WO2010043633A1

WO2010043633A1 - 2h-pyrazolo [4,3-d]pyrimidin-5-amine derivatives as h4 histamine receptor antagonists for the treatment of allergic, immunological and inflammatory diseases

Info

Publication number: WO2010043633A1
Application number: PCT/EP2009/063374
Authority: WO
Inventors: Elena CARCELLER GONZÁLEZ; Marina VIRGILI BERNADÓ
Original assignee: Palau Pharma, S. A.
Priority date: 2008-10-15
Filing date: 2009-10-13
Publication date: 2010-04-22
Also published as: TW201026701A; AR073881A1

Abstract

Pyrazolopyrimidine 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

2H-PYRAZOLO [4 , 3-D] PYRIMIDIN-5-AMINE DERIVATIVES AS H4 HISTAMINE RECEPTOR ANTAGONISTS FOR THE TREATMENT OF ALLERGIC , IMMUNOLOGICAL AND INFLAMMATORY DISEASES

Field of the invention

The present invention relates to a new series of pyrazolopyrimidine derivatives, processes to prepare them, pharmaceutical compositions comprising these compounds as well as their use in therapy.

Background of the invention

Histamine is one of the most potent mediators of immediate hypersensitivity reactions. While the effects of histamine on smooth muscle cell contraction, vascular permeability and gastric acid secretion are well known, its effects on the immune system are only now beginning to become unveiled. A few years ago, a novel histamine receptor, which was named H₄, was cloned by several research groups working independently (Oda T et al, J Biol Chem 2000, 275: 36781 -6; Nguyen T et a\, MoI Pharmacol 2001 , 59: 427-33). As the other members of its family, it is a G-protein coupled receptor (GPCR) containing 7 transmembrane segments. However, the H₄ receptor has low homology with the three other histamine receptors (Oda T et al); it is remarkable that it shares only a 35% homology with the H₃ receptor. While the expression of the H₃ receptor is restricted to cells of the central nervous system, the expression of the H₄ receptor has been mainly observed in cells of the haematopoietic lineage, in particular eosinophils, mast cells, basophils, dendritic cells and T-cells (Oda T et al). The fact that the H₄ receptor is highly distributed in cells of the immune system suggests the involvement of this receptor in immuno-inflammatory responses. Moreover, this hypothesis is reinforced by the fact that its gene expression can be regulated by inflammatory stimuli such as interferon, TNFα and IL-6. Nevertheless, the H₄ receptor is also expressed in other types of cells such as human synovial cells obtained from patients suffering from rheumatoid arthritis (Wojtecka-Lukasik E et al, Ann Rheum Dis 2006, 65 (Suppl II): 129; Ikawa Y et al, Biol Pharm Bull 2005, 28: 2016-8) and osteoarthritis (Grzybowska-Kowalczyk A et al, European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, P-1 1 ), and in the human intestinal tract (Sander LE et al, Gut 2006, 55: 498- 504). An increase in the expression of the H₄ receptor has also been reported in nasal polyp tissue in comparison to nasal mucosa of healthy people (Jόkύti A et al, Cell Biol lnt 2007, 31 : 1367-70). Recent studies with specific ligands of the H₄ receptor have helped to delimit the pharmacological properties of this receptor. These studies have evidenced that several histamine-induced responses in eosinophils such as chemotaxis, conformational change and CD1 1 b and CD54 up-regulation are specifically mediated by the H₄ receptor (Ling P et al, Br J Pharmacol 2004, 142:161 -71 ; Buckland KF et al, Br J Pharmacol 2003, 140:1 117-27). In dendritic cells, the H₄ receptor has been shown to affect maturation, cytokine production and migration of these cells (Jelinek I et al, 1 ^st Joint Meeting of European National Societies of Immunology, Paris, France, 2006, PA-1255). Moreover, the role of the H₄ receptor in mast cells has been studied. Although H₄ receptor activation does not induce mast cell degranulation, histamine and other proinflammatory mediators are released; moreover, the H₄ receptor has been shown to mediate chemotaxis and calcium mobilization of mast cells (Hofstra CL et al, J Pharmacol Exp Ther 2003, 305: 1212-21 ). With regard to T-lymphocytes, it has been shown that H₄ receptor activation induces T-cell migration and preferentially attracts a T- lymphocyte population with suppressor/regulatory phenotype and function (Morgan RK et al, American Thoracic Society Conference, San Diego, USA, 2006, P-536), as well as regulating the activation of CD4+ T cells (Dunford PJ et al, J Immunol 2006, 176: 7062-70). As for the intestine, the distribution of the H₄ receptor suggests that it may have a role in the control of peristalsis and gastric acid secretion (Morini G et al, European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, O-10).

The various functions of the H₄ receptor observed in eosinophils, mast cells and T-cells suggest that this receptor can play an important role in the immuno- inflammatory response. In fact, H₄ receptor antagonists have shown in vivo activity in murine models of peritonitis (Thurmond RL et al, J Pharmacol Exp Ther 2004, 309: 404-13), pleurisy (Takeshita K et al, J Pharmacol Exp Ther 2003, 307: 1072- 8) and scratching (Bell JK et al, Br J Pharmacol 2004,142 :374-80). In addition, H₄ receptor antagonists have demonstrated in vivo activity in experimental models of allergic asthma (Dunford PJ et al, 2006), inflammatory bowel disease (Varga C et al, Eur J Pharmacol 2005, 522:130-8), pruritus (Dunford PJ et al, J Allergy Clin Immunol 2007, 1 19: 176-83), atopic dermatitis (Cowden JM et al, J Allergy Clin Immunol 2007; 1 19 (1 ): S239 (Abs 935), American Academy of Allergy, Asthma and Immunology 2007 AAAAI Annual Meeting, San Diego, USA), ocular inflammation (Zampeli E et al, European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, 0-36), edema and hyperalgesia (Coruzzi G et al, Eur J Pharmacol 2007, 563: 240-4), and neuropathic pain (Cowart MD et al., J Med Chem. 2008; 51 (20): 6547-57). It is therefore expected that H₄ receptor antagonists can be useful for the treatment or prevention of allergic, immunological and inflammatory diseases, and pain.

Accordingly, it would be desirable to provide novel compounds having H₄ receptor antagonist activity and which are good drug candidates. In particular, preferred compounds should bind potently to the histamine H₄ receptor whilst showing little affinity for other receptors. In addition to binding to H₄ receptors, compounds should further exhibit good pharmacological activity in in vivo disease models. Moreover, compounds should reach the target tissue or organ when administered via the chosen route of administration and possess favourable pharmacokinetic properties. In addition, they should be non-toxic and demonstrate few side-effects.

Description of the invention

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

wherein:

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

(i) a heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said heterocyclic group can be optionally substituted with one or more Ci_-4 alkyl groups; and

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

7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; or Ri represents H or Ci_-4 alkyl, and R₂ represents azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, which can be optionally substituted with one or more Ci_-4 alkyl groups; R_a represents H or Ci_-4 alkyl;

R_b represents H or Ci_-4 alkyl; or R_a and R_b form, together with the N atom to which they are bound, an azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group that can be optionally substituted with one or more Ci_-4 alkyl groups; R₃ represents H or NH₂;

R₅ can be placed either at N¹ or N² of the pyrazole ring; when R₅ is attached to N¹, either R₄ represents R₆ and R₅ represents R₇, or R₄ represents R₇ and R₅ represents R₈, or R₄ and R₅ can be bonded together to form a -C3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; when R₅ is attached to N², R₄ represents R₆ and R₅ represents R₇;

R₆ represents H, C-i-n alkyl, C_3-8 cycloalkyl-Co-n alkyl, C_3-8 heterocycloalkyl-Co-n alkyl, aryl-Co-n alkyl, heteroaryl-Co-n alkyl, aryl-NH-Co-n alkyl, heteroaryl-NH-Co-n alkyl, R9-C0-11 alkyl or R10-W-C0-11 alkyl; R₇ represents H, Ci_-6 alkyl, C_3-8 cycloalkyl-C₀-₆ alkyl, Ci_-6 alkoxy-Ci_-6 alkyl or (C_3-8 cycloalkyl-Co-e alkyl)-O-Ci_-6 alkyl;

R₈ represents C_3-8 cycloalkyl-Co-11 alkyl, C_3-8 heterocycloalkyl-Co-11 alkyl, aryl-Co-11 alkyl, heteroaryl-Co-11 alkyl, aryl-NH-C₂-n alkyl, heteroaryl-NH-C₂-n alkyl, R₉-C_2-H alkyl or R₁₀-W-C₂-H alkyl;

R₉ represents -CONR₁₁ R₁₁, -NR₁₁COR₁₁, -NR₁₁SO₂R₁₁, -SO₂NR₁₁R₁₁,

-NR₁₁CONR₁₁ R₁₁, -CONHSO₂R₁₁, -CO₂R₁₁, -SO₂R₁₁, -NR₁₁ R₁₁ or 1 H-tetrazol-5-yl;

R₁₀ represents H, C_1-11 alkyl, R₁₁-O-C_1-11 alkyl, C_3-8 cycloalkyl-C₀-n alkyl, C_3- sheterocycloalkyl-Co-n alkyl, aryl-C₀-n alkyl, heteroaryl-C₀-n alkyl, aryl-NH-C_2-11 alkyl, heteroaryl-NH-C_2-11 alkyl or R₉-C_1-11 alkyl;

R₁₁ represents H, C_1-6 alkyl, C_3-8 cycloalkyl-Co-e alkyl or aryl-Co-e alkyl;

W represents O, S, SO or SO₂; wherein in R₆, R₈ and R₁₀ any alkyl group can be optionally substituted with one or more halogen atoms, and any cycloalkyl and heterocycloalkyl groups can be optionally substituted with one or more substituents independently selected from

C_1-6 alkyl, halogen, aryl and R₉; aryl represents phenyl optionally substituted with one or more groups R₁₂; heteroaryl represents an aromatic 5- or 6-membered monocyclic or 8- to 12- membered bicyclic ring containing up to four heteroatoms independently selected from nitrogen, oxygen, and sulfur, which can be optionally substituted with one or more groups R₁₂; and each R₁₂ independently represents C_1-6 alkyl, halogen, C_1-6 alkoxy, C_1-6 haloalkyl,

C_1-6 haloalkoxy, CN, hydroxy-C₀-₆ alkyl, CO₂R_{i r}Co-6 alkyl, CONHSO₂Rii-C₀-6 alkyl, (1 H-tetrazol-5-yl)-C₀-6 alkyl, -CONR₁₁ R₁₁, -SO₂NR₁₁ R₁₁, -SO₂-C_1-6 alkyl, -NR₁₁SO₂-

C_1-6 alkyl, -NR₁₁CONR₁₁ R₁₁, -NR₁₁COR₁₁ or -NR₁₁R₁₁.

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

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

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

wherein:

Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from: (i) a heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said heterocyclic group can be optionally substituted with one or more Ci_-4 alkyl groups; and

7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; or Ri represents H or Ci_-4 alkyl, and R₂ represents azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, which can be optionally substituted with one or more Ci_-4 alkyl groups;

R_a represents H or Ci_-4 alkyl;

R_b represents H or Ci_-4 alkyl; or R_a and R_b form, together with the N atom to which they are bound, an azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group that can be optionally substituted with one or more Ci_-4 alkyl groups;

R₃ represents H or NH₂;

R₅ can be placed either at N¹ or N² of the pyrazole ring; when R₅ is attached to N¹, either R₄ represents R₆ and R₅ represents R₇, or R₄ represents R₇ and R₅ represents R₈, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; when R₅ is attached to N², R₄ represents R₆ and R₅ represents R₇; R₆ represents H, Ci-H alkyl, C_3-8 cycloalkyl-Co-n alkyl, C_3-8 heterocycloalkyl-Co-n alkyl, aryl-C_0-n alkyl, heteroaryl-C_0-n alkyl, aryl-NH-C_0-n alkyl, heteroaryl-NH-C_0-n alkyl, R9-C0-11 alkyl or R10-W-C0-11 alkyl;

R₇ represents H, Ci_-6 alkyl, C_3-8 cycloalkyl-C₀-6 alkyl, Ci_-6 alkoxy-Ci_-6 alkyl or (C_3-8 cycloalkyl-Co-6 alkyl)-O-Ci_-6 alkyl;

R₈ represents C_3-8 cycloalkyl-Co-n alkyl, C_3-8 heterocycloalkyl-Co-n alkyl, aryl-C₀-n alkyl, heteroaryl-Co-n alkyl, aryl-NH-C₂-n alkyl, heteroaryl-NH-C₂-n alkyl, R₉-C₂-H alkyl or Ri₀-W-C₂-_H alkyl; R₉ represents -CONRn Rn, -NRnCORn, -NRnSO₂Rn, -SO₂NRn Rn, -NR₁₁CONR₁₁ R₁₁, -CONHSO₂R₁₁, -CO₂Rn, -SO₂Rn, -NR₁₁ R₁₁ or 1 H-tetrazol-5-yl; R10 represents H, Ci-π alkyl, Rπ-0-Ci-π alkyl, C_3-8 cycloalkyl-Co-π alkyl, C_3- ₈heterocycloalkyl-Co-ii alkyl, aryl-Co-π alkyl, heteroaryl-Co-n alkyl, aryl-NH-C_2-n alkyl, heteroaryl-NH-C_2-n alkyl or R₉-Ci-H alkyl; R-11 represents H, Ci_-6 alkyl, C_3-8 cycloalkyl-C₀-6 alkyl or aryl-C₀-6 alkyl; W represents O, S, SO or SO₂; wherein in R₆, R₈ and R10 any alkyl group can be optionally substituted with one or more halogen atoms, and any cycloalkyl and heterocycloalkyl groups can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉; aryl represents phenyl optionally substituted with one or more groups Ri₂; heteroaryl represents an aromatic 5- or 6-membered monocyclic or 8- to 12- membered bicyclic ring containing up to four heteroatoms independently selected from nitrogen, oxygen, and sulfur, which can be optionally substituted with one or more groups Ri₂; and each Ri₂ independently represents Ci_-6 alkyl, halogen, Ci_-6 alkoxy, Ci_-6 haloalkyl, Ci_-6 haloalkoxy, CN, hydroxy-C₀-₆ alkyl, CO₂Rπ-C₀-₆ alkyl, CONHSO₂R₁₁-C₀-6 alkyl, (1 H-tetrazol-5-yl)-Co-₆ alkyl, -CONRn Rn, -SO₂NRn Rn, -SO₂-Ci_-6 alkyl, -NR₁₁SO₂- Ci_-6 alkyl, -NR₁₁CONR₁₁ R₁₁, -NR₁₁COR₁₁ or -NR₁₁R₁₁ ; for use in therapy. Another aspect of the invention relates to a pharmaceutical composition which comprises a compound of formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease mediated by the histamine H₄ receptor. More preferably, the disease mediated by the histamine H₄ receptor is an allergic, immunological or inflammatory disease or pain. Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of an allergic, immunological or inflammatory disease or pain.

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

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

Another aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease mediated by the histamine H₄ receptor. More preferably, the disease mediated by the histamine H₄ receptor is an allergic, immunological or inflammatory disease or pain.

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

Another aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of an allergic, immunological or inflammatory disease. More preferably, the allergic, immunological or inflammatory disease is selected from respiratory diseases, ocular diseases, skin diseases, inflammatory bowel diseases, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection. Still more preferably, the allergic, immunological or inflammatory disease is selected from asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataracts, dermatitis (e.g. atopic dermatitis), psoriasis, urticaria, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection. Another aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of pain. More preferably, the pain is selected from inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-surgical pain, migraine, cancer pain, visceral pain, osteoarthritis pain and neuropathic pain. Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of a disease mediated by the histamine H₄ receptor. More preferably, the disease mediated by the histamine H₄ receptor is an allergic, immunological or inflammatory disease or pain. Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of an allergic, immunological or inflammatory disease or pain.

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

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

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

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

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

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

Another aspect of the present invention relates to a process for the preparation of a compound of formula I as defined above, comprising: (a) reacting a compound of formula Il with a compound of formula III (or an amino-protected form thereof)

wherein R₁, R_2, R_3, R₄ and R₅ have the meaning described above, followed if necessary by the removal of any protecting group that may be present; or

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

Mb

wherein R₁₃ represents a leaving group and R₁, R₂, R₃, R₄ and R₅ have the meaning described above, followed if necessary by the removal of any protecting group that may be present; or

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

In the previous definitions, the term C_x-_y alkyl refers to a linear or branched alkyl chain containing from x to y carbon atoms. For example, a Ci_-4 alkyl group refers to a linear or branched alkyl chain containing from 1 to 4 C atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. The term C₀ alkyl indicates that the alkyl group is absent.

A C-₁-₆ haloalkyl group means a group resulting from the substitution of one or more hydrogen atoms of a Ci_-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, thfluoromethyl, fluoromethyl, 1 -chloroethyl, 2-chloroethyl, 1 - fluoroethyl, 2-fluoroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2-thfluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 4-fluorobutyl, nonafluorobutyl, 5,5,5-thfluoropentyl and 6,6,6-thfluorohexyl.

A -C-₃-₅ alkylene- group, in relation to the group formed by R₄ and R₅, when R₅ is attached to N¹, in a compound of formula I, refers to a linear alkyl chain which contains from 3 to 5 carbon atoms, i.e. a group of formula -(CH₂)3-₅-. As indicated in the definition of a compound of formula I, the -C_3-5 alkylene- group can be optionally substituted with one or more Ci_-8 alkyl groups, preferably with one or more methyl groups. Examples of R₄ and R₅ forming together a -C3-5 alkylene- group include, among others:

A C_3-8 cycloalkyl group, either as a group or as part of a C_3-8 cycloalkyl-C₀-_y alkyl group, relates to a saturated carbocyclic ring having from 3 to 8 carbon atoms that can be a monocyclic or a bridged bicyclic group. Examples include, amongst others, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1 ]heptanyl and bicyclo[2.2.2]octanyl.

The term C_3-8 cycloalkyl-C₀-_y alkyl includes C_3-8 cycloalkyl and C_3-8 cycloalkyl-Ci-y alkyl.

A C_3-8 cycloalkyl-Ci-y alkyl group means a group resulting from the substitution of one or more hydrogen atoms of a Ci_-y alkyl group with one or more

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

2-cyclopropybutyl (1 -ethyl-cyclopropy I) methyl butyl group where 1 H atom on a C atom butyl group where 2 H atoms on a same C atom is substituted with a cyclopropyl group are substituted with a cyclopropyl group

Examples of C_3-8 cycloalkyl-C₁.₁₁ alkyl groups include, amongst others, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, bicyclo[2.2.1 ]heptanylmethyl, dicyclopropylmethyl, (1 -methyl-cyclopropyl)methyl, (1 -cyclopentylmethyl- cyclopropyl)methyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2- cyclohexylethyl, 2,2-dicyclopropyl-ethyl, 2-cyclohexyl-2-cyclopropyl-ethyl, 2-(1 - methyl-cyclopropyl)ethyl, 1 -cyclopropyl-1 -methylethyl, 1 -cyclopropylethyl, 1 - cyclobutylethyl, 1 -cyclopentylethyl, 1 -cyclohexylethyl, S-cyclopropylpropyl, 3- cyclobutylpropyl, 3-cyclopentylpropyl, 3-cyclohexylpropyl, 1 -cyclopropyl-2- methylpropyl, 4-cyclopropylbutyl, 3-cyclopropylbutyl, 2-cyclopropylbutyl, 1 - cyclopropylbutyl, 4-cyclobutylbutyl, 4-cyclopentylbutyl, 5-(1 -propyl-cyclobutyl)- pentyl, 7-(1 -methyl-cyclopropyl)-heptyl, 4-cyclohexylbutyl, 5-cyclopropylpentyl, 6- cyclopropylhexyl, 7-cyclopropylheptyl, 8-cyclopropyloctyl, 9-cyclopropylnonyl, 10- cyclopropyldecyl and 1 1 -cyclopropylundecyl.

In the definition of a compound of formula I, when indicating that a C_3-8 cycloalkyl group can be optionally substituted with one or more groups independently selected from Ci_-6 alkyl, halogen, aryl and R₉, said substituents can be the same or different and can be located on any available carbon atom of the C_3-8 cycloalkyl group, including the carbon binding the cycle to the rest of the molecule.

A C_3-8 heterocycloalkyl group, either as a group or part of a C_3-8 heterocycloalkyl-Co-11 alkyl group, relates to a saturated heterocyclic ring that can be a monocyclic or a bridged bicyclic group, having from 3 to 8 C atoms and up to three heteroatoms independently selected from N, O and S, wherein the N or S atoms can be oxidized. The ring may optionally contain up to two oxo groups on carbon or sulfur ring members. The heterocyclic ring may be attached to the rest of the molecule through any available C or N ring atom (e.g., morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, pyrrolidin-1 -yl, pyrrolidin-2-yl and pyrrolidin-3-yl). Examples include, amongst others, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrazolidinyl, isothiazolidinyl, piperidinyl, morpholinyl, piperazinyl, 2-oxo-tetrahydrofuranyl, 2-oxo-[1 ,3]dioxolanyl, 2-oxo- oxazolidinyl, 2-oxo-imidazolidinyl, 2-oxo-[1 ,3]oxazinanyl, 2-oxo-piperazinyl, thiomorpholinyl, 1 ,1 -dioxo-thiomorpholinyl, azepanyl, [1 ,4]diazepanyl, [1 ,4]oxazepanyl, 2-oxo-azepanyl, 1 ,1 -dioxo-[1 ,2]thiazepanyl, 2-oxo- [1 ,3]diazepanyl, 7-oxo-bicyclo[2.2.1 ]heptanyl and 1 ,3-diaza-bicyclo[2.2.2]octanyl.

The term C_3-8 heterocycloalkyl -C₀- 11 alkyl includes C_3-8 heterocycloalkyl and C_3-8 heterocycloalkyl-C-ι-₁₁ alkyl.

A C_3-8 heterocycloalkyl-Ci-11 alkyl group means a group resulting from the substitution of one or more hydrogen atoms of a C-i-n alkyl group with one or more C_3-8 heterocycloalkyl groups that can be the same or different. Preferably, the Ci-n alkyl group is substituted with one or two C_3-8 heterocycloalkyl groups, and more preferably it is substituted with one C_3-8 heterocycloalkyl group. Examples of C_3-8 heterocycloalkyl-Ci-11 alkyl groups include, amongst others, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, morpholin-3-ylmethyl, tetrahydrofuran-2-ylmethyl, (2-oxo- [1 ,3]oxazinan-6-yl)-methyl, 2-piperidin-3-yl-ethyl, 2-piperazin-1 -yl-propyl, 1 -methyl- 2-piperazin-1 -yl-ethyl, 2-methyl-3-(pyrrolidin-3-yl)-propyl, 3-methyl-4-piperazin-1 - yl-butyl, 4-(tetrahydrofuran-3-yl)-butyl, 5-(tetrahydrofuran-3-yl)-pentyl, 6-azetidin-1 - yl-hexyl, 7-morpholin-4-yl-heptanyl, 6-methyl-8-(pyrrolidin-1 -yl)-octyl, 9-azetidin-2- yl-nonyl, 10-piperazin-i -yl-decyl, 10-pyrrolidin-1 -yl-decyl, 10-(5-oxo-pyrrolidin-2- yl)-decyl, 11 -(tetrahydro-furan-3-yl)-undecyl and 1 1 -pyrrolidin-2-yl-undecyl.

In the definition of a compound of formula I, when indicating that a C_3-8 heterocycloalkyl group can be optionally substituted with one or more groups independently selected from Ci_-6 alkyl, halogen, aryl and R₉, said substituents can be the same or different and can be located on any available C or N atom of the C₃-S heterocycloalkyl group, including the C atom binding the cycle to the rest of the molecule.

The term aryl -C₀-_y alkyl includes aryl and aryl-Ci_-y alkyl. An aryl-C-i-y alkyl group means a group resulting from the substitution of one or more hydrogen atoms of a Ci_-y alkyl group with an aryl group. Preferably, the C-i-y alkyl group is substituted with one or two aryl groups, and more preferably it is substituted with one aryl group. Examples of aryl-Ci-n alkyl include, amongst others, benzyl, 1 -phenylethyl, 2-phenylethyl, 1 -phenyl-1 -methyl-ethyl, 2,2- diphenyl-ethyl, 3-phenylpropyl, 2-phenyl-1 -methyl-propyl, 4-phenylbutyl, 5- phenylpentyl, 6-phenylhexyl, 4-phenylhexyl, 2-methyl-3-phenylhexyl, 7- phenylheptyl, 5-phenylheptyl, 7,7-diphenyl-heptyl, 8-phenyloctyl, 7-phenyloctyl, 9- phenylnonyl, 6-methyl-7-phenyl-nonyl, 9,9-diphenyl-nonyl, 10-phenyldecyl, 9- phenyldecyl, 11 -phenylundecyl and 9-phenyl-undecyl, wherein the phenyl groups can be optionally substituted as indicated above in the definition of aryl.

The term heteroaryl, either as a group or part of a heteroaryl-Co-n alkyl group, refers to an aromatic 5- or 6-membered monocyclic or 8- to 12-membered bicyclic ring containing up to four heteroatoms independently selected from nitrogen, oxygen and sulfur. The heteroaryl group may be attached to the rest of the molecule through any available C or N atom within the aromatic ring (e.g., imidazol-1 -yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, or pyridin-6-yl). Examples of heteroaryl groups include among others 1 ,2,4-oxadiazole, 1 ,2,4-thiadiazole, 1 ,3,4-oxadiazole, 1 ,3,4- thiadiazole, furan, imidazole, isoxazole, isothiazole, oxazole, pyrazole, pyrrole, thiazole, thiophene, 1 ,2,3-triazole, 1 ,2,4-triazole, pyrazine, pyridazine, pyridine, pyrimidine, benzimidazole, benzofuran, benzothiazole, benzothiophene, imidazopyrazine, imidazopyridazine, imidazopyridine, imidazopyrimidine, indazole, indole, isoindole, isoquinoline, naphthiridine, pyrazolopyrazine, pyrazolopyridine, pyrazolopyrimidine, purine, quinazoline, quinoline and quinoxaline. In the definition of heteroaryl when the specified examples refer to a bicycle in general terms, all possible dispositions of the atoms are included. For example, the term pyrazolopyhdine is to be understood as including groups such as 1 H-pyrazolo[3,4- £>]pyridine, pyrazolo[1 ,5-a]pyridine, 1 /-/-pyrazolo[3,4-c]pyridine, 1 H-pyrazolo[4,3- c]pyridine and 1 /-/-pyrazolo[4,3-£>]pyridine; the term imidazopyrazine is to be understood as including groups such as 1 /-/-imidazo[4,5-£>]pyrazine, imidazo[1 ,2- a]pyrazine and imidazo[1 ,5-a]pyrazine and the term pyrazolopyrimidine is to be understood as including groups such as 1 H-pyrazolo[3,4-c/|pyhmidine, 1 H- pyrazolo[4,3-φyhmidine, pyrazolo[1 ,5-a]pyrimidine and pyrazolo[1 ,5-c]pyrimidine. The heteroaryl groups can be optionally substituted with one or more Ri₂ groups, which can be the same or different and can be placed at any available position.

The term heteroaryl-C₀-n alkyl includes heteroaryl and heteroaryl-C-i-n alkyl.

An heteroaryl-Ci-ii alkyl group means a group resulting from the substitution of one or more hydrogen atoms of a C-i-n alkyl group with an heteroaryl group that can be the same or different. Preferably, the C-i-n alkyl group is substituted with one or two heteroaryl groups, and more preferably it is substituted with one heteroaryl group. Examples of heteroaryl-Ci-n alkyl include, amongst others, furan-2-ylmethyl, pyridin-3-ylmethyl, quinolin-3-ylmethyl, oxazol- 2-ylmethyl, 1 H-pyrrol-2-ylmethyl, 1 -pyridin-3-yl-ethyl, 2-pyridin-2-yl-propyl, 3- pyhdin-3-yl-propyl, 1 -methyl-2-pyhdin-3-yl-propyl, 4-pyhdin-2-yl-butyl, 3-pyridin-2- yl-butyl 5-furan-2-yl-pentyl, 6-furan-2-yl-hexyl, 3-(1 H-pyrrol-2-yl)-hexyl, 7-(1 H- pyrrol-2-yl)-heptyl, 7-furan-2-yl-heptyl, 6-methyl-7-pyhdin-2-yl-heptyl, 8-furan-2-yl- octyl, 8-(3H-imidazol-4-yl)-octyl, 9-furan-2-yl-nonyl, 10-furan-2-yl-decyl, 10- isoxazol-3-yl-decyl, 1 1 -furan-2-yl-undecyl and 1 1 -pyhdin-2-yl-undecyl, wherein the heteroaryl groups can be optionally substituted as indicated above in the definition of heteroaryl.

The term aryl-NH-C₀-n alkyl includes aryl-NH- and aryl-NH-C-i-n alkyl. An aryl-NH-Cχ-ii alkyl group means a group resulting from the substitution of one hydrogen atom of a C_x-H alkyl group with an aryl-NH- group.

The term heteroaryl-N H-C₀-H alkyl includes heteroaryl-NH- and heteroaryl- NH-C1-11 alkyl.

An heteroaryl-NH-Cχ-11 alkyl group means a group resulting from the substitution of one hydrogen atom of a C_x-n alkyl group with an heteroaryl-NH- group.

The term R9-C0-11 alkyl includes R₉- and R₉-Ci-H alkyl. A Rg-C_x-H alkyl group means a group resulting from the substitution of one or more hydrogen atoms of a C_x-H alkyl group with a R₉ group that can be the same or different. Preferably, the C_x--_M alkyl group is substituted with one R₉ group. The term R10-W-C0-11 alkyl includes Ri₀-W- and RI₀-W-CI-H alkyl. A Ri₀-W-C_x-H alkyl group means a group resulting from the substitution of one or more hydrogen atoms of a C_x-n alkyl group with a Ri₀-W- group. Preferably, the C_x-n alkyl group is substituted with one Ri₀-W- group.

A C1-6 alkoxy group, either as a group or a part of a Ci_-6 alkoxy-Ci_-6 alkyl 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, isobutoxy, sec-butoxy, tert-buioxy, pentyloxy and hexyloxy.

A C₁-₆ alkoxy-Ci-₆ alkyl group means a group resulting from the replacement of one or more hydrogen atoms of a Ci_-6 alkyl group with one or more Ci_-6 alkoxy groups as defined above, which can be the same or different. Preferably, the Ci_-6 alkyl group is substituted with one Ci_-6 alkoxy group. Examples of Ci_-6 alkoxy-Ci_-6 alkyl include, among others, the groups methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, isobutoxymethyl, sec- butoxymethyl, tert-butoxymethyl, dimethoxymethyl, 1 -methoxyethyl, 2- methoxyethyl, 2-ethoxyethyl, 1 ,2-diethoxyethyl, 1 -butoxyethyl, 2-sec-butoxyethyl,

3-methoxypropyl, 2-butoxypropyl, 1 -methoxy-2-ethoxypropyl, 3-tert-butoxypropyl, 4-methoxybutyl, 3-methoxyhexyl and 2-butoxyhexyl.

A C-_I-6 haloalkoxy 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 iodo) that can be the same or different. Examples include, amongst others, thfluoromethoxy, fluoromethoxy, 1 - chloroethoxy, 2-chloroethoxy, 1 -fluoroethoxy, 2-fluoroethoxy, 2-bromoethoxy, 2- iodoethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 3-fluoropropoxy, 3- chloropropoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, heptafluoropropoxy, 4-fluorobutoxy, nonafluorobutoxy, 2-chloropentyloxy and 3- chlorohexyloxy.

The term hydroxy-C_0-6 alkyl includes hydroxy and hydroxy-Ci_-6 alkyl. A hydroxy-Ci-₆ alkyl group means a group resulting from the replacement of one or more hydrogen atoms of a Ci_-6alkyl group with one or more hydroxy groups. Preferably, the Ci_-6 alkyl group is substituted with one hydroxy group. Examples include, among others, the groups hydroxymethyl, 1 -hydroxyethyl, 2- hydroxyethyl, 1 ,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1 - hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 2- hydroxybutyl and 1 -hydroxybutyl. The term CO₂Rn -C_0-6 alkyl includes -CO₂Rn and CO₂R₁₁-C_1-6 alkyl.

A CO₂R₁₁-C_1-6 alkyl group means a group resulting from the replacement of one or more hydrogen atoms of a C_1-6alkyl group with one or more -CO₂R₁ groups. Preferably, the C_1-6 alkyl group is substituted with one -CO₂R₁₁ group.

The term CONHSO₂R₁₁-C_0-6 alkyl includes -CONHSO₂R₁₁ and CONHSO₂R₁₁-C_1-6 alkyl.

A CONHSO₂R₁₁-C_1-6 alkyl group means a group resulting from the replacement of one or more hydrogen atoms of a C_1-6alkyl group with one or more -CONHSO₂R₁₁ groups. Preferably, the C_1-6 alkyl group is substituted with one - CONHSO₂R₁₁ group. The term (1 H-tetrazol-5-yl)-C₀-₆ alkyl includes (1 H-tetrazol-5-yl)- and (1 H- tetrazol-5-yl)-C_1-6 alkyl.

A (1 /-/-tetrazol-5-yl)-C_1-6 alkyl group means a group resulting from the replacement of one or more hydrogen atoms of a C_1-6alkyl group with one or more (1 /-/-tetrazol-5-yl)- groups. Preferably, the C_1-6 alkyl group is substituted with one (1 H-tetrazol-5-yl)- group.

A (C₃-S cycloalkyl-Co-e alkyl)-O-C_1-6 alkyl group means a group resulting from the substitution of one or more hydrogen atoms of a C_1-6 alkyl group with a (C_3-8 cycloalkyl-Co-₆ alkyl)-O- group. Preferably, the C_1-6 alkyl group is substituted with one (C_3-8 cycloalkyl-C₀-₆ alkyl)-O- group. A R₁₁-O-C_1-11 alkyl group means a group resulting from the substitution of one or more hydrogen atoms of a C_1-11 alkyl group with a R₁₁-O- group that can be the same or different. Preferably, the C_1-11 alkyl group is substituted with one R₁₁- O- group. As indicated for a compound of formula I any alkyl group in R₆, R₈ and Ri₀ can be optionally substituted with one or more halogen groups. This refers to the C_1-11 alkyl group and the C_x-H alkyl group that forms part of the C₃-8 cycloalkyl-Co-n alkyl, C_3-8 heterocycloalkyl-Co-n alkyl, aryl-C₀-n alkyl, heteroaryl-C₀-n alkyl, aryl- NH-Cχ-11 alkyl, heteroaryl-NH-C_x-n alkyl, R₉-C_x-H alkyl, R₁₀-W-C_x-H alkyl and R₁₁-O- C_1-11 alkyl groups.

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 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.

In the definition of NR₁R₂ R₁ and R₂ together with the N atom to which they are bound can form a heterocyclic group of type (i) or (ii). A heterocyclic group of type (i) is a saturated heterocyclic group which contains 2 N atoms and does not contain any other heteroatom and which can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic. Examples include, among others, piperazinyl, homopiperazinyl, 2,5-diaza- bicyclo[2.2.1 ]heptanyl, 2,5-diaza-bicyclo[2.2.2]octanyl, octahydro-pyrrolo[1 ,2- a]pyrazinyl, octahydro-pyrrolo[3,4-b]pyridinyl, octahydro-pyrrolo[3,2-c]pyridinyl and octahydropyrrolo[3,4-c]pyrrolinyl. Said groups can be optionally substituted with one or more C_1-4alkyl groups which can be placed at any available C or N atom.

A heterocyclic group of type (ii) is a saturated heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR_aR_b group, and which can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic, preferably 4- to 7-membered monocyclic. Examples of (ii) include, among others, 3-amino-azetidinyl, 3-methylamino-azetidinyl, 3-dimethylamino- azetidinyl, 3-amino-pyrrolidinyl, 3-methylamino-pyrrolidinyl, 3-dimethylamino- pyrrolidinyl, 4-amino-piperidinyl, 4-methylamino-piperidinyl, 4-dimethylamino- piperidinyl and 6-methylamino-3-aza-bicyclo[3.1.0]hexane-3-yl. Said groups can be further optionally substituted, as indicated above in the definition of a compound of formula I.

In the definition of a compound of formula I, it is mentioned that R⁵ can be placed either at N¹ or N² of the pyrazole ring. Thus, the compounds of formula I include the following two types of compounds:

When in the definition of a substituent two or more groups with the same numbering are indicated (e.g. -CONR-n R-n, -S0₂NRn Rn, or -NRnRn, 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 group has enough positions available susceptible of being substituted. These substituents can be the same or different, and can be located at any available position.

Throughout the present specification, by the term "treatment" is meant eliminating, reducing or ameliorating the cause or the effects of a disease. For purposes of this invention treatment includes, but is not limited to, alleviation, amelioration or elimination of one or more symptoms of the disease; diminishment of the extent of the disease; stabilized (i.e. not worsening) state of disease; delay or slowing of disease progression; amelioration or palliation of the disease state; and remission of the disease (whether partial or total).

As used herein, "prevention" refers to preventing the occurrence of a disease in a subject that is predisposed to or has risk factors but does not yet display symptoms of the disease. Prevention includes also preventing the recurrence of a disease in a subject that has previously suffered said disease. The invention therefore relates to the compounds of formula I as defined above.

In another embodiment, the invention relates to compounds of formula I wherein: Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:

(i) a heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said heterocyclic group can be optionally substituted with one or more Ci_-4 alkyl groups; and (ii) a heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR_aR_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic groups (i) and (ii) can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic. In another embodiment, the invention relates to compounds of formula I wherein R_a and R_b independently represent H or Ci_-4 alkyl.

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

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

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

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

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

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

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

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

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

In another embodiment, the invention relates to compounds of formula I wherein R₁ and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:

wherein R_a and Rb have the meaning described above for compounds of formula I, Rc represents H or Ci_-4 alkyl, preferably H or methyl, more preferably H, and Rd represents H or Ci_-4 alkyl, preferably H or methyl.

In another embodiment, the invention relates to compounds of formula I wherein R₁ and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), and R_a, R_b, R_c and R_d independently represent H or Ci_-4 alkyl, preferably R_a, Rb, Rc and Rd independently represent H or methyl, and more preferably R_a, Rb and Rd independently represent H or methyl and R_c represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R_a and R_b have the meaning previously described for the compounds of formula I; and R_c represents H or C-_I-4 alkyl, preferably H.

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

In another embodiment, the invention relates to the compounds of formula I wherein R₁ and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), R_a represents H, R_b represents H or C_1-4 alkyl and R_c represents H.

In another embodiment, the invention relates to the compounds of formula I wherein R₁ and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), R₃ represents H, R_b represents H or methyl and R_c represents H. In another embodiment, the invention relates to the compounds of formula I wherein R₁ and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), R_a represents H, R_b represents methyl and R_c represents H.

In another embodiment, the invention relates to the compounds of formula I wherein R₁ and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), and R₃, R_b and R_c represent H.

In another embodiment, the invention relates to compounds of formula I wherein R₁ and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a)

(a) wherein R_a and R_b have the meaning previously described for the compounds of formula I and R_c represents H or Ci_-4 alkyl, and preferably R_c represents H.

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

In another embodiment, the invention relates to the compounds of formula I wherein Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), R_a represents H, R_b represents H or C-I_-4 alkyl and R_c represents H.

In another embodiment, the invention relates to the compounds of formula I wherein Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), R₃ represents H, R_b represents H or methyl and R_c represents H. In another embodiment, the invention relates to the compounds of formula I wherein Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), R_a represents H, R_b represents methyl and Rc represents H.

In another embodiment, the invention relates to the compounds of formula I wherein Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), and R₃, R_b and R_c represents H.

In another embodiment, the invention relates to compounds of formula I wherein R₁ and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b)

(b) wherein R_a and R_b have the meaning previously described for the compounds of formula I and R_c represents H or Ci_-4 alkyl, and preferably R_c represents H.

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

In another embodiment, the invention relates to the compounds of formula I wherein Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), R_a represents H, R_b represents H or C-I_-4 alkyl and R_c represents H.

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

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

In another embodiment, the invention relates to compounds of formula I wherein R₁ represents H or Ci_-4 alkyl and R₂ represents azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, which can be optionally substituted with one or more Ci_-4 alkyl groups.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents 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 R₃ is H.

In another embodiment, the invention relates to compounds of formula I wherein R₃ is NH₂.

In another embodiment, the invention relates to compounds of formula I wherein R₅ is attached to N¹.

In another embodiment, the invention relates to compounds of formula I wherein R₅ is attached to N². In another embodiment, the invention relates to compounds of formula I wherein R₅ is attached to N¹ ; and either R₄ represents R₆ and R₅ represents R₇, or R₄ represents R₇ and R₅ represents R₈.

In another embodiment, the invention relates to compounds of formula I wherein R₅ is attached to N¹ ; either R₄ represents R₆ and R₅ represents R₇, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups.

In another embodiment, the invention relates to compounds of formula I wherein R₅ is attached to N¹ ; R₄ represents R₆; and R₅ represents R₇.

In another embodiment, the invention relates to compounds of formula I wherein R₅ is attached to N¹ ; either R₄ represents R₇ and R₅ represents R₈, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups.

In another embodiment, the invention relates to compounds of formula I wherein R₅ is attached to N¹ ; R₄ represents R₇; and R₅ represents R₈. In another embodiment, the invention relates to compounds of formula I wherein R₅ is attached to N¹ ; and R₄ and R₅ are bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups. In another embodiment, the invention relates to compounds of formula I wherein R₅ is attached to N¹ ; and R₄ and R₅ are bonded together to form a - C₄alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups. In another embodiment, the invention relates to compounds of formula I wherein R₆ represents H, Ci-H alkyl, C_3-8 cycloalkyl-C₀-n alkyl, C_3-8 heterocycloalkyl-Co-11 alkyl, aryl-d-n alkyl, heteroaryl-d-n alkyl, aryl-NH-C₀-n alkyl, heteroaryl-NH-C₀-n alkyl, R₉-C₀-H alkyl or Ri₀- W-C₀-H alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro), and any cycloalkyl and heterocycloalkyl groups can be optionally substituted with one or more substituents independently selected from Ci-6 alkyl, halogen, aryl and R₉

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents H, Ci-n alkyl, C_3-8 cycloalkyl-Co-n alkyl, C_3-8 heterocycloalkyl-Cc-π alkyl, aryl-Ci-n alkyl, heteroaryl-Ci-n alkyl, aryl-NH-C₀-n alkyl, heteroaryl-NH-C₀-π alkyl, R₉-C₀-H alkyl or Ri₀- W-C₀-H alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents H, Ci-π alkyl, C₃.₈ cycloalkyl-C₀-π alkyl, R₉-C₀-_H alkyl or Ri₀-W-C₀-H alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro), and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci-₆ alkyl, halogen, aryl and R₉

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents H, Ci-π alkyl, C₃.₈ cycloalkyl-C₀-n alkyl, R₉-C₀-H alkyl or R₁₀-W-C₀-H alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents Ci-n alkyl, C₃.₈ cycloalkyl-C₀-π alkyl, R₉-C₀-H alkyl or Ri₀- W-C₀-H alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro), and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci-6 alkyl, halogen, aryl and R₉

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents Ci-n alkyl, C₃.₈ cycloalkyl-C₀-π alkyl, R₉-C₀-H alkyl or Ri₀- W-Co-11 alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents H, C-i-n alkyl or C₃-8 cycloalkyl-Co-n alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro), and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents H, C-i-n alkyl or C₃-8 cycloalkyl-C₀-n alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents Ci_-H alkyl or C_3-8 cycloalkyl-Co-n alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro), and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents Ci-n alkyl or C₃-8 cycloalkyl-C₀-n alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents d-n alkyl or C_3-8 cycloalkyl, preferably Ci_-6 alkyl or C_3-6 cycloalkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro), and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents Ci-n alkyl or C_3-8 cycloalkyl, preferably Ci_-6 alkyl or C_3-6 cycloalkyl. In another embodiment, the invention relates to compounds of formula I wherein R₆ represents Ci_-H alkyl or C_3-8 cycloalkyl, preferably Ci_-6 alkyl or C_3-6 cycloalkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro), and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl and halogen

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents Ci-n alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro). In another embodiment, the invention relates to compounds of formula I wherein R₆ represents Ci_-H alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents Ci_-6 alkyl. In another embodiment, the invention relates to compounds of formula I wherein R₆ represents C_3-8 cycloalkyl-Co-n alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro), and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉. In another embodiment, the invention relates to compounds of formula I wherein R₆ represents C_3-8 cycloalkyl, which can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents C_3-8 cycloalkyl, which can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl and halogen.

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents C_3-8 cycloalkyl, preferably C_3-6 cycloalkyl. .

In another embodiment, the invention relates to compounds of formula I wherein R₆ represents cyclobutyl. In another embodiment, the invention relates to compounds of formula I wherein R₆ represents Rio-W-C_O-n alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro).

In another embodiment, the invention relates to compounds of formula I wherein R₇ represents H, Ci_-6 alkyl or C_3-8 cycloalkyl-Co-e alkyl. In another embodiment, the invention relates to compounds of formula I wherein R₇ represents H or Ci_-6 alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₇ represents H, methyl or ethyl.

In another embodiment, the invention relates to compounds of formula I wherein R₇ represents H or methyl.

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

In another embodiment, the invention relates to compounds of formula I wherein R₇ represents Ci_-6 alkyl, preferably methyl.

In another embodiment, the invention relates to compounds of formula I wherein R₇ represents C_3-8 cycloalkyl-Co-6 alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₇ represents Ci_-6 alkoxy-Ci_-6 alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₈ represents C₃-₈ cycloalkyl-Co-n alkyl, aryl-Co-n alkyl or R₉-C₂-H alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro), and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉

In another embodiment, the invention relates to compounds of formula I wherein R₈ represents C₃-₈ cycloalkyl-Co-n alkyl, aryl-C₀-n alkyl or R₉-C₂-H alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₈ represents C₃.₈ cycloalkyl-Co-n alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro), and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉.

In another embodiment, the invention relates to compounds of formula I wherein R₈ represents aryl-C₀-n alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro).

In another embodiment, the invention relates to compounds of formula I wherein R₈ represents aryl-d-n alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro). In another embodiment, the invention relates to compounds of formula I wherein R₈ represents aryl-C_2-4 alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro).

In another embodiment, the invention relates to compounds of formula I wherein R₈ represents R₉-C_2-H alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro).

In another embodiment, the invention relates to compounds of formula I wherein R₈ represents Ri₀-W-C₂-H alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro). In another embodiment, the invention relates to compounds of formula I wherein R₉ represents -CO₂Rn, -CONR₁₁ R₁₁ or -SO₂R₁₁.

In another embodiment, the invention relates to compounds of formula I wherein R₁₀ represents C_1-11 alkyl, C₃-8 cycloalkyl-Co-n alkyl, aryl-C₀-n alkyl or R₉- C_1-11 alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from C_1-6 alkyl, halogen (preferably fluoro), aryl and R₉.

In another embodiment, the invention relates to compounds of formula I wherein W is O.

In another embodiment, the invention relates to compounds of formula I wherein R₁₁ represents H or C_1-6 alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₈ represents R₉-C_2-11 alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro); and R₉ represents -CO₂R₁₁, -CONR₁₁ R₁₁ or -SO₂R₁₁.

In another embodiment, the invention relates to compounds of formula I wherein R₁₀ represents R₉-C_1-11 alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro); and R₉ represents -CO₂R₁₁, -CONR₁₁ R₁₁ or -SO₂R₁₁.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; and R₅ is attached to N¹.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; and either R₄ represents R₆ and R₅ represents R₇, or R₄ represents R₇ and R₅ represents R₈.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; R₅ represents R₇; or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more C_1-8 alkyl groups. In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; and R₅ represents R₇.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₇; R₅ represents R₈; or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₇; and R₅ represents R₈.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; and R₄ and R₅ are bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; R₅ represents

R₇; or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; R₆ represents H, Ci_-H alkyl, C_3-8 cycloalkyl-Co-11 alkyl, R₉-C₀-H alkyl or Ri₀- W-Co-11 alkyl; and Ri₀ represents Ci-π alkyl, C_3-8 cycloalkyl-Co-π alkyl, aryl-Co-π alkyl or R9-C1-11 alkyl, wherein in R₆ and Ri₀ any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen (preferably fluoro), aryl and R₉.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; R₅ represents R₇; and R₆ represents H, Ci-π alkyl, C₃-s cycloalkyl-Co-π alkyl, R₉-C_0-H alkyl or Ri₀- W-C_0-H alkyl; and Ri₀ represents Ci-π alkyl, C₃.₈ cycloalkyl-Co-π alkyl, aryl-Co-π alkyl or R₉-C_{M 1} alkyl, wherein in R₆ and Ri₀ any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen (preferably fluoro), aryl and R₉.

R₇; or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; and R₆ represents H,

C1-11 alkyl or C_3-8 cycloalkyl-Co-π alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro), and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; Rs is attached to N¹ ; R₄ represents R₆; Rs represents R₇; and R₆ represents H, Ci-H alkyl or C_3-8 cycloalkyl-C₀-n alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉. In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; Rs is attached to N¹ ; R₄ represents R₆; R₅ represents R₇; or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; and R₆ represents Ci- ₁₁ alkyl or C_3-8 cycloalkyl, preferably Ci_-6 alkyl or C_3-6 cycloalkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro), and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; R₅ represents R₇; and R₆ represents Ci-H alkyl or C_3-8 cycloalkyl, preferably Ci_-6 alkyl or C_3-6 cycloalkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro), and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉ In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; R₅ represents R₇; and R₆ represents C_3-8 cycloalkyl, preferably C_3-6 cycloalkyl, wherein any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉, and more preferably R₆ represents cyclobutyl.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; R₅ represents R₇; and R₆ represents C_3-8 cycloalkyl, preferably C_3-6 cycloalkyl, which can be optionally substituted with one or more substituents independently selected from C-₁-₆ alkyl and halogen.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R5 is attached to N¹ ; R₄ represents R₆; R5 represents R₇; and R₆ represents C_3-8 cycloalkyl, preferably C_3-6 cycloalkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R5 is attached to N¹ ; R₄ represents R₆; R₅ represents R₇; and R₆ represents cyclobutyl

R₇; or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; and R₇ represents H,

C-_I-6 alkyl or C_3-8 cycloalkyl-C₀-₆ alkyl.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; R₅ represents R₇; and R₇ represents H, Ci_-6 alkyl or C_3-8 cycloalkyl-C₀-₆ alkyl.

R₇; or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; and R₇ represents H or Ci_-6 alkyl, preferably H or methyl.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; R₅ represents R₇; and R₇ represents H or Ci_-6 alkyl, preferably H or methyl. In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; R₅ represents R₇; or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; and R₇ represents Ci- 6 alkyl, preferably methyl. In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; R₅ represents R₇; and R₇ represents Ci_-6 alkyl, preferably methyl.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₇; R₅ represents R₈; or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; and R₈ represents C_3- ₈ cycloalkyl-Co-ii alkyl, aryl-Co-n alkyl or R9-C2-11 alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro), and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₇; R₅ represents R₈; and R₈ represents C_3-8 cycloalkyl-Co-n alkyl, aryl-C_0-n alkyl or R₉-C_2-H alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro), and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉. In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₇; R₅ represents R₈; and R₈ represents aryl-Co-11 alkyl, preferably aryl-C-i-n alkyl and more preferably aryl-C_2-4 alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro). In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₇; R₅ represents R₈; or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; and R₇ represents H or C-ι-6 alkyl, preferably H, methyl or ethyl. In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₇; R₅ represents R₈; and R₇ represents H or Ci_-6 alkyl, preferably H, methyl or ethyl.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₇; R₅ represents R₈; or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; and R₇ represents H.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₇; R₅ represents R₈; and R₇ represents H.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R5 is attached to N¹ ; R₆ represents H, C-i-n alkyl, C_3-8 cycloalkyl-Co-11 alkyl, R9-C0-11 alkyl or R-ιo-W-Co-11 alkyl; R₇ represents H, Ci_-6 alkyl or C_3-8 cycloalkyl-Co-6 alkyl; R₈ represents C_3-8 cycloalkyl-Co-11 alkyl, aryl-Co-n alkyl or R₉-C₂-H alkyl; and Ri₀ represents C-i-n alkyl, C₃-₈ cycloalkyl-C₀-n alkyl, aryl-C₀-n alkyl or R₉-C_M 1 alkyl; wherein in R₆, R₈ and R-m any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen (preferably fluoro), aryl and R₉.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R5 is attached to N¹ ; and either R₄ represents R₆ and

R₅ represents R₇, or R₄ represents R₇ and R₅ represents R₈; R₆ represents H, C-i-n alkyl, C₃-₈ cycloalkyl-C₀-n alkyl, R₉-C₀-H alkyl or R₁₀-W-C₀-n alkyl; R₇ represents H, C-I_-6 alkyl or C_3-8 cycloalkyl-C₀-₆ alkyl; R₈ represents C_3-8 cycloalkyl-Co-11 alkyl, aryl-

Co-11 alkyl or R₉-C₂-H alkyl; and R-m represents C-i-n alkyl, C₃-₈ cycloalkyl-C₀-n alkyl, aryl-Co-11 alkyl or R₉-Ci-H alkyl; wherein in R₆, R₈ and R-m any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci-₆ alkyl, halogen (preferably fluoro), aryl and R₉.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₆ represents H, Ci_-H alkyl or C_3- s cycloalkyl-Co-11 alkyl; R₇ represents H or Ci-₆ alkyl; and R₈ represents aryl-C₀-π alkyl; wherein in R₆ and R₈ any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro)

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; and either R₄ represents R₆ and R₅ represents R₇, or R₄ represents R₇ and R₅ represents R₈; R₆ represents H, Ci-π alkyl or C₃-₈ cycloalkyl-C₀-π alkyl; R₇ represents H or Ci-₆ alkyl; and R₈ represents aryl-Co-₁₁ alkyl; wherein in R₆ and R₈ any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro)

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; R₅ represents R₇; or R₄ and R₅ can be bonded together to form a -C₃-₅ alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; R₆ represents H, Ci_-H alkyl or C₃-8 cycloalkyl-Co-n alkyl; and R₇ represents H, Ci_-6 alkyl or C_3-8 cycloalkyl- Co-11 alkyl; wherein in group R₆ any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci-6 alkyl, halogen (preferably fluoro), aryl and R₉.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R5 is attached to N¹ ; R₄ represents R₆; R₅ represents R₇; R₆ represents H, d-n alkyl or C₃-₈ cycloalkyl-C₀-n alkyl; and R₇ represents H, Ci-6 alkyl or C_3-8 cycloalkyl-C₀-₆ alkyl; wherein in R₆ any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen (preferably fluoro), aryl and R₉. In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; R₅ represents R₇; or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; R₆ represents Ci_-H alkyl or C₃-₈ cycloalkyl-C₀-n alkyl; and R₇ represents H, Ci_-6 alkyl or C_3-8 cycloalkyl- Co-11 alkyl; wherein in group R₆ any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci-6 alkyl, halogen (preferably fluoro), aryl and R₉.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; R₅ represents R₇; R₆ represents Ci-H alkyl or C₃-₈ cycloalkyl-C₀-n alkyl; and R₇ represents H, Ci_-6 alkyl or C_3-8 cycloalkyl-C₀-₆ alkyl; wherein in R₆ any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen (preferably fluoro), aryl and R₉.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; R₅ represents R₇; or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; R₆ represents Ci_-H alkyl or C3-8 cycloalkyl-C0.11 alkyl; and R₇ represents H or Ci_-6 alkyl, preferably H or methyl, and more preferably methyl; wherein in group R₆ any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen (preferably fluoro), aryl and R₉.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R5 is attached to N¹ ; R₄ represents R₆; R₅ represents R₇; R₆ represents d-n alkyl or C_3-8 cycloalkyl-Co-11 alkyl; and R₇ represents H or C₁-₆ alkyl, preferably H or methyl, and more preferably methyl; wherein in R₆ any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen (preferably fluoro), aryl and R₉. In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R5 is attached to N¹ ; R₄ represents R₆; R₅ represents R₇; R₆ represents C_3-8 cycloalkyl-Co-11 alkyl; and R₇ represents H or Ci_-6 alkyl, preferably H or methyl, and more preferably methyl; wherein in R₆ any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro) and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen (preferably fluoro), aryl and R₉.

In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; R₅ represents R₇; R₆ represents C_3-8 cycloalkyl, preferably C_3-8 cycloalkyl, and more preferably cyclobutyl; and R₇ represents H or Ci_-6 alkyl, preferably H or methyl, and more preferably methyl; wherein any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen (preferably fluoro), aryl and R₉. In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; R₅ represents R₇; R₆ represents cyclobutyl; and R₇ represents H or Ci_-6 alkyl, preferably H or methyl, and more preferably methyl. In another embodiment, the invention relates to compounds of formula I wherein R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₇; R₅ represents R₈; and R₇ represents H or Ci_-6 alkyl, preferably H, methyl or ethyl, and more preferably H; and R₈ represents aryl-Co-n alkyl, preferably aryl-C-i-n alkyl and more preferably aryl-C₂-₄ alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms (preferably fluoro).

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

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

R₃ represents NH₂; and R₅ is attached to N¹.

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

R₃ represents NH₂; R₅ is attached to N¹.

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

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

R₃ represents NH₂; and R₅ is attached to N¹.

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

Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), and R₃, Rb and R_c independently represent H or Ci_-4 alkyl, preferably R₃, R_b and R_c independently represent H or methyl, and more preferably R_a and Rb independently represent H or methyl and R_c represents H; R₃ represents NH₂; and R₅ is attached to N¹. 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_a and R_b have the meaning described above for compounds of formula I and R_c represents H or Ci_-4 alkyl, and preferably R_c represents H;

R₃ represents NH₂; and R₅ is attached to N¹.

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_a, R_b and R_c independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R_c independently represent H or methyl, and more preferably R_a and Rb independently represent H or methyl and Rc represents H; R₃ represents NH₂; and

R₅ is attached to N¹.

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 (b) wherein R_a and R_b have the meaning described above for compounds of formula I and R_c represents H or Ci_-4 alkyl, and preferably Rc represents H; R₃ represents NH₂; and

R₅ is attached to N¹.

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 (b) wherein R_a, R_b and R_c independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R_c independently represent H or methyl, and more preferably R_a and Rb independently represent H or methyl and Rc represents H;

R₃ represents NH₂; and R₅ is attached to N¹.

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

(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_aR_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic groups (i) and (ii) can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; R₃ represents NH₂; R₅ is attached to N¹ ; either R₄ represents R₆ and R₅ represents R₇, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups.

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 which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR_aR_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic group can be 4- to 7-membered monocyclic, 7- to 8- membered bridged bicyclic or 8- to 12-membered fused bicyclic; R₃ represents NH₂; R₅ is attached to N¹ ; either R₄ represents R₆ and R₅ represents R₇, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups.

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

R₃ represents NH₂; R₅ is attached to N¹ ; either R₄ represents R₆ and R₅ represents R₇, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups.

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

Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), and R_a, Rb and R_c independently represent H or Ci_-4 alkyl, preferably R_a, Rb and R_c independently represent H or methyl, and more preferably R_a and Rb independently represent H or methyl and R_c represents H; R₃ represents NH₂; R₅ is attached to N¹ ; either R₄ represents R₆ and R₅ represents R₇, or R₄ and R₅ can be bonded together to form a -C₃-₅ alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups.

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_a and R_b have the meaning described above for compounds of formula I and R_c represents H or Ci_-4 alkyl, and preferably R_c represents H;

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_a, R_b and R_c independently represent H or Ci_-4 alkyl, and preferably R_a, R_b and R_c independently represent H or methyl, and more preferably R_a and R_b independently represent H or methyl and R_c represents H;

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 (b) wherein R_a and R_b have the meaning described above for compounds of formula I and R_c represents H or Ci_-4 alkyl, and preferably R_c represents H; R₃ represents NH₂; R₅ is attached to N¹ ; either R₄ represents R₆ and R₅ represents R₇, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups.

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 (b), wherein R_a, R_b and R_c independently represent H or Ci_-4 alkyl, and preferably R₃, Rb and R_c independently represent H or methyl, and more preferably R₃ and R_b independently represent H or methyl and R_c represents H;

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

(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_aR_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic groups (i) and (ii) can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; and

R₅ represents R₇.

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 which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR_aR_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic group can be 4- to 7-membered monocyclic, 7- to 8- membered bridged bicyclic or 8- to 12-membered fused bicyclic; R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; and R₅ represents R₇.

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

Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R_a and R_b have the meaning described above for compounds of formula I and R_c represents H or Ci_-4 alkyl and preferably R_c represents H; R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; and R₅ represents R₇.

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

Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), and R₃, Rb and R_c independently represent H or Ci_-4 alkyl, preferably R₃, Rb and R_c independently represent H or methyl, and more preferably R₃ and R_b independently represent H or methyl and R_c represents H; R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; and

R₅ represents R₇.

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_a and R_b have the meaning described above for compounds of formula I and R_c represents H or Ci_-4 alkyl, and preferably R_c represents H; R₃ represents NH₂;

R₅ is attached to N¹ ; R₄ represents R₆; and R₅ represents R₇.

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_a, R_b and R_c independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R_c independently represent H or methyl, and more preferably R_a and R_b independently represent H or methyl and R_c represents H;

R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; and R₅ represents R₇. 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 (b) wherein R_a and R_b have the meaning described above for compounds of formula I and R_c represents H or Ci_-4 alkyl, and preferably R_c represents H; R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; and R₅ represents R₇. 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 (b) wherein R_a, R_b and R_c independently represent H or Ci_-4 alkyl, and preferably R_a, R_b and R_c independently represent H or methyl, and more preferably R_a and R_b independently represent H or methyl and Rc represents H, and still more preferably R_a represents H, R_b represents methyl and R_c represents H; R₃ represents NH₂;

R₅ is attached to N¹ ; R₄ represents R₆; and R₅ represents R₇.

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

(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_aR_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic groups (i) and (ii) can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; R₃ represents NH₂; R₅ is attached to N¹ ; and R₄ and R₅ are bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups. 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 which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR_aR_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic group can be 4- to 7-membered monocyclic, 7- to 8- membered bridged bicyclic or 8- to 12-membered fused bicyclic; R₃ represents NH₂; R₅ is attached to N¹ ; and R₄ and R₅ are bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups.

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

Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R_a and R_b have the meaning described above for compounds of formula I and R_c represents H or Ci_-4 alkyl and preferably R_c represents H; R₃ represents NH₂;

R₅ is attached to N¹ ; and R₄ and R₅ are bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups.

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

Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), and R₃, Rb and R_c independently represent H or Ci_-4 alkyl, preferably R₃, R_b and R_c independently represent H or methyl, and more preferably R_a and Rb independently represent H or methyl and R_c represents H; R₃ represents NH₂; R₅ is attached to N¹ ; and R₄ and R₅ are bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups. 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 R₃ and Rb have the meaning described above for compounds of formula I and R_c represents H or Ci_-4 alkyl, and preferably R_c represents H; R₃ represents NH₂; R₅ is attached to N¹ ; and R₄ and R₅ are bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups.

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_a, R_b and R_c independently represent H or Ci_-4 alkyl, and preferably R_a, R_b and R_c independently represent H or methyl, and more preferably R₃ and R_b independently represent H or methyl and Rc represents H;

R₃ represents NH₂; R₅ is attached to N¹ ; and R₄ and R₅ are bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups.

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

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 (b), wherein R_a, R_b and R_c independently represent H or Ci_-4 alkyl, and preferably R_a, R_b and R_c independently represent H or methyl, and more preferably R_a and R_b independently represent H or methyl and Rc represents H; R₃ represents NH₂;

R₅ is attached to N¹ ; and R₄ and R₅ are bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups. In another embodiment, the invention relates to compounds of formula I wherein:

(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_aR_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic groups (i) and (ii) can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; R₃ represents NH₂; R₅ is attached to N¹ ; and either R₄ represents R₇ and R₅ represents R₈, or R₄ and R₅ can be bonded together to form a -C₃-₅ alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups.

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 which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR_aR_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic group can be 4- to 7-membered monocyclic, 7- to 8- membered bridged bicyclic or 8- to 12-membered fused bicyclic; R₃ represents NH₂; R₅ is attached to N¹ ; and either R₄ represents R₇ and R₅ represents R₈, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups.

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

R₃ represents NH₂; R₅ is attached to N¹ ; and either R₄ represents R₇ and R₅ represents R₈, or R₄ and R₅ can be bonded together to form a -C₃-₅ alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups.

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

Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), and R_a, Rb and R_c independently represent H or Ci_-4 alkyl, preferably R_a, Rb and R_c independently represent H or methyl, more preferably R_a and R_b independently represent H or methyl and R_c represents H; R₃ represents NH₂; R₅ is attached to N¹ ; and either R₄ represents R₇ and R₅ represents R₈, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups.

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_a and R_b have the meaning described above for compounds of formula I and R_c represents H or Ci_-4 alkyl, and preferably R_c represents H; R₃ represents NH₂; R₅ is attached to N¹ ; and either R₄ represents R₇ and R₅ represents R₈, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups.

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_a, R_b and R_c independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R_c independently represent H or methyl, and more preferably R_a and Rb independently represent H or methyl and R_c represents H;

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 (b), wherein R_a and R_b have the meaning described above for compounds of formula I and R_c represents H or Ci_-4 alkyl, and preferably R_c represents H; R₃ represents NH₂; R₅ is attached to N¹ ; and either R₄ represents R₇ and R₅ represents R₈, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups.

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 (b), wherein R_a, R_b and R_c independently represent H or Ci_-4 alkyl, and preferably R_a, R_b and R_c independently represent H or methyl, and more preferably R_a and Rb independently represent H or methyl and Rc represents H;

R₃ represents NH₂; R₅ is attached to N¹ ; and either R₄ represents R₇ and R₅ represents R₈, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups. In another embodiment, the invention relates to compounds of formula I wherein:

(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_aR_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic groups (i) and (ii) can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; R₃ represents NH₂; R₅ is attached to N¹ ; and R₄ represents R₇ and R₅ represents R₈.

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

R₃ represents NH₂; R₅ is attached to N¹ ; and

R₄ represents R₇ and R₅ represents R₈.

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

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

R₃ represents NH₂; R₅ is attached to N¹ ; and R₄ represents R₇ and R₅ represents R₈.

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_a and R_b have the meaning described above for compounds of formula I, preferably R_a and R_b independently represent H or Ci_-4 alkyl; and R_c represents H or Ci_-4 alkyl, preferably H. More preferably R_a, Rb and R_c independently represent H or methyl, and even more preferably R_a and Rb independently represent H or methyl and R_c represents H;

R₃ represents NH₂; R₅ is attached to N¹ ; and

R₄ represents R₇ and R₅ represents R₈.

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 (b), wherein R_a and Rb have the meaning described above for compounds of formula I, preferably R_a and Rb independently represent H or Ci_-4 alkyl; and R_c represents H or Ci_-4 alkyl, preferably H. More preferably R₃, R_b and R_c independently represent H or methyl, and even more preferably R₃ and R_b independently represent H or methyl and R_c represents H; R₃ represents NH₂;

R₅ is attached to N¹ ; and R₄ represents R₇ and R₅ represents R₈.

(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_aR_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic groups (i) and (ii) can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; R₃ represents NH₂; R₅ is attached to N¹ ; either R₄ represents R₆ and R₅ represents R₇, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; and

R₆ represents C-i-n alkyl, preferably Ci_-6 alkyl.

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 which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR_aR_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic group can be 4- to 7-membered monocyclic, 7- to 8- membered bridged bicyclic or 8- to 12-membered fused bicyclic; R₃ represents NH₂; R₅ is attached to N¹ ; either R₄ represents R₆ and R₅ represents R₇, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; and

R₆ represents Ci_-H alkyl, preferably Ci_-6 alkyl.

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

Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R_a and R_b have the meaning described above for compounds of formula I and R_c represents H or Ci_-4 alkyl and preferably R_c represents H; R₃ represents NH₂; R₅ is attached to N¹ ; either R₄ represents R₆ and R₅ represents R₇, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; and R₆ represents C-i-n alkyl, preferably Ci_-6 alkyl.

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

Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), and R₃, Rb and R_c independently represent H or Ci_-4 alkyl, preferably R₃, R_b and R_c independently represent H or methyl, more preferably R_a and Rb independently represent H or methyl and R_c represents H; R₃ represents NH₂; R₅ is attached to N¹ ; either R₄ represents R₆ and R₅ represents R₇, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; and

R₆ represents Ci_-H alkyl, preferably Ci_-6 alkyl.

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_a and R_b have the meaning described above for compounds of formula I and R_c represents H or Ci_-4 alkyl, and preferably R_c represents H; R₃ represents NH₂;

R₅ is attached to N¹ ; either R₄ represents R₆ and R₅ represents R₇, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; and R₆ represents Ci-n alkyl, preferably Ci_-6 alkyl.

R₃ represents NH₂; R₅ is attached to N¹ ; either R₄ represents R₆ and R₅ represents R₇, or R₄ and R₅ can be bonded together to form a -C₃-₅ alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; and

R₆ represents C-i-n alkyl, preferably Ci_-6 alkyl.

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 (b), wherein R_a and R_b have the meaning described above for compounds of formula I and R_c represents H or Ci_-4 alkyl, and preferably R_c represents H; R₃ represents NH₂; R₅ is attached to N¹ ; either R₄ represents R₆ and R₅ represents R₇, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; and

R₆ represents C-i-n alkyl, preferably Ci_-6 alkyl.

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 (b), wherein R_a, R_b and R_c independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R_c independently represent H or methyl, and more preferably R_a and Rb independently represent H or methyl and R_c represents H;

R₃ represents NH₂;

R₅ is attached to N¹ ; either R₄ represents R₆ and R₅ represents R₇, or R₄ and R₅ can be bonded together to form a -C₃-₅ alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; and

R₆ represents C-i-n alkyl, preferably Ci_-6 alkyl.

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

R₆ represents C_3-8 cycloalkyl-Co-n alkyl, preferably C_3-8 cycloalkyl, more preferably C_3-6 cycloalkyl, and still more preferably cyclobutyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms, and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉.

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 which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR_aR_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic group can be 4- to 7-membered monocyclic, 7- to 8- membered bridged bicyclic or 8- to 12-membered fused bicyclic; R₃ represents NH₂; R₅ is attached to N¹ ; either R₄ represents R₆ and R₅ represents R₇, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; and

R₆ represents C_3-8 cycloalkyl-C₀-n alkyl, preferably C_3-8 cycloalkyl, more preferably C_3-6 cycloalkyl, and still more preferably cyclobutyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms, and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉.

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

Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R_a and R_b have the meaning described above for compounds of formula I and R_c represents H or Ci_-4 alkyl and preferably R_c represents H; R₃ represents NH₂; R₅ is attached to N¹ ; either R₄ represents R₆ and R₅ represents R₇, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; and

R₆ represents C_3-8 cycloalkyl-C₀-n alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms, and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉.

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

Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), and R_a, Rb and R_c independently represent H or Ci_-4 alkyl, preferably R_a, R_b and R_c independently represent H or methyl, more preferably R₃ and R_b independently represent H or methyl and R_c represents H; R₃ represents NH₂; R₅ is attached to N¹ ; either R₄ represents R₆ and R₅ represents R₇, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; and R₆ represents C_3-8 cycloalkyl-C₀-n alkyl, preferably C_3-8 cycloalkyl, more preferably C_3-6 cycloalkyl, and still more preferably cyclobutyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms, and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉. 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_a and Rb have the meaning described above for compounds of formula I and R_c represents H or Ci_-4 alkyl, and preferably R_c represents H; R₃ represents NH₂; R₅ is attached to N¹ ; either R₄ represents R₆ and R₅ represents R₇, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; and

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

R₃ represents NH₂; R₅ is attached to N¹ ; either R₄ represents R₆ and R₅ represents R₇, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; and R₆ represents C_3-8 cycloalkyl-C₀-n alkyl, preferably C_3-8 cycloalkyl, more preferably C_3-6 cycloalkyl, and still more preferably cyclobutyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms, and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉. 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 (b), wherein R_a and Rb have the meaning described above for compounds of formula I and R_c represents H or Ci_-4 alkyl, and preferably R_c represents H;

R₃ represents NH₂;

R₅ is attached to N¹ ; either R₄ represents R₆ and R₅ represents R₇, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; and

R₆ represents C_3-8 cycloalkyl-C₀-n alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms, and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from C-_I-6 alkyl, halogen, aryl and R₉. 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 (b), wherein R_a, R_b and R_c independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R_c independently represent H or methyl, and more preferably R_a and Rb independently represent H or methyl and Rc represents H;

R₃ represents NH₂;

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

(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_aR_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic groups (i) and (ii) can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₇; R₅ represents R₈; and R₈ represents aryl-Co-n alkyl, preferably aryl-d-n alkyl and more preferably aryl -C_2-4 alkyl.

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 which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR_aR_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic group can be 4- to 7-membered monocyclic, 7- to 8- membered bridged bicyclic or 8- to 12-membered fused bicyclic; R₃ represents NH₂; R₅ is attached to N¹ ; and R₄ represents R₇; R₅ represents R₈; and

R₈ represents aryl-C₀-n alkyl, preferably aryl-C-i-n alkyl and more preferably aryl-C₂-₄ alkyl.

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) and (b), wherein R_a and Rb have the meaning described above for compounds of formula I, preferably R_a and Rb independently represent H or Ci_-4 alkyl; and R_c represents H or Ci_-4 alkyl, preferably H. More preferably R_a, R_b and R_c independently represent H or methyl, and even more preferably R₃ and R_b independently represent H or methyl and R_c represents H;

R₃ represents NH₂; R₅ is attached to N¹ ; and R₄ represents R₇; R₅ represents R₈; and

R₈ represents aryl-C₀-n alkyl, preferably aryl-C-i-n alkyl and more preferably ary I -C_2-4 alkyl.

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_a and R_b have the meaning described above for compounds of formula I, preferably R_a and Rb independently represent H or Ci_-4 alkyl; and R_c represents H or Ci_-4 alkyl, preferably H. More preferably R_a, Rb and R_c independently represent H or methyl, and even more preferably R_a and R_b independently represent H or methyl and R_c represents H; R₃ represents NH₂; R₅ is attached to N¹ ; and R₄ represents R₇; R₅ represents R₈; and

R₈ represents aryl-C_0-n alkyl, preferably aryl-C-i-n alkyl and more preferably ary I -C_2-4 alkyl.

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 (b), wherein R_a and R_b have the meaning described above for compounds of formula I, preferably R₃ and R_b independently represent H or Ci_-4 alkyl; and R_c represents H or Ci_-4 alkyl, preferably H. More preferably R₃, R_b and R_c independently represent H or methyl, and even more preferably R_a and R_b independently represent H or methyl and R_c represents H; R₃ represents NH₂; R₅ is attached to N¹ ; and R₄ represents R₇; R₅ represents R₈; and

R₈ represents aryl-Co-n alkyl, preferably aryl-d-n alkyl and more preferably ary I -C_2-4 alkyl.

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

R₃ represents NH₂;

R₅ is attached to N¹ ; either R₄ represents R₆ and R₅ represents R₇, or R₄ and R₅ can be bonded together to form a -C₃-₅ alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups;

R₆ represents H, C-i-n alkyl or C₃-8 cycloalkyl-Co-n alkyl; and R₇ represents H, Ci_-6 alkyl or C_3-8 cycloalkyl-Co-6 alkyl. 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 which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR_aR_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic group can be 4- to 7-membered monocyclic, 7- to 8- membered bridged bicyclic or 8- to 12-membered fused bicyclic; R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆;

R₅ represents R₇;

R₆ represents H, C-i-n alkyl or C₃-₈ cycloalkyl-C₀-n alkyl; and R₇ represents H, Ci_-6 alkyl or C_3-8 cycloalkyl-C₀-₆ alkyl. In another embodiment, the invention relates to compounds of formula I wherein:

R₅ is attached to N¹ ; R₄ represents R₆; R₅ represents R₇;

R₆ represents H, C-i-n alkyl or C₃-₈ cycloalkyl-C₀-n alkyl; and R₇ represents H, Ci_-6 alkyl or C_3-8 cycloalkyl-C₀-₆ alkyl.

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

Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), and R_a, R_b and R_c independently represent H or Ci_-4 alkyl, preferably R_a, R_b and R_c independently represent H or methyl, more preferably R_a and Rb independently represent H or methyl and R_c represents H; R₃ represents NH₂;

R₅ is attached to N¹ ; R₄ represents R₆; R₅ represents R₇;

R₆ represents H, C-i-n alkyl or C₃-8 cycloalkyl-C₀-n alkyl; and R₇ represents H, Ci_-6 alkyl or C_3-8 cycloalkyl-C₀-₆ alkyl.

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_a and R_b have the meaning described above for compounds of formula I and R_c represents H or Ci_-4 alkyl, and preferably R_c represents H; R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; R₅ represents R₇;

R₆ represents H, C-i-n alkyl or C₃-₈ cycloalkyl-C₀-n alkyl; and R₇ represents H, Ci_-6 alkyl or C_3-8 cycloalkyl-C₀-₆ alkyl. 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_a, R_b and R_c independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R_c independently represent H or methyl, and more preferably R_a and Rb independently represent H or methyl and Rc represents H; R₃ represents NH₂;

R₅ is attached to N¹ ; R₄ represents R₆; R₅ represents R₇; R₆ represents H, Ci-H alkyl or C3-8 cycloalkyl-C0.11 alkyl; and R₇ represents H, Ci_-6 alkyl or C₃-₈ cycloalkyl-C₀-₆ alkyl. 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 (b), wherein R_a and R_b have the meaning described above for compounds of formula I and R_c represents H or Ci_-4 alkyl, and preferably R_c represents H;

R₃ represents NH₂; R₅ is attached to N¹ ;

R₄ represents R₆; R₅ represents R₇;

R₆ represents H, C1-11 alkyl or C₃-8 cycloalkyl-Co-n alkyl; and R₇ represents H, Ci_-6 alkyl or C_3-8 cycloalkyl-C₀-₆ alkyl. In another embodiment, the invention relates to compounds of formula I wherein

R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; R₅ represents R₇;

R₆ represents H, Ci-n alkyl or C₃-₈ cycloalkyl-C₀-n alkyl; and R₇ represents H, Ci_-6 alkyl or C_3-8 cycloalkyl-C₀-₆ alkyl. In another embodiment, the invention relates to compounds of formula I wherein: Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:

R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆;

R₅ represents R₇; or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups;

R₆ represents C-i-n alkyl or C_3-8 cycloalkyl-C₀-n alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms, and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉; and

R₇ represents H or Ci_-6 alkyl, preferably H or methyl, more preferably methyl. In another embodiment, the invention relates to compounds of formula I wherein:

R₅ represents R₇; or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; R₆ represents C-i-n alkyl or C_3-8 cycloalkyl-Co-n alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms, and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉; and R₇ represents H or Ci_-6 alkyl, preferably H or methyl, more preferably methyl.

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) and (b), wherein R_a and R_b have the meaning described above for compounds of formula I, preferably R_a and Rb independently represent H or Ci_-4 alkyl; and R_c represents H or Ci_-4 alkyl, preferably H. More preferably R_a, Rb and R_c independently represent H or methyl, and even more preferably R_a and R_b independently represent H or methyl and R_c represents H;

R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; R₅ represents R₇; or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups;

R₇ represents H or Ci_-6 alkyl, preferably H or methyl, more preferably methyl.

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_a and R_b have the meaning described above for compounds of formula I, preferably R₃ and R_b independently represent H or Ci_-4 alkyl; and R_c represents H or Ci_-4 alkyl, preferably H. More preferably R_a, R_b and R_c independently represent H or methyl, and even more preferably R_a and R_b independently represent H or methyl and R_c represents H; R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆;

R₅ represents R₇; or R₄ and R₅ can be bonded together to form a -C₃-₅ alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups;

R₇ represents H or Ci_-6 alkyl, preferably H or methyl, more preferably methyl. 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 (b), wherein R_a and R_b have the meaning described above for compounds of formula I, preferably R_a and R_b independently represent H or Ci_-4 alkyl; and R_c represents H or Ci_-4 alkyl, preferably H. More preferably R_a, R_b and R_c independently represent H or methyl, and even more preferably R_a and R_b independently represent H or methyl and R_c represents H; R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆;

R₆ represents C-i-n alkyl or C_3-8 cycloalkyl-C₀-n alkyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms, and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉; and R₇ represents H or Ci_-6 alkyl, preferably H or methyl, more preferably methyl.

R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; R₅ represents R₇; R₆ represents C_3-8 cycloalkyl-C₀-n alkyl, preferably C_3-8 cycloalkyl, more preferably C_3-6 cycloalkyl and still more preferablyl cyclobutyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms, and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉; and R₇ represents H or Ci_-6 alkyl, preferably H or methyl, more preferably methyl.

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 which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR_aR_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic group can be 4- to 7-membered monocyclic, 7- to 8- membered bridged bicyclic or 8- to 12-membered fused bicyclic; R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; R₅ represents R₇;

R₆ represents C_3-8 cycloalkyl-Co-n alkyl, preferably C_3-8 cycloalkyl, more preferably C_3-6 cycloalkyl and still more preferablyl cyclobutyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms, and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉; and

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) and (b), wherein R_a and R_b have the meaning described above for compounds of formula I, preferably R₃ and R_b independently represent H or Ci_-4 alkyl; and R_c represents H or Ci_-4 alkyl, preferably H. More preferably R_a, Rb and R_c independently represent H or methyl, and even more preferably R_a and Rb independently represent H or methyl and R_c represents H;

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_a and Rb have the meaning described above for compounds of formula I, preferably R_a and Rb independently represent H or Ci_-4 alkyl; and R_c represents H or Ci_-4 alkyl, preferably H. More preferably R_a, R_b and R_c independently represent H or methyl, and even more preferably R₃ and R_b independently represent H or methyl and R_c represents H; R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆;

R₅ represents R₇;

R₆ represents C_3-8 cycloalkyl-C₀-n alkyl, preferably C_3-8 cycloalkyl, more preferably C_3-6 cycloalkyl and still more preferablyl cyclobutyl, wherein any alkyl group can be optionally substituted with one or more halogen atoms, and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉; and

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 (b), wherein R_a and R_b have the meaning described above for compounds of formula I, preferably R₃ and R_b independently represent H or Ci_-4 alkyl; and R_c represents H or Ci_-4 alkyl, preferably H. More preferably R₃, Rb and R_c independently represent H or methyl, and even more preferably R₃ and R_b independently represent H or methyl and R_c represents H; R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₆; R₅ represents R₇;

R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₇;

R₅ represents R₈;

R₇ represents H or Ci_-6 alkyl, preferably H, methyl or ethyl, and more preferably H; and

R₈ represents aryl-Co-n alkyl, preferably aryl-d-n alkyl and more preferably aryl -C_2-4 alkyl.

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 which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one -NR_aR_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic group can be 4- to 7-membered monocyclic, 7- to 8- membered bridged bicyclic or 8- to 12-membered fused bicyclic; R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₇; R₅ represents R₈; R₇ represents H or Ci_-6 alkyl, preferably H, methyl or ethyl, and more preferably H; and

R₈ represents aryl-Co-n alkyl, preferably aryl-d-n alkyl and more preferably aryl-C₂-₄ alkyl.

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) and (b), wherein R_a and Rb have the meaning described above for compounds of formula I, preferably R_a and Rb independently represent H or Ci_-4 alkyl; and R_c represents H or Ci_-4 alkyl, preferably H. More preferably R₃, Rb and R_c independently represent H or methyl, and even more preferably R₃ and R_b independently represent H or methyl and R_c represents H;

R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₇;

R₅ represents R₈;

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 R₃ and Rb have the meaning described above for compounds of formula I, preferably R₃ and R_b independently represent H or Ci_-4 alkyl; and R_c represents H or Ci_-4 alkyl, preferably H. More preferably R₃, R_b and R_c independently represent H or methyl, and even more preferably R₃ and R_b independently represent H or methyl and R_c represents H; R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₇; R₅ represents R₈; R₇ represents H or Ci_-6 alkyl, preferably H, methyl or ethyl, and more preferably H; and

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 (b), wherein R_a and Rb have the meaning described above for compounds of formula I, preferably R_a and Rb independently represent H or Ci_-4 alkyl; and R_c represents H or Ci_-4 alkyl, preferably H. More preferably R₃, Rb and R_c independently represent H or methyl, and even more preferably R₃ and R_b independently represent H or methyl and R_c represents H; R₃ represents NH₂; R₅ is attached to N¹ ; R₄ represents R₇; R₅ represents R₈;

R₈ represents aryl-Co-n alkyl, preferably aryl-d-n alkyl and more preferably ary I -C_2-4 alkyl. Moreover, the present invention includes all possible combinations of the particular and preferred embodiments described above.

In an additional embodiment, the invention relates to a compound of formula I selected from the list of examples 1 -58.

In an additional embodiment, the invention relates to compounds according to formula I which provide more than 50% inhibition of H₄ receptor activity at 10 μM, more preferably at 1 μM and even more preferably at 0.1 μM, in a H₄ receptor assay such as the one described in examples 59 or 60.

The compounds of the present invention contain one or more basic nitrogens and may, therefore, form salts with organic or inorganic acids. Examples of these salts include: salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; and salts with organic acids such as methanesulfonic acid, thfluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, fumaric acid, oxalic acid, acetic acid, maleic acid, ascorbic acid, citric acid, lactic acid, tartaric acid, malonic acid, glycolic acid, succinic acid and propionic acid, among others. The compounds of the present invention may contain one or more acidic protons and, therefore, they may also form salts with bases, which also form part of the present invention. Examples of these salts include: salts with inorganic cations such as sodium, potassium, calcium, magnesium, lithium, aluminium, zinc, etc; and salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxylalkylamines, lysine, arginine, Λ/-methylglucamine, procaine and the like. There is no limitation on the type of salt that can be used, provided that these are pharmaceutically acceptable when used for therapeutic purposes. The term pharmaceutically acceptable salt refers to those salts which are, according to medical judgement, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like. Pharmaceutically acceptable salts are well known in the art.

The salts of a compound of formula I can be obtained during the final isolation and purification of the compounds of the invention or can be prepared by treating a compound of formula I with a sufficient amount of the desired acid to give the salt in a conventional manner. The salts of the compounds of formula I can be converted into other salts of the compounds of formula I by ion exchange using ion exchange resins.

The compounds of formula I and their salts may differ in some physical properties but they are equivalent for the purposes of the present invention. All salts of the compounds of formula I are included within the scope of the invention. The compounds of the present invention may form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as solvates. As used herein, the term solvate refers to a complex of variable stoichiometry formed by a solute (a compound of formula I or a salt thereof) and a solvent. Examples of solvents include pharmaceutically acceptable solvents such as water, ethanol and the like. A complex with water is known as a hydrate. Solvates of compounds of the invention (or salts thereof), including hydrates, are included within the scope of the invention. The compounds of formula I may exist in different physical forms, i.e. amorphous and crystalline forms. Moreover, the compounds of the invention may have the ability to crystallize in more than one form, a characteristic which is known as polymorphism. Polymorphs can be distinguished by various physical properties well known in the art such as X-ray diffraction pattern, melting point or solubility. All physical forms of the compounds of formula I, including all polymorphic forms ("polymorphs") thereof, are included within the scope of the invention.

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

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

Hb wherein R-i, R₂, R3, R₄ and R₅ have the meaning described above with respect to a compound of formula I, and R13 represents a leaving group such as halogen or triflate.

The reaction between the compounds of formulas Il and III may be performed using a coupling agent such as for example PyBOP (benzotriazol-1 -yl- oxythpyrrolidinophosphonium hexafluorophosphate) in a suitable solvent such as 1 ,4-dioxane, tetrahydrofuran, dichloromethane, Λ/,Λ/-dimethylformamide, acetonithle or mixtures thereof, preferably in acetonithle, in the presence of a base, such as Λ/,Λ/-diisopropylethylamine, dimethylaniline, diethylamide, thethylamine or 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably thethylamine. The reaction can be carried out at room temperature or heating, preferably heating. Alternatively the compounds of formula I can be obtained by reacting a compound of formula III with a reactive derivative of the compound of formula Il

(Mb) obtained by conversion of the hydroxy group present in a compound of formula Il into a leaving group such as a halogen or triflate, preferably chloro, following standard procedures.

The -OH group from the compound of formula Il may be transformed into a leaving group such as halogen, preferably chloro, by reaction with a halogenating agent such as POCI₃, optionally in the presence of N,N-diethylaniline or N, N- dimethylaniline, or with POCVPCI₅ in the presence of a suitable solvent such as 1 ,4-dioxane or 1 ,2-dichloroethane. The reaction is performed by heating, preferably at a temperature comprised between 100 ⁰C and 140 ⁰C. The hydroxy group of the compound of formula Il can be transformed into a triflate group by reaction with trifluoromethanesulphonic anhydride in the presence of pyridine.

The reactive derivative of the compound of formula Il thus obtained (Mb) is then allowed to react with a compound of formula III to give a compound of formula I. The reaction is performed in a suitable solvent such as ethanol, methanol, butanol, Λ/,Λ/-dimethylformamide, dimethylsulphoxide, tetrahydrofuran, acetonitrile or toluene, preferably ethanol, in the presence of a base, including organic amines such as thethylamine, Λ/,Λ/-diisopropylethylamine, dimethylaniline and diethylamide among others, or inorganic bases, such as K₂CO₃, and heating, preferably at a temperature comprised between 50 ⁰C and 140 ⁰C. The heating may be thermal or by irradiating with microwaves at a wattage that allows to reach the temperature mentioned above.

In general, before conducting the reaction between the compounds of formula Il and III, or Mb and III, the amino substituents of the compounds of formula III are protected in order to prevent the formation of side products. Any suitable protective group may be used, such as for example a te/t-butoxycarbonyl (Boc) group. A subsequent deprotection step may be necessary when the amino substituents of the compounds of formula Il and/or III and/or Mb are protected, which is carried out under standard conditions. 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 thfluoroacetic acid in dichloromethane. The compounds of formula III are commercial or can be obtained by procedures described in the literature.

The compounds of formula Il can be obtained by reacting a compound of formula IV with either cyanamide or formamide depending on the nature of the substituent R₃ (NH₂ or H) as shown in the following scheme:

wherein R₃, R₄ and R₅ have the meaning described in formula I and Ri₄ represents methyl or ethyl. The reaction with cyanamide takes place in the presence of an acid such as

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

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

The compounds of formula IV can be obtained by reduction of a compound of formula V as shown in the following scheme:

V IV wherein R₄ and R₅ have the meaning described in formula I and R₁₄ represents methyl or ethyl. This reaction may be performed under the standard conditions used for catalytic hydrogenation such as H₂ or ammonium formate in the presence of a catalyst such as palladium-on-carbon.

The compounds of formula V can be obtained by nitration of a compound of formula Vl, as shown in the following scheme:

Vl V

VId wherein R₄ and R₅ have the meaning described in formula I and Ri₄ represents methyl or ethyl. The reaction takes place by reacting the compound of formula Vl with a mixture of nitric and sulfuric acids. This reaction is generally carried out without any additional solvent at a suitable temperature comprised between O ⁵C and reflux temperature, preferably at room temperature after initial addition of acids at O ⁵C. The ester group present in a compound of formula Vl may be hydrolyzed during the nitration step and thus, a subsequent estehfication step may be necessary. The nitration can also be carried out directly from compounds of formula Vl having a carboxylic acid group (i.e a compound of formula VId) under the previously disclosed conditions, although the nitration from acids is preferably carried out heating and more preferably at 60 ⁵C. A subsequent esterification step is performed to give the compound of formula V. The conversion of the carboxylic acid group into the ester can be carried out by reaction with the corresponding alcohol, under standard conditions such as for example HCI in 1 ,4-dioxane, at a temperature between room temperature or heating, preferably heating. Compounds of formula Vl, wherein R₄ represents either R₆ or R₇, and R₅ represents either R₇ or R₈ according to formula I (i.e. compounds of formula Via and VIb) are commercial or can be obtained by reacting a compound of formula VII with a compound of formula VIII as shown in the following scheme:

wherein R₄ and R₅ have the meaning described in formula I and Ri₄ represents methyl or ethyl. This reaction is carried out in a suitable solvent such as ethanol or acetic acid and heating, preferably to reflux.

Compounds of formula VII and formula VIII are commercially available or can be easily obtained from commercial compounds by known methods.

Compounds of formula V wherein R₅ is attached at N¹, and R₄ and R₅ are bonded together to form a -C₃-₅ alkylene- group (i.e., a compound Vc) can be prepared by nitration of a compound of formula VIc as shown in the following scheme:

VIc Vc wherein R₁₄ has the meaning previously disclosed. The reaction can be carried out under the nitration conditions previously disclosed for a compound of formula Vl. Preferably the reaction is performed adding the nitric-sulfuric acid solution over the compound VIc cooled at O ⁵C. In such conditions, deprotection of the ester group does not occur.

The compounds of formula VIc can be prepared by reacting a compound of formula IX with a compound of formula X following the scheme shown below:

ix x vie wherein R₁₄ has the meaning previously disclosed. This reaction can be carried out in a suitable solvent such as xylene and heating, preferably at reflux temperature.

The compounds of formula X are commercial or can be easily obtained from commercial compounds by known methods.

The compounds of formula IX can be obtained from a compound of formula Xl, as shown below:

xi ix Initial nitrosation takes place by adding concentrated HCI to the compound of formula Xl dissolved in water, and treating it with sodium nitrite at a suitable temperature, preferably room temperature. Subsequent addition of trifluoroacetic acid anhydride gives the cyclized compound of formula IX.

The compounds of formula Xl are commercial or can be obtained by procedures described in the literature.

Alternatively, the compounds of formula I wherein R₄ represents either R₆ or R₇, and R₅ represents either R₇ or R₈, according to general formula I (i.e. compounds of formula Ia and Ib) can be obtained by alkylation of a compound of formula I wherein R⁵ represents H (i.e. a compound of formula Ic) with an alkylating agent of formula R⁵-X (XII), as shown in the following scheme:

wherein R₁, R₂, R₃, R₄ and R₅ have the meaning described in general formula I and X represents a leaving group, for example halogen such as Cl, Br or I. This reaction may be carried out in the presence of a base such as Cs₂CO₃, K₂CO₃, NaOH or NaH, preferably NaH, in a suitable solvent, such as for example acetone, toluene, 1 ,2-dimethoxyethane, and preferably dimethylformamide, at a suitable temperature, comprised between room temperature and the reflux temperature, preferably room temperature. In general, the amino substituent (NRiR₂) present in a compound of formula Ic is conveniently protected before conducting the alkylation reaction.

Additionally, the alkylation can also be carried out in a previous step of the process to obtain a compound of formula I. For example, the alkylation can be carried out from a compound of formula V, wherein R₅ is H (i.e. a compound of formula Vd) with an alkylating agent R₅-X (XII) to give a compound of formula V as shown in the following scheme:

Vd XIl V wherein Ri₄ represents methyl or ethyl and X represents a leaving group, for example halogen such as Cl, Br or I. This reaction may be carried out under the alkylation conditions previously disclosed for a compound of formula Ic. It can also be carried out from a compound of formula Vl, wherein R₅ is H (i.e. a compound of formula VIc) with an alkylating agent R₅-X (XII) to give a compound of formula Vl as shown in the following scheme:

VIc XII Vl

wherein Ri₄ represents methyl or ethyl and X represents a leaving group, for example halogen such as Cl, Br or I. This reaction may be carried out again under the alkylation conditions previously disclosed for a compound of formula Ic.

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

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

Diseases mediated by the H₄ receptor that can be treated or prevented with the compounds of the present invention include, among others, allergic, immunological or inflammatory diseases, or pain. Examples of allergic, immunological or inflammatory diseases that can be treated or prevented with the compounds of the invention include without limitation: respiratory diseases, such as asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD); ocular diseases, such as allergic rhinoconjunctivitis, dry eye and cataracts; skin diseases, such as dermatitis (e.g. atopic dermatitis), psoriasis, urticaria and pruritus; inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease; rheumatoid arthritis; multiple sclerosis; cutaneous lupus; systemic lupus erythematosus; and transplant rejection.

Examples of pain conditions that can be treated or prevented with the compounds of the invention include, among others, inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-surgical pain, migraine, cancer pain, visceral pain, osteoarthritis pain and neuropathic pain.

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

Assays to determine the ability of a compound to interact with the histamine H₄ receptor are well known in the art. For example, one can use a H₄ receptor binding assay such as the one explained in detail in example 59. Another useful assay is a GTP [γ-³⁵S] binding assay to membranes that express the H₄ receptor. Functional assays with H₄ receptor-expressing cells can also be used, for example in a system measuring any kind of cellular activity mediated by a second messenger associated with the H₄ receptor such as intracellular cAMP levels or Ca²⁺ mobilization. In this regard, a very useful functional assay that can be used to determine anti-H₄ receptor activity is the Gated Autofluorescence Forward Scatter assay (GAFS) in eosinophils, for example human eosinophils, as disclosed in detail in example 60; this assay is well know in the art (see for example the method disclosed in Buckland KF et al, 2003, cited above in the Background section, which is incorporated herein by reference). In vivo assays that can be used to test the activity of the compounds of the invention are also well known in the art (see for example the various literature references listed for in vivo animal models in the Background section, particularly those relating to in vivo models of peritonitis, pleurisy, allergic asthma, inflammatory bowel disease, atopic dermatitis, pruritus and pain, which are all incorporated herein by reference).

The selectivity profile of the compounds of the invention can be tested using standard histamine receptor binding assays using the various histamine receptors similarly to the one disclosed in example 59. In addition, to test the selectivity for other receptors or ion channels, displacement assays of the corresponding radioligands can be used following the standard procedures reported in the literature (see for example Cerep-Le Bois I'Eveque 2008 catalogue and the references cited therein). To test the selectivity for enzymes, determination of enzymatic activity by product formation from its substrate can be used.

For selecting active compounds, testing at 10 μM must result in an activity of more than 50% inhibition of H₄ receptor activity in the test provided in example 59. More preferably, compounds should exhibit more than 50% inhibition at 1 μM and still more preferably at 0.1 μM in this assay. Preferred compounds should also exhibit potent activity in the GAFS assay of example 60; preferably, compounds should exhibit more than 50% inhibition at 10 μM, more preferably at 1 μM and still more preferably at 0.1 μM in this assay.

Preferred compounds should exhibit selective affinity for the H₄ receptor over other receptors, particularly the H₃, muscarinic, adrenergic, dopamine and serotonine receptors.

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

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

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

Powders and granulates for the preparation of oral suspensions by the additon of water can be obtained by mixing the active compound with dispersing or wetting agents; suspending agents and preservatives. Other excipients can also be added, for example sweetening, flavouring and colouring agents. Liquid forms for oral administration include emulsions, solutions, suspensions, syrups and elixirs containing commonly-used inert diluents, such as purified water, ethanol, sorbitol, glycerol, polyethylene glycols (macrogols) and propylene glycol. Said compositions can also contain coadjuvants such as wetting, suspending, sweetening, flavouring agents, preservatives and buffers. Injectable preparations, according to the present invention, for parenteral administration, comprise sterile solutions, suspensions or emulsions, in an aqueous or non-aqueous solvent such as propylene glycol, polyethylene glycol or vegetable oils. These compositions can also contain coadjuvants, such as wetting, emulsifying, dispersing agents and preservatives. They may be sterilized by any known method or prepared as sterile solid compositions which will be dissolved in water or any other sterile injectable medium immediately before use. It is also possible to start from sterile materials and keep them under these conditions throughout all the manufacturing process.

The compounds of the invention can also be formulated for their topical application for the treatment of pathologies occurring in zones or organs accessible through this route, such as eyes, skin and the intestinal tract.

Formulations include creams, lotions, gels, powders, solutions and patches wherein the compound is dispersed or dissolved in suitable excipients.

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

The dosage and frequency of doses will depend upon the nature and severity of the disease to be treated, the age, the general condition and body weight of the patient, as well as the particular compound administered and the route of administration, among other factors. As an example, a suitable dosage range is from about 0.01 mg/Kg to about 100 mg/Kg per day, which can be administered as a single or divided doses.

The invention is illustrated by the following examples. Examples

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

Boc: fe/t-butoxycarbonyl

Cone: concentrated

DMAP: 4-dimethylaminopyhdine

DMF: Λ/,Λ/-dimethylformamide EtOAc: ethyl acetate

EtOH: ethanol

H: hours

MeOH: methanol Min: minutes MS: mass spectrometry

PyBOP: (benzotriazol-1 -yloxy)tripyrrolidinophosphonium hexafluorophosphate THF: Tetrahydrofuran ._R: retention time

LC-MS: liquid chromatography-mass spectrometry

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

10%; 10 min A at 90%; 15 min A at 90%.

Method 2: Acquity UPLC BEH C18 1 ,7 μm (2.1 x 50 mm) column, temperature: 40

⁰C, rate: 0.50 mL/min, eluent: A = AcN, B = NH₄HCO₃ 10 mM, gradient: 0 min A at 10%; 0.25 min A at 10%; 3.00 min A at 90%; 3.75 min A at 90%.

REFERENCE EXAMPLE 1 tert-Butyl methyl[(3H)-pyrrolidin-3-yl]carbamate

(a) tert-Butyl[(3/7)-1-benzylpyrrolidin-3-yl] methylcarbamate Di-te/t-butyl dicarbonate (11.6 g, 53.07 mmol) dissolved in 15 mL of CH₂CI₂ is added to a solution of (3f?)-1 -benzyl-Λ/-methylpyrrolidin-3-amine (10 g, 52.55 mmol) in 115 mL of CH₂CI₂, cooled at 0 ⁰C. The resulting solution was stirred at room temperature for 18 hours. The solvent was evaporated and the crude product was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, providing 14.5 g of the desired compound (yield: 95%). LC-MS (Method 1 ): t_R = 9.55 min; m/z = 291 (MH⁺).

(b) Title compound

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

¹H NMR (300 MHz, CDCI₃)δ: 1.38 (s, 9H), 1.72 (m, 1 H), 1.96 (m, 1 H), 2.53 (s, NH), 2.80 (s, 3H), 2.87 (m, 1 H), 2.93 (m, 1 H), 3.1 1 (m, 2H), 4.58 (m, 1 H).

REFERENCE EXAMPLE 2 tert-Butyl azetidin-3-yl(methyl)carbamate

(a) tert-Butyl [i-CdiphenylmethyOazetidin-S-yllmethylcarbamate

Following a procedure similar to that described in section a) of reference example 1 , but using 1 -(diphenylmethyl)-Λ/-methylazetidin-3-amine instead of (3f?)-1 - benzyl-Λ/-methylpyrrolidin-3-amine, the desired compound was obtained with a 73% yield. LC-MS (Method 1 ): t_R = 10.14 min; m/z = 353 (MH⁺).

(b) Title compound A solution of the compound obtained above (6.18 g, 17.53 mmol) in 60 ml_ of MeOH and 15 ml_ of EtOAc was purged with argon. Pd/C (10%, 50% in water) (929 mg) was added and the solution was then purged again with argon and stirred in an H₂ atmosphere for 18 hours. The reaction was filtered through Celite^® and the filter was washed with EtOAc and MeOH. The solvent was evaporated to dryness, providing 5.66 g of a mixture of the title compound together with one equivalent of diphenylmethane that was used as such in the following steps. 1H NMR (300 MHz, CD₃OD)δ: 1.44 (s, 9H), 2.88 (s, 3H), 3.56 (m, 2H), 3.71 (m, 2H), 4.75 (m, 1 H).

REFERENCE EXAMPLE 3a

Ethyl 4-cyclobutyl-2,4-dioxobutanoate

Cyclobutyl methyl ketone (9.0 g, 91.7 mmol) was added to a solution of sodium ethoxide (29.7 g, 21 % in ethanol) in ethanol (70 ml_) and the resulting mixture was stirred for 10 min at room temperature. Diethyl oxalate (13.4 g, 91.7 mmol) was then slowly added and the mixture heated at 65^Q C for 4 hours. The reaction mixture was evaporated to dryness and diluted with 1 N HCI and EtOAc. The phases were separated and the aqueous phase was re-extracted with additional EtOAc. The combined organic phases were washed with water and brine, dried over Na₂SO₄ and concentrated to dryness, providing 15.6 g of the title compound (yield: 86%). LC-MS (Method 2): t_R = 1.23 min; m/z = 199 (MH⁺).

REFERENCE EXAMPLE 3b

Ethyl 6,6-dimethyl-2,4-dioxoheptanoate

Reference example 3b was obtained following a similar procedure to that described in reference example 3a but using 4,4-dimethyl-2-pentanone as starting material. LC-MS (Method 2): t_R = 1.81 min; m/z = 215 (MH⁺).

REFERENCE EXAMPLE 4a Ethyl 5-cyclobutyl-1 H-pyrazole-3-carboxylate

Hydrazine hydrate (2.02 g, 40.3 mmol) was added to a solution of the compound obtained in reference example 3a (8.0 g, 40.3 mmol) in absolute ethanol (25 mL), and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature and the precipitated solids were filtered and discarded. The filtrate was concentrated to dryness and acetic acid (30 mL) was added to the residue. After heating the mixture at 100^Q C for 8 h, the solvent was evaporated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 5.72 g of the desired compound (yield: 73%) LC-MS (Method 2): t_R = 1.82 min; m/z = 195 (MH⁺).

REFERENCE EXAMPLE 4b

Ethyl 5-neopentyl-1 H-pyrazole-3-carboxylate

Reference example 4b was obtained following a similar procedure to that described in reference example 4a but using reference example 3b as starting material. LC-MS (Method 2): t_R = 2.07 min; m/z = 21 1 (MH⁺).

REFERENCE EXAMPLE 5a Ethyl 5-cyclobutyl-4-nitro-1 W-pyrazole-3-carboxylate 65% Nitric acid (6 ml_) was slowly added at 0^Q C to cone sulfuric acid (23 ml_). This nitric-sulfuric acid solution was then slowly added to reference example 4a (4.0 g, 20.6 mmol), previously cooled in an ice-bath. The mixture was then allowed to reach room temperature, stirred for 3 hours, then poured over ice and extracted twice with chloroform. The combined organic phases were dried over Na₂SO₄ and concentrated to dryness, providing 4.48 g of the title compound (yield: 91 %). LC-MS (Method 2): t_R = 1.86 min; m/z = 238 (MH^").

REFERENCE EXAMPLE 5b Ethyl S-neopentyl-^nitro-I H-pyrazole-S-carboxylate

Reference example 5b was obtained following a similar procedure to that described in reference example 5a but using reference example 4b as starting material.

LC-MS (Method 2): t_R = 2.13 min; m/z = 256 (MH⁺).

REFERENCE EXAMPLE 5c Ethyl S-cyclobutyM-methyl-^nitro-i H-pyrazole-3-carboxylate

Reference example 5c was obtained following a similar procedure to that described in reference example 5a but using reference example 22 as starting material.

¹H NMR (300 MHz, CDCI₃)δ: 1.35 (t, 3H), 1.9-2.2 (m, 2H), 2.3-2.5 (m, 4H), 3.8 (m,

1 H), 3.85 (s, 3H), 4.4 (q, 2H).

REFERENCE EXAMPLE 6a 5-lsopropyl-4-nitro-1 W-pyrazole-3-carboxylic acid

65% Nitric acid (6.3 mL) was slowly added at 60^Q C to a solution of 5-isopropyl-1 H- pyrazole-3-carboxylic acid (5.0 g, 32.5 mmol) in cone, sulfuric acid (25 mL) and the mixture stirred at 60^Q C for additional 4 hours. It was then allowed to cool to room temperature and poured over ice. The precipitated solids were collected by filtration, washed with water and dried under vacuum, providing 5.7 g of the title compound (yield: 95%). LC-MS (Method 2): t_R = 0.55 min; m/z = 200 (MH⁺). REFERENCE EXAMPLES 6b-6c

The following compounds were obtained following a procedure similar to that described in reference example 6a, but using suitable starting materials instead of 5-isopropyl-1 /-/-pyrazole-3-carboxylic acid:

(1 ) The product was isolated as a mixture of ethyl ester and carboxylic acid. It did not precipitated from water and was extracted with chloroform.

REFERENCE EXAMPLE 7a Methyl 5-isopropyl-4-nitro-1 H-pyrazole-3-carboxylate

A mixture of reference example 6a (5.72 g, 31.2 mmol), MeOH (55 ml_) and 4 M HCI in 1 ,4-dioxane solution (55 ml_) was stirred at 70^Q C for 7 hours and then concentrated to dryness, providing 5.9 g of the title compound (yield: 89%). LC-MS (Method 2): t_R = 1.53 min; m/z = 212 (MH^").

REFERENCE EXAMPLES 7b-7d

The following compounds were obtained following a procedure similar to that described in reference example 7a, but using suitable starting materials:

(1 ) EtOH was used as the solvent instead of MeOH.

REFERENCE EXAMPLE 8a Methyl 5-isopropyl-1-methyl-4-nitro-1 H-pyrazole-3-carboxylate Methyl iodide (2.49 g, 17.5 mmol) was dropwise added at 0^Q C to a mixture of reference example 7a (3.4 g, 15.9 mmol) and cessium carbonate (5.19 g, 15.9 mmol) in DMF (15 ml_). The mixture was allowed to warm to room temperature and stirred overnight. The solvent was distilled off and the residue diluted with water and ethyl ether. The phases were separated and the aqueous phase was re-extracted with additional ethyl ether. The combined organic phases were dried over Na₂SO₄ and concentrated to dryness. The crude product obtained was a mixture of the two possible regioisomers and was purified by chromatography on silica gel using hexane/EtOAc mixtures of increasing polarity as eluent. Initially eluted 1.6 g (yield: 44%) of the regioisomer, methyl 5-isopropyl-2-methyl-4-nitro- 2/-/-pyrazole-3-carboxylate, and later 0.91 g of the desired compound (yield: 25%) LC-MS (Method 2): t_R = 1.90 min; m/z = 228 (MH⁺).

REFERENCE EXAMPLE 8b Methyl 1-methyl-4-nitro-5-propyl-1 W-pyrazole-3-carboxylate Reference example 8b 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): t_R = 1.91 min; m/z = 228 (MH⁺).

REFERENCE EXAMPLE 9a

Methyl 4-amino-5-isopropyl-1-methyl-1 H-pyrazole-3-carboxylate

A solution of reference example 8a (0.9 g, 3.97 mmol) in MeOH (34 mL) was purged with argon. 10% Pd/C (90 mg) was added and the solution was then purged again with argon and stirred in an H₂ atmosphere for 5 hours. The reaction was filtered through Celite^® and the filter was washed with MeOH. The solvent was evaporated to dryness, providing 0.76 g of the desired compound (yield: 98%). LC-MS (Method 2): t_R = 1.16 min; m/z = 198 (MH⁺). REFERENCE EXAMPLES 9b-9f

The following compounds were obtained following a procedure similar to that described in reference example 9a, but using suitable starting materials instead of reference example 8a:

(1 ) EtOH was used as the solvent instead of MeOH. 3 hydrogenation cycles were required to get the reaction to completion

(2) EtOH was used as the solvent instead of MeOH (3) ¹H NMR (300 MHz, CDCI₃)δ: 1 .4 (t, 3H), 1.9-2.2 (m, 2H), 2.3-2.5 (m, 4H), 3.3 (br s, 2H, NH₂), 3.55 (m, 1 H), 3.75 (s, 3H), 4.4 (q, 2H).

REFERENCE EXAMPLE 10a Ethyl 4-amino-5-tert-butyl-1 H-pyrazole-3-carboxylate A solution of ammonium formate (2.6 g, 41.4 mmol) in water (3 ml_) was added to a solution of reference example 7c (4.9 g, 20.7 mmol) in EtOH (56 ml_). Finally, 10% Pd/C (50% in water) (250 mg) was added and the mixture was then heated to reflux for 3 hours. The reaction was filtered through Celite^® and the filter was washed with EtOH. The solvent was evaporated to dryness and the residue diluted with water and EtOAc. The phases were separated and the aqueous phase was re-extracted with additional EtOAc. The combined organic phases were dried over Na₂SO₄ and concentrated to dryness, providing 3.93 g of the desired compound (yield: 90%). LC-MS (Method 2): t_R = 1.48 min; m/z = 212 (MH⁺).

REFERENCE EXAMPLE 10b

Ethyl 4-amino-5-neopentyl-1 H-pyrazole-3-carboxylate

Reference example 10b was obtained following a similar procedure to that described in reference example 10a but using reference example 5b as starting material. LC-MS (Method 2): t_R = 1.67 min; m/z = 226 (MH⁺).

REFERENCE EXAMPLE 11a 5-Amino-3-isopropyl-2-methyl-2H-pyrazolo[4,3-cflpyrimidin-7-ol

To a solution of the compound obtained in reference example 9a (766 mg, 3.88 mmol) in 1 ,4-dioxane (17.5 mL), cyanamide (653 mg, 15.5 mmol) was added and then, slowly, 4 M HCI in 1 ,4-dioxane solution (8 mL). The resulting suspension was stirred at room temperature for 2 hours and then at reflux overnight. The solvent was evaporated and 2 N NaOH aqueous solution (30 mL) was added, and the resulting mixture was heated at reflux for 2 hours. The reaction mixture was allowed to cool to room temperature and pH was adjusted to 6-7 with 2 N HCI aqueous solution. The resulting precipitate was collected by filtration, washed with water and then with ethyl ether, and finally dried under vacuum to afford 712 mg of the title compound (yield: 88%). LC-MS (Method 2): t_R = 0.94 min; m/z = 208 (MH⁺).

REFERENCE EXAMPLES 11 b-11 i

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

REFERENCE EXAMPLE 12a tert-Butyl 1-(5-amino-3-isopropyl-2«-pyrazolo[4,3-cflpyrimidin-7-yl) azetidin-3-yl(methyl)carbamate

To a suspension of the compound obtained in reference example 1 1 b (0.75 g, 3.88 mmol) in acetonitrile (38 ml_), triethylamine (22.1 ml_), PyBOP (2.45 g, 4.70 mmol) and reference example 2 (2.1 g of a 1 :1 mixture with diphenylmethane, equivalent to 1.08 g of amine, 5.79 mmol) were added. The resulting mixture was heated at 80 ⁵C overnight. The reaction mixture was concentrated to dryness and the residue was purified by chromatography over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 1.4 g of the desired compound (yield: quantitative) LC-MS (Method 2): t_R = 1.61 min; m/z = 362 (MH⁺). REFERENCE EXAMPLES 12b-12i

The following compounds were obtained following a procedure similar to that described in reference example 12a, but using suitable starting materials:

REFERENCE EXAMPLE 13 3,3-Diphenylpropyl methanesulfonate

Methanesulfonyl chloride (2.16 g, 18.8 mmol) was slowly added to an ice-cooled solution of 3,3-diphenylpropan-1 -ol ( 4.0 g, 18.8 mmol) and thethylamine (5.7 g, 56.5 mmol) in dichloromethane (18 ml_). The mixture was then allowed to warm to room temperature and stirred overnight. It was then diluted with water and dichloromethane. The phases were separated and the aqueous phase was re- extracted twice with dichloromethane. The combined organic phases were dried over Na₂SO₄ and concentrated to dryness, providing the desired compound as a crude that was directly used without further purification.

¹H NMR (300 MHz, CDCI₃) δ: 2.53 (m, 2H), 2.91 (s, 3H), 4.13-4.21 (m, 3H), 7.2- 7.35 (m, 10H).

REFERENCE EXAMPLE 14

4,5,6,7-Tetrahydro[1 ,2,3]oxadiazolo[3,4a]pyridin-8-ium-3-olate Cone HCI (6.6 ml_, 79.7 mmol) was added to a slurry of pipecolinic acid (10.1 g, 76.9 mmol) in water (55 ml_) and the solution thus obtained was cooled to -10/-5⁵ C. A solution of sodium nitrite (5.88 g, 85.1 mmol) in water (25 ml_) was slowly added, and the mixture was then stirred at room temperature for 3 hours. It was diluted with dichloromethane and phases were separated. The aqueous phase was saturated with sodium chloride and it was re-extracted twice with dichloromethane. The combined organic phases were dried over Na₂SO₄ and concentrated to dryness. The residue was dissolved in ethyl ether (200 ml_) with the aid of sonication and it was cooled at -5^Q C. Trifluoroacetic acid anhydride (17.9 g, 85.1 mmol) was slowly added and the mixture stirred at room temperature overnight. The reaction mixture was concentrated to dryness and the residue was purified by chromatography over silica gel using CH₂CI₂/MeOH mixtures of increasing polarity as eluent, to afford 13.8 g of the compound impurified with salts. The product was dissolved in water (75 ml_) and dichloromethane (75 ml_), phases were separated and the aqueous phase was re-extracted twice with dichloromethane. The combined organic phases were dried over Na₂SO₄ and concentrated to dryness, to afford 8.81 g of the desired compound (yield: 82%).

¹H NMR (300 MHz, CDCI₃) δ: 1.95 (m, 2H), 2.14 (m, 2H), 2.54 (bs, 1 H, OH?), 2.67 (t, 2H, J= 6.3 Hz), 4.28 (t, 2H, J= 6 Hz).

REFERENCE EXAMPLE 15 Ethyl 4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyridine-2-carboxylate Ethyl propiolate (2.4 ml_, 23.7 mmol) was slowly added to a solution of reference example 14 (2.99 g, 21.3 mmol) in xylene (mixture of isomers, 40 ml_). The mixture was heated to reflux for 6 hours and the solvent was distilled off. The residue was purified by chromatography over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 2.3 g of the desired compound (yield: 56%). LC-MS (Method 2): t_R = 1.63 min; m/z = 195 (MH⁺).

REFERENCE EXAMPLE 16 Ethyl 3-nitro-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyridine-2-carboxylate

Fuming nitric acid (20 ml_) was slowly added at 0^Q C to cone sulfuric acid (20 ml_). This nithc-sulfuhc acid solution was then slowly added to reference example 15 (4.5 g, 23.4 mmol), previously cooled in an ice-bath. The mixture was then allowed to reach room temperature and stirred overnight. It was then poured over ice and extracted twice with EtOAc. The combined organic phases were dried over Na₂SO₄ and concentrated to dryness. The residue was purified by chromatography over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 3.97 g of the desired compound (yield: 70%). LC-MS (Method 2): t_R = 1.89 min; m/z = 240 (MH⁺).

REFERENCE EXAMPLE 17

Ethyl 3-amino-4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyridine-2-carboxylate

A solution of ammonium formate (2.1 g, 33.2 mmol) in water (2.4 mL) was added to a solution of reference example 16 (3.97 g, 16.6 mmol) in EtOH (45 mL). Finally, 10% Pd/C (50% in water) (200 mg) was added and the mixture was then heated to reflux for 4 hours. The reaction was filtered through Celite^® and the filter was washed with EtOH. The solvent was evaporated to dryness and the residue was purified by chromatography over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 2.53 g of the desired compound (yield: 73%).

LC-MS (Method 2): t_R = 1.12 min; m/z = 210 (MH⁺). REFERENCE EXAMPLE 18

2-Amino-7,8,9,10-tetrahydropyrido[1 ',2':1 ,5]pyrazolo[4,3-o(]pyrimidin-4-ol

To a solution of the compound obtained in reference example 17 (2.53 g, 12.1 mmol) in 1 ,4-dioxane (55 ml_), cyanamide (2.03 g, 48.4 mmol) was added and then, slowly, 4 M HCI in 1 ,4-dioxane solution (24 ml_). The resulting suspension was stirred at room temperature for 3 hours and then at reflux overnight. The solvent was evaporated and 2 N NaOH aqueous solution (70 ml_) was added, and the resulting mixture was heated at reflux for 3 hours. The reaction mixture was allowed to cool to room temperature and pH was adjusted to 6-7 with 3 N HCI aqueous solution. The resulting precipitate was collected by filtration, washed with water and then with ethyl ether, and finally dried under vacuum to afford 2.04 g of the title compound (yield: 80%). LC-MS (Method 2): t_R = 0.59 min; m/z = 206 (MH+).

REFERENCE EXAMPLE 19 ferf-Butyl 1-(5-(bis-ferf-butoxycarbonylamino)-2,3-dimethyl-2H-pyrazolo [4,3-o(|pyrimidin-7-yl)azetidin-3-yl(methyl)carbamate

Di-te/t-butyl dicarbonate (2.0 g, 9.2 mmol), TEA (0.96 ml_, 6.9 mmol) and DMAP (42 mg, 0.34 mmol) were added to a solution of reference example 12i (1.0 g, 2.88 mmol) in THF (11 ml_). The resulting solution was stirred under argon at room temperature overnight. The solvent was evaporated and the crude product was purified by chromatography over silica gel using hexane/EtOAc mixtures of increasing polarity containing 0.5% TEA as eluent, providing 491 mg of the desired compound (yield: 31 %). LC-MS (Method 2): t_R = 2.55 min; m/z = 548 (MH⁺).

REFERENCE EXAMPLE 20 terf-Butyl 1-(5-(bis-ferf-butoxycarbonylamino)-3-(bromomethyl)-2-methyl-2W- pyrazolo[4,3-c(lpyrimidin-7-yl)azetidin-3-yl(methyl)carbamate Λ/-Bromosuccinimide (32.5 mg, 0.18 mmol) and benzoyl peroxide (2.3 mg, 0.009 mmol) were added to a solution of reference example 19 (100 mg, 0.18 mmol) in a mixture of carbon tetrachloride (2.5 mL) and chloroform (0.5 mL). The mixture was heated at 90 ⁵C under argon for 3 h, and then it was allowed to cool to room temperature. The reaction mixture was then diluted with chloroform and washed twice with NaHCO₃ saturated solution. The organic phase was dried over Na₂SO₄ and concentrated to dryness. The residue was purified by chromatography over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, providing 27 mg of the desired compound (yield: 24%).

¹H NMR (300 MHz, CDCI₃) δ:1.42 (s, 9 H), 1.45 (s, 9 H), 1.48 (s, 9 H), 2.98 (s, 3 H), 4.16 (s, 3 H), 4.3-4.7 (m, 4 H), 5.2 (br s, 1 H), 4.84 (s, 2 H).

REFERENCE EXAMPLE 21

(β)-1 -Methylpyrrolidin-3-amine dihydrochloride

(a) tert-Butyl (H)-1-methylpyrrolidin-3-ylcarbamate

A 37% aqueous solution of formaldehyde (1.19 ml_, 14.6 mmol) and, subsequently and gradually, sodium borohydride (0.61 g, 16.1 mmol) were added to a solution of tert-butyl (F?)-pyrrolidin-3-ylcarbamate (1.0 g, 5.34 mmol) in 23 ml_ of MeOH. The resulting mixture was stirred at room temperature under argon overnight. The solvent was evaporated and the crude product was dissolved in CHCI₃ and washed with brine and, then, with a saturated aqueous solution of NaHCO₃. The organic phase was dried over Na₂SO₄ and it was concentrated to dryness, providing 0.85 g of the desired compound (yield: 79%).

¹H NMR (300 MHz, CDCI₃) δ: 1.43 (s, 9H), 1.58 (m, 1 H), 2.25 (m, 2H), 2.33 (s, 3H), 2.52 (m, 2H), 2.77 (m, 1 H), 4.16 (m, 1 H), 4.86 (m, NH).

(b) Title compound

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

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

REFERENCE EXAMPLE 22 Ethyl 5-cyclobutyM-methyM H-pyrazole-3-carboxylate

Methyl hydrazine (70 mg, 1.5 mmol) was added to a solution of reference example 3a (0.3 g, 1.5 mmol) in acetic acid (2 ml_). The resulting solution was heated in a sealed tube at 100 ⁵C for 3 h. The solvent was evaporated, toluene was added and it was again concentrated to dryness. The crude product was purified by chromatography over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, providing 198 mg of the desired compound (yield: 63%). LC-MS (Method 2): t_R = 1.92 min; m/z = 209 (MH⁺).

REFERENCE EXAMPLE 23a terf-Butyl 1-(5-amino-2H-pyrazolo[4,3-cflpyrimidin-7-yl)azetidin-3- yl(methyl)carbamate

Following a similar procedure to that described in reference example 12a but using reference example 1 1 h and reference example 2 as starting materials, and purifying the crude compound by reverse phase chromatography using water/acetonitrile mixtures of increasing polarity as eluent, the title compound was obtained. LC-MS (Method 2): t_R = 1.37 min; m/z = 320 (MH⁺).

REFERENCE EXAMPLE 23b tert-Butyl 1-(5-amino-2W-pyrazolo[4,3-c(lpyrimidin-7-yl)pyrrolidin-(3/?)-3- yl(methyl)carbamate

Reference example 23b was obtained following a similar procedure to that described in reference example 23a but using reference example 1 1 h and reference example 1 as starting materials.

LC-MS (Method 2): t_R = 1.52 min; m/z = 334 (MH⁺).

REFERENCE EXAMPLE 24 4-acetamidophenethyl methanesulfonate Following a similar procedure to that described in reference example 13 but using Λ/-(4-(2-hydroxyethyl)phenyl)acetamide as starting material, the title compound was obtained. LC-MS (Method 2): t_R = 1.27 min; m/z = 258 (MH⁺). EXAMPLE 1

3-lsopropyl-2-methyl-7-((3/7)-3-(methylamino)pyrrolidin-1-yl) -2H-pyrazolo[4,3-o(]pyrimidin-5-amine To a suspension of the compound obtained in reference example 1 1 a (0.15 g, 0.72 mmol) in acetonitrile (8 ml_), triethylamine (4.4 ml_), PyBOP (0.49 g, 0.94 mmol) and reference example 1 (0.24 g, 1.16 mmol) were added. The resulting mixture was heated at 80 ⁵C overnight. The reaction mixture was concentrated to dryness and the residue was diluted with water and EtOAc, pH was brought to basic with 1 N NaOH solution and the phases were separated. The aqueous phase was re-extracted with EtOAc, and the combined organic phases were dried over Na₂SO₄ and concentrated to dryness, providing the intermediate precursor. HCI (4 M solution in 1 ,4-dioxane, 5 ml_) and 1 ,4-dioxane (20 ml_) were added to this intermediate and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated to dryness. The residue was dissolved in water and washed twice with EtOAc, that was discarded. 1 N NaOH solution was added to the acidic aqueous phase until basic pH and it was extracted three times with chloroform. The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated to dryness. The crude product obtained was purified by chromatography over silica gel using mixtures of chloroform/MeOH/NH_{3 CO}nc of increasing polarity as eluent, providing 122.6 mg of the title compound (yield: 59%). LC-MS ( Method 2): t_R = 1.19 min; m/z 290 (MH⁺).

EXAMPLES 2-7

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

EXAMPLE 8

3-lsopropyl-7-(3-(methylamino)azetidin-1-yl)-2W- pyrazolo[4,3-o(]pyrimidin-5-amine

HCI (4 M solution in 1 ,4-dioxane, 1 ml_) and 1 ,4-dioxane (10 ml_) were added to reference example 12a and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to dryness. The residue was dissolved in water and washed twice with EtOAc, that was discarded. 1 N NaOH solution was added to the acidic aqueous phase until basic pH and it was evaporated to dryness. The solid residue was slurried in a small amount of MeOH. The undissolved solids were filtered off and the filtrate was concentrated to dryness. The crude product thus obtained was purified by chromatography over silica gel using mixtures of chloroform/fvleOH/NH₃ cone of increasing polarity as eluent, providing 23.3 mg of the title compound (yield: 32%). LC-MS ( Method 2): t_R = 0.88 min; m/z 262 (MH⁺).

EXAMPLES 9-15

The following compounds were obtained following a procedure similar to that described in example 8, but using suitable starting materials:

EXAMPLE 16 2-Ethyl-3-isopropyl-7-((3H)-3-(methylamino)pyrrolidin-1-yl)

-2H-pyrazolo[4,3-o(]pyrimidin-5-amine a) (R)-tert-Buty\ 1-(5-amino-2-ethyl-3-isopropyl-2W-pyrazolo[4,3-c(lpyrimidin- 7-yl)pyrrolidin-3-yl(methyl)carbamate

Sodium hydride (34.9 mg of a 55% dispersion in mineral oil, 0.8 mmol) was slowly added to a solution of reference example 12b (300 mg, 0.8 mmol) in DMF (15 ml_), previously cooled at 0^Q C. The mixture was stirred at 0^Q C for 20 min and then ethyl iodide (99.7 mg, 0.64 mmol) was dropwise added. It was then allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched by adding some drops of water and the solvent was distilled off. The residue was purified by chromatography on silica gel using EtOAc/MeOH mixtures of increasing polarity as eluent, to afford 193 mg of the desired compound (yield:

60%)

LC-MS (Method 2): t_R = 2.29 min; m/z = 404 (MH⁺). b) Title compound

A mixture of the compound obtained in section a) (0.19 g, 0.48 mmol), 1 ,4-dioxane

(20 ml_) and 4 M HCI in 1 ,4-dioxane solution (2 ml_) was stirred at room temperature for 2 hours and then concentrated to dryness. The residue was dissolved in water and washed with EtOAc, that was discarded. 1 N NaOH solution was added to the acidic aqueous phase until basic pH and it was extracted three times with chloroform. The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated to dryness. The crude product obtained was purified by chromatography over silica gel using mixtures of chloroform/MeOH/NH_{3 CO}nc of increasing polarity as eluent, providing 43.3 mg of the title compound (yield: 30%).

LC-MS ( Method 2): t_R = 1.37 min; m/z 304 (MH⁺).

EXAMPLES 17-35

The following compounds were obtained following a procedure similar to that described in example 16, but using suitable starting materials:

(1 ) In the alkylation reaction, the two possible N-alkyl-pyrazole regiosomers were formed. They were separated by prep HPLC after Boc-deprotection.

(2) In the alkylation reaction, the two possible N-alkyl-pyrazole regiosomers were formed. They were separated by column chromatography and the two Boc-protected N-alkyl- pyrazole regioisomers were separately deprotected.

EXAMPLE 36

5-(5-Amino-3-isopropyl-7-((3/?)-3-(methylamino)pyrrolidin-1-yl)-2W- pyrazolo[4,3-o(]pyrimidin-2-yl)pentanoic acid, lithium salt Lithium hydroxide monohydrate (1.58 mg, 0.04 mmol) was added to a solution of example 34 (6.9 mg, 0.02 mmol) in a mixture of THF (0.17 ml_) and water (0.17 ml_), and it was stirred at room temperature overnight. Volatiles were evaporated to dryness, providing the title compound as its lithium salt in quantitative yield. LC-MS (Method 2): t_R = 0.85 min; m/z 376 (MH⁺).

EXAMPLE 37

4-[(3H)-3-(Methylamino)pyrrolidin-1 -yl]-7,8,9,10- tetrahydropyrido[1 ,2 :1 ,5]pyrazolo[4,3-o(|pyrimidin-2-amine

To a suspension of the compound obtained in reference example 18 (1.81 g, 8.79 mmol) in acetonitrile (64.5 mL), triethylamine (43 mL), PyBOP (5.95 g, 11.4 mmol) and reference example 1 (2.82 g, 14.1 mmol) were added. The resulting mixture was heated at 80 ⁵C overnight. Additional reference example 1 (1.41 g, 7.04 mmol) and PyBOP (3 g, 5.76 mmol) were added and the mixture heated at 80^Q C for another 24 hours. The reaction mixture was concentrated to dryness, the residue was diluted with 1 N NaOH solution and EtOAc, and the phases were separated. The aqueous phase was re-extracted with EtOAc, and the combined organic phases were dried over Na₂SO₄ and concentrated to dryness. The residue was purified by chromatography over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, providing the intermediate precursor. HCI (4 M solution in 1 ,4-dioxane, 30 ml_) and EtOH (15 ml_) were added to this intermediate and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to dryness. The residue was dissolved in water and washed with EtOAc, that was discarded. 1 N NaOH solution was added to the acidic aqueous phase until basic pH and it was extracted three times with chloroform. The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated to dryness. The crude product thus obtained was purified by chromatography over silica gel using mixtures of chloroform/MeOH/NH₃ cone of increasing polarity as eluent, and then further purified by chromatography over neutral alumina gel using mixtures of EtOAc/MeOH/NH_{3 conc} of increasing polarity as eluent, providing 607 mg of the title compound (yield: 24%). LC-MS (Method 2): t_R = 0.97 min; m/z 288 (MH⁺).

EXAMPLES 38-40

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

EXAMPLE 41

7-(3-(Methylamino)azetidin-1-yl)-2H-pyrazolo [4,3-cflpyrimidin-5-amine The title compound was obtained following a similar procedure to that described in example 1 but using reference examples 1 1 h and 2 as starting materials. LC-MS (Method 2): t_R = 0.39 min; m/z = 220 (MH⁺).

EXAMPLE 42 3-(Methoxymethyl)-2-methyl-7-(3-(methylamino)azetidin-1 -yl)-2 H- pyrazolo[4,3-o(]pyrimidin-5-amine

A mixture of reference example 20 (27 mg, 0.04 mmol) and sodium methoxide (0.5 ml_ of a 25% w/w solution in MeOH) in MeOH (1 ml_) was heated to reflux overnight. The reaction mixture (that was found dry) was diluted with water and the pH adjusted to 8 with 1 N HCI, and then it was extracted three times with chloroform. The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated to dryness. The crude product thus obtained was purified by preparative HPLC-MS (method: XBridge Prep C18 (5μm) OBD 19x100 mm column, rate: 20 mL/min, eluent: A = AcN, B = NH₄HCO₃ 75 mM, gradient: 0 min A at 10%; 1.00 min A at 10%; 8.00 min A at 80%) and the fractions containing the product were concentrated to dryness, providing 1.37 mg of the title compound (yield: 12%) LC-MS (Method 2): t_R = 0.84 min; m/z = 278 (MH⁺).

EXAMPLE 43 y-CS-CMethylaminoJazetidin-i-yO^-phenethyl^H-pyrazolo^^-cfl pyrimidin-5-amine

Sodium hydride (41 mg of a 55% dispersion in mineral oil, 0.94 mmol) was carefully added to a solution of reference example 23a (200 mg, 0.63 mmol) in

DMF (3 mL). The mixture was stirred at room temperature for 15 min and then phenethyl bromide (1 16 mg, 0.63 mmol) was dropwise added. It was then allowed to warm to room temperature and stirred overnight. The reaction was quenched by adding some drops of water and then concentrated to dryness. The residue was diluted with water and chloroform. The phases weres separated and the organic phase was washed with 1 N NaOH, dried over anhydrous Na₂SO₄ and concentrated to dryness. The crude product thus obtained was purified by chromatography over silica gel using EtOAc/MeOH mixtures of increasing polarity as eluent, to afford 60 mg of the Boc-protected precursor. To a solution of this intermediate in dichloromethane (4 ml_), thfluoroacetic acid (2 ml_) was added and the reaction mixture was stirred at room temperature for 3 hours and then concentrated to dryness. The residue was dissolved in MeOH (4.5 ml_) and Dowex resin (50Wx2, 100 mesh) was added, and the mixture stirred at room temperature for 15 min. It was then filtered and washed with MeOH, that was discarded. The resin containing the bounded product was stirred then with 2 N NH₃ solution in MeOH for 15 min and then filtered. The filtrate was evaporated to dryness providing 38.9 mg of the title compound (yield: 20%). LC-MS ( Method 2): t_R = 1.42 min; m/z 324 (MH⁺).

EXAMPLES 44-55

The following compounds were obtained following a procedure similar to that described in example 43, but using suitable starting materials:

EXAMPLES 56-58

(1 ) Final treatment with HCI in 1 ,4-dioxane was omitted.

EXAMPLE 59 Binding competition assay of [³H]-histamine to human histamine H₄ receptor To perform the binding assay, membrane extracts prepared from a stable

CHO recombinant cell line expressing the human histamine H₄ receptor (Euroscreen/Perkin-Elmer) were used.

Test compounds were incubated at the selected concentration in duplicate, with 10 nM [³H]-histamine and 15 μg membranes extract in a total volume of 250 μL of 50 mM Tris-HCI, pH 7.4, 1.25 mM EDTA for 60 minutes at 25 ⁵C. Nonspecific binding was defined in the presence of 100 μM unlabeled histamine. The reaction was stopped by filtration using a vacuum collector (Multiscreen Millipore) in 96-well plates (Multiscreen HTS Millipore) which had been previously soaked in a 0.5% polyethylenimine solution for 2 hours at 0 ⁵C. Subsequently, the plates were washed with 50 mM Tris (pH 7.4), 1.25 mM EDTA at 0 -C and filters were dried during 1 hour at 50-60 ⁵C, before adding the scintillation liquid to determine bound radioactivity by using a betaplate scintillation counter.

The compounds of examples 1 to 58 were assayed in this test and showed an inhibition of more than 50% of binding to human histamine receptor H₄ at 10 μM. The compounds of examples 1 to 58, except 3, 25b, 30b and 36, further showed an inhibition of more than 50% of binding to human histamine receptor H₄ at 1 μM.

EXAMPLE 60

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

In this assay the shape change induced by histamine in human eosinophils is determined by flow cytometry, detected as an increase in the size of the cells (forward scatter, FSC). Polymorphonuclear leucocytes (PMNL, fraction containing neutrophils and eosinophils) were prepared from whole blood of human healthy volunteers. Briefly, erythrocytes were separated by sedimentation in 1.2% Dextran (SIGMA), and the leucocyte-rich fraction (PMNL) was isolated from the top layer by centhfugation at 45Og for 20 min in the presence of Ficoll-Paque^® (Biochrom). PMNLs were resuspended in PBS buffer at a concentration of 1.1x10⁶ cells/ml/tube and were pretreated with different concentrations of test compounds (dissolved in PBS) for 30 min at 37^QC and then stimulated with 300 nM histamine (Fluka) for 5 min. Finally, paraformaldehyde (1 % final concentration in PBS) was added to terminate the reaction and maintain cell shape. Cell shape change was analyzed by flow cytometry (FACS Calibur, BD Biosystems). Eosinophils in PMNL were gated based on their higher autofluorescence relative to that of neutrophils (fluorescence channel FL2). Cell shape change was monitored in forward scatter signals (FSC). Results are expressed as percentage inhibition of shape change induced by histamine for each concentration of test compound.

The compounds of examples 1 , 2, 4 to 8, 10, 12 to 14, 16 to 24, 24b, 25, 26 to 30, 31 , 32, 34, 37 to 47, 49, 50, 52, 53 and 56 to 58 were assayed in this test and produced more than 50% inhibition of histamine-induced human eosinophil shape change at 1 μM.

Claims

1.- A compound of formula I

wherein:

7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; or R₁ represents H or C_1-4 alkyl, and R₂ represents azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, which can be optionally substituted with one or more C_1-4 alkyl groups;

R_a represents H or C_1-4 alkyl;

R_b represents H or C_1-4 alkyl; or R_a and Rb form, together with the N atom to which they are bound, an azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group that can be optionally substituted with one or more C_1-4 alkyl groups;

R₃ represents H or NH₂;

R₅ can be placed either at N¹ or N² of the pyrazole ring; when R₅ is attached to N¹, either R₄ represents R₆ and R₅ represents R₇, or R₄ represents R₇ and R₅ represents R₈, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups; when R₅ is attached to N², R₄ represents R₆ and R₅ represents R₇;

R₆ represents H, Ci-H alkyl, C_3-8 cycloalkyl-C₀-n alkyl, C_3-8 heterocycloalkyl-C₀-n alkyl, aryl-C₀-n alkyl, heteroaryl-Co-n alkyl, aryl-NH-C₀-n alkyl, heteroaryl-NH-Co-n alkyl, R₉-C₀-H alkyl or R₁₀-W-C₀-H alkyl; R₇ represents H, Ci_-6 alkyl, C_3-8 cycloalkyl-C₀-₆ alkyl, Ci_-6 alkoxy-Ci_-6 alkyl or (C_3-8 cycloalkyl-Co-e alkyl)-O-Ci_-6 alkyl;

R₈ represents C_3-8 cycloalkyl-Co-π alkyl, C_3-8 heterocycloalkyl-Co-π alkyl, aryl-Co-n alkyl, heteroaryl-Co-n alkyl, aryl-NH-C₂-n alkyl, heteroaryl-NH-C₂-n alkyl, Rg-C₂-H alkyl or Ri₀-W-C₂-H alkyl; R₉ represents -CONR₁₁ R₁₁, -NR₁₁COR₁₁, -NR₁₁SO₂R₁₁, -SO₂NR₁₁R₁₁, -NR₁₁CONR₁₁ R₁₁, -CONHSO₂R₁₁, -CO₂Rn, -SO₂Rn, -NR₁₁ R₁₁ or 1 H-tetrazol-5-yl; Ri₀ represents H, Ci-π alkyl, Rπ-O-d-π alkyl, C₃.₈ cycloalkyl-C₀-n alkyl, C₃-₈heterocycloalkyl-C₀-n alkyl, aryl-C₀-π alkyl, heteroaryl-Co-π alkyl, aryl-NH-C₂-n alkyl, heteroaryl-NH-C_2-n alkyl or R₉-Ci-H alkyl; R_H represents H, Ci_-6 alkyl, C_3-8 cycloalkyl-C₀.₆ alkyl or aryl-C₀.₆ alkyl; W represents O, S, SO or SO₂; wherein in R₆, R₈ and Ri₀ any alkyl group can be optionally substituted with one or more halogen atoms, and any cycloalkyl and heterocycloalkyl groups can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉; aryl represents phenyl optionally substituted with one or more groups Ri₂; heteroaryl represents an aromatic 5- or 6-membered monocyclic or 8- to 12- membered bicyclic ring containing up to four heteroatoms independently selected from nitrogen, oxygen, and sulfur, which can be optionally substituted with one or more groups Ri₂; and each Ri₂ independently represents Ci_-6 alkyl, halogen, Ci_-6 alkoxy, Ci_-6 haloalkyl, Ci_-6 haloalkoxy, CN, hydroxy-C_0-6 alkyl, CO₂Rn-C_0-6 alkyl, CONHSO₂R₁₁-C₀-₆ alkyl, (1 H-tetrazol-5-yl)-C_0-6 alkyl, -CONR₁₁ R₁₁, -SO₂NRn Rn, -SO₂-Ci_-6 alkyl, -NR₁₁SO₂- Ci_-6 alkyl, -NR₁₁CONR₁₁ R₁₁, -NR₁₁COR₁₁ or -NR₁₁R₁₁ ; or a salt thereof.

2.- A compound according to claim 1 wherein R₃ is NH₂.

3.- A compound according to any of claims 1 or 2 wherein R₅ is attached to N¹.

4.- A compound according to claim 3 wherein either R₄ represents R₆ and R₅ represents R₇, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups.

5.- A compound according to claim 3 wherein R₄ represents R₆ and R₅ represents

R₇.

6.- A compound according to claim 3 wherein either R₄ represents R₇ and R₅ represents R₈, or R₄ and R₅ can be bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more Ci_-8 alkyl groups.

7.- A compound according to claim 3 wherein R₄ represents R₇ and R₅ represents

R₈.

8.- A compound according to claim 3 wherein R₄ and R₅ are bonded together to form a -C_3-5 alkylene- group which can be optionally substituted with one or more

C-I_-8 alkyl groups.

9.- A compound according to any of claims 1 to 7 wherein R₇ represents H, Ci_-6 alkyl or C_3-8 cycloalkyl-C₀-₆ alkyl.

10.- A compound according to claim 9 wherein R₇ represents H or Ci_-6 alkyl.

11.- A compound according to claim 10 wherein R₇ represents H, methyl or ethyl.

12.- A compound according to claim 1 1 wherein R₇ represents methyl.

13.- A compound according to claim 1 1 wherein R₇ represents H.

14.- A compound according to any of claims 1 to 5 or 9 to 13 wherein R₆ represents H, d-n alkyl, C₃-₈ cycloalkyl-C₀-n alkyl, Cs-s heterocycloalkyl-Co-n alkyl, aryl-C-ι-11 alkyl, heteroaryl-C-i-n alkyl, aryl-NH-C₀-n alkyl, heteroaryl-NH-C₀-n alkyl,

R₉-C₀-₁₁ alkyl or R₁₀-W-C₀-₁₁ alkyl; wherein any alkyl group can be optionally substituted with one or more halogen atoms, and any cycloalkyl and heterocycloalkyl groups can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉.

15.- A compound according to claim 14 wherein R₆ represents H, C-_\.-_\-_\ alkyl, C_3-8 cycloalkyl -C_0- 11 alkyl, R₉-C_0-H alkyl or Ri₀-W-C_0-H alkyl; wherein any alkyl group can be optionally substituted with one or more halogen atoms, and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉.

16.- A compound according to claim 15 wherein R₆ represents H, Ci_-H alkyl or C₃.₈ cycloalkyl-Co-11 alkyl; wherein any alkyl group can be optionally substituted with one or more halogen atoms, and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉.

17.- A compound according to claim 16 wherein R₆ represents d-n alkyl or C₃.₈ cycloalkyl-Co-11 alkyl; wherein any alkyl group can be optionally substituted with one or more halogen atoms, and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci_-6 alkyl, halogen, aryl and R₉.

18.- A compound according to claim 17 wherein R₆ represents d-n alkyl or C_3-8 cycloalkyl.

19.- A compound according to claim 18 wherein R₆ represents Ci-n alkyl.

20.- A compound according to claim 19 wherein R₆ represents Ci_-6 alkyl.

21.- A compound according to claim 16 wherein R₆ represents C₃-₈ cycloalkyl-C₀-n alkyl; wherein any alkyl group can be optionally substituted with one or more halogen atoms, and any cycloalkyl group can be optionally substituted with one or more substituents independently selected from Ci-₆ alkyl, halogen, aryl and R₉.

22.- A compound according to claim 21 wherein R₆ represents C_3-8 cycloalkyl.

23.- A compound according to claim 22 wherein R₆ represents cyclobutyl.

24.- A compound according to any of claims 1 , 2, 3, 6, 7 or 9 to 13 wherein R₈ represents aryl-C₀-n alkyl.

25.- A compound according to claim 24 wherein R₈ represents aryl-C₂-₄ alkyl.

26.- A compound according to any of claims 1 to 25 wherein Ri and R₂ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:

(i) a heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said heterocyclic group can be optionally substituted with one or more Ci-₄ alkyl groups; and

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

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

N atom to which they are bound, a saturated heterocyclic group selected from:

wherein R_c and Rd independently represent H or C-i-₄alkyl.

28.- A compound according to claim 27 wherein R_c represents H.

29.- A compound according to claims 27 or 28 wherein Ri and R₂ 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 29 wherein Ri and R₂ form, together with the

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

31.- A compound according to claim 29 wherein R₁ and R₂ form, together with the

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

32.- A compound according to any of claims 1 to 31 wherein R_a and Rb independently represent H or Ci_-4 alkyl.

33.- A compound according to claim 32 wherein R_a and Rb independently represent H or methyl.

34.- A compound according to claim 33 wherein R_a represents H and R_b represents methyl.

35.- A compound according to claim 33 wherein R_a and Rb represent H.

36.- A pharmaceutical composition which comprises a compound of formula I according to any of claims 1 to 35 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

37.- A compound of formula I according to any of claims 1 to 35 or a pharmaceutically acceptable salt thereof for use in therapy.

38.- A compound according to any of claims 1 to 35 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease mediated by the histamine H₄ receptor.

39.- A compound according to claim 38, or a pharmaceutically acceptable salt thereof, wherein the disease mediated by the histamine H₄ receptor is an allergic, immunological or inflammatory disease, or pain.

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

41.- Use according to claim 40, wherein the disease mediated by the histamine H₄ receptor is an allergic, immunological or inflammatory disease, or pain.

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

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

wherein R₁, R_2, R_3, R₄ and R₅ have the meaning described in claim 1 , followed if necessary by the removal of any protecting group that may be present; or

Mb Ml wherein R₁₃ represents a leaving group and R₁ , R_2, R_3, R₄ and R₅ have the meaning described in claim 1 , followed if necessary by the removal of any protecting group that may be present; or