Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/48—Two nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• 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.
• 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.
• H 4 a novel histamine receptor, which was named H 4 , was cloned by several research groups working independently (Oda T et al, J Biol Chem 2000, 275: 36781 -6; Nguyen T 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.
• GPCR G-protein coupled receptor
• the H 4 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 H 3 receptor. While the expression of the H 3 receptor is restricted to cells of the central nervous system, the expression of the H 4 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 H 4 receptor is highly distributed in cells of the immune system suggests the involvement of this receptor in immuno-inflammatory responses.
• H 4 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).
• H 4 receptor An increase in the expression of the H 4 receptor has also been reported in nasal polyp tissue in comparison to nasal mucosa of healthy people (J ⁇ k ⁇ ti A et al, Cell Biol lnt 2007, 31 : 1367-70). Recent studies with specific ligands of the H 4 receptor have helped to delimit the pharmacological properties of this receptor. These studies have evidenced that several histamine-induced responses in eosinophils such as chemotaxis, conformational change and CD11 b and CD54 up-regulation are specifically mediated by the H 4 receptor (Ling P et al, Br J Pharmacol 2004, 142:161-71 ; Buckland KF et al, Br J Pharmacol 2003, 140:1117-27).
• the H 4 receptor In dendritic cells, the H 4 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 H 4 receptor in mast cells has been studied. Although H 4 receptor activation does not induce mast cell degranulation, histamine and other proinflammatory mediators are released; moreover, the H 4 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 ).
• H 4 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).
• the distribution of the H 4 receptor suggests that it may have a role in the control of peristalsis and gastric acid secretion (Morini G et al, European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, OR-10).
• H 4 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).
• H 4 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., Junford
• H 4 receptor antagonist activity it would be desirable to provide novel compounds having H 4 receptor antagonist activity and which are good drug candidates.
• preferred compounds should bind potently to the histamine H 4 receptor whilst showing little affinity for other receptors.
• compounds In addition to binding to H 4 receptors, compounds should further exhibit good pharmacological activity in in vivo models of immunoinflammation.
• 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.
• One aspect of the present invention relates to compounds of formula I
• 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;
• R 2 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 NR 3 Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR 3 Rb group, or contains 1 N atom and is substituted with one NR 3 R b group; or R 2 represents H or Ci -4 alkyl, and R 3 represents azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, which can be optionally substituted with one or more Ci -4 alkyl groups;
• R 3 represents H or Ci -4 alkyl
• R b represents H or Ci -4 alkyl; or R 3 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 H 4 histamine receptor.
• another aspect of the invention relates to a compound of formula I
• 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 NR 3 Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR 3 Rb group, or contains 1 N atom and is substituted with one NR 3 R b group; or R 2 represents H or Ci
• R 3 represents H or Ci -4 alkyl
• R b represents H or Ci -4 alkyl; or R 3 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
• a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
• 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.
• COPD chronic obstructive pulmonary disease
• 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.
• the pain is selected from inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-surgical pain, migraine, cancer pain, visceral pain, osteoarthritis pain and neuropathic pain.
• 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.
• COPD chronic obstructive pulmonary disease
• 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.
• 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.
• COPD chronic obstructive pulmonary disease
• 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.
• 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 H 4 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.
• 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.
• 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.
• COPD chronic obstructive pulmonary disease
• 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
• R 4 represents a leaving group and Ri, R 2 and R3 have the meaning described above;
• R 1 ' 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
• R 1 ' 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
• R 2 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.
• 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 R 2 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
• 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 H 4 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 H 4 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 H 4 receptor.
• Another aspect of the present invention relates to a method of treating a disease mediated by the histamine H 4 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.
• C x-y alkyl refers to a linear or branched alkyl chain containing from x to y carbon atoms.
• 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.
• C3 -7 cycloalkyl-Co -4 alkyl thus includes C 3-7 cycloalkyl and C 3-7 cycloalkyl-Ci -4 alkyl.
• 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 R 1 ', can be optionally substituted with one or more substituents independently selected from
• 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-cyclohexyl
• saturated refers to groups that do not contain any double or triple bond.
• 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”.
• 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.
• 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.
• 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.
• the above three types of saturated heterocyclic rings can be optionally substituted with one or more groups independently selected from Ci -4 alkyl and NR 3 Rb, with the proviso that the heterocyclic group either contains 2 N atoms and is not substituted with an NR 3 Rb group, or contains 1 N atom and is substituted with one NR 3 R b group.
• the heterocyclic ring contains only 1 N atom, then the ring must be substituted with one NR 3 Rb 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 NR 3 R 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Ri represents C 2 -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.
• the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl and isobutyl.
• the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl and isopropyl.
• the invention relates to compounds of formula I wherein Ri represents a group selected from propyl and isobutyl.
• 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.
• the invention relates to compounds of formula I wherein Ri represents C 3-7 cycloalkyl, and preferably cyclopentyl, cyclobutyl or cyclopropyl.
• the invention relates to compounds of formula I wherein Ri represents cyclopropyl.
• the invention relates to compounds of formula I wherein R 2 and R3 have the meaning described above for compounds of formula I, provided that when R 2 and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group, this is not piperazinyl.
• the invention relates to the compounds of formula I wherein R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:
• heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one NR 3 Rb group and 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 R 2 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.
• the invention relates to the compounds of formula I wherein R 2 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 NR 3 Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR 3 Rb group, or contains 1 N atom and is substituted with one NR 3 R b group.
• the invention relates to the compounds of formula I wherein R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:
• heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one NR 3 R 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.
• the invention relates to compounds of formula I wherein R 3 and R b independently represent H or Ci -4 alkyl.
• the invention relates to the compounds of formula I wherein R 3 and R b independently represent H, methyl or ethyl.
• the invention relates to compounds of formula I wherein R 3 and R b independently represent H or methyl. In another embodiment, the invention relates to the compounds of formula I wherein R 3 represents H and Rb represents H or Ci -4 alkyl.
• the invention relates to the compounds of formula I wherein R 3 represents H and Rb represents H, methyl or ethyl. In another embodiment, the invention relates to the compounds of formula I wherein R 3 represents H and Rb represents H or methyl.
• the invention relates to the compounds of formula I wherein R 3 represents H and Rb represents Ci -4 alkyl.
• the invention relates to the compounds of formula I wherein R 3 represents H and Rb represents methyl or ethyl.
• the invention relates to the compounds of formula I wherein R 3 represents H and Rb represents methyl.
• the invention relates to the compounds of formula I wherein R 3 and R b represent H.
• 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:
• R 3 and Rb have the meaning described above for compounds of formula I and R 0 represents H or Ci -4 alkyl, and preferably R 0 represents H.
• 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) to (h), and R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R 3 , Rb and R 0 independently represent H or methyl, and more preferably R a represents H, R b represents methyl and R 0 represents H.
• 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), (b), (c), (d), (f), (g) and (h), wherein Ra and Rb have the meaning previously described for the compounds of formula I and R 0 represents H or Ci -4 alkyl, and preferably R 0 represents H.
• the invention relates to compounds of formula I wherein R 2 and R 3 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 R 0 independently represent H or Ci -4 alkyl, and preferably R a , Rb and R 0 independently represent H or methyl, and more preferably R a represents H, R b represents methyl and R 0 represents H.
• the invention relates to compounds of formula I wherein R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (f), wherein R 3 and Rb have the meaning previously described for the compounds of formula I and R 0 represents H or Ci -4 alkyl, and preferably R 0 represents H.
• the invention relates to compounds of formula I wherein R 2 and R 3 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 R 0 independently represent H or Ci -4 alkyl, and preferably R a , Rb and R 0 independently represent H or methyl, and more preferably R a represents H, R b represents methyl and R 0 represents H.
• the invention relates to compounds of formula I wherein R 2 and R 3 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 R 0 represents H or Ci -4 alkyl, and preferably R 0 represents H
• 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) to (d), and R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R 3 , Rb and R 0 independently represent H or methyl, and more preferably R a represents H, R b represents methyl and R 0 represents H.
• the invention relates to compounds of formula I wherein R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R 3 and Rb have the meaning previously described for the compounds of formula I and R 0 represents H or Ci -4 alkyl, and preferably R 0 represents H.
• 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), and R a , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R a , Rb and R 0 independently represent H or methyl.
• the invention relates to the compounds of formula I wherein R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), R 3 represents H, R b represents H or Ci -4 alkyl and R 0 represents H.
• the invention relates to the compounds of formula I wherein R 2 and R 3 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 R 0 represents H.
• the invention relates to the compounds of formula I wherein R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), R 3 represents H, R b represents methyl and R 0 represents H.
• the invention relates to compounds of formula I wherein R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a)
• R 3 and Rb have the meaning previously described for the compounds of formula I and R 0 represents H or Ci -4 alkyl, and preferably R 0 represents H.
• the invention relates to the compounds of formula I wherein R 2 and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), and R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R 3 , Rb and R 0 independently represent H or methyl.
• the invention relates to the compounds of formula I wherein R 2 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 R 0 represents H.
• the invention relates to the compounds of formula I wherein R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), R 3 represents H, R b represents H or methyl and R 0 represents H.
• the invention relates to the compounds of formula I wherein R 2 and R 3 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 R 0 represents H or methyl.
• the invention relates to the compounds of formula I wherein R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), R 3 represents H, R b represents methyl and R 0 represents methyl.
• the invention relates to the compounds of formula I wherein R 2 and R 3 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 R 0 represents H.
• 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 of formula (b)
• R 3 and Rb have the meaning previously described for the compounds of formula I and R 0 represents H or Ci -4 alkyl, and preferably R 0 represents H.
• the invention relates to the compounds of formula I wherein R 2 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 R 0 independently represent H or Ci -4 alkyl, preferably R a , Rb and R 0 independently represent H or methyl, and more preferably R a represents H, R b represents methyl and R 0 represents H.
• the invention relates to the compounds of formula I wherein R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), R 3 represents H, R b represents H or Ci -4 alkyl and R 0 represents H.
• the invention relates to the compounds of formula I wherein R 2 and R 3 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 R 0 represents H.
• the invention relates to the compounds of formula I wherein R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (f)
• R 3 represents H or Ci -4 alkyl, and preferably R a represents H or methyl.
• the invention relates to the compounds of formula I wherein R 2 and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (h)
• R 3 represents H or Ci -4 alkyl, and preferably R a represents H or methyl.
• the invention relates to compounds of formula I wherein R 2 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 R 2 represents H and R3 represents 1 -methyl- pyrrol id in-3-yl.
• 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 R 2 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 NR 3 Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an atoms and
• 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:
• heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said heterocyclic group can be optionally substituted with one or more Ci -4 alkyl groups; and (ii) a heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one NR 3 R 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.
• 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; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), wherein R 3 , R b and R 0 have the meaning described above, and preferably R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, and more preferably R 3 , Rb and R 0 independently represent H or methyl.
• 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, isopropy
• 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 R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (f), wherein R 3 , R b and R 0 have the meaning described above, and preferably R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, and more preferably R a , Rb and R 0 independently represent H or methyl.
• 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, iso
• 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 R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (d), wherein R 3 , Rb and R 0 have the meaning described above, and preferably R a , Rb and R 0 independently represent H or Ci -4 alkyl, and more preferably R a , Rb and R 0 independently represent H or methyl.
• 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-
• 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; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R 3 , Rb and R 0 have the meaning described above, and preferably R a , Rb and R 0 independently represent H or Ci -4 alkyl, and more preferably R a , Rb and R 0 independently represent H or methyl.
• 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-but
• 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 R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R a , Rb and R 0 independently represent H or methyl.
• 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, buty
• 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 R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), wherein R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R a , Rb and R 0 independently represent H or methyl, and more preferably R a and Rb independently represent H or methyl and R 0 represents H.
• 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, iso
• 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 R 2 and R 3 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 NR 3 Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR 3 Rb group, or contains 1 N atom and is substituted with one NR 3 Rb group.
• Ri represents a group selected from
• 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 R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:
• heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said heterocyclic group can be optionally substituted with one or more Ci -4 alkyl groups; and (ii) a heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one NR 3 R 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.
• 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; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), and R 3 , R b and R 0 independently represent H or Ci -4 alkyl, and preferably R 3 , Rb and R 0 independently represent H or methyl, and more preferably R 3 represents H, R b represents methyl and R 0 represents H.
• Ri represents a group selected from te/t-butyl, isopropyl, propyl, isobutyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclopropyl
• R 2 and R 3 form, together with the N atom to which they
• 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; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (f), and R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R a , Rb and R 0 independently represent H or methyl, and more preferably R 3 represents H, R b represents methyl and R 0 represents H.
• Ri represents a group selected from te/t-butyl, isopropyl, propyl, isobutyl, cyclopropylmethyl, cyclobuthyl, cyclopenthyl and cyclopropyl
• R 2 and R 3 form, together with the N atom to
• 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; R 2 and R 3 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 R 0 independently represent H or Ci -4 alkyl, and preferably R a , Rb and R 0 independently represent H or methyl, and more preferably R 3 represents H, R b represents methyl and R 0 represents H.
• Ri represents a group selected from te/t-butyl, isopropyl, propyl, isobutyl, cyclopropylmethyl, cyclobuthyl, cyclopenthyl and cyclopropyl
• R 2 and R 3 form, together with the N atom
• 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; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), and R a , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R a , Rb and R 0 independently represent H or methyl, and more preferably R 3 represents H, R b represents methyl and R 0 represents H.
• Ri represents a group selected from te/t-butyl, isopropyl, propyl, isobutyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclopropyl
• R 2 and R 3 form, together with the N atom to which
• 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; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), and R a , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R a , Rb and R 0 independently represent H or methyl, and more preferably R a represents H, R b represents methyl and R 0 represents H.
• Ri represents a group selected from te/t-butyl, isopropyl, propyl, isobutyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclopropyl
• R 2 and R 3 form, together with the N atom to which they are bound
• 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; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), and R a , R b and R 0 independently represent H or Ci -4 alkyl, and preferably R a , Rb and R 0 independently represent H or methyl, and more preferably R a represents H, R b represents methyl and R 0 represents H.
• Ri represents a group selected from te/t-butyl, isopropyl, propyl, isobutyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclopropyl
• R 2 and R 3 form, together with the N atom to which they are
• 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 NR 3 Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR 3 Rb group, or contains 1 N atom and is substituted with one NR 3 R b group.
• Ri represents
• 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:
• heterocyclic group which contains 2 N atoms and does not contain any other heteroatom, wherein said heterocyclic group can be optionally substituted with one or more Ci -4 alkyl groups; and (ii) a heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one NR 3 R 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.
• 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; R 2 and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), wherein R 3 , R b and R 0 have the meaning described above, and preferably R 3 , R b and R 0 independently represent H or Ci -4 alkyl, and more preferably R 3 , R b and R 0 independently represent H or methyl.
• 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 R 3 , Rb and R 0 have the meaning described above, and preferably R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, and more preferably R 3 , Rb and R 0 independently represent H or methyl.
• 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 R 3 , Rb and R 0 have the meaning described above, and preferably R 3 , R b and R 0 independently represent H or Ci -4 alkyl, and more preferably R 3 , R b and R 0 independently represent H or methyl.
• 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; 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 R 3 , R b and R 0 have the meaning described above, and preferably R 3 , R b and R 0 independently represent H or Ci -4 alkyl, and more preferably R 3 , R b and R 0 independently represent H or methyl.
• 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 R 2 and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R 3 , R b and R 0 independently represent
• R 3 , R b and R 0 independently represent H or methyl.
• 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 R 2 and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), wherein R 3 , R b and R 0 independently represent H or C1-4 alkyl, and preferably R a , Rb and R 0 independently represent H or methyl, and more preferably R a and Rb independently represent H or methyl and R 0 represents H.
• 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 NR 3 Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR 3 Rb group, or contains 1 N atom and is substituted with one NR 3 R b group.
• Ri represents a group selected from te/t-butyl, isopropyl, propyl and isobutyl
• 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:
• heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one NR 3 R 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.
• the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl and isobutyl; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), and R 3 , R b and R 0 independently represent H or Ci -4 alkyl, and preferably R 3 , R b and R 0 independently represent H or methyl, and more preferably R 3 represents H, R b represents methyl and R 0 represents H.
• the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl and isobutyl; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (f), and R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R 3 , Rb and R 0 independently represent H or methyl, and more preferably R a represents H, R b represents methyl and R 0 represents H.
• the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl and isobutyl; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (d), and R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R 3 , Rb and R 0 independently represent H or methyl, and more preferably R a represents H, R b represents methyl and R 0 represents H.
• the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl and isobutyl; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), and R a , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R 3 , Rb and R 0 independently represent H or methyl, and more preferably R a represents H, R b represents methyl and R 0 represents H.
• the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl and isobutyl; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), and R a , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R a , Rb and R 0 independently represent H or methyl, and more preferably R a represents H, R b represents methyl and R 0 represents H.
• the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl, propyl and isobutyl; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), and R a , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R a , R b and R 0 independently represent H or methyl, and more preferably R a represents H, R b represents methyl and R 0 represents H.
• 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 NR 3 Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR 3 Rb group, or contains 1 N atom and is substituted with one NR 3 Rb group.
• 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 NR 3 R 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
• 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; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), and R 3 , R b and R 0 independently represent H or Ci -4 alkyl, and preferably R 3 , R b and R 0 independently represent H or methyl, and more preferably R 3 represents H, Rb represents methyl and R 0 represents H.
• 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; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (f), and R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R 3 , Rb and R 0 independently represent H or methyl, and more preferably R a represents H, Rb represents methyl and R 0 represents H.
• 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; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (d), and R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R 3 , Rb and R 0 independently represent H or methyl, and more preferably R a represents H, Rb represents methyl and R 0 represents H.
• 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; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), and R a , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R a , Rb and R 0 independently represent H or methyl, and more preferably R a represents H, Rb represents methyl and R 0 represents H.
• 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; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), and R a , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R a , Rb and R 0 independently represent H or methyl, and more preferably R a represents H, R b represents methyl and R 0 represents H.
• 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; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), and R a , R b and R 0 independently represent H or Ci -4 alkyl, and preferably R a , Rb and R 0 independently represent H or methyl, and more preferably R a represents H, R b represents methyl and R 0 represents H.
• the invention relates to compounds of formula I wherein Ri represents C 3- 7 cycloalkyl, preferably cyclopropyl; and R 2 and R 3 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 NR 3 Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR 3 Rb group, or contains 1 N atom and is substituted with one NR 3 Rb group.
• the invention relates to compounds of formula I wherein Ri represents and C3-7 cycloalkyl, preferably cyclopropyl; and R 2 and R 3 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
• heterocyclic group which contains 1 N atom and does not contain any other heteroatom, wherein said heterocyclic group is substituted with one NR 3 R 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.
• the invention relates to compounds of formula I wherein Ri represents C 3-7 cycloalkyl, preferably cyclopropyl; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), and R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R 3 , Rb and R 0 independently represent H or methyl, and more preferably R 3 represents H, R b represents methyl and R 0 represents H.
• the invention relates to compounds of formula I wherein Ri represents C 3-7 cycloalkyl, preferably cyclopropyl; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (f), and R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R 3 , Rb and R 0 independently represent H or methyl, and more preferably R a represents H, R b represents methyl and R 0 represents H.
• the invention relates to compounds of formula I wherein Ri represents C3-7 cycloalkyl, preferably cyclopropyl; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (d), and R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R a , Rb and R 0 independently represent H or methyl, and more preferably R a represents H, R b represents methyl and R 0 represents H.
• the invention relates to compounds of formula I wherein Ri represents C3-7 cycloalkyl, preferably cyclopropyl; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), and R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R a , Rb and R 0 independently represent H or methyl, and more preferably R 3 represents H, R b represents methyl and R 0 represents H.
• the invention relates to compounds of formula I wherein Ri represents C 3-7 cycloalkyl, preferably cyclopropyl; and R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), and R a , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R a , Rb and R 0 independently represent H or methyl, and more preferably R 3 represents H, R b represents methyl and R 0 represents H.
• the invention relates to compounds of formula I wherein Ri represents C 3-7 cycloalkyl, preferably cyclopropyl; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), and R a , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R a , Rb and R 0 independently represent H or methyl, and more preferably R a represents H, R b represents methyl and R 0 represents H.
• the invention relates to compounds of formula I wherein Ri represents C 2-8 alkyl or C 3-7 cycloalkyl-C 0-4 alkyl; R 2 and R 3 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 R 0 represents H.
• 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; R 2 and R 3 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 R 0 represents H.
• 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 R 0 represents H.
• the invention relates to compounds of formula I wherein Ri represents a group selected from propyl, isobutyl, cyclobutyl, cyclopentyl and cyclopropylmethyl; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a); and R 3 represents H, R b represents methyl and R 0 represents H.
• the invention relates to compounds of formula I wherein Ri represents a group selected from te/t-butyl, isopropyl and cyclopropyl; R 2 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
• R 0 represents H.
• the invention relates to compounds of formula I wherein Ri represents a group selected from propyl, isobutyl and cyclopropylmethyl; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a); and R 3 represents H, R b represents methyl and R 0 represents H.
• 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; R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula
• 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; R 2 and R 3 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 R 0 represents H.
• 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 R 3 represents H, R b represents methyl and R 0 represents H.
• the present invention includes all possible combinations of the particular and preferred embodiments described above for the compounds of formula I.
• the invention relates to a compound of formula I selected from: 4-(Cyclopropylmethyl)-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyhmidin-2-amine;
• the invention relates to compounds according to formula I which provide more than 50% inhibition of histamine H 4 receptor activity at 10 ⁇ M, more preferably at 1 ⁇ M and even more preferably at 0.1 ⁇ M, in a H 4 receptor binding assay such as that described in example 64.
• the invention relates to compounds of formula Vl wherein R 1 ' represents C 1-6 alkyl, and preferably isobutyl.
• the invention relates to compounds of formula Vl wherein R 1 ' represents Cs-z cycloalkyl-d ⁇ alkyl.
• the invention relates to compounds of formula Vl wherein R 2 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 NR 3 Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR 3 Rb group, or contains 1 N atom and is substituted with one NR 3 R b group.
• the invention relates to compounds of formula Vl wherein R 3 and R b independently represent H or Ci -4 alkyl.
• the invention relates to compounds of formula Vl wherein R 3 and R b independently represent H or methyl.
• the invention relates to compounds of formula Vl wherein R 2 and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from:
• R 3 and Rb have the meaning described above for compounds of formula I and R 0 represents H or Ci -4 alkyl.
• the invention relates to compounds of formula Vl 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).
• the invention relates to compounds of formula Vl wherein R 2 and R 3 form, together with the N atom to which they are bound a saturated heterocyclic group selected from (a) and (b), and R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R 3 , R b and R 0 independently represent H or methyl.
• the invention relates to compounds of formula Vl wherein R 2 and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a)
• R 3 and Rb have the meaning described above for compounds of formula I and R 0 represents H or Ci -4 alkyl, and preferably R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, and more preferably R a , Rb and R 0 independently represent H or methyl.
• the invention relates to compounds of formula Vl wherein R 2 and R3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b)
• R 3 and Rb have the meaning described above for compounds of formula I and R 0 represents H or Ci -4 alkyl, and preferably R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, and more preferably R 3 , Rb and R 0 independently represent H or methyl, and even more preferably R 3 and Rb independently represent H or methyl and R 0 represents H.
• the invention relates to compounds of formula Vl wherein R 2 represents H or Ci -4 alkyl and R 3 represents azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, which may be optionally substituted with one or more Ci -4 alkyl groups, and preferably R 2 represents H and R 3 represents 1 -methyl- pyrrol id in-3-yl.
• the invention relates to compounds of formula Vl wherein R 1 ' represents C 1-6 alkyl, preferably isobutyl; and R 2 and R 3 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 NR 3 Rb, provided that the heterocyclic group either contains 2 N atoms and is not substituted with an NR 3 Rb group, or contains 1 N atom and is substituted with one NR 3 Rb group.
• the invention relates to compounds of formula Vl wherein R 1 ' represents d-6 alkyl, preferably isobutyl; and R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) to (h), wherein R 3 , R b and R 0 have the meaning described above, and preferably R 3 , R b and R 0 independently represent H or C 1-4 alkyl, and more preferably R 3 , R b and R 0 independently represent H or methyl.
• the invention relates to compounds of formula Vl wherein R 1 ' represents C 1-6 alkyl, preferably isobutyl; and R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group selected from (a) and (b), wherein R 3 , R b and R 0 have the meaning described above, and preferably R 3 , Rb and R 0 independently represent H or C 1-4 alkyl, and more preferably R 3 , Rb and R 0 independently represent H or methyl.
• the invention relates to compounds of formula Vl wherein R 1 ' represents C 1-6 alkyl, preferably isobutyl; and R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (a), wherein R 3 , R b and R 0 independently represent H or C 1-4 alkyl, and preferably R 3 , Rb and R 0 independently represent H or methyl.
• the invention relates to compounds of formula Vl wherein R 1 ' represents C 1-6 alkyl, preferably isobutyl; and R 2 and R 3 form, together with the N atom to which they are bound, a saturated heterocyclic group of formula (b), wherein R 3 , Rb and R 0 independently represent H or Ci -4 alkyl, and preferably R a , Rb and R 0 independently represent H or methyl, and more preferably R a and Rb independently represent H or methyl and R 0 represents H.
• the present invention includes all possible combinations of the particular and preferred embodiments described above for the compounds of formula Vl..
• 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;
• the invention relates to compounds according to formula Vl that provide more than 50% inhibition of histamine H 4 receptor activity at 10 ⁇ M, more preferably at 1 ⁇ M and even more preferably at 0.1 ⁇ M, in a H 4 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.
• 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.
• salts there is no limitation on the type of salt that can be used, provided that these are pharmaceutically acceptable when used for therapeutic purposes.
• 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.
• solvate refers to a complex of variable stoichiometry formed by a solute (a compound of formula I or a salt thereof) and a solvent.
• 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.
• 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:
• R 4 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 PyBOP (benzotriazol-1-yl- oxythpyrrolidinophosphonium hexafluorophosphate) in a suitable solvent such as
• reaction can be carried out at a temperature comprised between room temperature and the reflux temperature.
• 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.
• a reactive derivative of the compound of formula Il MB
• 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.
• 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, ⁇ /, ⁇ /-dimethylformamide, dimethylsulphoxide, tetrahydrofuran or toluene, preferably ethanol, in the presence of a base, including organic amines such as triethylamine, ⁇ /, ⁇ /-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.
• the amino substituents of the compounds of formula III are protected in order to prevent the formation of side products.
• 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.
• 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.
• a strong acid such as HCI
• 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:
• 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.
• a base such as potassium carbonate, sodium te/t-butoxide or sodium ethoxide and preferably sodium methoxide
• 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 ).
• compounds of formula I wherein Ri represents Ri '-CH 2 -CH 2 i.e. compounds of formula I'
• compounds of formula I' can be obtained by reduction of a compound of formula Vl, as shown in the following scheme:
• R 1 ' 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 R 2 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 (H 2 ) 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.
• a suitable temperature usually comprised between room temperature and the reflux temperature, preferably at room temperature.
• 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:
• the reaction can be performed in the presence of a base, including organic amines such as pyridine, thethylamine, ⁇ /, ⁇ /-diisopropylethylamine, dimethylaniline and diethylamide among others, in a suitable solvent such as ethanol, methanol or butanol, and heating, preferably at reflux temperature.
• a base including organic amines such as pyridine, thethylamine, ⁇ /, ⁇ /-diisopropylethylamine, dimethylaniline and diethylamide among others
• a suitable solvent such as ethanol, methanol or butanol
• 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).
• 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:
• the reaction can be performed under the Sonogashira conditions, using a palladium catalyst such as for example tetrakis (thphenylphosphine)palladium(O)
• 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 6O 0 C-I OO 0 C.
• a solvent such as dioxane, /V,/V-dimethylformamide, toluene and preferably in tetrahydrofuran and heating at a temperature usually comprised between 6O 0 C-I OO 0 C.
• 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.
• the compounds of the present invention show potent histamine H 4 receptor antagonist activity. Therefore, the compounds of the invention are expected to be useful to treat diseases mediated by the H 4 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.
• allergic, immunological or inflammatory diseases examples 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.
• 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
• 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.
• the compounds of the invention are used for the treatment of an allergic, immunological or inflammatory disease.
• 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.
• 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.
• COPD chronic obstructive pulmonary disease
• 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.
• H 4 receptor binding assay such as the one explained in detail in example 64.
• Another useful assay is a GTP [ ⁇ - 35 S] binding assay to membranes that express the H 4 receptor.
• Functional assays with H 4 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 H 4 receptor such as intracellular cAMP levels or Ca 2+ mobilization.
• GAF Gated Autofluorescence Forward Scatter assay
• 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).
• the present invention also relates to a pharmaceutical composition
• 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.
• Solid compositions for oral administration include tablets, granulates and capsules.
• the manufacturing method is based on a simple mixture, dry granulation or wet granulation of the active compound with excipients.
• 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 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.
• 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.
• 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.
• 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 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.
• 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 0 C, 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 Na2SO 4 and concentrated to dryness, providing 0.13 g of the desired compound (yield: 91 %).
• 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 0 C, 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.
• 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.
• 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 Na2SO 4 and it was concentrated 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 %).
• 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.
• membrane extracts prepared from a stable CHO recombinant cell line expressing the human histamine H 4 receptor were used.
• the compounds to be tested were incubated at the desired concentration in duplicate with 10 nM [ 3 H]-histamine and 15 ⁇ g membrane extract in a total volume of 250 ⁇ L of 50 mM Tris-HCI, pH 7.4, 1.25 mM EDTA for 60 minutes at 25 0 C.
• Non-specific binding was defined in the presence of 100 ⁇ M 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 0 C.
• the plates were subsequently washed with 50 mM Tris (pH 7.4), 1.25 mM EDTA at 0 0 C, and the filters were dried for 1 hour at 50-60 0 C, before adding the scintillation liquid in order to determine bound radioactivity by means of a betaplate scintillation counter.
• 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).
• PMNL Polymorphonuclear leucocytes
• 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 1.1x10 6 cells/ml/tube and were pretreated with different concentrations of test compounds (dissolved in PBS) for 30 min at 37 0 C and then stimulated with 300 nM histamine (Fluka) for 5 min.

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