Co.

6 alkyl includes -C0 2 Rq and C0 2 R-Ci.6 alkyl. A C02R-Ci.s alkyl group means a group resulting from the replacement of one or more hydrogen atoms of a C1.6 alkyl group with one or more -C0 2 Re groups Preferably, the C,-6 alkyl group is substituted with one -C0 2 R group. 15 A -Cs alkylene- group, in relation to the group formed either by two R 6 groups on the same carbon atom or by two R 9 groups (which can be either on the same atom as e.g. in -CONR9R or on different atoms as e.g. in -NRqCOR or -NRqCONRgR 9 ), refers to a linear alkyl chain which contains from x to 5 carbon atoms, i.e. a group of formula -(CH 2 )s.

5 -. As indicated in the definition of a compound of formula I, the -Cs alkylene- group is optionally substituted with one or more C,.8 alkyl groups, preferably with one or more methyl groups. Examples of two Ron the 20 same carbon atom forming together a -C 2

.

5 alkylene- group include, among others: Examples of two R9 groups which together form a -Cm alkylene- group include, among others: 11 0 0 0 0 NN N 0 0 R4 N( A C3 1 o cycloalkyl group, either as a group or as part of a C.xo cycloalkyl-Co.4 alkyl group, relates to a saturated carbocyclic ring having from 3 to 10 carbon atoms that is monocyclic or polycyclic. One or two C atoms of the carbocyclic ring may optionally be oxidized forming CO groups. The cycloalkyl group may be bound through any 5 available C atom. Examples include, amongst others, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentanonyl, bicyclo[3.1.1]heptan-3-yl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl or adamantyl. The term C3.10 cycloalkyl-C.4 alkyl includes C3io cycloalkyl and Csio cycloalkyl-C- alkyl. A Ca 1 o cycloalkyl-C 4 alkyl group means a group resulting from the substitution of one or more hydrogen atoms of a C1 alkyl group with one or more cycloalkyl groups, which may be the same or different. Preferably, the 10 C 1 4 alkyl group is substituted with one or two cycloalkyl groups, and more preferably it is substituted with one cycloalkyl group. The cycloalkyl group may substitute either one H atom on a C atom or two H atoms on the same C atom of the alkyl group (in which case the cycloalkyl group shares one C atom with the alkyl group), such as in the groups shown as examples below: 2-cyclopropybutyl (1 -ethyl-cyclopropyl)methyl butyl group where 1 H atom on a C atom butyl group where 2 H atoms on a same C atom 15 is substituted with a cyclopropyl group are substituted with a cyclopropyl group Examples of C 3

.

10 cycloalkyl-C, 4 alkyl groups include, amongst others, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, bicyclo[2.2. 1 Iheptanylmethyl, dicyclopropylmethyl, (1-methyl-cyclopropyl)methyl, (1-ethyl-cyclopropyl)methyl, (1-cyclopentylmethyl 20 cyclopropyl)methyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 2,2-dicyclopropyl- 12 ethyl, 2-cyclohexyl-2-cyclopropyl-ethyl, 2-(1 -methyl-cyclopropyl)ethyl, 1 -cyclopropyl-1 -methylethyl, 1 cyclopropylethyl, 1-cyclobutylethyl, 1-cyclopentylethyl, 1-cyclohexylethy, 3-cyclopropylpropyl, 3-cyclobutylpropyl, 3 cyclopentylpropyl, 3-cyclohexylpropyl, 1-cyclopropyl-2-methylpropyl, 4-cyclopropylbutyl, 3-cyclopropylbutyl, 2 cyclopropylbutyl, 1-cyclopropylbutyl, 4-cyclobutylbutyl, 4-cyclopentylbutyl and 4-cyclohexylbutyl. 5 A heterocycloalkyl group, either as a group or as part of a heterocycloalkyl-C 0 4 alkyl group, relates to a saturated heterocyclic ring having from 3 to 10 carbon atoms and up to three heteroatoms independently selected from N, 0 and S that can be a monocyclic or polycyclic. From one to three C, N or S atoms of the heterocyclic ring may optionally be oxidized forming CO, NO, SO or SO 2 groups, respectively. The heterocycloalkyl group may be bound through any available C or N atom. Examples of heterocycloalkyl groups include, among others, oxiranyl, 10 azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrazolidinyl, isothiazolidinyl, piperidinyl, morphorinyl, piperazinyl, 2-oxo-tetrahydrofuranyl, 2-oxo-[1,3]dioxolanyl, 2-oxo-oxazolidinyl, 2-oxo-imidazoidinyl, 2-oxo-[1,3]oxazinanyl, 2-oxo piperaziny, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, azepanyl, 11,4]diazepanyl, [1,4]oxazepanyl, 2-oxo-azepanyl, 1,1-dioxo-[1,2]thiazepanyl, 2-oxo-[1,3]diazepany, 7-oxo-bicyclo(2.2.1]heptanyl and 1,3-diaza-bicyclo(2.2.2]octanyL. The term heterocycloalkyl-CO 4 alkyl includes heterocycloalkyl and heterocycloalkyl-C 4 alkyl. 15 A heterocycloalkyl-CI.

4 alkyl group relates to a group resulting from the substitution of one or more hydrogen atoms of a C. alkyl group with one or more heterocycloalkyl groups which may be the same or different. Preferably, the C 14 alkyl group is substituted with one or two heterocycloaikyl groups, and more preferably, is substituted with one heterocycloalkyl group. Examples of heterocycloalkyl-C14 alkyl groups include, among others, pyrrolidin-2 ylmethyl, pyrrolidin-3-ylmethyl, morpholin-3-ylmethyl, tetrahydrofuran-2-ylmethyl, (2-oxo-[1,3]oxazinan-6-yl)-methyl, 20 2-piperidin-3-yl-ethyl, 2-piperazin-1-yl-propyl, 1-methyl-2-piperazin-1-yl-ethyl, 2-methyl-3-(pyrrolidin-3-yl)-propyl, 3 methyl-4-piperazin-1-yl-butyl and 4-(tetrahydrofuran-3-yl)-butyl. The term aryl, either as a group or as part of an aryl-Co 4 alkyl group, relates to phenyl or naphthyl. Preferably, aryl represents phenyl, The term aryl also includes fused benzo-cycloalkyl groups, such as dihydroindenyl and tetrahydronaphthalenyl. The fused benzo-cycloalkyl group may be bound through any available C 25 atom of either the saturated or the aromatic fragment. The term aryl-COa4 alkyl includes aryl and aryl-C14 alkyl. An aryl-C.

4 alkyl group means a group resulting from the substitution of one or more hydrogen atoms of a C alkyl group with one or more aryl groups, preferably with one or two aryl groups and more preferably with one aryl group, which can be the same or different. Examples of aryl-C 1

.

4 alkyl include, amongst others, the groups 30 benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenyl-1-methylethyl, 2,2-diphenylethyl, 3-phenylpropyl, 2-phenyl-1 methylpropyl and 4-phenylbutyl. The term heteroaryl, either as a group or as part of a heteroaryl-CO- 4 alkyl group, relates to a monocyclic aromatic ring of 5 or 6 members or bicyclic aromatic ring of 8 to 12 members which contains up to four heteroatoms independently selected from nitrogen, oxygen and sulphur. The heteroaryl group may be bound to the residue of the 35 molecule through any available C or N atom. Examples of heteroaryl groups include among others 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazoly, 1,3,4-thiadiazolyl, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazolyl, pirrolyl, thiazolyl, thiophenyl, 1,2,3-trazolyl, 1,2,4-triazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, 13 benzimidazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, imidazopyraziny, imidazopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, pyrazolopyrazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, purinyl, quinazolinyl, quinolinyl and quinoxalinyl. In the definition of heteroaryl when the examples specified refer to a bicycle in general terms, they include all possible arrangements of the atoms. 5 For example, the term pyrazolopyridinyl includes groups such as 1H-pyrazolo[3,4-b]pyridiny, pyrazolofl,5 ajpyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[4,3-c]pyridinyl and 1H-pyrazolo[4,3-bpyridiny; the term imidazopyrazinyl includes groups such as 1H-imidazo[4,5-b]pyraziny, imidazo[1,2-alpyrazinyl and imidazo[1,5 a]pyrazinyl and the term pyrazolopyrimidinyl includes groups such as 1 H-pyrazolo[3,4-djpyrimidinyl, 1H-pyrazolo[4,3 d]pyrimidinyl, pyrazolo[1,5-ajpyrimidinyl and pyrazolo[1,5-c]pyrimidinyl. The term heteroaryl also includes fused 10 benzo-heterocycloalkyl groups, such as 2,3-dihydro-1H-indolyl and 2-oxo-2,3-dihydro-1H-indolyl. The fused benzo heterocycloalkyl group may be bound through any available C or N atom of the saturated fragment or through any available C atom of the the aromatic fragment. The term heteroaryl-Coalkyl includes heteroaryl and heteroaryl-C 1

.

4 alkyl. A heteroaryl-C, alkyl group relates to a group resulting from the substitution of one of more hydrogen 15 atoms of a CM alkyl group with one or more heteroaryl groups which may be the same or different. Preferably, the C1 alkyl group is substituted with one or two heteroaryl groups and, more preferably, is substituted with one heteroaryl group. Examples of heteroaryl-C.

4 alkyl include, among others, 1H-pyrazol-3-yl-methyl, furan-2-yl-methyl, pyridine-3-yl-methyl, quinolin-3-ylmethyl, oxazol-2-ylmethyl, 1H-pyrrol-2-ylmethyl, 1-pyridine-3-yl-ethyl, 2-pyridine-2 yl-propyl, 3-pyridine-3-yl-propyl, 1-methyl-2-pyridine-3-yl-propyl, 4-pyridine-2-yl-butyl and 3-pyridine-2-ybutyl. 20 In a compound of formula 1, as indicated in the definition of R 4 regarding the terms C3io cycloalkyl-Co 4 alkyl, heterocycloalkyl-CO.

4 alkyl, aryl-C" alky( or heteroaryl-Co alkyl, any alkyl group is optionally substituted with one or more R 6 groups. This refers to the Co alkyl group that forms part of the C3io cycloalkyl-Co.

4 alkyl, heterocycloalkyl Ca4 alkyl, aryl-Co 4 alkyl or heteroaryl-Co 0 alkyl groups. When R 6 represents CI8 alkyl, halogen, hydroxyCo.

6 alkyl, C3 i cycloalkyl optionally sustituted with one or more Ci- alkyl groups, or phenyl optionally sustituted with one or more 25 Rs, then preferably said Co4 alkyl group is optionally substituted with one R 6 group. As indicated in the definition of R 4 in a compound of formula 1, any of the cycloalkyl and heterocycloalkyl groups are optionally substituted with one or more substituents independently selected from C1-8 alkyl and halogen, and any of the aryl and heteroaryl groups are optionally substituted with one or more R 7 groups. Preferably the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted with one substituent. 30 A halogen group or its abbreviation halo means fluoro, chloro, bromo or iodo. Preferred halogen atoms are fluoro and chloro, and more preferably fluoro. The term "saturated" relates to groups that do not have any double or triple bonds. A "bridged bicyclic" group refers to a bicyclic system having two common atoms (bridgeheads) connecting three acyclic chains (bridges), so that the two bridges with the higher number of atoms form then the main ring and 35 the bridge with the lower number of atoms is the "bridge". A "fused bicyclic" group refers to a bicyclic system consisting of two adjacent rings sharing two atoms in common.

14 In the definition of NR 1

R

2

R

1 and R 2 together with the N atom to which they are bound form a heterocyclic group of type (i) or (ii). A heterocyclic group of type (i) is a saturated heterocyclic group which contains 2 N atoms and does not contain any other heteroatom and which is 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic. Examples include, among others, piperazinyl, homopiperazinyl, 2,5 5 diaza-bicyclo[2.2.1]heptanyl, 2,5-diaza-bicyclo[2.2.2]octanyl, octahydro-pyrrolo1,2-alpyraziny, octahydro pyrrolo[3,4-b]pyridinyl, octahydro-pyrrolo[3,2-cipyridiny and octahydropyrrolo[3,4-cpyrrolinyl. Said groups are optionally substituted with one or more C4 alkyl groups, which can be the same or different and which are placed at any available C or N atom. A heterocyclic group of type (ii) is a saturated heterocyclic group which contains 1 N atom and does not 10 contain any other heteroatom, wherein said heterocyclic group is substituted with one -NRaRb group, and which is 4 to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic, preferably 4- to 7-membered monocyclic. Examples of (ii) include, among others, 3-amino-azetidinyl, 3-methylamino-azetdinyl, 3 dimethylamino-azetidinyl, 3-amino-pyrrolidinyl, 3-methylamino-pyrrolidinyl, 3-dimethylamino-pyrrolidiny, 4-amino piperidinyt, 4-methylamino-piperdinyl, 4-dimethylamino-piperidinyl and 6-methylamino-3-aza-bicydo[3.1.0]hexane-3 15 yl. Said groups are further optionally substituted with one or more Cm alkyl groups, which can be the same or different, as indicated above in the definition of a compound of formula 1. In the definition of a compound of formula I n represents 1 or 2. The -(CR 5

R

5 )n- group thus represents a group of formula -CR 5

R

5 - or -CRsR 5

-CR

5 R5-. When in the definition of a substituent two or more groups with the same numbering are indicated (e.g. 20 -CR 5

R

5 -, -CON RqRq, -SO 2 NRqRq, or -NR 9 Rq. etc.), this does not mean that they must be the same. Each of them is independently selected from the list of possible meanings given for said group, and therefore they can be the same or different. The expression "optionally substituted with one or more" means that a group can be substituted with one or more, preferably 1, 2, 3 or 4, more preferably 1, 2 or 3, and more preferably 1 or 2 substituents, provided that said 25 group has enough positions available susceptible of being substituted. These substituents are always independently selected from the list of possible meanings given for said substitutent and can thus be the same or different, and can be located at any available position. Throughout the present specification, by the term "treatment is meant eliminating, reducing or ameliorating the cause or the effects of a disease. For purposes of this invention treatment includes, but is not limited to, 30 alleviation, amelioration or elimination of one or more symptoms of the disease; diminishment of the extent of the disease; stabilized (i.e. not worsening) state of disease; delay or slowIng of disease progression; amelioration or palliation of the disease state; and remission of the disease (whether partial or total). As used herein, "prevention" refers to preventing the occurrence of a disease in a subject that is predisposed to or has risk factors but does not yet display symptoms of the disease. Prevention includes also 35 preventing the recurrence of a disease in a subject that has previously suffered said disease. Any formula given herein is intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that 15 one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, "C, 13C, 4C, 15 N, 180, 170, 31P, 32p, 3S, 'IF, 36CI, and 1251. respectively, Such isotopically labelled compounds are useful in metabolic studies (preferably with 1C), reaction 5 kinetic studies (with, for example 2 H or 3H), detection or imaging techniques [such as positron emission tomography (PET) or single- photon emission computed tomography (SPECT)l including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an 'IF or "C labeled compound may be particularly preferred for PET or SPECT studies. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life 10 or reduced dosage requirements. Isotopically labeled compounds of the invention can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent. In addition to the unlabeled form, all isotopically labeled forms of the compounds of formula I are included within the scope of the invention. 15 The invention therefore relates to the compounds of formula I as defined above. In another embodiment, the invention relates to compounds of formula I wherein n is 1. In another embodiment, the invention relates to compounds of formula I wherein Rs is H. In another embodiment, the invention relates to compounds of formula I wherein R 3 is H or methyl. In another embodiment, the invention relates to compounds of formula I wherein R 3 Is H. 20 In another embodiment, the invention relates to compounds of formula I wherein: R, and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from: (i) a heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said heterocyclic group is optionally substituted with one or more C, alkyl groups; and 25 (ii) a heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR 3 Rb group and is optionally substituted with one or more C14 alkyl groups; wherein said heterocyclic groups (i) and (ii) are 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic. 30 In another embodiment the invention relates to compounds of formula I wherein Ra and Rb independently represent H or C, 4 alkyl, preferably H, methyl or ethyl and more preferably H or methyl. In another embodiment, the invention relates to the compounds of formula I wherein Ra represents H and Rb represents H or C,.4 alkyl, preferably H, methyl or ethyl and more preferably H or methyl. In another embodiment, the invention relates to the compounds of formula I wherein Ra represents H and Rb 35 represents C,- 4 alkyl, preferably methyl or ethyl and more preferably methyl. In another embodiment, the invention relates to compounds of formula I wherein Ra and Rb represent H. In another embodiment, the invention relates to compounds of formula I wherein R1 and R 2 form, together 16 with the N atom to which they are bound, a saturated heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NRaRb group and can be optionally substituted with one or more C 1 4 alkyl groups; wherein said heterocyclic group is 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic. 5 In another embodiment, the invention relates to compounds of formula I wherein R 1 and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from: Ra N Rb Ra N Rb Re Ro N-Rd N N (a) (b) (c) (d) Rd Rd Rd NN N N N (e) (f) (g) (h) 10 wherein Ra and Rb have the meaning described above for compounds of formula I, Re represents H or C 1 4 alkyl, preferably H or methyl, more preferably H, and Rd represents H or 01.4 alkyl, preferably H or methyl. In another embodiment, the invention relates to compounds of formula I wherein R 1 and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), and Ra, Rb, Rc and Rd independently represent H or C 1 - alkyl, preferably R, Rb, Re and R independently represent H or methyl, and 15 more preferably Ra, Rb and Rd independently represent H or methyl and Rb represents H. In another embodiment, the invention relates to compounds of formula I wherein R 1 and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a), (b) and (e), wherein R, and Rb have the meaning described above for compounds of formula 1, Re represents H or C14 alkyl and Rd represents H or C 1

.

4 alkyl; preferably Ra, Rb, R, and Rd independently represent H or C14 alkyl, more preferably R, 20 Rb, Re and Rd independently represent H or methyl, and still more preferably R, Rb and Rd independently represent H or methyl and Rd represents H, and even more preferably Rd represents H, Rb represents methyl, R represents H 17 and Re represents H or methyl. In another embodiment, the invention relates to compounds of formula I wherein R1 and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein Ra and Rb have the meaning described above for compounds of formula I and Re represents H or Ci alkyl, preferably R,, Re 5 and Re independently represent H or C 4 alkyl, more preferably Re, Rb and R, independently represent H or methyl, still more preferably Re and Rb independently represent H or methyl and Re represents H, even more preferably Ra represents H, Re represents H or methyl and Re represents H and particularly preferably Re represents H, Re represents methyl and Re represents H, In another embodiment, the invention relates to the compounds of formula I wherein R 1 and R 2 form, 10 together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein Re and Rb have the meaning described above for compounds of formula I and Re represents H or C-4 alkyl, preferably Re, Rb and Re independently represent H or C.4 alkyl, more preferably Re, Rb and Re independently represent H or methyl, still more preferably Re and Rb independently represent H or methyl and R represents H, even more preferably Re represents H, Rb represents H or methyl and R, represents H and particularly preferably R. represents H, Re 15 represents methyl and Rc represents H. In another embodiment, the invention relates to the compounds of formula I wherein R1 and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), wherein Re and Rb have the meaning described above for compounds of formula I and Re represents H or C4alkyl, preferably Re, Re and Rc independently represent H or Cl alkyl, more preferably Re, Rb and Re independently represent H or methyl, 20 still more preferably Re and Rb independently represent H or methyl and Re represents H, even more preferably Re represents H, Rb represents H or methyl and Re represents H and particularly preferably R 8 represents H, Re represents methyl and Re represents H. In another embodiment, the invention relates to compounds of formula I wherein R1 represents H or CA alkyl and R 2 represents azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, which are optionally substituted with one or 25 more Ct4 alkyl groups. In another embodiment, the invention relates to compounds of formula I wherein R 1 represents H and R2 represents 1-methyl-pyrrolidin-3-yl or pyrrolidin-3-yi. In another embodiment, the invention relates to compounds of formula I wherein R4 represents C1. alkyl, C3. 10 cycloalkyl-Co- alkyl, heterocycloalkyl-Co4alkyl, aryl-Co.

4 alkyl or heteroaryl-C 4 alkyl, wherein in the Ca3.ocycloalkyl 30 Co-4 alkyl, heterocycloalkyl-C4 alkyl, aryl-Co4 alkyl and heteroaryl-Co- alkyl groups any alkyl group is optionally substituted with one or more Rr groups, any of the cycloalkyl and heterocycloalkyl groups are optionally substituted with one or more substituents independently selected from Ci. alkyl and halogen, and any of the aryl and heteroaryl groups are optionally substituted with one or more R7groups. In another embodiment, the invention relates to compounds of formula I wherein R4 represents Ct alkyl, C3 35 10 cycloalkyl-CG alkyl or aryl-Co. alkyl, preferably Cao alkyl, Cs.ocycloalkyl-Co 1 alkyl or aryl-CO.

2 alkyl, wherein in the C3.1o cycloalkyl-CO 4 alkyl, aryl-COb alkyl, Ca1o cycloalkyl-Co.1 alkyl and aryl-Co .2 alkyl groups any alkyl is optionally substituted with one or more R6 groups, any cycloalkyl is optionally substituted with one or more substituents 18 independently selected from C,.8 alkyl and halogen, and any aryl is optionally substituted with one or more R 7 groups. In another embodiment, the invention relates to compounds of formula I wherein R 4 represents Ci.- alkyl, C 3 . 1ocycloalkyl-C 4 alkyl or aryl-C" alkyl, preferably Ca alkyl, Ca.-o cycloalkyl-Co, alkyl or aryl-Co 2 alkyl, wherein in the 5 C 31 0 cycloalkyl-Co alkyl, arylCo.4 alkyl, Clio cycloalkyl-Co.1 alkyl and aryl-Co.

2 alkyl groups any alkyl is optionally substituted with one or more R 6 groups, any cycloalkyl is optionally substituted with one or more substituents independently selected from Ci- alkyl and halogen, and any aryl is optionally substituted with one or more R 7 groups; and each R 6 independently represents Ci.8 alky; and optionally two R groups on the same carbon atom are 10 bonded together to form a -C3- alkylene- group which is optionally substituted with one or more Ci.o alkyl groups. In another embodiment, the invention relates to compounds of formula I wherein R 4 represents C1.8 alkyl, C. io cycloalkyl-Co.

4 alkyl or ary-Co.4 alkyl, preferably C3.8 alkyl, C 3

.

1 0 cycloalkyl-Co.

1 alkyl or ary-Co.2 alkyl; wherein in the aryl-Co- 4 aikyl and arylCo- 2 alkyl groups any aryl is optionally substituted with one or more R7groups. In another embodiment, the invention relates to compounds of formula I wherein R4 represents Ci.e alkyl 15 optionally substituted with one or more halogen, or Cio cycloalkyl-Co alkyl, wherein in the C3.10 cycloalkyl-Co4 alkyl group the alkyl group is optionally substituted with one or more R6 groups and the cycloalkyl group is optionally substituted with one or more substituents independently selected from Ct. alkyl and halogen. in another embodiment, the invention relates to compounds of formula I wherein R 4 represents C 1 .8 alkyl optionally substituted with one or more halogen or C30 cycloalkyl-Co alkyl, wherein in the Cio cycloalkyl-Co alkyl 20 group the cycloalkyl group is optionally substituted with one or more substituents independently selected from C1.8 alkyl and halogen. In another embodiment, the invention relates to compounds of formula I wherein R4 represents C1.o alkyl or C3.o cycloalkyl-Co4 alkyl, wherein in the C3.10 cycloalkyl-Co.

4 alkyl group the cycloalkyl group is optionally substituted with one or more substituents independently selected from Ci.s alkyl and halogen. 25 In another embodiment, the invention relates to compounds of formula I wherein R 4 represents C3.8 alkyl optionally substituted with one or more halogen or C 3.

6 cycloalkyl-Co- 1 alkyl, wherein in the C.8 cycloalkylCo 1 alkyl group the cycloalkyl group is optionally substituted with one or more substituents independently selected from C1-8 alkyl and halogen. In another embodiment, the invention relates to compounds of formula I wherein R 4 represents C. alkyl or 30 C3.8 cycloalkyl-Co.i alkyl, wherein in the C.0 cycloalkyl-Co 1 alkyl group the cycloalkyl group is optionally substituted with one or more substituents independently selected from Ci.s alkyl and halogen. In another embodiment, the invention relates to compounds of formula I wherein R 4 represents C1.8 alkyl, preferably C3.s alkyl. In another embodiment, the invention relates to compounds of formula I wherein R 4 represents C.o 35 cycloalkyl-Co- alkyl, preferably C.o cycloalkyl-C

.

, alkyl, and more preferably C 3. 6 cycloalkyl-Coi alkyl, wherein any alkyl is optionally substituted with one or more R6 groups and any cycloalkyl is optionally substituted with one or more substituents independently selected from Ct.8 alkyl and halogen.

19 In another embodiment, the invention relates to compounds of formula I wherein R 4 represents C 3 -1 o cycloalkyl-Co- alkyl, preferably C3 1 o cycloalkyl-Co.

1 alkyl, and more preferably C 3

.

6 cycloalkyl-Co.1 alkyl, wherein any alkyl is optionally substituted with one or more R 6 groups and any cycloalkyl is optionally substituted with one or more substituents independently selected from C. alkyl and halogen; and 5 each R6 independently represents C1. alkyl; and optionally two Rs groups on the same carbon atom are bonded together to form a -C 2 .s alkylene- group which is optionally substituted with one or more Cs.

6 alkyl groups. In another embodiment, the invention relates to compounds of formula I wherein RA represents C3-o cycloalkyl-Co- alkyl, preferably C3io cycloalkyl-Co.1 alkyl, and more preferably C3.6 cycloalkyl-Co.1 alkyl, wherein any cycloalkyl is optionally substituted with one or more substituents independently selected from C-8 alkyl and halogen. 10 In another embodiment, the invention relates to compounds of formula I wherein R 4 represents C0io cycloalkyl-Co- 4 alkyl, preferably C3io cycloalkyl-Co.1 alkyl, and more preferably C 3 scycloalkyl-Co.i alkyl. In another embodiment, the invention relates to compounds of formula I wherein R 4 represents GCio cycloalkyl-Cialkyl, preferably Cm cycloalkyl-C 1 alkyl, wherein any alkyl is optionally substituted with one or more R 6 groups and any cycloalkyl is optionally substituted with one or more substituents independently selected from C. 15 alkyl and halogen. In another embodiment, the invention relates to compounds of formula I wherein R 4 represents C 3

.

1 o cycloalkyl-Cialkyl, preferably Cmo cycloalkyl-C 1 alkyl, wherein any alkyl is optionally substituted with one or more R groups and any cycloalkyl is optionally substituted with one or more substituents independently selected from C. alkyl and halogen; and 20 each R 6 independently represents C. alkyl; and optionally two Rs groups on the same carbon atom are bonded together to form a -C2.6alkylene- group which is optionally substituted with one or more C1. alkyl groups. In another embodiment, the invention relates to compounds of formula I wherein R 4 represents C3.10 cycloalkyl-Cialkyl, preferably Co cycloalkyl-Ci alkyl, more preferably cyclopropylmethyl. In another embodiment, the invention relates to compounds of formula I wherein R 4 represents C3-1o 25 cycloalkyl, preferably C36 cycloalkyl and more preferably cyclopentyl, wherein any cycloalkyl is optionally substituted with one or more substituents independently selected from Ci.8 alkyl and halogen. In another embodiment, the invention relates to compounds of formula I wherein R 4 represents C3-1o cycloalkyl, preferably C3-6cycloalkyl and more preferably cyclopentyl. In another embodiment, the invention relates to compounds of formula I wherein R 4 represents aryl-Co-4 30 alkyl, preferably aryl-Co.

2 alkyl and more preferably phenyl-Co.2 alkyl, wherein any alkyl is optionally substituted with one or more R groups and any aryl is optionally substituted with one or more Rr groups. In another embodiment, the invention relates to compounds of formula I wherein R 4 represents aryl-Co alkyl, preferably aryl-Co.2 alkyl and more preferably phenyl-Co.2 alkyl, wherein any alkyl is optionally substituted with one or more R6 groups and any aryl is optionally substituted with one or more Rr groups; and 35 each Ra independently represents C. alkyl; and optionally two Rs groups on the same carbon atom are bonded together to form a -C2.5 alkylene- group which is optionally substituted with one or more C1- alkyl groups. In another embodiment, the invention relates to compounds of formula I wherein R 4 represents aryl-Co4 20 alkyl, preferably aryl-Co.

2 alkyl and more preferably phenyl-Co2 alkyl. In another embodiment, the invention relates to compounds of formula I wherein R 4 represents aryl-Ct.2 alkyl, preferably phenyl-C 1 2 alkyl, wherein any alkyl is optionally substituted with one or more R groups and any aryl is optionally substituted with one or more R 7 groups. 5 In another embodiment, the invention relates to compounds of formula I wherein R 4 represents aryl-C1.2 alkyl, preferably phenyl-C 1 .2 alkyl, wherein any alkyl is optionally substituted with one or more R 6 groups and any aryl is optionally substituted with one or more R7 groups; and each Rs independently represents C1e alkyl; and optionally two R groups on the same carbon atom are bonded together to form a -Cu alkylene- group which is optionally substituted with one or more C 18 alkyl groups. 10 In another embodiment, the invention relates to compounds of formula I wherein R 4 represents aryl, preferably phenyl, wherein any aryl is optionally substituted with one or more R 7 groups. In another embodiment, the invention relates to compounds of formula I wherein each R independently represents Cis alkyl; and optionally two R6 groups on the same carbon atom are bonded together to form a -C2 alkylene- group which is optionally substituted with one or more CS alkyl groups. 15 In another embodiment, the invention relates to compounds of formula I wherein each R 6 independently represents C,. alkyl. In another embodiment, the invention relates to compounds of formula I wherein two Rs groups on the same carbon atom are bonded together to form a -C2-5 alkylene- group which is optionally substituted with one or more C alkyl groups. 20 In another embodiment, the invention relates to compounds of formula I wherein each R7 independently represents C 15 alkyl, haloCos alkyl, halogen, C 1 - alkoxy, haloCle alkoxy, -CN, hydroxyCo.

6 alkyl, C0 2 R-0o.

6 alkyl, aryl or heteroaryl; wherein the aryl or heteroaryl groups in R 7 are optionally sustituted with one ore more Ca alkyl groups. In another embodiment, the invention relates to compounds of formula I wherein each R7 independently represents Ce alkyl. 25 In another embodiment, the invention relates to compounds of formula I wherein each R9 independently represents H or Cio alkyl. In another embodiment, the invention relates to compounds of formula I wherein n is 1; and R 5 is H. In another embodiment, the invention relates to compounds of formula I wherein n is 1; R 3 is H or methyl; and R 5 is H. 30 In another embodiment, the invention relates to compounds of formula I wherein n is 1; R 3 is H; and Rs is H. In another embodiment, the invention relates to compounds of formula I wherein R3 is H; and

R

4 represents Cs alkyl, C3.io cycloalkyl-Cu alkyl or aryl-CoA alkyl, preferably C3 alkyl, C3io cycloalkyl-Coi alkyl or aryl-Co.2 alkyl, wherein in the C3.1o cycloalkyl-Co4 alkyl, aryl-C-4 alkyl, Co cycloalkyl-Co., alkyl and aryl-Co.

2 alkyl groups any alkyl is optionally substituted with one or more R 6 groups, any cycloalkyl is optionally substituted 35 with one or more substituents independently selected from Ci.s alkyl and halogen, and any aryl is optionally substituted with one or more R7groups. In another embodiment, the invention relates to compounds of formula I wherein R 3 is H; 21

R

4 represents C1- alkyl, Clio cycloalkyl-Co.

4 alkyl or aryl-CoA alkyl, preferably C.s alkyl, C310 cycloalkyl-C& alkyl or aryl-Co.

2 alkyl, wherein in the C3.10 cycloalkyl-Co- alkyl, aryl-Co4 alkyl, C30 cycloalkyl-Co alkyl and aryl-Coo alkyl groups any alkyl is optionally substituted with one or more R 6 groups, any cycloalkyl is optionally substituted with one or more substituents independently selected from CiB alkyl and halogen, and any aryl is optionally 5 substituted with one or more R 7 groups; and each R.6 independently represents C1s alkyl; and optionally two R6 groups on the same carbon atom are bonded together to form a -C25 alkylene- group which is optionally substituted with one or more Ci-s alkyl groups. In another embodiment, the invention relates to compounds of formula I wherein R 3 is H; and R4 represents Ci-alkyl, preferably C8alkyl. 10 In another embodiment, the invention relates to compounds of formula I wherein R3 is H; and

R

4 represents C3.10 cycloalkyl-CoA alkyl, preferably C 3 0 cycloalkyl-Coi alkyl, and more preferably CU cycloalkyl-Co- alkyl, wherein any alkyl is optionally substituted with one or more R 6 groups and any cycloalkyl is optionally substituted with one or more substituents independently selected from C18 alkyl and halogen. In another embodiment, the invention relates to compounds of formula I wherein R 3 is H; and R 4 represents 15 Ca.iocycloalkyl-CO.

4 alkyl, preferably C3.iocycloalkyl-Co alkyl, and more preferably Cmocycloalkyl-Co., alkyl. In another embodiment, the invention relates to compounds of formula I wherein Ra is H; and R 4 represents Caio cycloalkyl-C. alkyl, preferably C3.6 cycloalkyl-C 1 alkyl, more preferably cyclopropylmethyl, wherein any alkyl is optionally substituted with one or more Rs groups and any cycloalkyl is optionally substituted with one or more substituents independently selected from C1- alkyl and halogen. 20 In another embodiment, the invention relates to compounds of formula I wherein R 3 is H; and R 4 represents C3.10 cycloalkyl-C 1 alkyl, preferably Cm cycloalkyl-C 1 alkyl, more preferably cyclopropylmethyl. In another embodiment, the invention relates to compounds of formula I wherein R 3 is H; and R 4 represents C03o cycloalkyl, preferably Cm cycloalkyl and more preferably cyclopentyl, wherein any cycloalkyl is optionally substituted with one or more substituents independently selected from C-8 alkyl and halogen. 25 In another embodiment, the invention relates to compounds of formula I wherein R 3 is H; and R 4 represents C3li cycloalkyl, preferably Cu cycloalkyl and more preferably cyclopentyl. In another embodiment, the invention relates to compounds of formula I wherein n is 1;

R

3 is H; and

R

4 represents C.8 alkyl, C3.1o cycloalkyl-C. alkyl or aryl-Co. alkyl, preferably Cualkyl, C310 cycloalkyl-Coi 30 alkyl or aryl-CO- alkyl, wherein in the C3.1o cycloalkyl-Co. alkyl, aryl-Co alkyl, C3.10 cycloalkyl-Coi alkyl and aryl-Co2 alkyl groups any alkyl is optionally substituted with one or more Re groups, any cycloalkyl is optionally substituted with one or more substituents independently selected from C8 alkyl and halogen, and any aryl is optionally substituted with one or more R 7 groups. In another embodiment, the invention relates to compounds of formula I wherein n is 1; 35 R 3 is H;

R

4 represents C8 alkyl, C30 cycloalkyl-CoA alkyl or aryl-C alkyl, preferably C3o alkyl, Ca1o cycloalkyl-Co.1 alkyl or ary-Co- alkyl, wherein in the C3.10 cycloalkyl-Co.

4 alkyl, ary-Co.

4 alkyl, C3.10 cycloalkyl-Co- alkyl and aryl-Co 2 22 alkyl groups any alkyl is optionally substituted with one or more Re groups, any cycloalkyl is optionally substituted with one or more substituents independently selected from Cis alkyl and halogen, and any aryl is optionally substituted with one or more R 7 groups; and each Re independently represents Ci.s alkyl; and optionally two Re groups on the same carbon atom are 5 bonded together to form a -C25 alkylene- group which is optionally substituted with one or more C 1 . alkyl groups. In another embodiment, the invention relates to compounds of formula I wherein n is 1;

R

3 is H; and

R

4 represents Ci alkyl, preferably Cualkyl. In another embodiment, the invention relates to compounds of formula I wherein n is 1; 10 R 3 is H; and

R

4 represents Ca4O cycloalkyl-Co- alkyl, preferably Caio cycloalkyl-Coa. alkyl, and more preferably Cu cycloalkyl-Co.i aikyl, wherein any alkyl is optionally substituted with one or more Re groups and any cycloalkyl is optionally substituted with one or more substituents independently selected from Cs 8 alkyl and halogen. In another embodiment, the invention relates to compounds of formula I wherein n is 1; R 3 is H; and R 4 15 represents C 310 cycloalkyl-Co alkyl, preferably Caio cycloalkyl-Co, alkyl, and more preferably C36 cycloalkyl-Com alkyl. In another embodiment, the invention relates to compounds of formula I wherein n is 1; R 3 is H; and R4 represents C31o cycloalkyl-C1 alkyl, preferably C3e cycloalkyl-C 1 alkyl, more preferably cyclopropylmethyl, wherein any alkyl is optionally substituted with one or more Re groups and any cycloalkyl is optionally substituted with one or 20 more substituents independently selected from C1-8 alkyl and halogen. In another embodiment, the invention relates to compounds of formula I wherein n is 1; R 3 is H; and R4 represents C3-1o cycloalkyl-C, alkyl, preferably Cu cycloalkyl-C, alkyl, more preferably cyclopropylmethyl. In another embodiment, the invention relates to compounds of formula I wherein wherein n is 1; R 3 is H; and

R

4 represents C3o cycloalkyl, preferably Cu cycloalkyl and more preferably cyclopentyl, wherein any cycloalkyl is 25 optionally substituted with one or more substituents independently selected from C,. alkyl and halogen. In another embodiment, the invention relates to compounds of formula I wherein wherein n is 1; R3 is H; and

R

4 represents C.iocycloalkyl, preferably C3ocycloalkyl and more preferably cyclopentyl. In another embodiment, the invention relates to compounds of formula I wherein n is 1;

R

3 is H; 30 R 4 represents C1.8 alkyl, C3.1o cycloalkyl-Co alkyl or aryl-Co4 alkyl, preferably C3 alkyl, Co cycloalkyl-Coi alkyl or aryl-Co2 alkyl, wherein in the C3io cycloalkyl-Co.4 alkyl, aryl-Co-4 alkyl, C3.10 cycloalkyl-Co.1 alkyl and aryl-Co2 alkyl groups any alkyl is optionally substituted with one or more Rs groups, any cycloalkyl is optionally substituted with one or more substituents independently selected from Cis alkyl and halogen, and any aryl is optionally substituted with one or more R 7 groups; and 35 Rs is H. In another embodiment, the invention relates to compounds of formula I wherein n is 1;

R

3 is H; 23

R

4 represents C.8 alkyl, Ca-0 cycloalkyl-C" alkyl or aryl-Co alkyl, preferably Cm.3 alkyl, Ca1 cycloalkyl-Co 1 alkyl or aryl-Co-2 alkyl, wherein in the C3o cycloalkyl-C- alkyl, aryl-Co.. alkyl, C3a-jo cycloalkyl-Co. alkyl and aryl-COa2 alkyl groups any alkyl is optionally substituted with one or more Rs groups, any cycloalkyl is optionally substituted with one or more substituents independently selected from Ci_ alkyl and halogen, and any aryl is optionally 5 substituted with one or more R 7 groups; R5 is H; and each Ra independently represents C,_ alkyl; and optionally two R6 groups on the same carbon atom are bonded together to form a -C-5 alkylene- group which is optionally substituted with one or more C1_ alkyl groups. In another embodiment, the invention relates to compounds of formula I wherein n is 1; 10 R3 is H or methyl, preferably H; R4 represents C.8 alkyl optionally substituted with one or more halogen or C3.iocycloalkyl-Co.

4 alkyl, wherein in the C3a0 cycloalkyl-Cu alkyl group the cycloalkyl group is optionally substituted with one or more substituents independently selected from Ces alkyl and halogen; and

R

5 is H. 15 In another embodiment, the invention relates to compounds of formula I wherein n is 1; R3 is H or methyl, preferably H;

R

4 represents C 3

.

8 alkyl optionally substituted with one or more halogen or C3-6 cycloalkyl-Co- alkyl, wherein in the C3.6 cycloalkyl-Co. alkyl group the cycloalkyl group is optionally substituted with one or more substituents independently selected from C1.6 alkyl and halogen; and 20 R 5 is H. In another embodiment, the invention relates to compounds of formula I wherein n is 1; R3 is H; R4 represents Ci_ alkyl, preferably C-a alkyl; and R is H. 25 In another embodiment, the invention relates to compounds of formula I wherein n is 1; R3 is H or methyl, preferably H; R4 represents C3-jc cycloalkyl-Co.4 alkyl, preferably C3-jo cycloalkyl-Coi alkyl, and more preferably C3.M cycloalkyl-Co.i alkyl, wherein any alkyl is optionally substituted with one or more Re groups and any cycloalkyl is optionally substituted with one or more substituents independently selected from Cs alkyl and halogen; and 30 R 5 is H. In another embodiment, the invention relates to compounds of formula I wherein n is 1;

R

3 is H:

R

4 represents C3-I cycloalkyl-C.4 alkyl, preferably Calo cycloalkyl-Co.

1 alkyl, and more preferably C3-6 cycloalkyl-Co. alkyl, wherein any alkyl is optionally substituted with one or more R groups and any cycloalkyl is 35 optionally substituted with one or more substituents independently selected from Ces alkyl and halogen; Rs is H; and each Re independently represents C8 alkyl; and optionally two Re groups on the same carbon atom are 24 bonded together to form a -C 25 alkylene- group which is optionally substituted with one or more C1.8 alkyl groups. In another embodiment, the invention relates to compounds of formula I wherein n is 1;

R

3 is H or methyl, preferably H;

R

4 represents C3.6 cycloalkyl-Co.

1 alkyl, wherein the cycloalkyl is optionally substituted with one or more 5 substituents independently selected from C1-s alkyl and halogen; and Rs is H. In another embodiment, the invention relates to compounds of formula I wherein n is 1; R 3 is H or methyl; P 4 represents Csio cycloalkyl-C.

4 alkyl, preferably Cwo cycloalkyl-Co.1 alkyl, and more preferably CM cycloalkyl-Co alkyl; and R 5 is H. 10 In another embodiment, the invention relates to compounds of formula I wherein n is 1; R 3 is H; R 4 represents C3.o cycloalkyl-Cou alkyl, preferably C3o cycloalkyl-Co- 1 alkyl, and more preferably C3 cycloalkyl-Co.

1 alkyl; and Rs is H. In another embodiment, the invention relates to compounds of formula I wherein n is 1; Ra is H; R 4 represents C3.1o cycloalkyl-C 1 alkyl, preferably C3.6 cycloalkyl-Ci alkyl, more preferably cyclopropylmethyl, wherein 15 any alkyl is optionally substituted with one or more R 6 groups and any cycloalkyl is optionally substituted with one or more substituents independently selected from C1-8 alkyl and halogen; and Rs is H. In another embodiment, the invention relates to compounds of formula I wherein n is 1; R 3 is H or methyl; R4 represents C3.10 cycloalkyl-C alkyl, preferably C3.6 cycloalkyl-Ci alkyl, more preferably cyclopropylmethyl; and Rs is H. In another embodiment, the invention relates to compounds of formula I wherein n is 1; R 3 is H; R4 20 represents C3.10 cycloalkyl-C 1 alkyl, preferably C cycloalkyl-Cl alkyl, more preferably cyclopropylmethyl; and R% is H. In another embodiment, the invention relates to compounds of formula I wherein n is 1; R 3 is H or methyl, preferably H; R 4 represents C3.to cycloalkyl, preferably Cm cycloalkyl and more preferably cyclopentyl, wherein any cycloalkyl is optionally substituted with one or more substituents independently selected from C,-8 alkyl and halogen; and R 5 is H. 25 In another embodiment, the invention relates to compounds of formula I wherein n is 1; R 3 is H or methyl; R 4 represents C3.10 cycloalkyl, preferably Cu cycloalkyl, more preferably cyclopentyl; and P is H. In another embodiment, the invention relates to compounds of formula I wherein n is 1; R 3 is H; R 4 represents C3.10 cycloalkyl, preferably Cm cycloalkyl and more preferably cyclopentyl; and R.

5 is H. In another embodiment, the invention relates to compounds of formula I wherein: 30 Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from: (i) a heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said heterocyclic group is optionally substituted with one or more C14 alkyl groups; and (ii) a heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said 35 heterocyclic group is substituted with one -NRaRb group and is optionally substituted with one or more C, alkyl groups; wherein said heterocyclic groups (i) and (ii) are 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 25 8- to 12-membered fused bicyclic; n is 1; R3 is H; and Rs is H. 5 In another embodiment, the invention relates to compounds of formula I wherein: R, and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NRaRb group and is optionally substituted with one or more C, alkyl groups; wherein said heterocyclic group is 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; 10 n is 1;

R

3 is H; and

R

5 is H. In another embodiment, the invention relates to compounds of formula I wherein:

R

1 and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected 15 from (a) and (b), wherein R, and Rb have the meaning described above for compounds of formula I and Re represents H or C.4 alkyl, preferably Re, Rb and R, independently represent H or C4 alkyl, more preferably Ra, Rb and R, independently represent H or methyl, still more preferably Ra and Rb independently represent H or methyl and Rc represents H, even more preferably Ra represents H, Rb represents H or methyl and R, represents H and particularly preferably R, represents H, Rb represents methyl and R, represents H; 20 n is 1; R3 is H; and Rs is H. In another embodiment, the invention relates to compounds of formula I wherein:

R

1 and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula 25 (a), wherein Rb and Rb have the meaning described above for compounds of formula I and Rb represents H or C14 alkyl, preferably R., Rb and Re independently represent H or C4 alkyl, more preferably Ra, Rb and R independently represent H or methyl, still more preferably R. and Rb independently represent H or methyl and R represents H, even more preferably Ra represents H, Rb represents H or methyl and Re represents H and particularly preferably R. represents H. Rb represents methyl and Re represents H; 30 n is 1; Rb is H; and R, is H. In another embodiment, the invention relates to compounds of formula I wherein:

R

1 and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected 35 from: (i) a heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said heterocyclic group is optionally substituted with one or more C14 alkyl groups; and 26 (ii) a heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NRaRb group and is optionally substituted with one or more C1. alkyl groups; wherein said heterocyclic groups (i) and (ii) are 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 5 8- to 12-membered fused bicyclic; n is 1;

R

3 is H; Ra represents Ci.s alkyl, Ca3o cycloalkyl-Co 4 alkyl or aryl-C 0 4 alkyl, preferably C.a alkyl, C3 1 o cycloalkyl-Cot alkyl or aryl-Co.2 alkyl, wherein in the C3.io cycloalkyl-Co alkyl, aryl-Co4 alkyl, C3.io cycloalkyk-o alkyl and aryl-Co.2 10 alkyl groups any alkyl is optionally substituted with one or more R6 groups, any cycloalkyl is optionally substituted with one or more substituents independently selected from C1-8 alkyl and halogen, and any aryl is optionally substituted with one or more R7 groups; and R5 is H. In another embodiment, the invention relates to compounds of formula I wherein: 15 R 1 and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR 8 Rb group and is optionally substituted with one or more C1A alkyl groups; wherein said heterocyclic group is 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; n is 1; 20 R 3 is H; R4 represents C1.s alkyl, Cio cycloalkyl-CO 4 alkyl or aryl-COA alkyl, preferably C3 alkyl, C3.1o cycloalkyl-Co. alkyl or aryl-Co-2 alkyl, wherein in the C31o cycloalkyl-CA alkyl, afyl-CoA alkyl, C3o cycloalkyl-Co- 1 alkyl and aryl-Co.2 alkyl groups any alkyl is optionally substituted with one or more R 6 groups, any cycloalkyl is optionally substituted with one or more substituents independently selected from C- alkyl and halogen, and any aryl is optionally 25 substituted with one or more R 7 groups; and Rs is H. In another embodiment, the invention relates to compounds of formula I wherein:

R

1 and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R, and Rb have the meaning described above for compounds of formula I and Rc 30 represents H or C14 alkyl, preferably Ra, Rb and Re independently represent H or C- alkyl, more preferably Ra, Rb and Re independently represent H or methyl, still more preferably Ra and Rb independently represent H or methyl and R, represents H, even more preferably Ra represents H, Rb represents H or methyl and R represents H and particularly preferably R, represents H, Rb represents methyl and R represents H; n is 1; 35 R 3 isH; R4 represents Ct-e alkyl, C3.1o cycloalky-Co.

4 alkyl or aryl-Co 4 alkyl, preferably C" alkyl, C3io cycloalky-Co.i alkyl or aryl-Co-2 alkyl, wherein in the C3at cycloalkyl-Co 4 alkyl, aryl-Co alkyl, C3-10 cycloalkyl-Co- alkyl and aryl-Co.2 27 alkyl groups any alkyl is optionally substituted with one or more R 6 groups, any cycloalkyl is optionally substituted with one or more substituents independently selected from C1.6 alkyl and halogen, and any aryl is optionally substituted with one or more R7 groups; and R5 is H. 5 In another embodiment, the invention relates to compounds of formula I wherein:

R

1 and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R. and Rb have the meaning described above for compounds of formula I and Rc represents H or C1 4 alkyl, preferably Ra, Rb and R, independent represent H or Ci- alkyl, more preferably R,, Rb and R independently represent H or methyl, still more preferably R, and Rb independently represent H or methyl and R, represents H, 10 even more preferably Ra represents H, Rb represents H or methyl and Rb represents H and particularly preferably Ra represents H, Rb represents methyl and Re represents H; n is 1; R3 is H;

R

4 represents Ci.

6 alkyl, Cio cycloalkyl-Co alkyl or aryl-Cou alkyl, preferably C3.8 alkyl, C3to cycloalkyl-Co.

1 15 alkyl or aryl-Co.2 alkyl, wherein in the C 3.1 0 cycloalkyl-Co alkyl, aryl-CO 4 alkyl, C3i0 cycloalkyl-Co.

1 alkyl and aryl-Co- 2 alkyl groups any alkyl is optionally substituted with one or more R groups, any cycloalkyl is optionally substituted with one or more substituents independently selected from C. alkyl and halogen, and any aryl is optionally substituted with one or more R 7 groups; and Re is H. 20 In another embodiment, the invention relates to compounds of formula I wherein:

R

1 and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from: (i) a heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said heterocyclic group is optionally substituted with one or more C- alkyl groups; and 25 (ii) a heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NRaRb group and is optionally substituted with one or more C14 alkyl groups; wherein said heterocyclic groups (i) and (ii) are 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; 30 n is 1; R3 is H; R4 represents Ct. alkyl optionally substituted with one or more halogen or C 3

-

10 cycloalkyl-Co.

4 alkyl, wherein in the C3.10 cycloalkyl-CoA alkyl group the cycloalkyl group is optionally substituted with one or more substituents independently selected from C1.3 alkyl and halogen, and preferably R4 represents C38 alkyl optionally substituted with 35 one or more halogen or Cu cycloalkyl-Co.

1 alkyl, wherein in the C36 cycloalkyl-Co alkyl group the cycloalkyl group is optionally substituted with one or more substituents independently selected from C.e alkyl and halogen; and Ro is H.

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

R

1 and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NRRb group and is optionally substituted with one or more C1 alkyl groups; wherein said heterocyclic group is 5 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; n is 1; R3is H;

R

4 represents C.B alkyl optionally substituted with one or more halogen or Cito cycloalkyl-Co 4 alkyl, wherein in the C 3 .

,o cycloalkyl-Co.

4 alkyl group the cycloalkyl group is optionally substituted with one or more substituents 10 independently selected from C1a alkyl and halogen, and preferably R 4 represents C alkyl optionally substituted with one or more halogen or C6 cycloalkyl-C 1 alkyl, wherein in the Cm cycloalkyl-Co., alkyl group the cycloalkyl group is optionally substituted with one or more substituents independently selected from C1 alkyl and halogen; and R5 is H. In another embodiment, the invention relates to compounds of formula I wherein: 15 R, and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R, and Rb have the meaning described above for compounds of formula I and R, represents H or C.4alkyl, preferably Ra, Rb and R, independently represent H or C1 alkyl, more preferably Ra, Rb and Re independently represent H or methyl, still more preferably Ra and Rb independently represent H or methyl and R, represents H, even more preferably R, represents H, R5 represents H or methyl and R represents H and 20 particularly preferably Ra represents H, Rb represents methyl and R represents H; n is 1;

R

3 is H;

R

4 represents C- alkyl optionally substituted with one or more halogen or C 3

-

1 cycloalkyl-C 0 4 alkyl, wherein in the C3.o cycloalkyl-Co- alkyl group the cycloalkyl group is optionally substituted with one or more substituents 25 independently selected from Ci.a alkyl and halogen, and preferably R 4 represents C 3.8 alkyl optionally substituted with one or more halogen or Cm cycloalkyl-Co- alkyl, wherein in the C3.6 cycloalkyl-Co. alkyl group the cycloalkyl group is optionally substituted with one or more substituents independently selected from Ci- alkyl and halogen; and Rs is H. In another embodiment, the invention relates to compounds of formula I wherein: 30 R 1 and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein Ra and Rb have the meaning described above for compounds of formula I and Re represents H or Ci alkyl, preferably Ra, Rb and R, independently represent H or C1.4alkyl, more preferably Ra, Rb and Re independently represent H or methyl, still more preferably Ra and Rb independently represent H or methyl and Rc represents H, even more preferably Ra represents H, Rb represents H or methyl and Rc represents H and particularly preferably Ra 35 represents H, Rb represents methyl and R, represents H; n is 1;

R

3 is H; 29

R

4 represents C.8 alkyl optionally substituted with one or more halogen or C3.

1 0 cycloalkyl-CO4 alkyl, wherein in the C 3

.

1 0 cycloalkyl-C. alkyl group the cycloalkyl group is optionally substituted with one or more substituents independently selected from Ces alkyl and halogen, and preferably R 4 represents C3a0 alkyl optionally substituted with one or more halogen or Cm cycloalkyl-CO.

1 alkyl, wherein in the C3.6 cycloalkyl-C.

1 alkyl group the cycloalkyl group is 5 optionally substituted with one or more substituents independently selected from C 1

.

8 alkyl and halogen; and

R

5 is H. In another embodiment, the invention relates to compounds of formula I wherein:

R

1 and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from: 10 (i) a heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said heterocyclic group is optionally substituted with one or more C.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 -NRR, group and is optionally substituted with one or more CIA alkyl groups; 15 wherein said heterocyclic groups (i) and (ii) are 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; n is 1;

R

3 is H;

R

4 represents Ci-e alkyl, preferably C3 alkyl; and 20 RsIsH, in another embodiment, the invention relates to compounds of formula I wherein:

R

1 and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NRaRb group and is optionally substituted with one or more C1A alkyl groups; wherein said heterocyclic group is 25 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; n is 1;

R

3 is H; R4 represents C1.8 alkyl, preferably Cu alkyl; and Rs is H. 30 In another embodiment, the invention relates to compounds of formula I wherein: Ri and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein Ra and R 8 have the meaning described above for compounds of formula I and R, represents H or C-4 alkyl, preferably R., Rb and R independently represent H or CA alkyl, more preferably R., Rb and R, independency represent H or methyl, still more preferably Ra and Rb independently represent H or methyl and 35 R, represents H, even more preferably Ra represents H, Rb represents H or methyl and R, represents H and particularly preferably Ra represents H, Rb represents methyl and R represents H: n is 1; 30 Ra is H; R4 represents Ciealkyl, preferably C3.8alkyl; and Rs is H. In another embodiment, the invention relates to compounds of formula I wherein: 5 R, and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R. and Rb have the meaning described above for compounds of formula I and R, represents H or C1 alkyl, preferably Ra, Rb and R, independently represent H or C1.4alkyl, more preferably R, Rb and Re independently represent H or methyl, still more preferably Rb and R independently represent H or methyl and Rb represents H, even more preferably R. represents H, Rb represents H or methyl and R, represents H and particularly preferably Rb 10 represents H, Rb represents methyl and Rb represents H; n is 1; Ra is H;

R

4 represents C, alkyl, preferably Cm alkyl; and R is H. 15 In another embodiment, the invention relates to compounds of formula I wherein:

R

1 and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from: (i) a heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said heterocyclic group is optionally substituted with one or more C.4 alkyl groups; and 20 (Ii) a heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NRbRb group and is optionally substituted with one or more Cl alkyl groups; wherein said heterocyclic groups (i) and (ii) are 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; 25 n is 1; R3is H; R4 represents C310 cycloalkyl-C.

4 alkyl, preferably C3io cycloalky-C., alkyl, and more preferably C3.r cycloalkyl-Co-, alkyl, wherein any alkyl is optionally substituted with one or more R6 groups and any cycloalkyl is optionally substituted with one or more substituents independently selected from CI alkyl and halogen; and 30 R 5 is H. In another embodiment, the invention relates to compounds of formula I wherein: R, and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR.Rb group and is optionally substituted with one or more Cu alkyl groups; wherein said heterocyclic group is 35 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; n is 1; R3 is H; 31 R4 represents Caio cycloalkyl-Cuo alkyl, preferably C3 0 o cycloalkyl-Co 1 alkyl, and more preferably CMe cycloalkyl-Co. alkyl, wherein any alkyl is optionally substituted with one or more R 6 groups and any cycloalkyl is optionally substituted with one or more substituents independently selected from CI8 alkyl and halogen; and R5 is H. 5 In another embodiment, the invention relates to compounds of formula I wherein: R1 and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein Ra and Rb have the meaning described above for compounds of formula I and R represents H or C14 alkyl, preferably R., Rb and R, independently represent H or C14 alkyl, more preferably Ra, Rb and Re independently represent H or methyl, still more preferably R. and Rb independently represent H or methyl and 10 Re represents H, even more preferably R 6 represents H, R represents H or methyl and R, represents H and particularly preferably Ra represents H, Rb represents methyl and R, represents H; n is 1; R3 is H; R4 represents C3.0 cycloalkyl-Co 4 alkyl, preferably C3i cycloalkyl-Co 1 alkyl, and more preferably C3. 15 cycloalkyl-CO.

1 alkyl, wherein any alkyl is optionally substituted with one or more R6 groups and any cycloalkyl is optionally substituted with one or more substituents independently selected from C,.e alkyl and halogen; and R5 is H. In another embodiment, the invention relates to compounds of formula I wherein: R, and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula 20 (a), wherein Ra and Rb have the meaning described above for compounds of formula I and k represents H or C14 alkyl, preferably R, Rb and Re independently represent H or O1 alkyl, more preferably Ra, Rb and Re independently represent H or methyl, still more preferably R, and Rb independently represent H or methyl and Re represents H, even more preferably R, represents H, Rb represents H or methyl and R represents H and particularly preferably Rb represents H, Rb represents methyl and R represents H; 25 n is 1; R3 is H; R4 represents Caio cycloalkyl-CG 4 alkyl, preferably Ca1o cycloalkyl-Co. alkyl, and more preferably C3s cycloalkyl-CO., alkyl, wherein any alkyl is optionally substituted with one or more Rs groups and any cycloalkyl is optionally substituted with one or more substituents independently selected from Cia alkyl and halogen; and 30 R 5 is H. In another embodiment, the invention relates to compounds of formula I wherein:

R

1 and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from: (i) a heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said 35 heterocyclic group is optionally substituted with one or more C, 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 -NRRb group and is optionally substituted with one or more C alkyl 32 groups; wherein said heterocyclic groups (i) and (ii) are 4- to 7-membered monocycic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; n is 1; 5 R3 is H;

R

4 represents C34o cycloalkyl-C alkyl, preferably Cu cycloalkyl-C 1 alkyl, more preferably cyclopropylmethyl; and

R

5 is H. In another embodiment, the invention relates to compounds of formula I wherein: 10 R 1 and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NRaRb group and is optionally substituted with one or more CiA alkyl groups; wherein said heterocyclic group is 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; n is 1; 15 R 3 is H; R4 represents C3.

0 cycloalkyl-C 1 alkyl, preferably C3-6 cycloalkyl-C alkyl, more preferably cyclopropylmethyl; and R5 is H. In another embodiment, the invention relates to compounds of formula I wherein: 20 R 1 and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein Ra and Rb have the meaning described above for compounds of formula I and Re represents H or C 1 - alkyl, preferably R,, Rb and R, independently represent H or Ci4 alkyl, more preferably Ra, Rb and R, independently represent H or methyl, still more preferably R, and Rb independently represent H or methyl and R, represents H, even more preferably R represents H, Rb represents H or methyl and Rc represents H and 25 particularly preferably Ra represents H, Rb represents methyl and Re represents H; n is 1;

R

3 is H; R4 represents C3o cycloalkyl-C alkyl, preferably Cm cycloalkyl-C, alkyl, cyclopropylmethyl; and Rs is H. 30 In another embodiment, the invention relates to compounds of formula I wherein: Ri and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R, and Rb have the meaning described above for compounds of formula I and R represents H or C alkyl, preferably Rb, Rb and Rb independently represent H or C 14 alkyl, more preferably Re, Rb and R independently represent H or methyl, still more preferably Ra and Rb independently represent H or methyl and R, represents H, 35 even more preferably R. represents H, Rb represents H or methyl and Rb represents H and particularly preferably Ra represents H, Rb represents methyl and Rb represents H; n is 1; 33 R3 is H;

R

4 represents C3io cycloalkyl-C 1 alkyl, preferably C3- cycloalkyl-C 1 alkyl, more preferably cyclopropylmethyl; and

R

5 is H. 5 In another embodiment, the invention relates to compounds of formula I wherein:

R

1 and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from: (I) a heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said heterocyclic group is optionally substituted with one or more C14 alkyl groups; and 10 (ii) a heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NRaRb group and is optionally substituted with one or more C alkyl groups; wherein said heterocyclic groups (I) and (ii) are 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; 15 n is 1; Rais H; R4 represents C3.o cycloalkyl, preferably C6 cycloalkyl and more preferably cyclopentyl; and Rs is H. In another embodiment, the invention relates to compounds of formula I wherein: 20 R, and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NReRb group and is optionally substituted with one or more C.

4 alkyl groups; wherein said heterocyclic group is 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; n is 1; 25 R 3 is H; R4 represents CGo cycloalkyl, preferably C, cycloalkyl and more preferably cyclopentyl; and R5 is H. In another embodiment, the invention relates to compounds of formula I wherein:

R

1 and R2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected 30 from (a) and (b), wherein R, and Rb have the meaning described above for compounds of formula I and R, represents H or CA alkyl, preferably Ra, Rb and Re independently represent H or C1.4 alkyl, more preferably Ra, Rb and Re independently represent H or methyl, still more preferably Ra and Rb independently represent H or methyl and Re represents H, even more preferably Ra represents H, Rb represents H or methyl and Re represents H and particularly preferably R, represents H, Rb represents methyl and Re represents H; 35 nis1; R3 is H; R4 represents C3.0ocycloalkyl, preferably Cm cycloalkyl and more preferably cyclopentyl; and 34 R5 is H. In another embodiment, the invention relates to compounds of formula I wherein:

R

1 and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein Ra and Rb have the meaning described above for compounds of formula I and R, represents H or CA 5 alkyl, preferably R, Rb and R, independently represent H or C4 alkyl, more preferably Ra, Rb and Rb independently represent H or methyl, still more preferably R and Rb independently represent H or methyl and R, represents H, even more preferably R, represents H, Rb represents H or methyl and R, represents H and particularly preferably Rb represents H, Rb represents methyl and Re represents H; n is 1; 10 R 3 is H; R4 represents C3iocycloalkyl, preferably C6cycloalkyl and more preferably cyclopentyl; and Rs is H. Moreover, the present invention includes all possible combinations of the particular and preferred embodiments described above. 15 In an additional embodiment, the invention relates to a compound of formula I selected from the list of compounds of examples la-6j. In a further embodiment, the invention relates to a compound of formula I selected fom: 4 -((Cyclopropylmethylamino)methyl)-6-(3-(methylamino)azetidin-1 -yl)pyimidin-2-amine; 4-((2-Adamantylamino)methyl)-6-(3-(methylamino)azetidin-1 -yl)pyrimidin-2-amine; 20 4-(((2,2-Diethylcyclopropyl) methylamino)methyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine; 4 -((Cyclopentylamino)methyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine; 4-(3-(Methylamino)azetidin-1-yl)-6-((pentylamino)methyl)pyrimidin-2-amine; 4 -((Cyclopentyl(methyl)amino)methyl)-6-(3-(methylamino)azetidin-1 -yi)pyrimidin-2-amine; 4-((Isobutylamino)methyl)-6-(3-(methylamino)azetidin-1-yl)pyrmidin-2-amine; 25 4 -((Cyclopropylamino)methyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine; 4-((tert-Butylamino)methyl)-6-(3-(methylamino)azetidin-1 -yl)pyrimidin-2-amine; 4 -((Isopropylamino)methyl)-6-(3-(methylamino)azetidin-1 -yl)pyrimidin-2-amine; 4-(3-(methylamino)azetidin-1 -yl)-6-((2,2,2-trifluoroethylamino)methyl)pyrimidin-2-amine; 4-(((1 R,2R,4S)-bicyclo[2.2.1]heptan-2-ylamino)methyl)-6-(3-(methylamino)azetidin-1-yl)pyrmidin-2-amine; 30 (S)-4-((sec-butylamino)methyl)-6-(3-(methylamino)azetdin-1-yl)pyrmidin-2-amine; and (R)-4-((sec-butylamino)methyl)-6-(3-methylamino)azetidin-1-yl)pyrmidin-2-amine; or a salt thereof. In a further embodiment, the invention relates to a compound of formula which is 4 ((Cyclopropylmethylamino)methyl)-6-(3-(methylamino)azetdin-1-yl)pyrimidin-2-amine; or a salt thereof.

35 In a further embodiment, the invention relates to a compound of formula I which is 4-((2 Adamantylamino)methyl)-6-(3(methylamino)azetidin-1-yl)pyrimidin-2-ami ne; or a salt thereof. In a further embodiment, the invention relates to a compound of formula I which is 4-(((2,2 Diethylcyclopropyl) methylamino)methyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine; or a salt thereof. 5 in a further embodiment, the invention relates to a compound of formula I which is 4 ((Cyclopentylamino)methyl)-6-(3-(methylamino)azetidin-l-yI)pyrimidin-2-amine; or a salt thereof. in a further embodiment, the invention relates to a compound of formula I which is 4-(3 (Methyamino)azetdin-1-yl)-6-((pentylamino)methyl)pyrmidin-2-amine; or a salt thereof. In a further embodiment, the invention relates to a compound of formula I which is 4 10 ((Cyclopenty(methyl)amino)methyl)-6-(3-(methylamino)azetidin-1-yl)pyrmidin-2-amine; or a salt thereof. In a further embodiment, the invention relates to a compound of formula I which is 4 ((Isobutylamino)methyl)-6-(3-(methylamino)azetidin-1-yi)pyrimidin-2-amine; or a salt thereof. In a further embodiment, the invention relates to a compound of formula I which Is 4 ((Cyclopropylamino)methyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine; or a salt thereof. 15 in a further embodiment, the invention relates to a compound of formula I which is 4-((tert Butylamino)methyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine; or a salt thereof. In a further embodiment, the invention relates to a compound of formula I which is 4 ((Isopropylamino)methyl)-6-(3-(methylamino)azetidin-1 -yl)pyrimidin-2-amine; or a salt thereof. in a further embodiment, the invention relates to a compound of formula I which is 4-(3 20 (methylamino)azetidin-1-yl)-6-((2,2,2-trifluoroethylamino)methyl)pyrmidin-2-amine; or a salt thereof. In a further embodiment, the invention relates to a compound of formula I which is 4-(((IR,2R,4S) bicyclo[2.2.1]heptan-2-ylamino)methyl)-6-(3-(methylamino)azetidin-1-yl)pyrmidin-2-amine; or a salt thereof. In a further embodiment, the invention relates to a compound of formula I which is (S)-4-((sec butylamino)methyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine; or a salt thereof. 25 In a further embodiment, the invention relates to a compound of formula I which is (R)-4-((sec butylamino)methyl)-6-(3-(methylamino)azetidin- 1-yl)pyrimidin-2-amine; or a salt thereof. In an additional embodiment, the invention relates to compounds according to formula I which provide more than 50% inhibition of H 4 receptor activity at 10 [M, more preferably at 1 paM and even more preferably at 0.1 4M, in a H 4 receptor assay such as the one described in examples 7 or 8. 30 The compounds of the present invention contain one or more basic nitrogens and may, therefore, form salts with organic or inorganic acids. Examples of these salts include: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; and salts with organic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p toluenesulfonic acid, fumaric acid, oxalic acid, acetic acid, maleic acid, ascorbic acid, citric acid, lactic acid, tartaric 35 acid, malonic acid, glycolic acid, succinic acid and propionic acid, among others. The compounds of the present 36 invention may contain one or more acidic protons and, therefore, they may also form salts with bases, which also form part of the present invention. Examples of these salts include: salts with inorganic cations such as sodium, potassium, calcium, magnesium, lithium, aluminium, zinc, etc; and salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxylalkylamines, lysine, arginine, N-methylglucamine, procaine and the 5 like. There is no limitation on the type of salt that can be used, provided that these are pharmaceutically acceptable when used for therapeutic purposes. The term pharmaceutically acceptable salt refers to those salts which are, according to medical judgement, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like. Pharmaceutically acceptable salts are well 10 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 (or base) 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. 15 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 20 solvate refers to a complex of variable stoichiometry formed by a solute.(a compound of formula I or a salt thereof) and a solvent. Examples of solvents include pharmaceutically acceptable solvents such as water, ethanol and the like. A complex with water is known as a hydrate. Solvates of compounds of the invention (or salts thereof), including hydrates, are included within the scope of the invention. The compounds of formula I may exist in different physical forms, i.e. amorphous and crystalline forms. 25 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 patten, 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 30 diastereolsomers. 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 1. Optically pure isomers can also be individually obtained using enantlospecific synthesis. The present invention covers all individual isomers as well as mixtures thereof (for example racemic mixtures or mixtures of 35 diastereomers), whether obtained by synthesis or by physically mixing them. The present invention further covers all unlabeled and isotopically labeled forms of the compounds of formula 1.

37 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 5 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, 3d 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 1. In general, compounds of formula I wherein n is 1 can be obtained by reacting a compound of formula Il 10 with a compound of formula Ill, as shown in the following scheme:

NH

2

NH

2 N N N N R5 + HNR 3

R

4 :P R 4

R

3 N

NR

1

R

2

NR

1

R

2 O R5 wherein R 1 , R 2 , R 3 , R 4 and R 5 have the meaning described above with respect to a compound of formula I. The reaction between the compounds of formulae 11 and IlIl may be performed using a suitable reducing agent such as sodium cyanoborohydride and preferably sodium triacetoxyborohydride, optionally in the presence of 15 an acid catalyst such as acetic acid and in a suitable solvent such as dichloromethane, dichloroethane, methanol or toluene, preferably dichloromethane, at a suitable temperature, usually at room temperature. Other suitable reducing agents include phenylsilane, in the presence of a catalyst such as dibutyltin dichloride and in a suitable solvent such as tetrahydrofuran, or hydrogen gas in the presence of a palladium catalyst. The compounds of formula Ill are commercial or can be obtained by procedures described in the literature. 20 The compounds of formula II wherein n is 1 and R 5 is hydrogen (i.e compounds of formula Ila) can be obtained by oxidation of a compound of formula VI as shown in the following scheme: 38

NH

2 NH N N N N

NR

1

R

2 H

NR

1

R

2 OH 0 VI Ila wherein R, and R 2 have the meaning described in formula 1. The reaction takes place by reacting the primary alcohol VI with an oxidizing agent such as oxalyl chloride/dimethylsulfoxide in dichlormethane and in the presence of triethylamine (Swem oxidation), manganese 5 oxide in dichloromethane or tetrahydrofuran or, preferably, with sulfur trioxide pyridine complex in dimethylsulfoxide or dimethylsulfoxide-dichloromethane mixtures in the presence of an organic base such as triethylamine at a suitable temperature, usually at room temperature. The amino substituents of the compounds of formula I and VI may be protected in order to prevent the formation of side products, if necessary. Any suitable amino-protective group may be used, such as for example a 10 terf-butoxycarbonyl (Boc) group. A subsequent deprotection step may be necessary when the amino substituents of the compounds of formula 11 and/or VI are protected, which is carried out under standard conditions. When the protective group is Boc, the deprotection can be conducted by adding a solution of a strong acid such as HCl in a suitable solvent such as 1,4-dioxane, diethyl ether or methanol, or with trifluoroacetic acid in dichloromethane. The compounds of formula VI can be obtained by reacting a compound of formula VII or Vllb with a 15 compound of formula V, as shown in the following scheme: 39

NH

2 NH 2 NH 2 N N N~ N N~ N + HNR1R2II OH

NR

1

R

2 NR1R 2 OP OP OH VII V VI (protected form) VI

NH

2 +V NN

R

1 0 OP VIlb wherein R 1 and R 2 have the meaning described above with respect to a compound of formula 1, R 10 represents a leaving group such as halogen (preferably chloro), mesyate, tosylate or triflate, and P represents a protecting group. The reaction between the compounds of formulae VII and V may be performed using a coupling agent such 5 as for example PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate) in a suitable solvent such as 1,4-dioxane, tetrahydrofuran, dichloromethane, NN-dimethylformamide, acetonitrile or mixtures thereof, preferably in acetonitrile or a mixture of acetonitrile/dioxane, in the presence of a base, such as N,N diisopropylethylamine, dimethylaniline, diethylaniline, triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably triethylamine. The reaction can be carried out at a temperature comprised between room temperature and 10 the reflux temperature, preferably heating. Alternatively the compounds of formula VI can be obtained by reacting a compound of formula V with a reactive derivative of a compound of formula VII (ie a compound Vilb) obtained by conversion of the hydroxy group present in a compound of formula VII into a leaving group such as halogen, mesylate, tosylate or triflate. The -OH group from a compound of formula VII may be transformed into a leaving group such as halogen, 15 preferably chloro, by reaction with a halogenating agent such as POCl 3 , optionally in the presence of a suitable solvent, optionally in the presence of a base such as tetraethylammonium chloride, diisopropylethylamine or diethylaniline, among others; or with POCI 3

/PCI

5 or NN-dimethylformamide/oxalyl chloride mixtures in the presence of a suitable solvent such as 1,4-dioxane or 1,2-dichloroethane. The reaction is performed by heating, preferably at a temperature comprised between 50 *C and 100 *C, preferably 70 0C. The hydroxy group of a compound of formula 20 Vil can be transformed into a triflate group by reaction with trifluoromethanesulphonic anhydride in the presence of 40 pyridine. The hydroxy group of a compound of formula VI1 can be transformed into a tosylate or mesylate group by reaction with p-toluenesulfonyl chloride or methanesuffonyl chloride in a suitable solvent such as dichloromethane in the presence of a base such as triethylamine or pyridine. The reactive derivative of a compound of formula VII thus obtained (Vilb) is then allowed to react with a 5 compound of formula V to give a compound of formula VI. The reaction is performed in a suitable solvent such as ethanol, methanol, butanol, NN-dimethylformamide, dimethylsuiphoxide, tetrahydrofuran, acetonitrile or toluene, in the presence of a base, including organic amines such as triethylamine, NN-diisopropylethylamine, dimethylaniline and diethylaniline among others, and heating, preferably at a temperature comprised between 50 and 140 *C. The heating may be thermal or by irradiating with microwaves at a wattage that allows to reach the temperature 10 mentioned above. In general, before conducting the reaction between the compounds of formula VII and V, or Vllb and V, the amino substituents of the compounds of formula V are protected in order to prevent the formation of side products. Similarly, the amino group of the compounds of formula VII and Vilb can also be protected if necessary. Any suitable amino-protective group may be used, such as for example a tert-butoxycarbonyl (Boc) group. A subsequent 15 deprotection step may be necessary when the amino substituents of the compounds of formula VI1 and/or Vilb and/or V are protected, which is caried out under standard conditions. When the protective group is Boc, the deprotection can be conducted directly upon the crude product obtained by adding a solution of a strong acid such as HCI in a suitable solvent such as 1,4-dioxane, diethyl ether or methanol, or trifluoroacetic acid in dichloromethane. The primary alcohol in starting materials VII and Vilb is also protected in a suitable form to carry out the 20 reaction with the compound V. Any suitable alcohol-protective group may be used, such as for example a benzyl group. The subsequent deprotection step is performed under standard conditions. The compounds of formula V are commercial or can be obtained by procedures described in the literature. The compounds of formula VII can be obtained by reacting a compound of formula Vill with a guanidine source, preferably guanidine hydrochloride, as shown in the following scheme:

H

2 N NH NH 2 O O HCI1

NH

2 N N

OR

11 'e OH OP 25 VillI Vil wherein Rii represents methyl or ethyl. The reaction takes place in the presence of a base such as potassium carbonate, sodium tert-butoxide or sodium ethoxide and preferably sodium methoxide, in a suitable solvent, preferably ethanol. The reaction can be performed by heating at a suitable temperature usually comprised between room temperature and the reflux 41 temperature, preferably under reflux. The compounds of formula Vill are commercial or can be easily obtained from commercial compounds by known methods. Alternatively, the compounds of formula I wherein n is 1 and R is hydrogen (i.e compounds of formula la) 5 can be obtained from a compound of formula IV or a reactive derivative thereof (lVb) by reaction with a compound of formula V under similar conditions to those described for the transformation of VII and Vllb into VI, as shown in the following scheme:

NH

2 NH 2 N N N I HNR

R

2 31.

R

4

R

3 N OH R 4

R

3 N NR 1

R

2 IV V Ia

NH

2 N ) N

R

4

R

3 N R10 IVb 10 wherein R 1 , R 2 , R 3 and R 4 have the meaning described above with respect to a compound of formula 1, and Rio represents a leaving group such as halogen (preferably chloro), mesylate, tosylate or triflate. The compounds of formula IV can be obtained by reacting a compound of formula IX with a guanidine source such as guanidine hydrochoride, under similar conditions previously disclosed for the preparation of a compound of formula VII, as shown in the following scheme: 15 42

H

2 N NH NH 2 O O HCI

R

4

R

3 N OR, NH 2 NC R4R3 N

OR

1 R 4

R

3 N,- OH lx IV wherein Ra and R4 have the meaning described in formula 1, and Rn, represents methyl or ethyl. The compounds of formula IX can be obtained by reacting a compound of formula X with an excess of a compound of formula Ill in a suitable solvent such as dichloromethane, as shown in the following scheme: 0 0 0 0 C O 1 HNR 3

R

4

R

4

R

3 N 5 X III IX wherein R 3 and R4 have the meaning described in formula I and Ri, represents methyl or ethyl. The compounds of formula X are commercial or can be easily obtained from commercial compounds by known methods. The compounds of formula IVb can obtained from a compound of formula IV by conversion of the -OH 10 group into a leaving group, following the procedures described above for the conversion of VII to VlIb. Alternatively, the compounds of formula 11 wherein n is 1 and R 5 is alkyl (i.e. compounds of formula lib) can be prepared by reaction between compounds of formulae XI and XII as shown in the following scheme:

NH

2

NH

2 N N N N +

R

5 MgX h R NC NR 1

R

2 R 5

NR

1

R

2 0 XI XIl lib wherein R 1 and R 2 have the meaning described in formula I, R 5 is alkyl, and X represents halogen , preferably lodo or 15 bromo (see Heterocydes 2007, 71, 5, 1107). The reaction can be carried out in a suitable solvent such as diethyl ether or tetrahydrofuran, at a suitable temperature, preferably room temperature. The compounds of formula XI can be obtained by reacting a compound of formula XIII with a cyanide 43 source such as Zn(CN) 2 , as shown in the following scheme:

NH

2

NH

2 N N N N C1

NR

1

R

2 NC

NR

1

R

2 XIl X1 wherein R 1 and R 2 have the meaning described in formula I (see Heterocycles 2007, 71, 5, 1107). The conversion of a compound of formula XII to a compound of formula XI can be cared out by reacting 5 XIII with a cyanide source such as zinc cyanide in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) in a suitable solvent such as tetrahydrofuran, toluene and preferably in dimethylformamide or N-methylpyrrolidone and heating, preferably at 100 *C. Alternatively, compounds of formula lIb wherein R represents methyl can be readily obtained by reacting a compound of formula XII1 with tributyl(1-ethoxyvinyl)tin in the presence of a palladium catalyst such as 10 tetrakis(triphenylphosphine)palladium(0), in the presence of a base such as potassium carbonate, in a suitable solvent such as tetrahydrofuran, toluene, dimethylformamide or dimethylacetamide and heating (see Tetrahedron 1997, 53, 6, 2291). The compounds of formula X11 are commercial or can be easily obtained from commercial compounds by known methods. 15 Other compounds of formula I (i.e compounds of formula Ic, which correspond to compounds of formula I wherein either n=1 and R represents H, or n=2 and (CR 5

R

5

)

2 represents -(CH 2

)-(CR

5

R

5 )-) can be obtained from a compound of formula XIV, as shown below:

NH

2

NH

2 O N N N N

R

4

R

3 N m NR 1

R

2

R

4

R

3 N m NR 1

R

2

R

5

R

5 R 5

R

5 XIV IC 20 wherein R 1 , R2, R 3 , R4and Rg have the meaning described in formula 1, and m represents 0 or 1. The reaction takes place in the presence of a reducing agent such as lithium aluminium hydride or borane in 44 a suitable solvent such as tetrahydrofuran at a suitable temperature, comprised between room temperature and the reflux temperature. Compounds of formula XIV, wherein m represents 0 (i.e compounds XIVa) can be obtained by reacting a compound of formula XV with compounds of formula IlIl and V, as shown in the following scheme:

NH

2

NH

2 i) HNR 3

R

4 N N I N N HOOC OH ii) HNR 1

R

2 NR 1

R

2 V

NR

3

R

4 5 XV XIVa wherein R 1 , R 2 , R 3 and R 4 have the meaning described in formula I. The reaction can be carried out by addition of the amine compound IlIl and a coupling agent such as for example PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate) or HBTU (0-benzotriazol-1 yl-N,N,N',N',-tetramethyuronium hexafluorophosphate), in a suitable solvent such as 1,4-dioxane, tetrahydrofuran, 10 dichloromethane, N,N-dimethylformamide or acetonitrile in the presence of a base, such as NN4 diisopropylethylamine, dimethylaniline, diethylaniline, triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), followed by a second coupling step between the intermediate thus generated and the amine compound V using a coupling agent such as PyBOP under the coupling conditions described above for the reaction between Ill and XV. Alternatively, when PyBOP is used as the coupling agent, the reaction can be carried out in none pot" by performing 15 the second coupling step without isolation of the intermediate reaction product from XV and Ill. The reaction can be carried out at a temperature comprised between room temperature and the reflux temperature, preferably at room temperature for the first coupling step and preferably heating for the second coupling step. The compound of formula XV is commercial. Compounds of formula XIV, wherein m represents 1 (i.e compounds XIVb) can be obtained by reacting a 20 compound of formula XVI with a compound of formula Ill as shown in the following scheme:

NH

2 NH 2 N N O N) N I+ HNR 3

R

4 - P I N HOOC

NR

1

R

2

R

4

R

3 N

NR

1

R

2

R

5

R

5

R

5

R

5 XVI Ill XIVb 45 wherein R 1 , R 2 , R 3 , R 4 and R6 have the meaning described in general formula 1. The reaction between the compounds of formulae XVI and Ill may be performed using a coupling agent such as for example HBTU (0-benzotriazol-1-yl-N,N,N'N'-tetramethyluronium hexafluorophosphate) or PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate) in a suitable solvent such as 1,4-dioxane, 5 tetrahydrofuran, dichloromethane, acetonitrile, preferably in NN-dimethyformamide, in the presence of a base, such as NN-diisopropylethylamine, dimethylaniline, diethylaniline, triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably triethylamine. The reaction can be carried out at a temperature comprised between room temperature and the reflux temperature, preferably room temperature. The compounds of formula XVI can be obtained by hydrolysis of an ester compound of formula XVII under 10 standard basic conditions, as shown in the following scheme:

NH

2

NH

2 o N; N a N) N O

NR

1

R

2 HO

NR

1

R

2

R

5

R

5 R 5

R

5 XVII XVI wherein Ri, R 2 and Rs have the meaning described in formula I and R, 1 represents methyl or ethyl. The compounds of formula XVII can be prepared by reacting a compound of formula XVIII with a compound 15 of formula V under similar conditions previously disclosed for the reaction between compounds of formula VII and V, as shown in the following scheme:

NH

2

NH

2 O N N N + HNR 1

R

2 b- I R1 O OH R1 O

NR

1

R

2

R

5

R

5

R

5

R

5 XVill V XVII wherein R 1 , R 2 and R 5 have the meaning described in formula I and R, 1 represents methyl or ethyl. The reaction of a compound of formula XIX with a guanidine source such as guanidine hydrochloride under 20 similar conditions previously disclosed for the preparation of a compound of formula VII and IV gives rise to compounds of formula XVIII, as shown below: 46 HN NH 2 NH 2 0H2 .HCI O N N

R

1 1 .1 R R 5

R

5 R O OH

R

5

R

5 XIX XVill wherein R 5 has the meaning described in formula I and R 1 , represents methyl or ethyl. The compounds of formula XIX are commercial or can be easily obtained from commercial compounds by known methods. 5 Alternatively, compounds of formula I wherein n is 1 can be obtained by reacting a compound of formula XX with a compound of formula IlIl, as shown in the following scheme:

NH

2

NH

2 N )-'N N N

R

12 R 4

R

3 N

NR

1

R

2

HNR

3

R

4

NR

1

R

2 R5 IlR5 wherein R 1 , R 2 , R 3 , R 4 and R 5 have the meaning described above with respect to a compound of formula I and R 1 2 10 represents a leaving group such as halogen, mesylate, tosylate or triflate. The reaction of displacement between the compounds of formulae XX and III may be performed In the presence of a suitable base and solvent. The base can be an excess of Ill or alternatively a bulky tertiary amine such as diisopropylethylamine or dimethylaniline, among others. As suitable solvents, acetonitrile, dichloromethane, chloroform, tetrahydrofurane, or dioxane, among others, can be used . The reaction can be performed at a 15 temperature comprised between room temperature and 100"C with pressure or without. The compounds of formula XX wherein Ra is C 1 .Balkyl can be obtained by reduction of ketone il (wherein Rs is C 1 .s alkyl) to give compound XJ (wherein R 5 is C 1 .8 alkyl) followed by conversion of the -OH group of compound of formula XXI into a leaving group R 1 2 Similarly, the compounds of formula XX wherein R6 is H can be obtained by transforming the -OH group of compound of formula VI into a leaving group R 1 2 as shown in the following 20 scheme: 47

NH

2

NH

2

NH

2 N I N N > N N > N

NR

1

R

2 H

NR

1

R

2 'N

NR

1

R

2 O R,5 R5 II XXI XX

NH

2 N N NR1R 2 VI wherein R 1 , R 2 and R 6 have the meaning described above with respect to a compound of formula I and R 1 2 represents a leaving group such as halogen, mesylate, tosylate or triflate. The reaction of reduction of I to give XXI may be performed using a suitable reducing agent such as 5 sodium borohydride, lithium aluminium hydride, selectride or borane in a suitable solvent such as tetrahydrofuran at a suitable temperature, comprised between room temperature and the reflux temperature. The -OH group in compound XXI or VI may be transformed into a leaving group such as halogen, preferably chloro, by reaction with a halogenating agent such as thionyl chloride, in the presence of a suitable solvent such us tetrahydrofurane or dichloromethane, optionally in the presence of a base such pyridine; the -OH 10 group in compound XXI or VI can be transformed into a triflate group by reaction with trifluoromethanesulphonic anhydride in the presence of pyridine or can be transformed into a tosylate or mesylate group by reaction with p toluenesulfonyl chloride or methanesufonyl chloride in a suitable solvent such as dichloromethane in the presence of a base such as triethylamine or pyridine. Moreover, certain compounds of the present invention can also be obtained starting from other compounds 15 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. In general, before conducting any of the above reaction step wherein an amino group (NH 2 ) and/or an amino group in NRR 2 are present, it may be advisable to protect said groups with a suitable protecting group, preferably a tert-butoxycarbonyl (Boc) group. If Boc is used, deprotection can be conducted directly upon the crde 20 product obtained by adding a solution of a strong acid such as HCI in a suitable solvent such as 1,4-dioxane, diethyl ether or methanol, or trifluoroacetic acid in dichloromethane.

48 As previously mentioned, the compounds of the present invention show potent histamine H 4 receptor antagonist activity. Therefore, the compounds of the invention are expected to be useful to treat or prevent diseases mediated by the H 4 receptor in mammals, including human beings. Diseases mediated by the H 4 receptor that can be treated or prevented with the compounds of the present 5 invention include, among others, allergic, immunological or inflammatory diseases, pain or cancer. Examples of allergic, immunological or inflammatory diseases that can be treated or prevented with the compounds of the invention include without limitation: respiratory diseases, such as asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD); ocular diseases, such as allergic rhinoconjunctivitis, dry eye and cataracts; skin diseases, such as eczema, dermatitis (e.g. atopic dermatitis), psoriasis, urticaria, pemphigus, 10 dermatitis herpetiformis, cutaneous vasculitis and pruritus; inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease; autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus, and systemic vasculitis such as allergic vasculitis and periarteritis nodosa; and transplant rejection. Examples of pain conditions that can be treated or prevented with the compounds of the invention include, 15 among others, inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-surgical pain, migraine, cancer pain, visceral pain, osteoarthrtis pain and neuropathic pain. In a preferred embodiment, the compounds of the invention are used for the treatment or prevention of an allergic, immunological or inflammatory disease. In a more preferred embodiment, the compounds of the invention are used for the treatment or prevention of an allergic, immunological or inflammatory disease selected from a 20 respiratory disease, an ocular disease, a skin disease, an inflammatory bowel disease, an autoimmune disease, 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, eczema, dermatitis (e.g. atopic dermatitis), psoriasis, urticaria, pemphigus, dermatitis herpetiformis, cutaneous vasculitis, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous 25 lupus, systemic lupus erythematosus, systemic vasculitis, and transplant rejection. In another preferred embodiment, the compounds of the invention are used for the treatment or prevention of pain, preferably inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-surgical pain, migraine, cancer pain, visceral pain, osteoarthritis pain or neuropathic pain. Assays to determine the ability of a compound to interact with the histamine H 4 receptor are well known in 30 the art. For example, one can use a H 4 receptor binding assay such as the one explained in detail in example 7. Another useful assay is a GTP [0-3 5 S] 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 Cal mobilization. In this regard, a very useful functional assay that can be used to determine anti-H 4 receptor activity is 35 the Gated Autofluorescence Forward Scatter assay (GAFS) in eosinophils, for example human eosinophils, as disclosed in detail in example 8; this assay is well know in the art (see for example the method disclosed in Buckland KF etal, 2003, cited above in the Background section, which is incorporated herein by reference). In vivo assays that 49 can be used to test the activity of the compounds of the invention are also well known in the art (see for example the various literature references listed for in vivo animal models in the Background section, particularly those relating to in vivo models of peritonitis, pleurisy, allergic asthma, inflammatory bowel disease, atopic dermatitis, pruritus and pain, which are all incorportated herein by reference). Other in vivo assays that can be used, particularly to test 5 compounds administered topically, are the delayed type hypersensitivity to oxazolone assay (Tarayre, JP et al., Arzneimittel-Forschung, 40(10): 1125-1131 (1990), which is herein incorporated by reference) and a mice atopic dermatitis model by multiple oxazolone challenges such as the one disclosed in detail in example 10 (. The selectivity profile of the compounds of the invention can be tested using standard histamine receptor binding assays using the various histamine receptors similarly to the one disclosed in example 7. In addition, to test 10 the selectivity for other receptors or ion channels, displacement assays of the corresponding radioligands can be used following the standard procedures reported in the literature and well known in the art. To test the selectivity for enzymes, determination of enzymatic activity by product formation from its substrate can be used. The toxicity and safety profile of the compounds of the invention can be determined using standard tests that are well known in the art. An assay that is indispensable in order to determine cardiac safety profile of a drug 15 candidate is the assessment of inhibition of the hERG channel using a patch-clamp test such as the one described in more detail in example 9. Other standard in vitro toxicity assays that can be carried out are: viability panel in different cell lines (i.e. HepG2, Jurkat, U937, A549, Hela, CHO-Ki), Ames test, micronuclel assay, glutathione depletion, or drug induced phospholipidosis assay (. Regarding in vivo toxicity, several tests can be performed: acute and repeated toxicity in rodents and other species for general toxicity, and Murine Local Lymph Node Assay (LLNA) 20 and maximization test in guinea-pig for skin sensitization potential. To be devoid of unwanted central nervous system effects, peripherally acting drugs must show limited ability to cross BBB. To test the ability to of a drug penetrate in CNS system, plasma/brain ratio after administration of drug can be determined. For selecting active compounds, testing at 10 pM must result in an activity of more than 50% inhibition of H 4 25 receptor activity in the test provided in example 7. More preferably, compounds should exhibit more than 50% inhibition at 1 pM and still more preferably at 0.1 pM in this assay. Preferred compounds should also exhibit potent activity in the GAFS assay of example 8; preferably, compounds should exhibit more than 50% inhibition at 10 pM, more preferably at 1 pM and still more preferably at 0.1 pM in this assay. Preferred compounds should exhibit selective affinity for the H 4 receptor over other receptors, particularly 30 the H 3 , muscarinic, adrenergic, dopamine and serotonine receptors, and over ion channels, particularly hERGK+ channel. The compounds of the present invention exhibit advantageous properties. In addition to having potent activity as H 4 receptor modulators, compounds of the invention have been found to exhibit good cardiac safety profile in the Herg channel inhibition assay. Moreover, the compounds of examples lb and 1t have been shown to exhibit 35 outstanding in vivo activity in the atopic dermatitis model of example 10. 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 50 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 5 administration. Any route of administration may be used, for example oral, parenteral, nasal, ocular, topical and rectal administration. In a preferred embodiment, the compounds of the invention are administered orally. In another embodiment, the compounds of the invention are administered topically. Solid compositions for oral administration include tablets, granulates and capsules. In any case the manufacturing method is based on a simple mixture, dry granulation or wet granulation of the active compound with 10 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 exciplents by using known techniques with the purpose of delaying their disintegration and absorption in the gastrointestinal tract and thereby provide a 15 sustained action over a longer period, or simply to improve their organoleptc 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 20 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, 25 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 30 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 35 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.

51 The dosage and frequency of doses may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials and by taking into account factors such as 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, its pharmacokinetic profile, and the route of administration, among other factors. As an example, a 5 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. 10 Examples The following abbreviations are used in the examples: AcN: acetonitrile Boc: tert-butoxycarbonyl 15 conc: concentrate DIPEA: diisopropylethylamine DMSO: dimethylsulfoxide EtOAc: ethyl acetate EtOH: ethanol 20 MeOH: methanol Min: minutes TEA: triethylamine THF: tetrahydrofuran tR: retention time 25 LC-MS: liquid chromatography-mass spectrometry One of the following methods was used to determine the LC-MS spectrums: Method 1: X-Terra MS C18 column 5 tm (100 mm x 2.1 mm), temperature: 30 0 C, rate: 0.35 mL/min, eluent: A = AcN, 8 = NH4HC0 3 10 mM, gradient: 0 min A at 10%; 10 min A at 90%; 15 min A at 90%. 30 Method 2: Acquity UPLC BEH C18 column 1.7 jim (2.1 x 50 mm), temperature: 40 OC, rate: 0.50 mUmin, eluent: A = AcN, B = NH4HCO 3 10 mM, gradient: 0 min A at 10%; 0.25 min A at 10%; 3.00 min A at 90%; 3.75 min A at 90%. When indicated, the compounds were purified by preparative HPLC according to the following general method: X-Bridge Prep C18 columna 5 jim OBD (19 x 100 mm), flow: 20 mUmin, eluent: A = AcN, B = NH 4 HC0 3 75 35 mM, gradient: 0 min A at 5-10%; 9.0 min A at 95-90% (gradient was adapted when required to ensure proper purification).

52 REFERENCE EXAMPLE I tert-Butyl methyll(3R)-pyrrolidin-3.yljcarbamate (a) tert-Butyl[(3R)-1-benzylpyrrolidin-3-yl]methylcarbamate Di-tetf-butyl dicarbonate (11.6 g, 53.07 mmol) dissolved in 15 mL of CH 2

CI

2 was added to a solution of (3R)-1 5 benzyl-N-methylpyrrolidin-3-amine (10 g, 52.55 mmol) in 115 mL of CH2C1 2 , cooled at 0 *C. The resulting solution was stirred at room temperature for 18 hours. The solvent was evaporated and the crude product was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, providing 14.5 g of the desired compound (yield: 95%). LC-MS (Method 1): tR = 9.55 min; m/z = 291 (MH*). 10 (b) Title compound A mixture of the compound obtained above (14.5 g, 50.14 mmol), Pd/C (10%, 50% in water) (3 g) and ammonium formate (12.7 g, 200.5 mmol) in MeOH (390 mL) and water (45 mL) was heated under reflux for 5 hours. The reaction mixture was filtered through Celite* and the filter was washed with EtOAc and MeOH. The solvent was evaporated to dryness, providing 10.6 g of the title compound as an oil (yield: 100%). 15 1 H NMR (300 MHz, CDC13) 5: 1.38 (s, 9H), 1.72 (m, 1H), 1.96 (m, 1H), 2.53 (s, NH), 2.80 (s, 3H), 2.87 (m, 1H), 2.93 (m, 1H), 3.11 (m, 2H), 4.58 (m, 1H). REFERENCE EXAMPLE 2 feff-Butyl azetidin-3-yl(methyl)carbamate (a) tert-Butyl [1-(diphenylmethyl)azetidin-3-yl]methylcarbamate 20 Following a procedure similar to that described in section a) of reference example 1, but using 1-(diphenylmethyl)-N methylazetidin-3-amine instead of (3R)-1-benzyl-N-methylpyrrolidin-3-amine, the desired compound was obtained with a 73% yield. LC-MS (Method 1): tR = 10.14 min; m/z = 353 (MH+). (b) Title compound 25 A solution of the compound obtained above (6.18 g, 17.53 mmol) in 60 mL of MeOH and 15 mL of EtOAc was purged with argon. Pd/C (10%, 50% in water) (929 mg) was added and the mixture was then purged again with argon and stirred in a H2 atmosphere for 18 hours. The reaction was filtered through Celite* and the filter was washed with EtOAc and MeOH. The solvent was evaporated to dryness, providing 5.66 g of a mixture of the title compound together with one equivalent of diphenylmethane, that was used as such in the following steps. 30 1H NMR (300 MHz, CD 3 0D) 5: 1.44 (s, 9H), 2.88 (s, 3H), 3.56 (m, 2H), 3.71 (m, 2H), 4.75 (m, 1H). REFERENCE EXAMPLE 3 Ethyl 4-(benzyloxy)-3-oxobutanoate Benzyl alcohol (19.7 g, 182.3 mmol) was slowly added to a suspension of sodium hydride (15.9 g 55% in mineral oil, 364.5 mmol) in anhydrous diethyl ether (116 mL) and the resulting mixture was stirred at room temperature for 1 35 hour. It was then diluted with some diethyl ether to ensure good stirring. Ethyl 4-chloro-3-oxobutanoate (12.3 mL, 91.1 mmol) was then slowly added and the mixture was stirred at room temperature overnight. The reaction mixture 53 was cooled with an ice bath and then diluted with cold water and diethyl ether. pH was adjusted to 4 with 5 N HCI and it was extracted three times with diethyl ether containing some ethyl acetate. The combined organic phases were dried over Na2SO 4 and it was concentrated to dryness, thus obtaining the title compound with quantitative yield as a crude product that was used as such in the following step. 5 LC-MS (Method 2): tR = 2.03 min: r/z = 235 (MH-). REFERENCE EXAMPLE 4 2-Amino-6-(benzyloxymethyl)pyrimidin-4ol Guanidine hydrochloride (13.07 g, 136.7 mmol) and sodium methoxide (7.38 g, 136.7 mmol) were added to a 10 solution of the crude compound obtained in reference example 3 (91.1 mmol, in theory) in absolute ethanol (580 mL) and the mixture was heated under reflux overnight. The solvent was evaporated to dryness. The residue was diluted with water and pH was, then, adjusted to 6 with aqueous HCI. The precipitated solids were collected by filtration, washed with a small amount of diethyl ether and dried in a vacuum oven, providing 17.9 g of the title compound (yield: 85%, from ethyl 4-chloro-3-oxobutanoate). 15 LC-MS ( Method 2): tR = 1.25 min; m/z 232 (MH'). REFERENCE EXAMPLE 5 4-(Benzyloxymethyl)-6-chloropyrimidin-2-amine Phosphorus oxychloride (28.6 mL, 312.6 mmol) was added to a mixture of the compound obtained in reference example 4 (7.23 g, 31.2 mmol) in 1,4-dioxane (115 mL) and the mixture was heated at 70 *C overnight. The 20 POCIs/dioxane mixture was distilled off. EtOAc was added and then stripped off and this operation was repeated twice more to ensure complete removal of phosphorus oxychioride. The residue was diluted with water and pH was adjusted to 7 with aqueous NaOH. EtOAc was then added and the phases were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over Na 2

SO

4 and concentrated to dryness, thus obtaining 6.37 g of the title compound as a crude product that was used as such in the following step 25 (yield: 81%) LC-MS (Method 2): tR = 2.07 min; m/z = 250/252 (MH-). REFERENCE EXAMPLE 6a (R)-tert-Butyl i-( 2 -amino-6-(benzyloxymethyl)pyrimidin-4-yl)pyrrolidin-3-yl(methyl)carbamate A mixture of the compound obtained in reference example 5 (6.37 g, 25.5 mmol), the compound obtained in 30 reference example 1 (5.11 g, 25.5 mmol) and DIPEA (4.4 mL, 25.5 mmol) in EtOH (64 mL) was heated at reflux ovemight. The reaction mixture was evaporated to dryness and the residue was purified by chromatography over silica gel using mixtures of hexane/EtOAc of increasing polarity as eluent, providing 6.61 g of the title compound (yield: 63%). LC-MS (Method 2): ta = 2.32 min; m/z 414 (MH'). 35 REFERENCE EXAMPLE 6b tert-Butyl 1-( 2 -amino-6-(benzyloxymethyl)pyrimidin-4-yl)azetidin-3-yl(methyl)carbamate 54 The title compound was obtained following a similar procedure to that described in reference example 6a but using reference example 5 and reference example 2 as starting materials. LC-MS (Method 2): tR= 2.25 min; m/z 400 (MH+). REFERENCE EXAMPLE 7a 5 tert-Butyl 1-( 2 -amino-6-(hydroxymethyl)pyrimidin-4.yl)azetidin-3-yl(methyl)carbamate A solution of ammonium formate (1.67 g, 26.5 mmol) in water (6.9 mL) was added to a mixture of the compound obtained in reference example 6b (5.3 g, 13.2 mmol) and Pd/C (10%, 50% in water) (0.52 g) in EtOH (390 mL) and the resulting mixture was heated under reflux for 3 hours. The reaction mixture was filtered through Celite* and the filter aid was washed with EtOH. The solvent was evaporated to dryness and the crude thus obtained was subjected 10 to a second hydrogenation cycle, providing 3.97 g of the title compound (yield: 97%). LC-MS (Method 2): tR= 1.38 min; m/z 310 (MH+). REFERENCE EXAMPLE 7b (R)-tert-Butyl 1-( 2 -amino-6-(hydroxymethyl)pydmidin4.yl)pyrrolidin-3-yi(methyl)carbamate The title compound was obtained following a similar procedure to that described in reference example 7a but using 15 reference example 6a as starting material. LC-MS (Method 2): tR = 1.55 min; m/z 324 (MH+). REFERENCE EXAMPLE 8a fert-Butyl 1-( 2 -amino-6-formylpyrimldin4yl)azetidin-3-yl(methyl)carbamate A solution of the compound obtained in reference example 7a (2 g, 6.46 mmol) in dichloromethane (51.5 mL) was 20 cooled to 0 *C with an ice bath under an argon atmosphere. Triethylamine (2.7 mL, 19.4 mmol) was added and, finally, a solution of sulphur trioxide pyridine complex (3 g, 19.4 mmol) in DMSO (17.5 mL) was slowly added. The mixture was stirred at room temperature for 3 hours. It was again cooled to 0 *C and diluted with chloroform and ice. The phases were separated and the aqueous phase was extracted twice again with chloroform. The combined organic phases were washed with sodium bicarbonate saturated solution, dried over Na 2

SO

4 and concentrated to 25 dryness, thus obtaining 2.2 g of the title compound as a crude product that was used as such in the following step (quantitative yield) LC-MS (Method 2): tR = 1.61 min (broad peak); m/z = 308 (MH+). REFERENCE EXAMPLE 8b (R)-tert-Butyl 1-( 2 -amino-6-formylpyrimidin-4yl)pyrrolidin-3-yi(methyl)carbamate 30 The title compound was obtained following a similar procedure to that described in reference example 8a but using reference example 7b as starting material, LC-MS (Method 2): ta = 1.78 min (broad peak); m/z 322 (MH-). REFERENCE EXAMPLE 9 tert-Butyl 1-( 2 -amino-6-(chloromethy)pyrimidin-4-yl)azetidin-3-yl(methyl)carbamate 35 Thionyl chloride (508 mg, 4.2 mmol) was added to a solution of the compound obtained in reference example 7a (1.2 g, 3.8 mmol) in THF (12 mL) and the resulting mixture was stirred under argon atmosphere for 1.5 h. The mixture is cooled to 04C and diisopropylethylamine (1.35 mL, 97.75 mmo)) was added. The solvent was evaporated 55 keeping the water bath temperature below 30*C to give a crude material that was used as such in the following steps. LC-MS (Method 2): ta= 1.86 min; m/z 328 (MH+). EXAMPLE la 5 4 -((Benzylamino)methyl)-6-(3-(methylamino) azetidin-1-yI)pyrimidin-2-amine A mixture of the compound obtained in reference example 8a (100 mg, 0.32 mmol), benzylamine (35 mg, 0.32 mmol), sodium triacetoxyborohydride (103.4 mg, 0.49 mmol) and acetic acid (28 gL, 0.49 mmol) in dichloromethane (6 ml) was stirred at room temperature overnight. The reaction mixture was evaporated to dryness and the residue 10 was purified by chromatography over silica gel using mixtures of chloroform/MeOH of increasing polarity as eluent, providing the Boc-protected precursor with quantitative yield. HC (4 M solution in 1,4-dioxane, 5 mL) and MeOH (4 mL) were added to this intermediate and the mixture was stirred at room temperature for 2 hours and then it was evaporated to dryness. The residue was dissolved in MeOH (2 mL) and loaded on a sulfonic resin cartridge (Bond elut SCX-Varian, previously washed with MeOH). The cartridge was eluted with MeOH, that was discarded. It was 15 then eluted with 2 N NHa solution in MeOH, that was collected and evaporated to dryness providing 65.7 mg of the title compound (yield: 67%). LC-MS ( Method 2): tR = 1.21 min; m/z 299 (MH*). EXAMPLES lb-it The following compounds were obtained following a similar procedure to that described in example la, but using the 20 corresponding starting materials in each case: 1Method (LC- 1 (mi ) rz Example Name Starting materials MS tR (mi) b ((Cyclopropylmethylamino)methy)- Ref Ex 8a and 6-(3-(methylamino)azetidin-1- cyclopropylmethylamin 2 0.85 263 yl)pyrimidin-2-amine e 4-((4-Fluorophenylamino)methyl)- Ref Ex 8a and 4 10 16-(3-(methylamino)azetidin-1- Rfl E 8an nd 4 2 1.36 303 yl pyrimidin-2-aminefiranie Ethyl 4-(((2-amino-6-(3 1d (methylamino)azetidin-1- Ref Ex 8a and ethyl 4- 2 1.47 357 yl)pyrimidin-4- aminobenzoate (1) yl)methyl)amino)benzoate Methyl 3-(3-(((2-amino-6-(3- Ref Ex 8a and methyl (methylamino)azetidin-1- 3(3 le yl)pymiamino)phenyl)propanoat nophenyl)propano 2 1.46 371 - e ateI 56 Ethyl 2-(4-(((2-amino-6-(3- Ref Ex 8a and ethyl 2 if (methylamino)azetidin-l- (4- 215 7 yl)pyrimidin-4- aminopheri)acetate 215 7 _____yl)methyl)amino)phenyl)acetate (1) 4-(3-(Methylamino)azeidin-1-y)-6- Ref Ex 8a and pyrazin ig ((pyrazin-2- 2-amnine 2 0.82 287 ylamino)methyl)pynmidin-2-amine (2) (3) 4-((Cyclopentylamino)methyl)-6- Ref Ex 8b and 210 9 1 h ((3R)-3-(methylamino)pynrolidin-1- - ylpnyane210 9 yl)pyrimidin-2-amine ccoetlmn 4-((Benzylamino)methy)-6-((3R)-3-Re Ex 8 an 1 i (methylamino)pyrrolidin-l- benzylamnine 2 1.23 313 yl)pyiimidln.2-amine 4-((3R)-3-(Methylamino)pyrrolidin- Ref Ex 8b and i I-yI)-6- phenetylamine 2 1.34 327 2-amine (3) 4-((2,3-Dihydro-1 H-inden-2 1 k ylamino)methyl)-6-(3- Ref Ex 8a and 2- 2 1.43 325 (methylaniino)azetidin-l- aminoindan yl)pyrimidin-2-amine 4-((Cyclohexylamino)methyl)-6-(3- Ref Ex 8a and 211 9 11 (methylamino)azetidin-1- ylhxarie219 21 yl)pydmidin-2-aminecyoeylmn 4-((((( R,2S,5R)-6,6 Dimethylbicyclo[3.1 .1 heptan-2- RfE aad()cs 1 m yI)methyl)amino)methyl)-6-(3- mRfEtanyand ()-i 2 1.72 345 (methylamino)azeidin-1-mytname yl)pyrimidin-2-amine In Cyclopentylethylamino~methyl)-6- Ref Ex 8a and 2- 2 1.45 305 yI)pyrimidin-2-amine (S)-4-((2,3-Dihydro-1 H-inden-1 1o ylamino)methyl)-6-(3- Ref Ex 8a and (S)-1- 2 1.43 325 (methylamnino)azeidlin-1- aminoindan yl)pyrimicin-2-amnine 4-((2-Adamantylamino)methyl)-6- Ref Ex 8a and 2 Ip (3-(methylamino)azefidin-1- adamantylamine 2 1.64 343 yI)pyrimidin-2-amine hydrochloride 57 4-(((2,2-Diethylcyclopropyl) Ref Ex 8a and (2,2 methylamino)methyl)-6-(3- diethylcyclopropyl)met 1q (methylamino)azetidin-1- hylamine 2 1,53 318 yl)pyrmidin-2-amine (3) (R)-4-((2,3-Dihydro-1H-inden-1- Ref Ex 8a and (R)-1 1r ylamino)methyl)-6-(3- aminoindan 2 1.45 325 (methylamino)azetidin-1 yl)pyrmidin-2-amine (3) Ethyl 3-(((2-amino-6-(3- Ref Ex 8a and ethyl 3 Is (methylamino)azetidin-1- aminobenzoate 2 1.52 357 yl)pyimidin-4 yl)methyl)amino)benzoate (1) 4-((Cyclopentylamino)methyl)-6-(3- Ref Ex Ba and 1t (methylamino)azetidin-1- cyclopentylamine 2 1.00 277 yl)pyrimidin-2-amine (1) EtOH was used instead of MeOH in the Boc-deprotection step. (2) 1,2-Dichloroethane was used instead of dichloromethane in the reductive amination step. (3) Final product was purified by preparative HPLC EXAMPLE It alternativee method) 5 4-((Cyclopentylamino)methyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine (a) 2-Amino-N-cyclopentyl-6-hydroxypyrimidine-4-carboxamide Diisopropylethylamine (1.1 mL) and O-Benzotrazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate (611 mg, 1.6 mmol) were added to a solution of 2-amino-6-hydroxypyrimidine-4-carboxylic acid (250 mg, 1.6 mmol) and cyclopenthylamine (137 mg, 1.6 mmol) in DMF (17 mL). The resulting mixture was stirred at room temperature 10 overnight. The solvent was evaporated and the residue was purified by chromatography over silica gel using mixtures of ethyl acetate/MeOH of increasing polarity as eluent, providing 100 mg of the desired compound (yield: 28%) LC-MS ( Method 2): tR =1.02 min; mz 223 (MH). (b) tert-Butyl 1-(2-amino-6-(cyclopentylcarbamoyl)pyrimidin-4-yl)azetidin-3-yl(methyl)carbamate 15 A mixture of the compound obtained in section (a) (102 mg, 0.46mmol), the compound obtained in reference example 2 (222mg, 0.59mmol, 50%), triethylamine (2.7mL), (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (382.1g, 0.73mmol) in acetonitrile (4.5 mL) was heated in a pressure tube at 80*C for 24h. The solvent was evaporated and the residue was dissolved in water, pH adjusted to pH=8-9 and extracted three times with chloroform.. The combined organic phases were dried over Na 2 SO4, concentrated to dryness, and 20 the residue was purified by chromatography over silica gel using mixtures of hexane/ethyl acetate of increasing polarity as eluent, providing 73 mg of the desired compound (yield: 41%) LC-MS ( Method 2): ta = 2.04 min; m/z 391 (MH+). (c) Title compound A 1M solution of borane in THF (0.94 mL) was added to a solution of compound prepared in section (b) (73 mg, 0.19 25 mmol) in THF (0.78 mL) cooled to O'C and previously purged under argon atmosphere. The resulting mixture was stirred at room temperature overnight. Additional 1M Borane in THF solution (0.94 mL) was added and the resulting 58 mixture was stirred at room temperature for 4hours. A mixture 1:1 of acetic acid: MeOH (0.8 mL) was added and the resulting mixture was stirred overnight. Solvents were eliminated under vacuum to give the BOC-precursor. 4N aqueous HCI was added and the resulting solution was stirred at room temperature for 2h and then it was evaporated to dryness. The residue was diluted with water, pH adjusted to pH=1-2 and extracted twice with 5 chloroform. 2N NaOH was added to the aqueous phase until pH=8-9 and extracted three times with chloroform. The combined organic phases were dried over Na2SO 4 , concentrated to dryness and the residue purified by preparative HPLC providing 2.95 mg of the tile compound (5% yield). LC-MS (Method 2): tR = 0.99 min; m/z 277 (MH*). EXAMPLE 2a 10 4-(3-(Methylamino)azetidin-1-yl)-6-((pentylamino) methyl)pyrimidin-2-amine A mixture of the compound obtained in reference example 8a (70 mg, 0.23 mmol), pentylamine (20 mg, 0.23 mmol), sodium triacetoxyborohydride (72.4 mg, 0.34 mmol) and acetic acid (20 pL, 0.34 mmol) in dichloromethane (5 mL) was stirred at room temperature overnight. The reaction mixture was evaporated to dryness, providing the Boc 15 protected precursor as a crude product. A 2:1 vA mixture of dichloromethane and trifluoroacetic acid (2 mL) was added to this intermediate and the mixture was stirred at room temperature for 2 hours and then it was evaporated to dryness. The residue was dissolved in MeOH (2 mL) and loaded on a sulfonic resin cartridge (Bond elut SCX-Varian, previously washed with MeOH). The cartridge was eluted with MeOH, that was discarded. It was then eluted with 2 N

NH

3 solution in MeOH, that was collected and evaporated to dryness providing 46.1 mg of the title compound (yield: 20 72%). LC-MS ( Method 2): tR= 1.25 min; m/z 279 (MH+). EXAMPLES 2b-2am The following compounds were obtained following a similar procedure to that described in example 2a, but using the corresponding starting materials in each case: 25 Example Name Starting materials Method (m m (LC-MS) (MH+) 4-(3-(Methylamino)azetidin-1-yl)-6 2b ((3- Ref Ex 8a and 3- 2 1.43 327 phenylpropylamino)methyl)pyrimidi phenylpropylamine n-2-amine 4-(3-(Methylamino)azetidin-1 -yl)-6 2c ((4- Ref Ex 8a and 4- 2 1.56 341 phenylbutylamino)methyl)pyrimidin phenylbutylamine -2-amine 4 ((Cyclohexylmethylamino)methyl)- Ref Ex 8a and 2d 6-(3-(methylamino)azetidin-1- cyclohexylmethylamin 2 1.41 305 yl)pyrmidin-2-amine e 59 2e 4-(3-(Methylamino)azetidin- 1-yl)-6- Ref Ex 8a and* 213 33 2e ((phenethylamino)methyl)pyimidin- phenettiylamine 213 1 4-(3-(Methylamino)azetidin-1-y)-6- Ref Ex 8a and 3-(2 2f (ethylain3 eh-~ yiidn2 aminoethyl)pyiidine 2 0.92 314 amnine(1 4-(3-(Methytamino)azefidin-1-yI)-6- Ret Ex 8a and (1 2g p(l-eyccorplmtyaiom phenylcyclopropyi)met 2 1.49 339 thyl)pycimidin-2-amine hlmn 4-((Cycloheptylamino)methy)-6-(3- Ref Ex 8a and 213 0 2h (methylamino)azetidin-1- ccoetlrie213 0 yl)pyrimldin-2-amine ccoetlmn 2 4-((4-Chlofobenzylamino)methyl). Ref Ex a and 4- 231.4 Z 6-(3-(methylamino)azetidin-1 - chlorobenzyiamine 2 .9 335 yl)pyrimidin-2-amine 4-(3-(Methylamino)azeidin-1-yi)-6 2j (((l1R)-1I- Ref Ex 8a and (R)-1- 2 1.41 313 phenylethylamino)methyl)pyimidin phenylethylamnine -2-amine 4-(3-(Methylamino)azefidin-i-y)-6 2k (((1S)-1- Ref Ex 8a and (S)-1- 2 1.41 313 phenylethylamino)methy~pyimidin phenylethylamnine -2-amine 4-(3-(Methyiamino)azetidn-1-y)-6- Ref Ex 8a and 1 21 ((naphthalen-1- ahhlnmtymi 215 34 ylmethylamino)methyl)pyrimidin-2- napae nmtymi 215 34 amnine n 4-(2-(((2-Amino-6-(3- Ref Ex 8a and 4-(2 2m (methylamino)azetidin-1- aminoethyl)benzonitrif 212 3 2m yl)pydmidln-4- e 212 3 yI)methyl)amino)ethyl)benzonitie (1) 4-((2,3-Oihydro-1 H-inden-5- Ref Ex 8a and 5 2n ylamino)methyl)-6-(3- aminoindan 2 1.69 325 (methylamino)azetidin-1 yl)pyrimidin-2-amine (1) 4-((4-(1 H-Pyrazol-1- Re x8 ad4 2o yI)phenyiamino)methyl)-6-(3- pRfE azo- landln 24-.3 35 (methylmino)azetidin-1- yao1-Iniie2.3 35 yl)pyrimidin-2-amine (1) 4-(((2-Amino-6-(3- Ref Ex Ba and 4 2p (methylamino)azetidin-1- aminobenzonitrile 2 1.26 310 yI)pynmidin-4-(1 60 4-{(3-(Methylamino)azetidlin-1I-yl)-6- Ref Ex 8a and 3-(2 2q ((3-(2-methyfthiazof-4- methyfthiazol-4- 215 8 yl)phenylamino)methyl)pydidiin-2 yl)aniline 215 8 amine (1)_____ 3-(((2-Amino-64-(3 Ref Ex 8a and 3 2r (methyla mino)azetidin-1I- aminobenzonitrue 2 1.34 310 yl)pyrimidin-4 yl)methyi)amino)benzonitrile (1) 4-((((2-Aminio.6-(3 (methylamino)azetidin- 1- Ref Ex 8a and 4 2s yI)pydmidin-4- (aminomethyl)benzonit 2 1.20 324 yl)methyl)amino)methyl)benzonitrIj rile eI 4-((2,3-Dihydro-1 H-inden-4- Ref Ex 8a and 4 2t yfamino)methyl)-6-(3- aminoindan 2 1.68 325 (methylamino)azetidin-1 yl)pydnmidin-2-amine (1) Methyl 3-((((2-amino-6-(3- Ref Ex 8a and methyl 2u (methylamino)azetidin-i- 3 2u )PynmIdin4 (aminomethyl)benzoat 2 1.29 357 yl)methyl)amnino)rnethiyl)benzoate e 4-(3-(Methylamino)azetidin-1-yi)-6- Ref Ex 8a and 4 2v ((4- methylbenzylamine 2 1.38 313 Imethylbenzylamino)methyl)pyrimjd jn-2-amine (1) 2w 4-((2e- hlaio~ehy)6 Ref Ex 8a and 2-(2 2w 3-(mohethylamino)et- chlorophenyl)ethylamF 2 1.48 3491 _____yl)pyrimidin-2-amine n 2x Chlorophenethylamino)methyl)-6- clRonle Ex a man 2-(34 3471 (3-(methylamino)azetidin-I chope nleh m 231.5 yI)pydmidin-2-amine n 2y 4-((Benzhydrylamino)metiyl)-6-(3- Ref Ex 8a and 218 7 (methylamino)azetidin-1- benzhydrylamine 218 7 yi~pyrmidlin-2-aniine 2-(((2-Amino-6-(3- Ref Ex 8a and 2 2z (methylamino)azetidin-l- aminobenzonitrile 2 1.40 310 yl)pydmidin- _____yl)mefhyl)amino)benzonitrie (jl) S2-(((2-Amino-6-(3- ]~fE aad2 2aa (mtyaioaeii--amino- I -phenylethanol 2 1.12 329 yl)pynmidin-4-yl)methyl)amino)-1 phenylethanol (1) _ __ 61 (2R)-2-(((2-Amino-6-(3- Ref Ex 8a and (R)-2 2ab (methylamino)azetidin-l- amino-3 yl)pyrimidin-4-yi)methyl)amino)-3. phenylpropan-l-ol 2 j1.22 343 phenylpmopan-1-ol (1) _ ____1 Ethyl 2-(((2-amino-6-(3- Ref Ex Ba and ethyl 2 2ac (methylamino)azefidin-1- aminobenzoate 2 1.78 357 yl)pyiimidin-4 yl)methyl)amino)benzoate (1) 2d 4-((2-Ethylphenylamino)methyl)-6- Ref Ex 8a and 2- 216 1 2d (3-(rnethylamino)azetidin-1 - etIhylaniline 216 1 yl)pyiimidin-2-amine 4-((2-Ref Ex 8a and 2-(2 2ae Fluorophenethylamino)methyt)-6- fluorophenyl)ethylamin 213 3 (3-(methylamino)azefidin-l- e 8.3 3 yl)pydidin-2-amine (1) 4-((1,2-Ref Ex 8a and 1,2 2f Dip henyllethylamnino)methyl)--3 ihnltyaie218 8 ,2f (methylamino)azetidin-l- ) ( ihnltyaie218 8 yI)pydrnidin-2-amine (1) 4-((4-Ref Ex Ba and 2-(4 2ag Chlorophenethylamino))methyl)-6- chlorophenyl~thylami 2 1.57 37 (3-(methylamino)azebdin-1- ne 349 yl)py~midin-2-amine (1) 4-((2,2-Ref Ex 8a and 2,2 2ah Diphenylethylamino)methyl)-6-(3- dipheny'lethylamnine 2 1.78 389 (methylamino)azetidin-1 yl)pyrimidin-2-amine (1) 4-(3-(Methylamino)azetidin-1-yl)-6- Ref Ex 8a and (R)-2 2ai (((2R)-2- hnllpoyaie 214 37 phenylpropylamino~methyl)pyrimidIphyl1royaie 2.4 37 n-2-amine (1) 4-(3-(Methylamino)azetidin-1-yl)-6- Ref Ex 8a and (S)-2 2aj (((2S)-2-.hnllpoyaie 214 2 phenylpropylamino)methydmIdipenl1roymie 2.4 37 n-2-amine (1) 4-((3-Ref Ex 8a and 2-(3 2ak Fluorophenethylamino)methyl)-6. fluorophenyl)ethylamin 2 1.38 331 (3- (methylamino)azetidin-1 - e _________yl)pyrimidin-2-amine ()___ 4.((4-Ref Ex 8a and 2-(4 2F Fluorophenethylamino)methyl)-6- fluorophenyl)ethylamin 213 3 2 (3-(methylamino)azetidin-1- e 213 3 _____yl)pyrimidin-2-amine(1 2m ((Methyl(phenethyl)amino)methyl)- Reheef thy&a ane N 2 1.55 327 2m 6-(3-(methyfamino)azeidin-1- - ehlhnehlm yl)pyrimidin-2-amine (1) 62 (1) Final product was purified by preparative HPLC EXAMPLE 3a 4-(3-(Methylamino)azetidin-1-yl)-6-((pyridin-3-yamino)methyl) pyrimidin-2-amine 5 3-Aminopyridine (11.3 mg, 0.12 mmol) and dibutyltin dichloride (3.7 mg, 0.012 mmol) were added to a solution of the compound obtained in reference example 8a (37 mg, 0.12 mmol) in THF (1.5 mL) and the mixture was stirred at room temperature for 5 min. Phenylsilane (26.1 mg, 0.24 mmol) was then added and the reaction mixture was stirred at room temperature ovemight. It was evaporated to dryness and the residue was purified by chromatography over silica gel using mixtures of EtOAc/MeOH of increasing polarity as eluent, providing 17 mg of the Boc-protected 10 precursor (yield: 36%). HCI (4 M solution in 1,4-dioxane, 2 mL) and MeOH (4 mL) were added to this intermediate and the mixture was stirred at room temperature for 2 hours and then it was evaporated to dryness. The residue was dissolved in MeOH (2 mL) and loaded on a sulfonic resin cartridge (Bond elut SCX-Varian, previously washed with MeOH). The cartridge was eluted with MeOH, that was discarded, it was then eluted with 2 N NH 3 solution in MeOH, that was collected and evaporated to dryness providing 9.5 mg of the title compound (yield: 76%). 15 LC-MS ( Method 2): tR = 0.95 min; m/z 286 (MH+). EXAMPLE 3b 4-(3-(Methylamino)azetdin-1.yl).6-((pyridin-2-ylamino)methyl) pyrimidin-2-amine The title compound was obtained following a similar procedure to that described in example 3a but using reference 20 example 8a and 2-aminopyridine as starting materials. LC-MS (Method 2): tR 1.08 min; mz 286 (MH). EXAMPLE 4a 3

-(

3

-(((

2 -Amino-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-yl)methyl)amino)phenyl)propan-1-ol Lithium aluminum hydride (0.27 mL of a 1 N solution in THF, 0.27 mmol) was slowly added under argon to a solution 25 of example le (25 mg, 0.07 mmol) in THF (1 mL) cooled at 0 *C. The ice bath was removed and it was allowed to warm, stirring at room temperature ovemight. It was then diluted with 1 M sodium tartrate solution and chloroform, phases were separated and the aqueous phase was extracted with chloroform. The combined organic phases were dried over anhydrous Na 2

SO

4 and concentrated to dryness, providing 17.8 mg of the title compound (yield: 77%). LC-MS ( Method 2): tR = 1.23 min; m/z 343 (MH*). 30 EXAMPLES 4b-4c The following compounds were obtained following a similar procedure to that described in example 4a, but using the corresponding starting material in each case: Method m/z Example Name Starting material tR (min) (LC-MS)

(MW)

63 2-(4-(((2-Amino-6-(3 4b (methylamino)azetidin-1- E f2 10 2 4b yl)pyrimidin-4- Ex 1f 2 1.06 329 yl)methyl)amino)phenyl)ethanol (4-(((2-Amino-6-(3 4c (methylamino)azetidin-1- Ex id 2 0.95 315 yl)pyrimidin-4 yl)methyl)amino)phenyl)methanol EXAMPLE 5 4 -((Cyclopentyl(methyl)amino)methyl)-6-(3-(methylamino)azetidin-1-yl)pyrimidin-2-amine (a) tert-Butyl 1-( 2 -amino- 6 -((cyclopentylamino)methyl)pyrimidin-4-yl)azetidin-3-y(methy)carbamate 5 A mixture of the compound obtained in reference example 8a (200 mg, 0.65 mmol), cyclopentylamine (55.4 mg, 0.65 mmol), sodium triacetoxyborohydride (206.9 mg, 0.98 mmol) and acetic acid (56 pL, 0.98 mmol) in dichloromethane (6 mL) was stirred at room temperature overnight. The reaction mixture was evaporated to dryness and the residue was purified by chromatography over silica gel using mixtures of chloroform/MeOH of increasing polarity as eluent, providing 217 mg of the desired compound (yield: 88%). 10 LC-MS (Method 2): tR = 1.74 min; m/z 377 (MH'). (b) Title compound A mixture of the compound obtained in section (a) (110 mg, 0.29 mmol), paraformaldehyde (17.5 mg, 0.58 mmol), sodium triacetoxyborohydride (185.8 mg, 0.88 mmol) and acetic acid (50 jt, 0.88 mmol) in dichloromethane (7.3 mL) was stirred at room temperature overnight. The reaction mixture was evaporated to dryness, providing the Boc 15 protected precursor impurified with starting material. HC (4 M solution in 1,4-dioxane, 5 mL) and MeOH (4 mL) were added to this intermediate and the mixture was stirred at room temperature for 2 hours and then it was evaporated to dryness. The crude product thus obtained was purified by preparative HPLC and the fractions containing the product were evaporated to dryness, providing 3.1 mg of the title compound (yield: 4%). LC-MS ( Method 2): tR = 1.25 min; m/z 291 (MW). 20 EXAMPLE 6a 4-((Isobutylamino)methyl)-6(3-(methylamino)azetidin-1-yl)pyrimdin-2-amine A mixture of the compound obtained in reference example 9 (70 mg, 0.21 mmol) isobutylamine (156mg, 2.1 mmol) in acetonitrlle (2 mL) was heated at 75"C overnight. The reaction mixture was evaporated to dryness and diluted with chloroform and water. The phases were separated and the aqueous phase was extracted twice again with 25 chloroform. The combined organic phases were dried over MgSO 4 and concentrated to dryness, thus obtaining 78 mg of the Boc-protected precursor. A 2:1 v/v mixture of dichloromethane and trifluoroacetic acid (1.5 mL) was added to this intermediate and the mixture was stirred at room temperature for 1 hour and then it was evaporated to dryness. The residue was diluted with chloroform and water. The phases were separated and the aqueous phase was extracted twice again with chloroform. 2N NaOH was added to the aqueous phase until pH=8-9 and extracted 30 twice again with chloroform. The combined organic phases were dried over MgSO4 , concentrated to dryness and the residue purified by preparative HPLC providing 11mg of the title compound (20% yield).

64 LC-MS ( Method 2): tR = 1.11 min; m/z 265 (MH+). EXAMPLES 6b 4 -((Cyclopentylmethylamino)methyl)-6-(3-(methylamino)azetidin-1 -yl)pyrimidln-2-amine A mixture of the compound obtained in reference example 9 (100 mg, 0.30 mmol) cyclopentylmethylamine (303 mg, 5 3 mmol) in acetonitrile (2 mL) was heated at 750C in a pressure tube overnight. The reaction mixture was evaporated to dryness and diluted with chloroform and water. The phases were separated and the aqueous phase was extracted twice again with chloroform. The combined organic phases were dried over MgS04, concentrated to dryness, and the residue was purified by chromatography over silica gel using mixtures of chloroform/MeOH of increasing polarity as eluent, providing 50 mg of Boc-protected precursor (yield: 42%). HCI (4 M solution in 1,4-dioxane, 5 mL) and 10 MeOH (4 mL) were added to this intermediate and the mixture was stirred at room temperature for 1 hour and then it was evaporated to dryness. The residue was dissolved in MeOH (2 mL) and loaded on a sulfonic resin cartridge (Bond elut SCX-Varian, previously washed with MeOH). The cartridge was eluted with MeOH, that was discarded. It was then eluted with 2 N NHa solution in MeOH, that was collected and evaporated to dryness providing 34 mg of the title compound (yield: 83%). 15 LC-MS ( Method 2): tR = 1 32min; m/z 291 (MH). EXAMPLES 6c-6j The following compounds were obtained following a similar procedure to that described in example 6a, but using the corresponding starting material in each case: Example Name Starting material Method tR (min) (LC-MS) (MH*) 4-((Cyclopropylamino)methyl)-6-(3 6c (methylamino)azetidin-1- Ref Ea9 nd 2 0.89 249 yl)pyrimidin-2-amine cyclopropylamine 4-((tert-Butylamino)methyl)-6-(3- Ref Ex 9 and tert 6d (methylamino)azetidin-1- befEand tet 2 0.92 265 yl)pyrimidin-2-amine 4-((Isopropylamino)methyl)-6-(3- Ref Ex 9 and | e (methylamino)azetidin-1- f x an d 2 0.72 251 yl)pyrimidin-2-amine 4-((44-Ref Ex 9 and 4,4 6f Difluorocyclohexylamino)methyl)-6- difluorocyclohexylamin 2 1.27 327 (3-(methylamino)azetidin-1- e yl)pyrimidin-2-amine 4-(3-(methylamino)azetidin-1-yo-6 ' 6 ((2,2,2- Ref Ex 9 and 2,2,2 6g trifluoroethylamino)methyl)pyrimidi trifluoroethylamine 2 1.07 290 n-2-amine 65 4-(((1R,2R,4S) bicyclo[2.2.1]heptan-2- Ref Ex 9 and 6h ylamino)methyl)-6-(3- (1R,2R,4S)-2 126 302 (methylamino)azetidin-1- bicyclo[2.2.1]heptan-2 yl)pyrimidin-2-amine ylamine (S)-4-((sec-butylamino)methyl)-6- Ref Ex 9 and (S)-sec 6i (3-(methylamino)azetidin-1- butylamine 2 1.07 264 yl)pyrimidin-2-amine (R)-4-((sec-butylamino)methyl)-6- Ref Ex 9 and (R)-sec (3-(methylamino)azetidin-1- Retxand 2 1.07 264 yl)pyrimidin-2-amilne butylamine (1) Ref Ex 9 and tert-butylamine were heated for 3 days instead of overnight EXAMPLE 7 Competitive binding assay for PH]-histamine to the human histamine H 4 receptor Membrane extracts were used to perform the test that were prepared from a stable recombinant CHO cell 5 line expressing the human histamine H 4 receptor (Euroscreen/Perkin-Elmer). The compounds to be tested were incubated at the desired concentration in duplicate with 10 nM PH] histamine and 15 jig of membrane extract in a total volume of 250 piL of 50 mM Tris-HCI, pH 7.4, 1.25 mM EDTA for 60 minutes at 25 "C. Non-specific binding was defined in the presence of 100 ptM of unlabelled histamine. The reaction was interrupted by filtration by means of a vacuum manifold (Multiscreen Millipore) in 96 well plates 10 (MultiScreen HTS Millipore) that were previously treated with 0.5% polyethylenimine for 2 hours at 0 "C. The plates were subsequently washed with 50 mM Tris (pH 7.4), 1.25 mM EDTA at 0 "C, and the filters were dried for 1 hour at 50-60 0C before adding the scintillation liquid in order to determine bound radioactivity by means of a beta scintillation counter. All the compounds described in the examples were assayed in this test and exhibited more than 50% 15 inhibition of binding to human histamine receptor H 4 at a 1 jpM concentration. EXAMPLE 8 Histamine-induced shape change assay (gated autofluorescence forward scatter assay, GAFS) in human eosinophils In this assay the shape change induced by histamine in human eosinophils is determined by flow cytometry, 20 detected as an increase in the size of the cells (forward scatter, FSC). Polymorphonuclear leucocytes (PMNL, fraction containing neutrophils and eosinophils) were prepared from whole blood of human healthy volunteers. Briefly, erythrocytes were separated by sedimentation in 1.2% Dextran (SIGMA), and the leucocyte-rich fraction (PMNL) was isolated from the top layer by centrifugation at 450g for 20 min in the presence of Ficoll-Paquee (Biochrom). PMNLs were resuspended in PBS buffer at a concentration of 1.1x10 6 25 cells/ml/tube and were pretreated with different concentrations of test compounds (dissolved in PBS) for 30 min at 370C and then stimulated with 300 nM histamine (Fluka) for 5 min. Finally, paraformaldehyde (1% final concentration in PBS) was added to terminate the reaction and maintain cell shape. Cell shape change was analyzed by flow 66 cytometry (FACS Calibur, BD Biosystems). Eosinophils in PMNL were gated based on their higher autofluorescence relative to that of neutrophils (fluorescence channel FL2). Cell shape change was monitored in forward scatter signals (FSC). Results are expressed as percentage inhibition of shape change induced by histamine for each concentration of test compound. 5 All the compounds described in the examples except examples 1h, li, ij, 4a, 4b, 4c and 6a to 6j were assayed in this test and produced more than 50% inhibition of histamine-induced human eosinophil shape change at 1 sM. EXAMPLE9 hERG assay 10 The inhibition of the hERG channel was determined by an automated modification of the conventional patch clamp method. The compounds to be tested were assayed at the desired concentration(s) and the result was expressed as % inhibition. Several compounds of the invention were tested in this assay and gave less than 50% inhibition at 10 pM. EXAMPLE 10 15 Murine atopic dermatitis model by multiple oxazolone challenges Method: Male BALB/c mice (n = 5-7 per group) were sensitised on Day 1 by the topical application of 50 pL of 1% oxazolone in acetone/olive oil (4:1) on the abdominal skin. On days 8, 10, 12, 15, 17, 19, 22, 24 and 26, animals received repeated challenges with 25 pL of 0.2% oxazolone, applied topically on the inner side of their right ear. On days 8-26, 25 pL of a solution of the test compound (prepared by dissolving compound in acetone/olive oil 20 4:1 and heating) at the desired concentration were administered on the outer side of the right ears. On days 12, 19 and 26, right ear thickness was determined with a calliper one hour after oxazolone application. The compounds of examples lb and 1t were tested in this assay and gave > 70 % inhibition of oxazolone induced ear inflammation at day 26 when administered at a concentration of 0.5 %.

Claims (42)

1.- A compound of formula I NH 2 R3 N N N 4 n NR 1 R 2 R 5 R 5 5 wherein: R 1 and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from: (i) a heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said heterocyclic group is optionally substituted with one or more C.4 alkyl groups; and (ii) a heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said 10 heterocyclic group is substituted with one -NRaRb group and is optionally substituted with one or more C 1 . 4 alkyl groups; wherein said heterocyclic groups (i) and (ii) are 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or

8- to 12-membered fused bicyclic; or R, represents H or C4 alkyl, and R2 represents azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, which are optionally 15 substituted with one or more C,-4 alkyl groups; Ra represents H or CI alkyl; R 5 represents H or C 14 alkyl; or Ra and Rb form, together with the N atom to which they are bound, an azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group that is optionally substituted with one or more C1.4 alkyl groups; 20 Ra represents H or C 1 .B alkyl; R 4 represents C 1 . 5 alkyl optionally substituted with one or more halogen, Cro cycloalkyl-Co 4 alkyl, heterocycloalkyl C 04 alkyl, aryl-C. 4 alkyl or heteroaryi-CO 4 alkyl, wherein in the C 3 . 1 o cycloalkyl-Co alkyl, heterocycloalkyl-C alkyl, aryl-Co 4 alkyl and heteroaryl-Co alkyl groups any alkyl group is optionally substituted with one or more P 5 groups, any of the cycloalkyl and heterocycloalkyl groups are optionally substituted with one or more substituents 25 independently selected from Ci.e alkyl and halogen, and any of the aryl and heteroaryl groups are optionally substituted with one or more R7 groups; each R 5 independently represents H or Ci-a alkyl; each Rs independently represents C- alkyl, halogen, hydroxyCo. 6 alkyl, C310 cycloalkyl optionally sustituted with one or more Ct-s alkyl groups, or phenyl optionally sustituted with one or more R8; and optionally two PN groups on the 30 same carbon atom are bonded together to form a -C2.s alkylene- group which is optionally substituted with one or 68 more Coe alkyl groups; each R 7 independently represents Ces alkyl, haloCio alkyl, halogen, C1s alkoxy, haloC 16 alkoxy, -CN, C1s alkylthio, C2_ alkynyl, hydroxyCo- 6 alkyl, C0 2 R-Co. 6 alkyl, -CONR 9 Ra, -SO 2 NRgRg, -S0 2 -Ci.s alkyl, -NR9S0 2 -C 1 alkyl, NR9CONRR, -NRoCOR, -NRR, Caio cycloalkyl, heterocycloalkyl. aryl or heteroaryl; wherein any of the cycloalkyl, 5 heterocycloalkyl, aryl or heteroaryl groups in R 7 are optionally sustituted with one ore more C1.0 alkyl groups; each Ra independently represents Ci_ alkyl, haloC. 6 alkyl, halogen, C1. alkoxy. haloCi_ alkoxy or -CN; each R 9 independently represents H or C,_ alkyl; and optionally two R 9 groups are bonded together to form a -C3.5 alkylene- group which is optionally substituted with one or more Cl.8 alkyl groups; and n represents 1 or 2; 10 or a salt thereof. 2.- A compound according to claim I wherein n is 1. 3.- A compound according to any of claims 1 or 2 wherein R 5 is H. 4.- A compound according to any of claims 1 to 3 wherein R 3 is H or methyl. 5.- A compound according to claim 4 wherein R 3 is H. 15 6.- A compound according to any of claims 1 to 5 wherein R 4 represents Ces alkyl, C 3 . 1 o cycloalkyl-CO.4 alkyl, heterocycloalkyl-Cc alkyl, aryl-Co.4 alkyl or heteroaryl-C4 alkyl, wherein in the C3o cycloalkyl-Co 4 alkyl, heterocycloalkyl-C" alkyl, aryl-Co.4 alkyl and heteroaryl-C04 alkyl groups any alkyl group is optionally substituted with one or more R 6 groups, any of the cycloalkyl and heterocycloalkyl groups are optionally substituted with one or more substituents independently selected from C1_8 alkyl and halogen, and any of the aryl and heteroaryl groups are 20 optionally substituted with one or more R7 groups. 7.- A compound according to any of claims 1 to 5 wherein R 4 represents C 1 _ alkyl, C3.1o cycloalkyl-C04 alkyl or aryl Co." alkyl, wherein in the C3.o cycloalkyl-Co alkyl and aryl-Co.4 alkyl groups any alkyl is optionally substituted with one or more R6 groups, the cycloalkyl is optionally substituted with one or more substituents independently selected from C18 alkyl and halogen, and the aryl is optionally substituted with one or more R 7 groups. 25 8.- A compound according to any of claims 1 to 5 wherein R 4 represents Ci-s alkyl optionally substituted with one or more halogen, or C:.10 cycloalkyl-Co4 alkyl, wherein in the C3o cycloalkyl-Co alkyl group the alkyl group is optionally substituted with one or more R6 groups and the cycloalkyl group is optionally substituted with one or more substituents independently selected from C,.s alkyl and halogen.

9.- A compound according to any of claims I to 5 wherein R 4 represents C.8 alkyl optionally substituted with one or 30 more halogen or C310 cycloalkyl-Co. 4 alkyl, wherein in the C3io cycloalkyl-C. alkyl group the cycloalkyl group is optionally substituted with one or more substituents independently selected from C,_ alkyl and halogen.

10.- A compound according to any of claims 1 to 5 wherein R 4 represents C1.8 alkyl or C3.io cycloalky-CA alkyl, wherein in the Co cycloalkyl-CoA alkyl group the cycloalkyl group is optionally substituted with one or more substituents independently selected from C18 alkyl and halogen. 35 11.- A compound according to any of claims 1 to 5 wherein R 4 represents Cmo alkyl optionally substituted with one or more halogen or Cm cycloalkyl-Co. alkyl, wherein in the C- cycloalkyl-Co-I alkyl group the cycloalkyl group is optionally substituted with one or more substituents Independently selected from C1s alkyl and halogen. 69 12, A compound according to any of claims 1 to 5 wherein R 4 represents Cas alkyl or C. cycloalkyl-Co. alkyl, wherein in the C-6 cycloalkyl-Co alkyl group the cycloalkyl group is optionally substituted with one or more substituents independently selected from C,.8 alkyl and halogen.

13.- A compound according to any of claims 1 to 5 wherein R4 represents C 1 .aalkyl. 5 14.- A compound according to any of claims 1 to 5 wherein R 4 represents C3 alkyl.

15.- A compound according to any of claims 1 to 5 wherein R 4 represents C30iocycloalkyl-Co4 alkyl, wherein the alkyl is optionally substituted with one or more R 6 groups and the cycloalkyl is optionally substituted with one or more substituents independently selected from C,. 8 alkyl and halogen.

16.- A compound according to any of claims 1 to 5 wherein R 4 represents C3-ocycloalkyl-Co.i alkyl, wherein the alkyl 10 is optionally substituted with one or more R6 groups and the cycloalkyl is optionally substituted with one or more substituents independently selected from 01.8 alkyl and halogen.

17.- A compound according to any of claims I to 5 wherein R 4 represents C3 cycloalkyl-Co., alkyl, wherein the alkyl is optionally substituted with one or more R6 groups and the cycloalkyl is optionally substituted with one or more substituents independently selected from C18 alkyl and halogen. 15 18.- A compound according to any of claims 1 to 5 wherein R 4 represents C3.6 cycloalkyl-Co-, alkyl, wherein the cycloalkyl is optionally substituted with one or more substituents independently selected from C 1 . 8 alkyl and halogen.

19.- A compound according to any of claims 1 to 5 wherein R4 represents C 3 1 0 cycloalkyl-C 1 alkyl.

20.- A compound according to any of claims 1 to 5 wherein R 4 represents C, cycloalkyl-C1 alkyl.

21.- A compound according to any of claims 1 to 5 wherein R 4 represents cyclopropylmethyl. 20 22.- A compound according to any of claims I to 5 wherein R 4 represents Ca.o cycloalkyl.

23.- A compound according to any of claims 1 to 5 wherein R 4 represents C3-8 cycloalkyl.

24.- A compound according to any of claims 1 to 5 wherein R 4 represents cyclopentyl.

25.- A compound according to any of claims 1 to 5 wherein R 4 represents aryl-Co. 2 alkyl, preferably phenyl-Co- alkyl, wherein any alkyl is optionally substituted with one or more R8 groups and any aryl is optionally substituted with one 25 or more R 7 groups.

26.- A compound according to any of claims I to 5 wherein R 4 represents aryl, preferably phenyl, which is optionally substituted with one or more R 7 groups.

27.- A compound according to any of claims 1 to 26 wherein R, and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from: 70 Ra N Rb Ra N Rb NN- R N N N (a) (b) (c) (d) Rd Rd Rd NN N IV N (e) (f) (g) (h) wherein Re and Rd independently represent H or C 1 4alkyl.

28.- A compound according to claim 27 wherein Ri and R2 form, together with the N atom to which they are bound, a 5 saturated heterocyclic group selected from (a), (b) and (e).

29.- A compound according to claim 27 wherein R 1 and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b).

30.- A compound according to claim 27 wherein R 1 and R 2 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a). 10 31.- A compound according to claim 29 or 30 wherein R, represents H.

32.- A compound according to any of claims 1 to 31 wherein Ra and Rb independently represent H or methyl.

33.- A compound according to claim 32 wherein Ra represents H and Rb represents methyl.

34.- A compound according to claim 1, which is 4 -((Cyclopropylmethylamino)methyl)-6-(3-(methylamino)azetidin-1 yl)pyrimidin-2-amine, or a salt thereof. 15 35.- A compound according to claim 1, which is 4-((2-Adamantylamino)methyl)-6-(3-(methylamino)azetidin-1 y)pyrimidin-2-amine, or a salt thereof.

36.- A compound according to claim 1, which is 4-(((2,2-Diethylcyclopropyl) methylamino)methyl)-6-(3 (methylamino)azetdin-1-yl)pyrimidin-2-amine, or a salt thereof.

37.- A compound according to claim 1, which Is 4-((Cyclopentylamino)methyl)-6-(3-(methylamino)azetidin-l 20 yl)pyrimidin-2-amine, or a salt thereof. 71

38.- A compound according to claim 1, which is 4 -(3-(Methylamino)azetidin-1-yl)-6-((pentylamino)methyl)pyrimidin 2-amine, or a salt thereof.

39.- A compound according to claim 1, which is 4 -((Cyclopentyl(methyl)amino)methyl)-6-(3-(methylamino)azetidin-1 yl)pyrimidin-2-amine,; or a salt thereof. 5 40.- A compound according to claim 1, which is 4-((Isobutylamino)methyl)-6-(3-(methylamino)azeidin-1.yl)pyimidin 2-amine, or a salt thereof.

41.- A compound according to claim 1, which is 4-((Cyclopropylamino)methyl)-6-(3-(methylamino)azetidin-1 yl)pyrimidin-2-amine, or a salt thereof.

42.- A compound according to claim 1, which is 4-((ert-Butylamino)methyl)-6-(3-(methylamino)azetidin-1 10 yl)pyrimidin-2-amine, or a salt thereof.

43.- A compound according to claim 1, which is 4 -((Isopropylamino)methyl)-6-(3-(methylamino)azetidin-1 yl)pyrimidin-2-amine, or a salt thereof.

44.- A compound according to claim 1, which is 4-(3-(methylamino)azetidin-1-y)-6-((2,2,2 trifluoroethylamino)methyl)pyrimidin-2-amine, or a salt thereof. 15 45.- A compound according to claim 1, which is 4-(((1R,2R,4S)-bicyclo[2.2.lheptan-2-ylamino)methyl)-6-(3 (methylamino)azetidin-1-yl)pyrtmidin-2-amine, or a salt thereof. 46, A compound according to claim 1, which is (S)-4-((sec-butylamino)methyl)-6-(3-(methylamino)azedin-1 yl)pyrimidin-2-amine,or a salt thereof.

47.- A compound according to claim 1, which is (R)-4-((sec-butylamino)methyl)-6-(3-(methylamino)azetidin-1 20 yl)pyrimidin-2-amine, or a salt thereof.

48.- A pharmaceutical composition which comprises a compound according to any of claims 1 to 47 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

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

50.- A compound according to any of claims 1 to 47 or a pharmaceutically acceptable salt thereof for use in the 25 treatment or prevention of a disease mediated by the histamine H 4 receptor.

51.- A compound according to any of claims 1 to 47 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of an allergic, immunological or inflammatory disease, pain or cancer.

52.- A compound according to claim 51 for use in the treatment or prevention of an allergic, immunological or inflammatory disease. 30 53.- A compound according to claim 52, wherein the allergic, immunological or inflammatory disease is selected from respiratory diseases, ocular diseases, skin diseases, inflammatory bowel diseases, autoimmune diseases, and transplant rejection.

54.- A compound according to claim 52, wherein the allergic, immunological or inflammatory disease is selected from asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, 35 cataracts, eczema, dermatitis (e.g. atopic dermatitis), psoriasis, urticaria, pemphigus, dermatitis herpetiformis, 72 cutaneous vasculitis, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus, systemic vasculitis and transplant rejection.

55.- A method of treating or preventing a disease mediated by the histamine HA receptor in a subject in need thereof, which comprises administering to said subject an amount of compound according to any of claims 1 to 47 or a 5 pharmaceutically acceptable salt thereof effective to treat or prevent said disease.

56.- A method of treating or preventing an allergic, immunological or inflammatory disease, pain or cancer in a subject in need thereof, which comprises administering to said subject an amount of a compound according to any of claims 1 to 47 or a pharmaceutically acceptable salt thereof effective to treat or prevent said allergic, immunological or inflammatory disease, pain or cancer. 10 57.- A method of treating or preventing an allergic, immunological or inflammatory disease in a subject in need thereof, which comprises administering to said subject an amount of a compound according to any of claims 1 to 47 or a pharmaceutically acceptable salt thereof effective to treat or prevent said disease.

58.- The method of claim 57, wherein the allergic, immunological or inflammatory disease is selected from respiratory diseases, ocular diseases, skin diseases, inflammatory bowel diseases, autoimmune diseases, and 15 transplant rejection.

59.- The method of claim 57, wherein the allergic, immunological or inflammatory disease Is selected from asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataracts, eczema, dermatitis (e.g. atopic dermatitis), psoriasis, urticaria, pemphigus, dermatitis herpetiformis, cutaneous vasculitis, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, 20 systemic lupus erythematosus, systemic vasculitis and transplant rejection.

60.- A process for the preparation of a compound of formula I according to claim 1, which comprises: (a) when in a compound of formula I n is 1, reacting a compound of formula II with a compound of formula IlIl (or an amino-protected form thereof) in the presence of a reducing agent NH 2 N N I HNR 3 R 4 R 5 NR 1 R 2 0 25 wherein R1, R 2 , R 3 , R 4 and R5 have the meaning described in claim 1, followed if necessary by the removal of any protecting group that may be present or (b) when in a compound of formula I n is 1 and R; represents hydrogen, reacting a compound of formula IV with a compound of formula V (or an amino-protected form thereof) 73 NH 2 N N R 4 R 3 N OH HNR1R2 IV V wherein Ri, R 2 , R 3 and R 4 have the meaning described in claim 1, followed if necessary by the removal of any protecting group that may be present; or (c) when in a compound of formula I n is 1 and R 5 represents hydrogen, reacting a compound of formula IVb 5 with a compound of formula V (or an amino-protected form thereof) NH 2 N N R4R3NI RI HNR 1 R 2 IVb V wherein Rio represents a leaving group and R 1 , R 2 . R3 and R 4 have the meaning described in claim 1, followed if necessary by the removal of any protecting group that may be present; or 10 (d) when in a compound of formula I n is 1, reacting a compound of formula XX with a compound of formula IllI (or an amino-protected from thereof) NH2 N IN NR 1 R 2 HNR 3 R 4 wherein R 1 2 represents a leaving group and R 1 , R 2 .R 3 R 4 and R have the meaning described in claim 1, followed if necessary by the removal of any protecting group that may be present; or 15 (e) when in a compound of formula I n=1 and R 5 represents H or n=2 and (CR 5 R 5 ) 2 represents -(CH 2 )-(CRsR 5 )- 74 treating a compound of formula XIV with a reducing agent NH 2 O N IN R 4 R 3 N m NR 1 R 2 R 5 R 5 xIv wherein Ri, RZ R 3 R 4 and R 5 have the meaning described in claim I and m is 0 or 1; or (f) transforming a compound of formula I into another compound of formula I in one or in several steps. Palau Pharma, S.A. Patent Attorneys for the Applicant/Nominated Person SPRUSON & FERGUSON