WO2009068512A1

WO2009068512A1 - 2 -amino-pyrimidine derivatives as histamine h4 antagonists

Info

Publication number: WO2009068512A1
Application number: PCT/EP2008/066110
Authority: WO
Inventors: Elena CARCELLER GONZÁLEZ; Eva María MEDINA FUENTES; Josep MARTÍ VIA; Marina VIRGILI BERNADÓ
Original assignee: Palau Pharma, S. A.
Priority date: 2007-11-30
Filing date: 2008-11-25
Publication date: 2009-06-04
Also published as: CL2008003537A1; TW200936570A; PE20091035A1; AR069480A1

Abstract

2-Aminopyrimidine 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

2 -AMINO- PYRIMIDINE DERIVATIVES AS HISTAMINE H4 ANTAGONISTS

Technical field of the invention

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

Background of the invention

Histamine is one of the most potent mediators of immediate hypersensitivity reactions. While the effects of histamine on smooth muscle cell contraction, vascular permeability and gastric acid secretion are well known, its effects on the immune system are only now beginning to become unveiled. A few years ago, a novel histamine receptor, which was named H₄, was cloned by several research groups working independently (Oda T et al, J Biol Chem 2000, 275: 36781 -6; Nguyen T et al, MoI Pharmacol 2001 , 59: 427-33). As the other members of its family, it is a G-protein coupled receptor (GPCR) containing 7 transmembrane segments. However, the H₄ receptor has low homology with the three other histamine receptors (Oda T et al); it is remarkable that it shares only a 35% homology with the H₃ receptor. While the expression of the H₃ receptor is restricted to cells of the central nervous system, the expression of the H₄ receptor has been mainly observed in cells of the haematopoietic lineage, in particular eosinophils, mast cells, basophils, dendritic cells and T-cells (Oda T et al). The fact that the H₄ receptor is highly distributed in cells of the immune system suggests the involvement of this receptor in immuno-inflammatory responses. Moreover, this hypothesis is reinforced by the fact that its gene expression can be regulated by inflammatory stimuli such as interferon, TNFα and IL-6. Nevertheless, the H₄ receptor is also expressed in other types of cells such as human synovial cells obtained from patients suffering from rheumatoid arthritis (Wojtecka-Lukasik E et al, Ann Rheum Dis 2006, 65 (Suppl II): 129; Ikawa Y et al, Biol Pharm Bull 2005, 28: 2016-8) and osteoarthritis (Grzybowska-Kowalczyk A et al, European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, P-11 ), and in the human intestinal tract (Sander LE et al, Gut 2006, 55: 498- 504). An increase in the expression of the H₄ receptor has also been reported in nasal polyp tissue in comparison to nasal mucosa of healthy people (Jόkύti A et al, Cell Biol lnt 2007, 31 : 1367-70). Recent studies with specific ligands of the H₄ receptor have helped to delimit the pharmacological properties of this receptor. These studies have evidenced that several histamine-induced responses in eosinophils such as chemotaxis, conformational change and CD11 b and CD54 up-regulation are specifically mediated by the H₄ receptor (Ling P et al, Br J Pharmacol 2004, 142:161-71 ; Buckland KF et al, Br J Pharmacol 2003, 140:1117-27). In dendritic cells, the H₄ receptor has been shown to affect maturation, cytokine production and migration of these cells (Jelinek I et al, 1^st Joint Meeting of European National Societies of Immunology, Paris, France, 2006, PA-1255). Moreover, the role of the H₄ receptor in mast cells has been studied. Although H₄ receptor activation does not induce mast cell degranulation, histamine and other proinflammatory mediators are released; moreover, the H₄ receptor has been shown to mediate chemotaxis and calcium mobilization of mast cells (Hofstra CL et al, J Pharmacol Exp Ther 2003, 305: 1212-21 ). With regard to T-lymphocytes, it has been shown that H₄ receptor activation induces T-cell migration and preferentially attracts a T- lymphocyte population with suppressor/regulatory phenotype and function (Morgan RK et al, American Thoracic Society Conference, San Diego, USA, 2006, P-536), as well as regulating the activation of CD4+ T cells (Dunford PJ et al, J Immunol 2006, 176: 7062-70). As for the intestine, the distribution of the H₄ receptor suggests that it may have a role in the control of peristalsis and gastric acid secretion (Morini G et al, European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, OR-10).

The various functions of the H₄ receptor observed in eosinophils, mast cells and T-cells suggest that this receptor can play an important role in the immuno- inflammatory response. In fact, H₄ receptor antagonists have shown in vivo activity in murine models of peritonitis (Thurmond RL et al, J Pharmacol Exp Ther 2004, 309: 404-13), pleurisy (Takeshita K et al, J Pharmacol Exp Ther 2003, 307: 1072- 8) and scratching (Bell JK et al, Br J Pharmacol 2004,142 :374-80). In addition, H₄ receptor antagonists have demonstrated in vivo activity in experimental models of allergic asthma (Dunford PJ et al, 2006), inflammatory bowel disease (Varga C et al, Eur J Pharmacol 2005, 522:130-8), pruritus (Dunford PJ et al, J Allergy CHn Immunol 2007, 119: 176-83), atopic dermatitis (Cowden JM et al, J Allergy Clin Immunol 2007; 119 (1 ): S239 (Abs 935), American Academy of Allergy, Asthma and Immunology 2007 AAAAI Annual Meeting, San Diego, USA), ocular inflammation (Zampeli E et al, European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, OR-36), edema and hyperalgesia (Coruzzi G et al, Eur J Pharmacol 2007, 563: 240-4), and neuropathic pain (Cowart MD et al., J Med Chem. 2008; 51 (20): 6547-57). It is therefore expected that H₄ receptor antagonists can be useful for the treatment or prevention of allergic, immunological and inflammatory diseases, and pain.

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

The compound 4-(4-ethyl-piperazin-1 -yl)-6-propyl-pyhmidin-2-amine has been described in the literature, specifically in S. Ohno et al.; Chem. Pharm. Bull 1986, 34(10), 4150. This article describes the synthesis and hypoglycaemic activity of a series of derivatives of 7,8-dihydro-6H-thiopyran[3,2-d]pyhmidine. This compound is described therein simply as a compound resulting from the reaction of a derivative of 7,8-dihydro-6H-thiopyran[3,2-d]pyhmidine with Ni/Raney and no therapeutic uses thereof are described.

Description of the invention

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

wherein:

Ri represents C_2-S alkyl or C3-7 cycloalkyl-C_0-4 alkyl, wherein said C3-7 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, phenyl and fluorine;

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

R₃ represents H or Ci_-4 alkyl;

R_b represents H or Ci_-4 alkyl; or R₃ and Rb form, together with the N atom to which they are bound, an azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group that can be optionally substituted with one or more Ci_-4 alkyl groups; provided that the compound of formula I is not 4-(4-ethyl-piperazin-1 -yl)-6-propyl- pyrimidin-2-amine. The present invention also relates to the salts and solvates of the compounds of formula I.

Some compounds of formula I may have chiral centres that can give rise to various stereoisomers. The present invention relates to each of these stereoisomers and also to mixtures thereof. The compounds of formula I show high affinity for the H₄ histamine receptor. Thus, another aspect of the invention relates to a compound of formula I

wherein:

Ri represents C2-8 alkyl or C3_-7 cycloalkyl-Co_-4 alkyl, wherein said C3_-7 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, phenyl and fluorine; R2 and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl and NR₃Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃Rb group, or contains 1 N atom and is substituted with one NR₃R_b group; or R₂ represents H or Ci_-4 alkyl, and R3 represents azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, which can be optionally substituted with one or more Ci_-4 alkyl groups;

R₃ represents H or Ci_-4 alkyl;

R_b represents H or Ci_-4 alkyl; or R₃ and Rb form, together with the N atom to which they are bound, an azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group that can be optionally substituted with one or more Ci_-4 alkyl groups; provided that the compound of formula I is not 4-(4-ethyl-piperazin-1 -yl)-6-propyl- pyrimidin-2-amine; for use in therapy.

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

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

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

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

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

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

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

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

Another aspect of the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of pain.

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

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

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

Another aspect of the present invention relates to a method of treating pain in a subject in need thereof, specially a human being, which comprises administering to said subject a compound of formula I or a pharmaceutically acceptable salt thereof. More preferably, the pain is selected from inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-surgical pain, migraine, cancer pain, visceral pain, osteoarthritis pain and neuropathic pain. Another aspect of the present invention relates to a process for the preparation of a compound of formula I as defined above, comprising: (a) reacting a compound of formula Il with a compound of formula III

wherein Ri, R₂ and R3 have the meaning described above; or

(b) reacting a compound of formula MB with a compound of formula

MB

wherein R₄ represents a leaving group and Ri, R₂ and R3 have the meaning described above; or

(c) when in a compound of formula I Ri represents Ri '-CH₂-CH₂-, treating a compound of formula Vl with a suitable reducing agent

wherein R₁' represents C_1-6 alkyl or C3-7 cycloalkyl-Co-2 alkyl, wherein said C3-7 cycloalkyl group may be optionally substituted with one or more substituents independently selected from C_1-4 alkyl, phenyl and fluorine, and R2 and R3 have the meaning described above; or

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

The new compounds of formula Vl, useful as intermediates in the preparation of compounds of formula I, constitute another aspect of the present invention. Thus, another aspect of the invention relates to a compound of formula Vl

wherein:

R₁' represents C_1-6 alkyl or C3-7 cycloalkyl-Co-2 alkyl, wherein said C3-7 cycloalkyl group may be optionally substituted with one or more substituents independently selected from C_1-4 alkyl, phenyl and fluorine; and

R₂ and R3 have the meaning described for compounds of formula I.

The present invention also relates to the salts and solvates of the compounds of formula Vl. Some compounds of formula Vl may have chiral centres giving rise to several stereoisomers. The present invention relates to each of these stereoisomers and also to mixtures thereof.

The compounds of formula Vl have also been found to have H₄ receptor antagonist activity Thus, another aspect of the invention relates to a compound of formula Vl

wherein:

Ri' represents Ci_-6 alkyl or C3-7 cycloalkyl-Co-2 alkyl, wherein said C3-7 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, phenyl and fluorine; and R₂ and R3 have the meaning described for compounds of formula I; for use in therapy.

Another aspect of the invention relates to a pharmaceutical composition comprising a compound of formula Vl 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 Vl or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease mediated by the H₄ histamine receptor. Another aspect of the present invention relates to a compound of formula Vl or a pharmaceutically acceptable salt thereof for use in the treatment of a disease mediated by the H₄ histamine receptor.

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

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

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 includes the groups methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and te/t-butyl. The term Co alkyl indicates that the alkyl group is absent. The term C3_-7 cycloalkyl-Co_-4 alkyl thus includes C_3-7 cycloalkyl and C_3-7 cycloalkyl-Ci_-4 alkyl.

The term C3_-7 cycloalkyl, as a group or as part of a group, relates to a saturated carbocyclic ring from 3 to 7 carbon atoms that may be monocyclic or bridged bicyclic. Examples include, amongst others, the groups cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and bicyclo[2.2.1]heptanyl. As described above, the C3-7 cycloalkyl groups, both in Ri and in R₁', can be optionally substituted with one or more substituents independently selected from

C_1-4 alkyl, phenyl and fluorine. Said substituents may be located on any available carbon atom of the C_3-7 cycloalkyl group, including the carbon binding the ring to the rest of the molecule.

A C3-7 cycloalkyl-C_1-4 alkyl group means a group resulting from the substitution of a hydrogen atom of a C_1-4 alkyl group with a C3-7 cycloalkyl group as those defined above. Examples of C3_-7 cycloalkyl-C_1-4 alkyl include amongst others the groups cyclopropylmethyl, cyclobutyl methyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2- cyclopentylethyl, 2-cyclohexylethyl, 3-cyclopropyl propyl, 3-cyclobutylpropyl, 3- cyclopentyl propyl, 3-cyclohexylpropyl, 4-cyclopropylbutyl, 4-cyclobutylbutyl, 4- cyclopentyl butyl and 4-cyclohexylbutyl, where the cycloalkyl rings may be optionally substituted as defined above.

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

A "bridged bicyclic" group refers to a bicyclic system having two common atoms (bridgeheads) connecting three acyclic chains (bridges), so that the two bridges with the higher number of atoms form then the main ring and the bridge with the lower number of atoms is the "bridge".

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

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

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

As indicated above for the term NR2R3 in the definition of a compound of formula I, the above three types of saturated heterocyclic rings (monocyclic, bridged bicyclic and fused bicyclic) can be optionally substituted with one or more groups independently selected from Ci_-4 alkyl and NR₃Rb, with the proviso that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃Rb group, or contains 1 N atom and is substituted with one NR₃R_b group. Thus, if the heterocyclic ring contains only 1 N atom, then the ring must be substituted with one NR₃Rb group and can additionally be optionally substituted with one or more

Ci_-4 alkyl groups. If the ring contains 2 N atoms, it can be optionally substituted with one or more Ci_-4 alkyl groups while it cannot be substituted with any NR₃R_b group. The substituents, if present, can be placed on any available position of the ring, including on a N atom in the case of Ci_-4 alkyl groups.

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

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

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

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from C2-5 alkyl and C3_-7 cycloalkyl-Co-1 alkyl.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl, 2,2- dimethyl-propyl, butyl, isobutyl, cyclopropylmethyl and cyclopropyl.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl, isobutyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclopropyl.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl, isobutyl, cyclopropylmethyl and cyclopropyl. In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from propyl, isobutyl, cyclobutyl, cyclopentyl and cyclopropylmethyl.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from C2-5 alkyl and C3-7 cycloalkyl, and preferably a group selected from te/t-butyl, isopropyl and cyclopropyl.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from C2-5 alkyl and C3_-7 cycloalkyl-Ci alkyl, and preferably a group selected from propyl, isobutyl and cyclopropylmethyl. In another embodiment, the invention relates to compounds of formula I wherein Ri represents C₂-8 alkyl, preferably C_2-5 alkyl, and more preferably a group selected from te/t-butyl, isopropyl, propyl, 2,2-dimethyl-propyl, butyl and isobutyl.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl and isobutyl.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl and isopropyl.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from propyl and isobutyl.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents C3-7 cycloalkyl-Ci_-4 alkyl, preferably C_3-7 cycloalkyl-Ci alkyl, and more preferably cyclopropyl methyl.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents C_3-7 cycloalkyl, and preferably cyclopentyl, cyclobutyl or cyclopropyl.

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

In another embodiment, the invention relates to compounds of formula I wherein R₂ and R3 have the meaning described above for compounds of formula I, provided that when R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group, this is not piperazinyl.

In another embodiment, the invention relates to the compounds of formula I wherein R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:

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

(ii) a heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one NR₃Rb group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic groups (i) and (ii) can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; or R₂ represents H or Ci_-4 alkyl, and R3 represents azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, which can be optionally substituted with one or more Ci_-4 alkyl groups.

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

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

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

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

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

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

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

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

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

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

In another embodiment, the invention relates to compounds of formula I wherein R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:

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

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

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

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

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

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

In another embodiment, the invention relates to compounds of formula I wherein R ₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R₃ and Rb have the meaning previously described for the compounds of formula I and R₀ represents H or Ci_-4 alkyl, and preferably R₀ represents H.

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

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

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

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

(a) wherein R₃ and Rb have the meaning previously described for the compounds of formula I and R₀ represents H or Ci_-4 alkyl, and preferably R₀ represents H.

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

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

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

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

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

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

(b) wherein R₃ and Rb have the meaning previously described for the compounds of formula I and R₀ represents H or Ci_-4 alkyl, and preferably R₀ represents H.

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

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

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

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

(f) wherein R₃ represents H or Ci_-4 alkyl, and preferably R_a represents H or methyl.

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

wherein R₃ represents H or Ci_-4 alkyl, and preferably R_a represents H or methyl.

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

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from C_2-5 alkyl and C3-7 cycloalkyl-C_0-i alkyl and preferably a group selected from te/t-butyl, isopropyl, propyl, 2,2- dimethyl-propyl, butyl, isobutyl, cyclopropylmethyl and cyclopropyl; and R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl and NR₃Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃Rb group, or contains 1 N atom and is substituted with one NR₃R_b group. In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from C2-5 alkyl and C3_-7 cycloalkyl-Co-1 alkyl and preferably a group selected from te/t-butyl, isopropyl, propyl, 2,2- dimethyl-propyl, butyl, isobutyl, cyclopropylmethyl and cyclopropyl; and R2 and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:

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

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from C2-5 alkyl and C3-7 cycloalkyl-Co-1 alkyl and preferably a group selected from te/t-butyl, isopropyl, propyl, 2,2- dimethyl-propyl, butyl, isobutyl, cyclopropylmethyl and cyclopropyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), wherein R₃, R_b and R₀ have the meaning described above, and preferably R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, and more preferably R₃, Rb and R₀ independently represent H or methyl.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from C2-5 alkyl and C3-7 cycloalkyl-Co-1 alkyl and preferably a group selected from te/t-butyl, isopropyl, propyl, 2,2- dimethyl-propyl, butyl, isobutyl, cyclopropylmethyl and cyclopropyl; and R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (f), wherein R₃, R_b and R₀ have the meaning described above, and preferably R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, and more preferably R_a, Rb and R₀ independently represent H or methyl.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from C2-5 alkyl and C3-7 cycloalkyl-C_0-i alkyl and preferably a group selected from te/t-butyl, isopropyl, propyl, 2,2- dimethyl-propyl, butyl, isobutyl, cyclopropylmethyl and cyclopropyl; and R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (d), wherein R₃, Rb and R₀ have the meaning described above, and preferably R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, and more preferably R_a, Rb and R₀ independently represent H or methyl. In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from C2-5 alkyl and C3-7 cycloalkyl-C_0-i alkyl and preferably a group selected from te/t-butyl, isopropyl, propyl, 2,2- dimethyl-propyl, butyl, isobutyl, cyclopropylmethyl and cyclopropyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R₃, Rb and R₀ have the meaning described above, and preferably R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, and more preferably R_a, Rb and R₀ independently represent H or methyl.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from C_2-5 alkyl and C3-7 cycloalkyl-C_0-i alkyl and preferably a group selected from te/t-butyl, isopropyl, propyl, 2,2- dimethyl-propyl, butyl, isobutyl, cyclopropylmethyl and cyclopropyl; and R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ independently represent H or methyl. In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from C_2-5 alkyl and C_3-7 cycloalkyl-Co-i alkyl and preferably a group selected from te/t-butyl, isopropyl, propyl, 2,2- dimethyl-propyl, butyl, isobutyl, cyclopropylmethyl and cyclopropyl; and R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), wherein R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ independently represent H or methyl, and more preferably R_a and Rb independently represent H or methyl and R₀ represents H.

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

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl, isobutyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclopropyl; and R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl, isobutyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclopropyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), and R₃, R_b and R₀ independently represent H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ independently represent H or methyl, and more preferably R₃ represents H, R_b represents methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl, isobutyl, cyclopropylmethyl, cyclobuthyl, cyclopenthyl and cyclopropyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (f), and R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ independently represent H or methyl, and more preferably R₃ represents H, R_b represents methyl and R₀ represents H. In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl, isobutyl, cyclopropylmethyl, cyclobuthyl, cyclopenthyl and cyclopropyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (d), and R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ independently represent H or methyl, and more preferably R₃ represents H, R_b represents methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl, isobutyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclopropyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), and R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ independently represent H or methyl, and more preferably R₃ represents H, R_b represents methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl, isobutyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclopropyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), and R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ independently represent H or methyl, and more preferably R_a represents H, R_b represents methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl, isobutyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclopropyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), and R_a, R_b and R₀ independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ independently represent H or methyl, and more preferably R_a represents H, R_b represents methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents C2-8 alkyl, preferably C2-5 alkyl, and more preferably a group selected from te/t-butyl, isopropyl, propyl, 2,2-dimethyl-propyl, butyl and isobutyl; and R2 and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl and NR₃Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃Rb group, or contains 1 N atom and is substituted with one NR₃R_b group.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents C_2-S alkyl, preferably C2-5 alkyl, and more preferably a group selected from te/t-butyl, isopropyl, propyl, 2,2-dimethyl-propyl, butyl and isobutyl; and R2 and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:

In another embodiment, the invention relates to compounds of formula I wherein Ri represents C2-8 alkyl, preferably C2-5 alkyl, and more preferably a group selected from te/t-butyl, isopropyl, propyl, 2,2-dimethyl-propyl, butyl and isobutyl; R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), wherein R₃, R_b and R₀ have the meaning described above, and preferably R₃, R_b and R₀ independently represent H or Ci_-4 alkyl, and more preferably R₃, R_b and R₀ independently represent H or methyl.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents C2-8 alkyl, preferably C2-5 alkyl, and more preferably a group selected from te/t-butyl, isopropyl, propyl, 2,2-dimethyl-propyl, butyl and isobutyl; and R2 and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (f), wherein R₃, Rb and R₀ have the meaning described above, and preferably R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, and more preferably R₃, Rb and R₀ independently represent H or methyl.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents C2-8 alkyl, preferably C2-5 alkyl, and more preferably a group selected from te/t-butyl, isopropyl, propyl, 2,2-dimethyl-propyl, butyl and isobutyl; and R2 and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (d), wherein R₃, Rb and R₀ have the meaning described above, and preferably R₃, R_b and R₀ independently represent H or Ci_-4 alkyl, and more preferably R₃, R_b and R₀ independently represent H or methyl. In another embodiment, the invention relates to compounds of formula I wherein Ri represents C2-8 alkyl, preferably C2-5 alkyl, and more preferably a group selected from te/t-butyl, isopropyl, propyl, 2,2-dimethyl-propyl, butyl and isobutyl; R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R₃, R_b and R₀ have the meaning described above, and preferably R₃, R_b and R₀ independently represent H or Ci_-4 alkyl, and more preferably R₃, R_b and R₀ independently represent H or methyl.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents C2-8 alkyl, preferably C2-5 alkyl, and more preferably a group selected from te/t-butyl, isopropyl, propyl, 2,2-dimethyl-propyl, butyl and isobutyl; and R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R₃, R_b and R₀ independently represent

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

In another embodiment, the invention relates to compounds of formula I wherein Ri represents C_2-S alkyl, preferably C_2-5 alkyl, and more preferably a group selected from te/t-butyl, isopropyl, propyl, 2,2-dimethyl-propyl butyl and isobutyl; and R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), wherein R₃, R_b and R₀ independently represent H or C1-4 alkyl, and preferably R_a, Rb and R₀ independently represent H or methyl, and more preferably R_a and Rb independently represent H or methyl and R₀ represents H.

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

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from selected from te/t-butyl, isopropyl, propyl and isobutyl; and R2 and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl and isobutyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), and R₃, R_b and R₀ independently represent H or Ci_-4 alkyl, and preferably R₃, R_b and R₀ independently represent H or methyl, and more preferably R₃ represents H, R_b represents methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl and isobutyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (f), and R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ independently represent H or methyl, and more preferably R_a represents H, R_b represents methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl and isobutyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (d), and R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ independently represent H or methyl, and more preferably R_a represents H, R_b represents methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl and isobutyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), and R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ independently represent H or methyl, and more preferably R_a represents H, R_b represents methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl and isobutyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), and R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ independently represent H or methyl, and more preferably R_a represents H, R_b represents methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl and isobutyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), and R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, and preferably R_a, R_b and R₀ independently represent H or methyl, and more preferably R_a represents H, R_b represents methyl and R₀ represents H.

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

In another embodiment, the invention relates to compounds of formula I wherein Ri represents C3_-7 cycloalkyl-Ci_-4 alkyl, preferably C3_-7 cycloalkyl-Cialkyl and more preferably cyclopropylmethyl; and R2 and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from: (i) a heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said heterocyclic group can be optionally substituted with one or more Ci_-4 alkyl groups; and (ii) a heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one NR₃R_b group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic groups (i) and (ii) can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic. In another embodiment, the invention relates to compounds of formula I wherein Ri represents C3_-7 cycloalkyl-Ci_-4 alkyl, preferably C3_-7 cycloalkyl-Ci alkyl and more preferably cyclopropylmethyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), and R₃, R_b and R₀ independently represent H or Ci_-4 alkyl, and preferably R₃, R_b and R₀ independently represent H or methyl, and more preferably R₃ represents H, Rb represents methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents C3_-7 cycloalkyl-Ci_-4 alkyl, preferably C3_-7 cycloalkyl-Ci alkyl and more preferably cyclopropyl methyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (f), and R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ independently represent H or methyl, and more preferably R_a represents H, Rb represents methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents C_3-7 cycloalkyl-Ci_-4 alkyl, preferably C_3-7 cycloalkyl-Ci alkyl and more preferably cyclopropylmethyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (d), and R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ independently represent H or methyl, and more preferably R_a represents H, Rb represents methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents C3_-7 cycloalkyl-Ci_-4 alkyl, preferably C3_-7 cycloalkyl-Ci alkyl and more preferably cyclopropylmethyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), and R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ independently represent H or methyl, and more preferably R_a represents H, Rb represents methyl and R₀ represents H. In another embodiment, the invention relates to compounds of formula I wherein Ri represents C3-7 cycloalkyl-Ci_-4 alkyl, preferably C3-7 cycloalkyl-Ci alkyl and more preferably cyclopropylmethyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), and R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ independently represent H or methyl, and more preferably R_a represents H, R_b represents methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents C3-7 cycloalkyl-Ci_-4 alkyl, preferably C3-7 cycloalkyl-Ci alkyl and more preferably cyclopropylmethyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), and R_a, R_b and R₀ independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ independently represent H or methyl, and more preferably R_a represents H, R_b represents methyl and R₀ represents H. In another embodiment, the invention relates to compounds of formula I wherein Ri represents C_3-7 cycloalkyl, preferably cyclopropyl; and R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl and NR₃Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃Rb group, or contains 1 N atom and is substituted with one NR₃Rb group.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents and C3-7 cycloalkyl, preferably cyclopropyl; and R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from: (i) a heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said heterocyclic group can be optionally substituted with one or more Ci_-4 alkyl groups; and

In another embodiment, the invention relates to compounds of formula I wherein Ri represents C_3-7 cycloalkyl, preferably cyclopropyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), and R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ independently represent H or methyl, and more preferably R₃ represents H, R_b represents methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents C_3-7 cycloalkyl, preferably cyclopropyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (f), and R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ independently represent H or methyl, and more preferably R_a represents H, R_b represents methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents C3-7 cycloalkyl, preferably cyclopropyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (d), and R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ independently represent H or methyl, and more preferably R_a represents H, R_b represents methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents C3-7 cycloalkyl, preferably cyclopropyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), and R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ independently represent H or methyl, and more preferably R₃ represents H, R_b represents methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents C_3-7 cycloalkyl, preferably cyclopropyl; and R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), and R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ independently represent H or methyl, and more preferably R₃ represents H, R_b represents methyl and R₀ represents H. In another embodiment, the invention relates to compounds of formula I wherein Ri represents C_3-7 cycloalkyl, preferably cyclopropyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), and R_a, Rb and R₀ independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ independently represent H or methyl, and more preferably R_a represents H, R_b represents methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents C_2-8 alkyl or C_3-7 cycloalkyl-C_0-4 alkyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a); and R_a represents H, R_b represents methyl and R₀ represents H. In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from C_2-5 alkyl and C_3-7 cycloalkyl-Co-i alkyl and preferably a group selected from te/t-butyl, isopropyl, propyl, isobutyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclopropyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a); and R_a represents H, R_b represents methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl, isobutyl, cyclopropylmethyl and cyclopropyl; R2 and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a); and R_a represents H, R_b represents methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from propyl, isobutyl, cyclobutyl, cyclopentyl and cyclopropylmethyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a); and R₃ represents H, R_b represents methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl and cyclopropyl; R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a); and R_a represents H, R_b represents methyl and

R₀ represents H.

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

In another embodiment, the invention relates to compounds of formula I wherein Ri represents C_2-S aIkVl, preferably C_2-5 alkyl, and more preferably a group selected from te/t-butyl, isopropyl, propyl and isobutyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula

(a); and R₃ represents H, R_b represents methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents C3-7 cycloalkyl-Ci_-4 alkyl, preferably C3-7 cycloalkyl-Ci alkyl and more preferably cyclopropylmethyl; R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a); and R_a represents H, R_b represents methyl and R₀ represents H.

In another embodiment, the invention relates to compounds of formula I wherein Ri represents C_3-7 cycloalkyl and preferably cyclopentyl, cyclobutyl and cyclopropyl; R2 and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a); and R₃ represents H, R_b represents methyl and R₀ represents H. Moreover, the present invention includes all possible combinations of the particular and preferred embodiments described above for the compounds of formula I.

In an additional embodiment, the invention relates to a compound of formula I selected from: 4-(Cyclopropylmethyl)-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyhmidin-2-amine;

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

4-Cyclopropylmethyl-6-((3R)-3-aminopyrrolidin-1 -yl)pyhmidin-2-amine;

4-Cyclopropylmethyl-6-(piperazin-1 -yl)pyrimidin-2-amine;

4-Cyclopropylmethyl-6-(3-methyl-3-(methylamino)azetidin-1 -yl)pyhmidin-2-amine; 4-(3-Aminoazetidin-1 -yl)-6-cyclopropylmethylpyhmidin-2-amine;

4-Cyclopropylmethyl-6-(1 ,4-diazepan-1 -yl)pyhmidin-2-amine;

4-(4-Aminopipehdin-1-yl)-6-cyclopropylmethylpyhmidin-2-amine;

4-Cyclopropylmethyl-6-((4af?,7af?)-octahydropyrrolo[3,4-ib]pyhdine-6-yl)pyrimidin-

2-amine; 4-Cyclopropylmethyl-6-((3S)-3-(methylamino)pyrrolidin-1 -yl)pyhmidin-2-amine;

(R)-4-Cyclopropylmethyl-6-[(Λ/-methylpyrrolidin-3-yl)amine]pyhmidin-2-amine;

(S)-4-Cyclopropylmethyl-6-(3-methylpiperazin-1 -yl)pyhmidin-2-amine;

(R)-4-Cyclopropylmethyl-6-(3-methylpiperazin-1 -yl)pyhmidin-2-amine;

4-Cyclopropylmethyl-6-[3-(pyrrolidin-1 -yl)azetidin-1 -yl]pyhmidin-2-amine; 4-(Cyclopropylmethyl)-6-(hexahydropyrrolo[1 ,2-a]pyrazin-2(1 H)-yl)pyrimidin-2- amine;

(S)-4-(Cyclopropylmethyl)-6-(hexahydropyrrolo[1 ,2-a)]-2(1 /-/)-yl)pyhmidin-2-amine;

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

4-lsopropyl-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyhmidin-2-amine; 4-fe/t-Butyl-6-(3-(methylamino)azetidin-1 -yl)pyrimidin-2-amine;

4-fe/t-Butyl-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyhmidin-2-amine;

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

4-((3R)-3-(Methylamino)pyrrolidin-1 -yl)-6-propylpyhmidin-2-amine; 4-Cyclopropyl-6-(3-(methylaπnino)azetidin-1 -yl)pyπnnidin-2-annine;

4-Cyclopropyl-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyπnnidin-2-annine;

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

4-Ethyl-6-((3R)-3-(methylannino)pyrrolidin-1-yl)pyπnnidin-2-annine; 4-Butyl-6-(3-(methylannino)azetidin-1 -yl)pyrinnidin-2-annine;

4-Butyl-6-((3R)-3-(methylannino)pyrrolidin-1-yl)pyπnnidin-2-annine;

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

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

4-lsobutyl-6-((3R)-3-(methylannino)pyrrolidin-1-yl)pyπnnidin-2-annine; 4-lsobutyl-6-(3-(methylamino)azetidin-1 -yl)pyrinnidin-2-annine;

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

4-(2,2-Dimethylpropyl)-6-(3-(methylamino)azetidin-1 -yl)pyπmidin-2-amine; frans-4-(2-Phenylcyclopropyl)-6-((3R)-3-(nnethylannino)pyrrolidin-1 -yl)pyπnnidin-2- amine; (R)-4-fe/t-Butyl-6-[(N-methylpyrrolidin-3-yl)annine]pynnnidin-2-annine;

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

4-(2-Cyclopentylethyl)-6-(3-(methylannino)azetidin-1 -yl)pynnnidin-2-annine;

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

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

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

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

4-(4-Cyclohexylbutyl)-6-(3-(methylannino)azetidin-1 -yl)pyπnnidin-2-annine;

(S)-4-(2-Cyclopropylethyl)-6-(3-methylpiperazin-1 -yl)pyrinnidin-2-annine; 4-(3-Aminoazetidin-1 -yl)-6-(cyclopentylnnethyl)pyπnnidin-2-annine;

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

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

4-Cyclopentyl-6-(3-(methylamino)azetidin-1-yl)pyhmidin-2-amine; 4-((3R)-3-(Methylamino)pyrrolidin-1 ^0-6-(2,2,3,S- tetramethylcyclopropyl)pyrimidin-2-amine;

4-lsobutyl-6-(3-methyl-3-(methylamino)azetidin-1 -yl)pyhmidin-2-amine;

4-(3-Methyl-3-(methylamino)azetidin-1 -yl)-6-neopentylpyhmidin-2-amine; (S)-4-(3-Methylpiperazin-1 -yl)-6-neopentylpyrimidin-2-amine;

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

(f?)-4-(Cyclopropylmethyl)-6-(hexahydropyrrolo[1 ,2-a]pyrazin-2(1 /-/)-yl)pynnnidin-2- amine; 4-Cyclopentyl-6-(3-methyl-3-(methylamino)azetidin-1 -yl)pyπmidin-2-amine;

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

4-(3-Methyl-3-(methylamino)azetidin-1 -yl)-6-(2,2,3,3- tetramethylcyclopropyl)pyrinnidin-2-annine;

(S)-4-(3-Methylpiperazin-1 -yl)-6-(2,2,3,3-tetramethylcyclopropyl)pyπmidin-2-amine; 4-(3-(Methylamino)azetidin-1 -yl)-6-(pentan-3-yl)pyrinnidin-2-annine;

4-((3R)-3-(Methylamino)pyrrolidin-1 -yl)-6-(pentan-3-yl)pyrinnidin-2-annine;

4-((1 S,2S,4S)-Bicyclo[2.2.1]heptan-2-yl)-6-(3-(methylamino)azetidin-1 - yl)pyrimidin-2-annine; and

4-((1 S,2R,4S)-Bicyclo[2.2.1]heptan-2-yl)-6-(3-(methylamino)azetidin-1 - yl)pyrimidin-2-annine.

In an additional embodiment, the invention relates to compounds according to formula I which provide more than 50% inhibition of histamine H₄ receptor activity at 10 μM, more preferably at 1 μM and even more preferably at 0.1 μM, in a H₄ receptor binding assay such as that described in example 64. In another embodiment, the invention relates to compounds of formula Vl wherein R₁' represents C_1-6 alkyl, and preferably isobutyl.

In another embodiment, the invention relates to compounds of formula Vl wherein R₁ ' represents Cs-z cycloalkyl-d^ alkyl.

In another embodiment, the invention relates to compounds of formula Vl wherein R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7-membered monocyclic, 7- to 8- membered bridged bicyclic or 8- to 12-membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from C_1-4 alkyl and NR₃Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃Rb group, or contains 1 N atom and is substituted with one NR₃R_b group.

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

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

In another embodiment, the invention relates to compounds of formula Vl wherein R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:

wherein R₃ and Rb have the meaning described above for compounds of formula I and R₀ represents H or Ci_-4 alkyl.

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

In another embodiment, the invention relates to compounds of formula Vl wherein R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a)

(a) wherein R₃ and Rb have the meaning described above for compounds of formula I and R₀ represents H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, and more preferably R_a, Rb and R₀ independently represent H or methyl.

In another embodiment, the invention relates to compounds of formula Vl wherein R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b)

(b) wherein R₃ and Rb have the meaning described above for compounds of formula I and R₀ represents H or Ci_-4 alkyl, and preferably R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, and more preferably R₃, Rb and R₀ independently represent H or methyl, and even more preferably R₃ and Rb independently represent H or methyl and R₀ represents H.

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

In another embodiment, the invention relates to compounds of formula Vl wherein R₁' represents C_1-6 alkyl, preferably isobutyl; and R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group that can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12- membered fused bicyclic, wherein said heterocyclic group can contain up to two N atoms and does not contain any other heteroatoms, and can be optionally substituted with one or more substituents independently selected from C_1-4 alkyl and NR₃Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR₃Rb group, or contains 1 N atom and is substituted with one NR₃Rb group.

In another embodiment, the invention relates to compounds of formula Vl wherein R₁' represents d-6 alkyl, preferably isobutyl; and R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), wherein R₃, R_b and R₀ have the meaning described above, and preferably R₃, R_b and R₀ independently represent H or C_1-4 alkyl, and more preferably R₃, R_b and R₀ independently represent H or methyl. In another embodiment, the invention relates to compounds of formula Vl wherein R₁' represents C_1-6 alkyl, preferably isobutyl; and R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R₃, R_b and R₀ have the meaning described above, and preferably R₃, Rb and R₀ independently represent H or C_1-4 alkyl, and more preferably R₃, Rb and R₀ independently represent H or methyl.

In another embodiment, the invention relates to compounds of formula Vl wherein R₁' represents C_1-6 alkyl, preferably isobutyl; and R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R₃, R_b and R₀ independently represent H or C_1-4 alkyl, and preferably R₃, Rb and R₀ independently represent H or methyl.

In another embodiment, the invention relates to compounds of formula Vl wherein R₁' represents C_1-6 alkyl, preferably isobutyl; and R₂ and R₃ form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), wherein R₃, Rb and R₀ independently represent H or Ci_-4 alkyl, and preferably R_a, Rb and R₀ independently represent H or methyl, and more preferably R_a and Rb independently represent H or methyl and R₀ represents H.

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

In an additional embodiment, the invention relates to a compound of formula Vl selected from: 4-(2-cyclopentylethinyl)-6-(3-(R)-3-(methylamino)pyrrolidin-1-yl)pyhmidin-2-amine; 4-(2-Cyclopentylethinyl)-6-(3-(methylamino)azetidin-1 -yl)pyhmidin-2-amine;

4-(2-Cyclopropylethinyl)-6-(3-(R)-3-(methylamino)pyrrolidin-1-yl)pyhmidin-2-amine; 4-(2-lsobutylethinyl)-6-(3-(R)-3-(methylamino)pyrrolidin-1 -yl)pyhmidin-2-amine; 4-(2-lsobutylethinyl)-6-(3-(methylamino)azetidin-1 -yl)pyrimidin-2-amine; 4-(4-Cyclohexyl-1-butinyl)-6-(3-(R)-3-(methylamino)pyrrolidin-1 -yl)pyhmidin-2- amine;

4-(4-Cyclohexyl-1-butinyl)-6-(3-(methylamino)azetidin-1-yl)pyhmidin-2-amine; 4-(3-Cyclopentyl-1 -propinyl)-6-(3-(R)-3-(methylamino)pyrrolidin-1 -yl)pyhmidin-2- amine; and (S)-4-(2-Cyclopropylethinyl)-6-(3-methylpiperazin-1 -yl)pyhmidin-2- amine. In an additional embodiment, the invention relates to compounds according to formula Vl that provide more than 50% inhibition of histamine H₄ receptor activity at 10 μM, more preferably at 1 μM and even more preferably at 0.1 μM, in a H₄ receptor binding assay such as the one described in example 64.

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

There is no limitation on the type of salt that can be used, provided that these are pharmaceutically acceptable when used for therapeutic purposes. The term pharmaceutically acceptable salt refers to those salts which are, according to medical judgement, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like. Pharmaceutically acceptable salts are well known in the art.

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

The compounds of formula I and their salts may differ in some physical properties but they are equivalent for the purposes of the present invention. All salts of the compounds of formula I are included within the scope of the invention. The compounds of the present invention may form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as solvates. As used herein, the term solvate refers to a complex of variable stoichiometry formed by a solute (a compound of formula I or a salt thereof) and a solvent. Examples of solvents include pharmaceutically acceptable solvents such as water, ethanol and the like. A complex with water is known as a hydrate. Solvates of compounds of the invention (or of salts thereof), including hydrates, are included within the scope of the invention.

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

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

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

In general, the compounds of formula I can be obtained by reacting a compound of formula Il with a compound of formula III, as shown in the following scheme:

HB wherein Ri, R₂ and R3 have the meaning described above with respect to a compound of formula I, and R₄ represents a leaving group such as a halogen atom or thflate. The reaction between the compounds of formulae Il and III may be performed using a coupling agent such as for example PyBOP (benzotriazol-1-yl- oxythpyrrolidinophosphonium hexafluorophosphate) in a suitable solvent such as

1 ,4-dioxane, tetrahydrofurane, dichloromethane, Λ/,Λ/-dimethylformamide or acetonithle, preferably in acetonitrile, in the presence of a base, such as N,N- diisopropylethylamine, dimethylaniline, diethylaniline or triethylamine, preferably triethylamine. The reaction can be carried out at a temperature comprised between room temperature and the reflux temperature.

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 atom or triflate, preferably chlorine.

The -OH group from the compound of formula Il may be transformed into a leaving group such as a halogen atom, preferably chlorine, by reaction with a halogenating agent such as POCI3, optionally in the presence of a suitable solvent, or with POCI3/PCI5 or /V,/V-dimethylfornnannide/oxalyl chloride mixtures in the presence of a suitable solvent such as 1 ,4-dioxane or 1 ,2-dichloroethane. The reaction is performed by heating, preferably at a temperature comprised between 100 °C and 140 °C. Similarly, the hydroxy group of a compound of formula Il can be transformed into a triflate group by reaction with thfluoromethanesulphonic anhydride in the presence of pyridine.

The reactive derivative of a compound of formula Il thus obtained (MB) is then allowed to react with a compound of formula III to give a compound of formula I. The reaction is performed in a suitable solvent such as ethanol, methanol, butanol, Λ/,Λ/-dimethylformamide, dimethylsulphoxide, tetrahydrofuran or toluene, preferably ethanol, in the presence of a base, including organic amines such as triethylamine, Λ/,Λ/-diisopropylethylamine, dimethylaniline and diethylamide among others, and heating, preferably at a temperature comprised between 50 and 100 °C. The heating may be thermal or by irradiating with microwaves at a wattage that allows to reach the temperatures mentioned above.

In general, before conducting reaction between the compounds of formula Il and III, or MB and III, the amino substituents of the compounds of formula III are protected in order to prevent the formation of side products. Similarly, the amino group of the compounds of formula Il and MB can also be protected if necessary. Any suitable protective group may be used, such as for example a tert- butoxycarbonyl (Boc) group. A subsequent deprotection step may be necessary when the amino substituents of the compounds of formula Il and/or III and/or MB are protected, which is carried out under standard conditions. When the protective group is Boc, the deprotection can be conducted directly upon the crude product obtained by adding a solution of a strong acid such as HCI in a suitable solvent such as 1 ,4-dioxane, diethyl ether or methanol, or trifluoroacetic acid in dichloromethane.

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

IV

wherein Ri has the meaning described in formula I.

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

The compounds of formula IV are commercial or can be easily obtained from commercial compounds by known methods (see for example Journal of Organic Chemistry 2000, 8402 and Tetrahedron Letters 1991 , 7731 ).

Alternatively, compounds of formula I wherein Ri represents Ri '-CH₂-CH₂ (i.e. compounds of formula I') can be obtained by reduction of a compound of formula Vl, as shown in the following scheme:

wherein R₁' represents C_1-6 alkyl or C3-7 cycloalkyl-C_0-2 alkyl, wherein said C3-7 cycloalkyl group may be optionally substituted with one or more substituents independently selected from C_1-4 alkyl, phenyl and fluorine; and R₂ and R3 have the meaning described above for compounds of formula I.

The reaction takes place in a reducing medium that preferably consists of a source of hydrogen, preferably in gas form (H₂) and a metal catalyst, preferably palladium in homogeneous or heterogeneous form, and more preferably Pd/C, in a suitable solvent such as for example methanol or ethanol. The reaction can be performed by heating at a suitable temperature usually comprised between room temperature and the reflux temperature, preferably at room temperature.

In general, the compounds of formula Vl can be obtained by reacting a compound of formula V with a compound of formula III, as shown in the following scheme:

wherein FV has the meaning described above and R2 and R3 have the meaning described for compounds of formula I.

The reaction can be performed in the presence of a base, including organic amines such as pyridine, thethylamine, Λ/,Λ/-diisopropylethylamine, dimethylaniline and diethylamide among others, in a suitable solvent such as ethanol, methanol or butanol, and heating, preferably at reflux temperature.

Similarly to what has been described above for the synthesis of compounds of formula I, the amino substituents of the compounds of formula III are protected to avoid the formation of side products, before carrying out the reaction between the compounds of formula V and III (above, for the reaction between compounds of formula Il and III). Similarly, the amino group of the compounds of formula V can also be protected if necessary. A subsequent deprotection step may be necessary when the amino substituents of the compounds of formula III and/or V are protected, which is carried out under standard conditions.

The compounds of formula V may in turn be obtained by the coupling reaction of an alkyne of formula VII with the commercially available 2-amino-4,6- dichloropyhmidine, as shown in the following scheme:

wherein Ri' has the meaning described above.

The reaction can be performed under the Sonogashira conditions, using a palladium catalyst such as for example tetrakis (thphenylphosphine)palladium(O)

(Pd(PPh₃)₄), or bis(triphenylphosphine)dichloropaladium(ll) (Pd(Ph₃P)₂CI₂) in the presence of triphenylphosphine, a copper catalyst (I) as a co-catalyst, such as for example CuI, and a base, such as for example Λ/,Λ/-diisopropylethylamine and preferably triethylamine. The reaction is usually carried out under anhydrous and anaerobic conditions. The reaction may be carried out in a solvent such as dioxane, /V,/V-dimethylformamide, toluene and preferably in tetrahydrofuran and heating at a temperature usually comprised between 6O⁰C-I OO⁰C.

The compounds of formula VII are commercial or may be easily obtained from commercial compounds using standard procedures. Moreover, some compounds of formula I or Vl can be obtained from other compounds of formula I or Vl, respectively, by appropriate conversion reactions of functional groups, in one or more steps, using reactions that are well known in organic chemistry under standard experimental conditions.

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

Diseases that can be treated with the compounds of formula I and Vl of the present invention include, among others, allergic, immunological or inflammatory diseases or pain.

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

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

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

Assays to determine the ability of a compound to interact with the histamine H₄ receptor are well known in the art. For example, one can use a H₄ receptor binding assay such as the one explained in detail in example 64. Another useful assay is a GTP [γ-³⁵S] binding assay to membranes that express the H₄ receptor. Functional assays with H₄ receptor-expressing cells can also be used, for example in a system measuring any kind of cellular activity mediated by a second messenger associated with the H₄ receptor such as intracellular cAMP levels or Ca²⁺ mobilization. Another useful functional assay that can be used is the Gated Autofluorescence Forward Scatter assay (GAFS) in eosinophils, for example human eosinophils, such as the one explained in detail in example 65; this assay is well know in the art (see for example the method disclosed in Buckland KF et al, 2003, cited above in the Background section, which is incorportated herein by reference). In vivo assays that can be used to test the activity of the compounds of the invention are also well known in the art (see for example the various literature references listed for in vivo animal models in the Background section, particularly those relating to in vivo models of peritonitis, pleurisy, allergic asthma, inflammatory bowel disease, atopic dermatitis and pruritus, which are all incorportated herein by reference).

For selecting active compounds, testing at 10 μM must result in an activity of more than 50% inhibition of H₄ receptor activity in the test provided in example 64. More preferably, compounds should exhibit more than 50% inhibition at 1 μM and still more preferably at 0.1 μM. The present invention also relates to a pharmaceutical composition comprising a compound of formula I or Vl (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients. The excipients must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof. The compounds of the present invention can be administered in the form of any pharmaceutical formulation, the nature of which, as it is well known, will depend upon the nature of the active compound and its route of administration. Any route of administration may be used, for example oral, parenteral, nasal, ocular, topical and rectal administration. Solid compositions for oral administration include tablets, granulates and capsules. In any case the manufacturing method is based on a simple mixture, dry granulation or wet granulation of the active compound with excipients. These excipients can be, for example, diluents such as lactose, microcrystalline cellulose, mannitol or calcium hydrogenphosphate; binding agents such as for example starch, gelatin or povidone; disintegrants such as sodium carboxymethyl starch or sodium croscarmellose; and lubricating agents such as for example magnesium stearate, stearic acid or talc. Tablets can be additionally coated with suitable excipients by using known techniques with the purpose of delaying their disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period, or simply to improve their organoleptic properties or their stability. The active compound can also be incorporated by coating onto inert pellets using natural or synthetic film-coating agents. Soft gelatin capsules are also possible, in which the active compound is mixed with water or an oily medium, for example coconut oil, mineral oil or olive oil.

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

Liquid forms for oral administration include emulsions, solutions, suspensions, syrups and elixirs containing commonly-used inert diluents, such as purified water, ethanol, sorbitol, glycerol, polyethylene glycols (macrogols) and propylene glycol. Said compositions can also contain coadjuvants such as wetting, suspending, sweetening, flavouring agents, preservatives and buffers.

Injectable preparations, according to the present invention, for parenteral administration, comprise sterile solutions, suspensions or emulsions, in an aqueous or non-aqueous solvent such as propylene glycol, polyethylene glycol or vegetable oils. These compositions can also contain coadjuvants, such as wetting, emulsifying, dispersing agents and preservatives. They may be sterilized by any known method or prepared as sterile solid compositions which will be dissolved in water or any other sterile injectable medium immediately before use. It is also possible to start from sterile materials and keep them under these conditions throughout all the manufacturing process. The compounds of the invention can also be formulated for their topical application for the treatment of pathologies occurring in zones or organs accessible through this route, such as eyes, skin and the intestinal tract. Formulations include creams, lotions, gels, powders, solutions and patches wherein the compound is dispersed or dissolved in suitable excipients. For the nasal administration or for inhalation, the compound can be formulated as an aerosol, from which it can be conveniently released using suitable propellants. The dosage and frequency of doses will depend upon the nature and severity of the disease to be treated, the age, the general condition and body weight of the patient, as well as the particular compound administered and the route of administration, among other factors. As an example, a suitable dosage range is from about 0.01 mg/Kg to about 100 mg/Kg per day, which can be administered as a single or divided doses.

The invention is illustrated with the following examples.

Examples

The following abbreviations are used in the examples:

AcN: acetonitrile

EtOAc: ethyl acetate n-BuOH: 1 -butanol cone: concentrate

DIEA: Λ/,Λ/-diisopropylethylamine

EtOH: ethanol g: gas

MeOH: methanol PyBOP: (benzothazol-i -yloxy)tripyrrolidinophosphonium hexafluorophosphate

TEA: triethylamine t_R: retention time

LC-MS: liquid chromatography-mass spectrometry

One of the following methods was used to determine the LC-MS spectrums: Method 1 : X-Terra MS C18 5 μm (100 mm x 2.1 mm) column, temperature: 30 °C, rate: 0.35 mL/min, eluent: A = AcN, B = NH₄HCO₃ 10 mM, gradient: 0 min A at 10%; 10 min A at 90%; 15 min A at 90%. Method 2: Acquity UPLC BEH C18 1 ,7 μm (2.1 x 50 mm) column, temperature: 40 °C, rate: 0.50 mL/min, eluent: A = AcN, B = NH₄HCO₃ 10 mM, gradient: 0 min A at 10%; 0.25 min A at 10%; 3.00 min A at 90%; 3.75 min A at 90%. REFERENCE EXAMPLE 1A tert-Butyl methyl[(3R)-pyrrolidin-3-yl]carbamate

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

Di-te/t-butyl dicarbonate (11.6 g, 53.07 mmol) dissolved in 15 ml_ of CH₂Cb was added to a solution of (3R)-1 -benzyl-Λ/-methylpyrrolidin-3-amine (10 g, 52.55 mmol) in 115 ml_ of CH₂CI₂, cooled at 0 °C. The resulting solution was stirred at room temperature for 18 hours. The solvent was evaporated and the crude product was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, providing 14.5 g of the desired compound (yield: 95%).

LC-MS (Method 1 ): t_R = 9.55 min; m/z = 291 (MH⁺).

(b) Title compound

A mixture of the compound obtained above (14.5 g, 50.14 mmol), Pd/C (10%, 50% in water) (3 g) and ammonium formate (12.7 g, 200.5 mmol) in MeOH (390 mL) and water (45 mL) was heated under reflux for 5 hours. The reaction was filtered through CeI ite^® and the filter cake was washed with EtOAc and MeOH. The solvent was evaporated to dryness, providing 10.6 g of the title compound in the form of an oil (yield: 100%). 1H NMR (300 MHz, CDCI₃) δ: 1.38 (s, 9H), 1.72 (m, 1 H), 1.96 (m, 1 H), 2.53 (s, NH), 2.80 (s, 3H), 2.87 (m, 1 H), 2.93 (m, 1 H), 3.11 (m, 2H), 4.58 (m, 1 H).

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

The title compound was obtained by following a procedure similar to that described in reference example 1A but using the corresponding (S) enantiomer as the starting material.

¹H NMR (300 MHz, CDCI₃) δ: 1.46 (s, 9H), 1.71 (m, 1 H), 1.77 (s, NH), 1.96 (m, 1 H), 2.76 (m, 1 H), 2.78 (s, 3H), 2.89 (m, 1 H), 3.06 (m, 2H), 4.61 (m, 1 H).

REFERENCE EXAMPLE 2

Terf-butyl azetidin-3-yl(methyl)carbamate (a) tert-Butyl [1-(diphenylmethyl)azetidin-3-yl]methylcarbamate Following a procedure similar to that described in section a) of reference example 1A, but using 1 -(diphenylmethyl)-Λ/-methylazetidin-3-amine instead of (3R)-1- benzyl-Λ/-methylpyrrolidin-3-amine, the desired compound was obtained in 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 cake 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 3 terf-Butyl (4a/?,7a/?)-octahydro-1H-pyrrolo[3,4-d] pyridin-1-carboxylate (a) terf-Butyl (4aR,7aR-6-benzyloctahydro-1H-pyrrole[3.4-b]pyridine-1- carboxylate

Triethylamine (0.95 ml_, 6.84 mmol) and di-te/f-butyl dicarbonate (0.75 3.42 mmol) dissolved in CH₂CI₂ (2 ml_), were added to a solution of (R,R)-6- benzyloctahydropyrrolo[3.4-ib]pyhdine (0.9 g, 3.11 mmol) in CH₂CI₂ (9 ml_). The resulting solution was stirred overnight at room temperature. The solvent was evaporated and the crude product was chromatographed over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, providing 0.79 g of the desired compound (yield: 72%). LC-MS (Method 2): t_R = 2.94 min; m/z = 317 (MH⁺). (b) Title compound

A solution of the compound obtained in section a) (0.79 g, 2.49 mmol) in 10 mL of MeOH was purged with argon. Pd/C (10%, 50% in water) (157 mg) was added and the solution was then purged again with argon and stirred overnight in an H₂ atmosphere. The reaction was filtered through Celite^® and the filter cake was washed with MeOH. The solvent was evaporated to dryness, providing 0.61 of the desired compound with quantitative yield.

LC-MS (Method 2): t_R = 1.29 min; m/z = 227 (MH⁺).

REFERENCE EXAMPLE 4 terf-Butyl 3-methylazetidin-3-yl(methyl)carbamate

(a) tert-Butyl [1 -(diphenylmethylJ-S-methylazetidin-S-yllmethylcarbamate

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

¹H NMR (300 MHz, CDCI3) δ: 1.53 (s, 12H), 2.59 (s, 3H), 2.89 (m, 2H), 3.16 (m,

2H), 4.30 (s, 1 H), 7.17 (m, 1 H), 7.26 (m, 2H), 7.42 (m, 1 H). (b) Title compound

A solution of the compound obtained in section a) (6.06 g, 16.5 mmol) in 60 ml_ of

MeOH and 15 ml_ of EtOAc was purged with argon. Pd/C (10%) (814 mg) was added and the mixture was then purged again with argon and stirred overnight in an H₂ atmosphere. The reaction was filtered through Celite^® and the filter cake was washed with EtOAc and MeOH. The solvent was evaporated to dryness, providing 4.55 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, CDCI₃) δ: 1.45 (s, 12H), 2.67 (s, 3H), 3.28 (m, 1 H), 3.61 (m,

1 H), 3.87 (m, 1 H), 4.00 (m, 1 H)

REFERENCE EXAMPLE 5 (R)-1-Methylpyrrolidin-3-amine dihydrochloride

(a) terf-Butyl (R)-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 te/t-butyl (R)-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 a saturated aqueous solution of NaCI 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) 2.15 (m, 1 H), 2.55 (m, 1 H), 2.91 (s, 3H), 3.15 (m, 1 H), 3.3-3.85 (m, 3H), 4.10 (m, 1 H).

REFERENCE EXAMPLE 6 2-Amino-6-cyclopropylmethylpyrimidin-4-ol

Guanidine hydrochloride (0.46 g, 4.8 mmol) and sodium methoxide (0.26 g, 4.8 mmol) were added to a solution of ethyl 4-cyclopropyl-3-oxobutyrate (0.71 g, 4.2 mmol) in absolute ethanol (40 ml_) and the mixture was heated under reflux overnight. The solvent was evaporated to dryness and the residue was purified by chromatography over silica gel using mixtures of hexane/EtOAc of increasing polarity as eluent, providing 0.21 g of the title compound (yield: 31 %) LC-MS (Method 2): t_R = 0.85 min; m/z = 166 (MH⁺).

REFERENCE EXAMPLES 7-16

The following compounds were obtained by following a procedure similar to that described in reference example 6, but using suitable starting materials instead of ethyl 4-cyclopropyl-3-oxobutyrate:

REFERENCE EXAMPLE 17 4-(2-Cyclopentylethynyl)-6-chloropyrimidin-2-amine

4,6-Dichloropynmidin-2-annine (0.5 g, 3.05 mmol), triphenylphosphine (16 mg, 0.06 mmol), bis(triphenylphosphine)dichloropaladium (II) (21 mg, 0.03 mmol) and copper iodide (11 mg, 0.06 mmol) were placed in a flask. A mixture of THF- triethylamine 2:3 (5.6 ml_) was added and the system was inertized with vacuum/ argon cycles (3 times). Finally cyclopentylacetylene (0.38 ml_, 3.35 mmol) was added and the resulting mixture was heated at 60 ⁰C for 1 h. The reaction mixture was evaporated to dryness and the crude product thus obtained was purified by chromatography over silica gel using mixtures of hexane/EtOAc of increasing polarity as eluent, providing 0.67 g of the title compound (yield: 61 %) LC-MS (Method 2): t_R = 2.36 min; m/z = 222/224 (MH⁺).

REFERENCE EXAMPLES 18-21

The following compounds were obtained by following a procedure similar to that described in reference example 17, but using suitable starting materials instead of cyclopentylacetylene:

REFERENCE EXAMPLE 22

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

(a) terf-Butyl (R)-1 -(2-amino-6-(2-cyclopentylethynyl)pyrimidin-4- yl)pyrrolidin-3-yl(methyl)carbamate

The compound obtained in reference example 1A (0.18 g, 0.9 mmol) was added to a mixture of the compound obtained in reference example 17 (0.2 g, 0.9 mmol) and DIEA (0.16 g, 0.9 mmol) in EtOH (4 mL) and the resulting mixture was heated in a sealed tube at 100 °C for 24 hours. It was allowed to cool and the solvent was evaporated to dryness. The crude product obtained was purified by chromatography over silica gel using mixtures of hexane/EtOAc of increasing polarity as eluent, providing 0.19 g of the desired compound (yield: 56%). LC-MS (Method 2): t_R = 2.53 min; m/z = 386 (MH⁺). (b) Title compound

Thfluoroacetic acid (0.97 ml_) was added to a solution of the compound obtained in section a) (0.19 g, 0.5 mmol) in anhydrous dichloromethane (19.4 ml_) cooled at 0 ⁰C, and the resulting mixture was stirred at room temperature for 3 hours. The solvent was evaporated to dryness and the crude product was dissolved in CHCI3 and water. The pH was adjusted to 9 with 1 N NaOH aqueous solution and the phases were separated. The aqueous phase was re-extracted twice with chloroform and the combined organic phases were dried over Na2SO₄ and concentrated to dryness, providing 0.13 g of the desired compound (yield: 91 %). LC-MS (Method 2): t_R = 1.64 min; m/z = 286 (MH⁺).

REFERENCE EXAMPLES 23-29

The following compounds were obtained by following a procedure similar to that described in reference example 22, but using suitable starting materials:

REFERENCE EXAMPLE 30 (SH-^-CyclopropylethynylJ-e-^-methylpiperazin-i-ylJpyrimidin^-amine

The title compound was obtained by following a procedure similar to that described in reference example 22, section a), but using reference example 18 and (S)-2-methylpiperazine as starting materials. LC-MS (Method 2): t_R = 1.29 min; m/z = 258 (MH⁺).

REFERENCE EXAMPLE 31 Ethyl 3-(1-methylcyclopropyl)-3-oxopropanoate

(a) 1-Methylcyclopropanecarbonyl chloride

Oxalyl chloride (6.7 mL, 77.0 mmol) was slowly added to a suspension of 1- methylcyclopropanecarboxylic acid (7.0 g, 70 mmol) in anhydrous dichloromethane (30 mL), cooled at 0 ⁰C, and finally two drops of DMF were added. The mixture was stirred overnight at room temperature. The solvent was evaporated to dryness, anhydrous dichloromethane was added and it was evaporated to dryness again, providing 7.61 g of the intended compound (yield: 92%), which was used as such in the following step of the synthesis.

(b) Title compound Butyl-lithium (152 mL of a 1.6 M solution in hexanes, 245 mmol) was slowly added to a solution of ethyl monomalonate (14.5 mL, 122.5 mmol) in anhydrous THF (306 mL), cooled at -78 ⁰C by means of an acetone-CO2 bath under an argon atmosphere. The bath was withdrawn and the internal temperature was allowed to rise to -5 ⁰C. The reaction mixture was then cooled again to -65 ⁰C and a solution of the compound obtained in the previous section (7.61 g, 64.2 mmol) in THF (10 mL) was added, after which it was stirred for one hour at -65 ⁰C. The temperature was allowed to rise a little and the reaction crude was diluted with water. THF was evaporated to dryness, the residue was diluted with 1 N HCI and extracted three times with diethyl ether. The combined organic phases were dried over Na2SO₄ and concentrated to dryness, obtaining the title compound with quantitative yield in the form of a crude product that was used as such in the following step of the synthesis. 1H NMR (300 MHz, CDCI₃) δ: 0.80 (m, 2H), 1.20-1.30 (m, 2H + 3H), 1.35 (s, 3H), 3.43 (s, 2H), 4.16 (q, 2H).

REFERENCE EXAMPLE 32 Ethyl 3-oxo-3-(2,2,3,3-tetramethylcyclopropyl)propanoate The intended compound was obtained following a procedure similar to that described in reference example 31 , but using 2,2,3,3- tetramethylcyclopropanecarboxylic acid as starting material.

¹H NMR (300 MHz, CDCI₃) δ: 1.15-1.35 (m, 1 H + 3H + 12H), 3.42 (s, 2H), 4.22 (q,

2H). REFERENCE EXAMPLE 33

Ethyl 4-ethyl-3-oxohexanoate

The intended compound was obtained following a procedure similar to that described in reference example 31 section b), but using 2-ethylbutanoyl chloride as starting material. LC-MS ( Method 2): t_R = 2.28 min; m/z = 185 (MH^").

REFERENCE EXAMPLES 34-39

REFERENCE EXAMPLES 40 and 41 terf-Butyl 1-(2-amino-6-((1/?,2S,4S)-bicyclo[2.2.1]hept-5-en-2-yl)pyrimidin-4- yl)azetidin-3-yl(methyl)carbamate and enantiomer (exo isomers) (ref ex 40) and terf-Butyl 1-(2-amino-6-((1/?,2/?,4S)-bicyclo[2.2.1]hept-5-en-2-yl)pyrimidin-4- yl)azetidin-3-yl(methyl)carbamate and enantiomer (endo isomers) (ref ex 41) A mixture of the compound obtained in reference example 36 (0.30 g, 1.48 mmol), the amine obtained in reference example 2 (0.88 g, equivalent to 0.44 g 100%, 2.3 mmol) and PyBOP (1.0 g, 1.92 mmol) in a mixture of TEA (9 ml_) and acetonitrile (15 ml_) was stirred at 85 ⁰C overnight. The reaction mixture was evaporated to dryness and the residue was diluted with water and ethyl acetate. 1 N NaOH aq solution was added until basic pH, the phases were separated and the organic phase was washed again with 1 N NaOH solution. The organic phase was dried over anhydrous Na2SO₄ and it was concentrated to dryness. The crude product containing a mixture of exo/endo isomers was purified by preparative HPLC (method: X-Bhdge Prep C18 OBD 5 μm (100 mm x 19 mm) column, temperature: 30 °C, rate: 20.0 mL/min, eluent: A = AcN, B = NH₄HCO₃ 75 mM, gradient: 0 min A at 30%; 1 min A at 30%; 9.50 min A at 90%; 10 min A at 90%), and the fractions containing the products were evaporated to dryness. The more polar peak corresponded to the exo isomers, providing 261 mg of reference example 40 as a racemic mixture (yield: 47%). The less polar peak corresponded to the endo isomers, providing 280 mg of reference example 41 as a racemic mixture (yield: 51 %).

Ref Ex 40 LC-MS (Method 2): t_R = 2.29 min; m/z 372 (MH⁺). Ref Ex 41 LC-MS (Method 2): t_R = 2.39 min; m/z 372 (MH⁺).

EXAMPLE 1

^(CyclopropylmethyO-e-^SRJ-S^methylaminoJpyrrolidin-i-yOpyrimidin^- amine a) terf-Butyl (RJ-i-^-amino-β^cyclopropylmethylJpyrimidin^-ylJpyrrolidin-S- yl(methyl)carbamate

A mixture of the compound obtained in reference example 6 (1.0 g, 6.06 mmol), the amine obtained in reference example 1A (1.95 g, 9.7 mmol) and PyBOP (4.1 g, 7.9 mmol) in a mixture of TEA (37 mL) and 1 ,4-dioxane (63 mL) was stirred at room temperature for 4 days, after which more of the compound obtained in reference example 1A (1.95 g, 9.7 mmol), PyBOP (4.1 g, 7.9 mmol) and TEA (19 mL) were added and it was stirred at room temperature for one more day. The reaction mixture was evaporated to dryness, the residue was diluted with water and chloroform and 2 N NaOH solution was added until basic pH. The phases were separated and the aqueous phase was extracted twice with chloroform. The combined organic phases were dried over anhydrous Na2SO₄ and it was concentrated to dryness. The crude product obtained was purified by chromatography over silica gel using mixtures of hexane/EtOAc of increasing polarity as an eluent, providing 2.5 g of the desired compound. LC-MS (Method 2): t_R = 2.17 min; m/z 348 (MH⁺). b) Title compound

The compound obtained in section a) was dissolved in MeOH (12 mL) and HCI (4 M solution in 1 ,4-dioxane, 45 mL) was added, stirring the mixture 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. 2 N NaOH solution was added to the acidic aqueous phase until basic pH and it was extracted twice with EtOAc. The combined organic phases were dried over anhydrous Na2SO₄ and it was concentrated to dryness. The crude product obtained was purified by chromatography over silica gel using mixtures of chloroform/MeOH/NH_{3 ∞}nc of increasing polarity as eluent, providing 0.91 g of the title compound (yield: 61 %). LC-MS (Method 2): t_R = 1.20 min; m/z 248 (MH⁺).

EXAMPLES 2-10

The following compounds were obtained by following a procedure similar to that described in example 1 , but using suitable amines instead of te/t-butyl methyl[(3R)-pyrrolidin-3-yl]carbamate:

(*) The reaction was carried out in acetonitrile and heating at 80 ⁰C

EXAMPLES 11-16

The following compounds were obtained by following a procedure similar to that described in example 1 , section a), but using suitable amines instead of te/t-butyl methyl [(3R)-pyrrol id in-3-yl]carbamate, acetonitrile as the solvent and heating at 80 0C:

EXAMPLES 17-35 The following compounds were obtained by following a procedure similar to that described in example 1 , but using the corresponding starting materials in each case:

(*) The reaction was carried out in acetonitrile and heating at 80 ⁰C

EXAMPLE 36

The following compound was obtained by following a procedure similar to that described in example 1 , section a), but using suitable starting materials, acetonitrile as the solvent and heating at 80 ⁰C:

EXAMPLE 37

4-(2-Cyclopentylethyl)-6-((3/?)-3-(methylamino)pyrrolidin-1-yl) pyrimidin-2-amine

A solution of reference example 22 (80.0 mg, 0.28 mmol) in 1.6 ml_ of MeOH was purged with argon. Pd/C (5%, 50% in water) (24 mg) was added and the mixture was then purged again with argon and stirred overnight in an H₂ atmosphere. The reaction mixture was filtered through CeI ite^® and the filter cake was washed with MeOH. The solvent was evaporated to dryness and the crude product obtained was purified by chromatography over silica gel using mixtures of chloroform/MeOH/NH_{3 COnc} of increasing polarity as eluent, providing 54.5 mg of the title compound (yield: 67%). LC-MS (Method 2): t_R = 1.72 min; m/z 290 (MH⁺).

EXAMPLES 38-45

The following compounds were obtained by following a procedure similar to that described in example 37, but using the corresponding starting materials in each case:

EXAMPLES 46-61

The following compounds were obtained by following a procedure similar to that described in example 1 , but using suitable starting materials, acetonitrile as the solvent and heating at 80 ⁰C:

(*) HCI treatment as described in example 1 section b) was obviated.

EXAMPLE 62

4-((1S,2S,4S)-Bicyclo[2.2.1]heptan-2-yl)-6-(3-(methylamino)azetidin-1- yl)pyrimidin-2-amine and enantiomer

(exo isomer, as a racemic mixture) A 0.5 M solution of reference example 40 (261 mg, 0.70 mmol) in MeOH was hydrogenated in an H-Cube™ system using the following conditions: 10% Pd/C cartridge, flow 1 mL/min, temperature 25 ⁰C and pressure 1 bar of H₂. The solvent was evaporated and the residue was treated with HCI (4 M solution in 1 ,4-dioxane, 10 ml_), stirring the mixture 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. 2 N NaOH solution was added to the acidic aqueous phase until basic pH and it was extracted twice with chloroform. The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated to dryness, providing 60.5 mg of the title compound as a racemic mixture (yield: 32%). LC-MS (Method 2): t_R = 1.59 min; m/z 274 (MH⁺).

EXAMPLE 63

^((IS^R^SJ-Bicyclo^^.ilheptan^-yO-e^S^methylaminoJazetidin-i- yl)pyrimidin-2-amine and enantiomer

(endo isomer, as a racemic mixture)

The title compound was obtained as a racemic mixture by following a procedure similar to that described in example 62 but using reference example 41 as the starting material.

LC-MS (Method 2): t_R = 1.62 min; m/z 274 (MH⁺).

EXAMPLE 64

Competitive binding assay of [³H]-histamine to the 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.

The compounds to be tested were incubated at the desired concentration in duplicate with 10 nM [³H]-histamine and 15 μg membrane extract in a total volume of 250 μL of 50 mM Tris-HCI, pH 7.4, 1.25 mM EDTA for 60 minutes at 25 ⁰C.

Non-specific binding was defined in the presence of 100 μM of unlabelled histamine. The reaction was stopped by filtration using a vacuum collector (Multiscreen Millipore) in 96-well plates (Multiscreen HTS Millipore) that had been previously soaked in 0.5% polyethylenimine for 2 hours at 0 ⁰C. The plates were subsequently washed with 50 mM Tris (pH 7.4), 1.25 mM EDTA at 0 ⁰C, and the filters were dried for 1 hour at 50-60 ⁰C, before adding the scintillation liquid in order to determine bound radioactivity by means of a betaplate scintillation counter.

The compounds of examples 1 to 63 were assayed in this test and exhibited more than 50% inhibition of histamine binding to human histamine H₄ receptor at 1 μM. Similarly, the compounds of formula Vl described in reference examples 22,

23, 25, 26, 28 and 29 showed more than 50% inhibition of histamine binding to the human histamine H₄ receptor at 1 μM.

EXAMPLE 65 Histamine-induced shape change assay (gated autofluorescence forward scatter assay, GAFS) in human eosinophils

In this assay the shape change induced by histamine in human eosinophils is determined by flow cytometry, detected as an increase in the size of the cells (forward scatter, FSC).

Polymorphonuclear leucocytes (PMNL, fraction containing neutrophils and eosinophils) were prepared from whole blood of human healthy volunteers. Briefly, erythrocytes were separated by sedimentation in 1.2% Dextran (SIGMA), and the leucocyte-rich fraction (PMNL) was isolated from the top layer by centrifugation at 45Og for 20 min in the presence of Ficoll-Paque^® (Biochrom). PMNLs were resuspended in PBS buffer at a concentration of 1.1x10⁶ cells/ml/tube and were pretreated with different concentrations of test compounds (dissolved in PBS) for 30 min at 37⁰C and then stimulated with 300 nM histamine (Fluka) for 5 min. Finally, paraformaldehyde (1 % final concentration in PBS) was added to terminate the reaction and maintain cell shape. Cell shape change was analyzed by flow cytometry (FACS Calibur, BD Biosystems). Eosinophils in PMNL were gated based on their higher autofluorescence relative to that of neutrophils (fluorescence channel FL2). Cell shape change was monitored in forward scatter signals (FSC). Results are expressed as percentage inhibition of shape change induced by histamine for each concentration of test compound.

The compounds of examples 1 to 63 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:

Ri represents C2-8 alkyl or C3_-7 cycloalkyl-Co_-4 alkyl, wherein said C3_-7 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, phenyl and fluorine;

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

R₃ represents H or Ci_-4 alkyl;

R_b represents H or Ci_-4 alkyl; or R₃ and Rb form, together with the N atom to which they are bound, an azetidinyl, pyrrolidinyl, piperidinyl or azepanyl group that can be optionally substituted with one or more Ci_-4 alkyl groups; provided that the compound of formula I is not 4-(4-ethyl-piperazin-1 -yl)-6-propyl- pyrimidin-2-amine; or a salt thereof.

2.- A compound according to claim 1 wherein Ri represents C₂-₈ alkyl.

3.- A compound according to claim 2 wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl and isobutyl.

4.- A compound according to claim 2 wherein Ri represents a group selected from te/t-butyl and isopropyl.

5.- A compound according to claim 2 wherein Ri represents a group selected from propyl and isobutyl.

6.- A compound according to claim 1 wherein Ri represents C3_-7 cycloalkyl-Ci_-4 alkyl.

7.- A compound according to claim 6 wherein Ri represents cyclopropylmethyl.

8.- A compound according to claim 1 wherein Ri represents Cs^ cycloalkyl.

9.- A compound according to claim 8 wherein Ri represents cyclobutyl, cyclopentyl or cyclopropyl.

10.- A compound according to claim 8 wherein Ri represents cyclopropyl.

11.- A compound according to claim 1 wherein Ri represents a group selected from C2-5 alkyl and C3_-7 cycloalkyl-Co-i alkyl.

12.- A compound according to claim 11 wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl, isobutyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclopropyl.

13.- A compound according to claim 11 wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl, isobutyl, cyclopropylmethyl and cyclopropyl.

14.- A compound according to claim 11 wherein Ri represents a group selected from propyl, isobutyl, cyclobutyl, cyclopentyl and cyclopropylmethyl.

15.- A compound according to claim 11 wherein Ri represents a group selected from te/t-butyl, isopropyl and cyclopropyl.

16.- A compound according to claim 11 wherein Ri represents a group selected from propyl, isobutyl, and cyclopropylmethyl.

17.- A compound of formula Vl

wherein:

Ri' represents Ci_-6 alkyl or C3-7 cycloalkyl-Co-2 alkyl, wherein said C3-7 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci_-4 alkyl, phenyl and fluorine;

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

R₃ represents H or Ci_-4 alkyl;

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

18.- A compound according to claim 17 wherein FV is Ci-6 alkyl.

19.- A compound according to claim 18 wherein FV is isobutyl.

20.- A compound according to any of claims 1 to 19 wherein R₂ and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:

(ii) a heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one NR₃Rb group and can be optionally substituted with one or more Ci_-4 alkyl groups; wherein said heterocyclic groups (i) and (ii) can be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic.

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

wherein R₀ represents H or Ci_-4 alkyl.

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

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

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

(a).

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

(b).

26.- A compound according to claim 21 wherein R₂ and R₃ form, together with the

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

27.- A compound according to claim 21 wherein R₂ and R₃ form, together with the

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

28.- A compound according to any of claims 1 to 25 wherein R₃ and Rb independently represent H or Ci_-4 alkyl.

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

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

31.- A compound according to claim 30 wherein R₃ represents H and Rb represents methyl.

32.- A compound according to claim 1 selected from:

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

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

4-Cyclopropylmethyl-6-((3R)-3-aminopyrrolidin-1 -yl)pyhmidin-2-amine;

4-Cyclopropylmethyl-6-(piperazin-1 -yl)pyrimidin-2-amine; 4-Cyclopropylmethyl-6-(3-methyl-3-(methylamino)azetidin-1 -yl)pyhmidin-2-amine;

4-(3-Aminoazetidin-1 -yl)-6-cyclopropylmethylpyhmidin-2-amine;

4-Cyclopropylmethyl-6-(1 ,4-diazepan-1 -yl)pyhmidin-2-amine;

4-(4-Aminopipehdin-1-yl)-6-cyclopropylmethylpyhmidin-2-amine;

4-Cyclopropylmethyl-6-((4af?,7af?)-octahydropyrrolo[3,4-ib]pyhdine-6-yl)pyrimidin- 2-amine;

4-Cyclopropylmethyl-6-((3S)-3-(methylamino)pyrrolidin-1 -yl)pyhmidin-2-amine;

(R)-4-Cyclopropylmethyl-6-[(Λ/-methylpyrrolidin-3-yl)amine]pyhmidin-2-amine;

(S)-4-Cyclopropylmethyl-6-(3-methylpiperazin-1 -yl)pyhmidin-2-amine; (f?)-4-Cyclopropylmethyl-6-(3-methylpiperazin-1 -yl)pyrinnidin-2-annine;

4-Cyclopropylmethyl-6-[3-(pyrrolidin-1 -yl)azetidin-1 -yl]pyrinniclin-2-annine;

4-(Cyclopropylmethyl)-6-(hexahydropyrrolo[1 ,2-a]pyrazin-2(1 /-/)-yl)pyrinniclin-2- amine; (S)-4-(Cyclopropylmethyl)-6-(hexahydropyrrolo[1 ,2-a)]-2(1 /-/)-yl)pyrinnidin-2-annine;

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

4-lsopropyl-6-((3R)-3-(methylannino)pyrrolidin-1 -yl)pyπnnidin-2-annine;

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

4-fe/t-Butyl-6-((3R)-3-(methylannino)pyrrolidin-1 -yl)pynnnidin-2-annine; 4-(3-(Methylamino)azetidin-1 -yl)-6-propylpyrinnidin-2-annine;

4-((3R)-3-(Methylamino)pyrrolidin-1 -yl)-6-propylpyrinnidin-2-annine;

4-Cyclopropyl-6-(3-(methylannino)azetidin-1 -yl)pyπnnidin-2-annine;

4-Cyclopropyl-6-((3R)-3-(methylannino)pyrrolidin-1 -yl)pyπnnidin-2-annine;

4-Ethyl-6-(3-(methylamino)azetidin-1 -yl)pyrimidin-2-amine; 4-Ethyl-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyrinnidin-2-annine;

4-Butyl-6-(3-(methylannino)azetidin-1 -yl)pyπnnidin-2-annine;

4-Butyl-6-((3R)-3-(methylannino)pyrrolidin-1-yl)pyπnnidin-2-annine;

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

4-Cyclopentylmethyl-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyπmidin-2-amine; 4-lsobutyl-6-((3R)-3-(methylannino)pyrrolidin-1-yl)pyπnnidin-2-annine;

4-lsobutyl-6-(3-(methylannino)azetidin-1 -yl)pyπnnidin-2-annine;

4-(2,2-Dimethylpropyl)-6-(3-(methylamino)azetidin-1 -yl)pyπmidin-2-amine; frans-4-(2-Phenylcyclopropyl)-6-((3R)-3-(nnethylannino)pyrrolidin-1 -yl)pyπnnidin-2- amine;

(R)-4-fe/t-Butyl-6-[(N-methylpyrrolidin-3-yl)amine]pyhmidin-2-amine;

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

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

4-(2-Cyclopropylethyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyhmidin-2-amine; 4-((3R)-3-(Methylamino)pyrrolidin-1 -yl)-6-(4-methylpentyl)pyrimidin-2-amine;

4-(3-(Methylamino)azetidin-1 -yl)-6-(4-methylpentyl)pyhmidin-2-amine;

4-(3-Cyclopentylpropyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyhmidin-2-amine;

4-(4-Cyclohexylbutyl)-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyhmidin-2-amine; 4-(4-Cyclohexylbutyl)-6-(3-(methylamino)azetidin-1 -yl)pyπmidin-2-amine;

(S)-4-(2-Cyclopropylethyl)-6-(3-methylpiperazin-1 -yl)pyrinniclin-2-annine;

4-(3-Aminoazetidin-1 -yl)-6-(cyclopentylmethyl)pyrimidin-2-amine;

4-(3-(Methylamino)azetidin-1 -yl)-6-(2,2,3,3-tetrannethylcyclopropyl)pyπnnidin-2- amine;

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

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

4-((3R)-3-(Methylamino)pyrrolidin-1 -yl)-6-(2,2,3,3- tetramethylcyclopropyl)pyrinnidin-2-annine; 4-lsobutyl-6-(3-methyl-3-(nnethylannino)azetidin-1 -yl)pyrinnidin-2-annine;

4-(3-Methyl-3-(methylamino)azetidin-1 -yl)-6-neopentylpyπmidin-2-amine;

(S)-4-(3-Methylpiperazin-1 -yl)-6-neopentylpyrinnidin-2-annine;

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

(R)-4-(Cyclopropylmethyl)-6-(hexahydropyrrolo[1 ,2-a]pyrazin-2(1 /-/)-yl)pyrinnidin-2- amine;

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

4-Cyclobutyl-6-(3-methyl-3-(methylamino)azetidin-1 -yl)pyhmidin-2-amine;

4-(3-Methyl-3-(methylamino)azetidin-1 -yl)-6-(2,2,3,3- tetramethylcyclopropyl)pyrimidin-2-amine; (S)-4-(3-Methylpiperazin-1 -yl)-6-(2,2,3,3-tetramethylcyclopropyl)pyhmidin-2-amine;

4-(3-(Methylamino)azetidin-1 -yl)-6-(pentan-3-yl)pyrimidin-2-amine;

4-((3R)-3-(Methylamino)pyrrolidin-1 -yl)-6-(pentan-3-yl)pyrimidin-2-amine;

4-((1 S,2S,4S)-Bicyclo[2.2.1]heptan-2-yl)-6-(3-(methylamino)azetidin-1 - yl)pyrimidin-2-amine; and 4-((1 S,2R,4S)-Bicyclo[2.2.1]heptan-2-yl)-6-(3-(methylamino)azetidin-1 - yl)pyrimidin-2-amine; or a salt thereof.

33.- A pharmaceutical composition which comprises a compound of formula I according to any of claims 1 to 32 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

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

35.- Use of a compound according to any of claims 1 to 32 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease mediated by histamine H₄ receptor.

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

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

(a) reacting a compound of formula Il with a compound of formula III

wherein Ri, R₂ and R₃ have the meaning described in claim 1 ; or (b) reacting a compound of formula MB with a compound of formula

MB

wherein R₄ represents a leaving group and Ri, R₂ and R3 have the meaning described in claim 1 ; or

wherein R₁' represents C_1-6 alkyl or C3-7 cycloalkyl-Co-2 alkyl, wherein said C3-7 cycloalkyl group may be optionally substituted with one or more substituents independently selected from C_1-4 alkyl, phenyl and fluorine; and R2 and R3 have the meaning described in claim 1 ; or