TW200936570A - 2-aminopyrimidine derivatives - Google Patents

Abstract

2-Aminopyrimidine derivatives of formula I, wherein the meaning of the different substituents are those indicated in the description. These compounds are useful as histamine H4 receptor antagonists.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel series of 2-aminopyrimidine derivatives, a process for the preparation thereof, a pharmaceutical composition comprising the same, and their therapeutic use. [Prior Art] ό Histamine is one of the most potent mediators of immediate allergic reactions. Although the effects of histones on smooth muscle cell contraction, vascular permeability, and gastric acid secretion are well known, their effects on the immune system are beginning to be revealed. A few years ago, several independent research groups selected a novel histamine receptor called H4 (Oda Τ et al., J Biol Chem 2000, 275: '3 67 8 1 -6; Nguyen T et al. Person, Mol Pharmacol 200 1, 5 9 : 427-3 3 ). Like other members of its family, it is a G-protein coupled receptor (GPCR) containing seven transmembrane segments. However, the Η* receptor has low homology with the other three groups of 织-amine receptors (〇da τ et al.); apparently has only 35% homology with the H3 receptor. Although the performance of the H3 receptor is limited to central-neural cells, the H4 receptor is mainly expressed in cells of the hematopoietic tissue, especially eosinophils, mast cells, basophils, dendritic cells, and T-cells. It has been observed (oda τ et al) that the fact that the H4 receptor is highly distributed in cells of the immune system suggests that this receptor is involved in an immune-inflammatory response. Moreover, this hypothesis is more plausible because its gene $ is now regulated by inflammation, such as sputum, TNFcx, and IL-6. Of course, the 'H4 receptor also behaves in other cell types' such as from rheumatoid arthritis (W〇jtecka_ 200936570)

Lukasik E et al, Ann Rheum Dis 2006, 6 5 (S upp 1 II): 12 9 ; Ikawa Y et al, Biol Pharm Bull 2005, 28:20 1 6-8 ) and osteoarthritis (Grzy bo wska-Ko Wal czyk A et al., European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, P-11) Human synovial cells from patients and in human gut (Sander LE et al., Gut 2006, 5 5:498 - 5 04 ). It has also been reported that the H4 receptor exhibits increased nasal mucosa in healthy polyps (J0kiiti A et al., Cell Biol Int 2007, 31:1367-70). Recent studies of specific ligands for the H4 receptor have helped to define the boundaries of the pharmaceutical properties of this receptor. These studies demonstrate that several histamine-induced responses in eosinophils, such as chemotaxis, conformational changes, and CDllb and CD54 upregulation, are specifically mediated by H4 receptors (Ling P et al. , Br J Pharmacol 2004, 142:161-71; Buckland KF et al, Br J Pharmacol 2003, 1 40:1 1 1 7-27 ). In dendritic cells, H4 receptors have been shown to affect the maturation, interleukin production and migration of these cells (Jelinek I et al, 1st Joint Meeting of European National Societies of Immunology, Paris, France, 2006, PA-1255). . Moreover, the role of the H4 receptor in mast cells has been investigated. Although H4 receptor activation does not trigger mast cell degranulation, histamine and other pro-inflammatory mediators are released; moreover, H4 receptors have been shown to mediate chemotaxis and movement of mast cells (Hofstra CL et al' J Pharmacol Exp Ther 2003, 3 05:1 2 1 2-2 1 ). As for T-lymphocytes, activation of H4 receptors has been shown to trigger T-cell migration, favorably attracting T-lymphocyte populations with inhibitory/regulatory phenotypes and functions (Morgan RK et al.' American 200936570)

Thoracic Society Conference, San Diego, USA, 2006, P-536), and modulates activation of CD4+ T cells (Dunford PJ et al, J Immunol 2006, 1 76:7062-70). As for the intestine, the distribution of the H4 receptor indicates that it may play a role in the control of peristalsis and gastric acid secretion (Morini G et al., European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, OR-10). The various functions of the H4 Q receptor observed in eosinophils, mast cells and T-cells indicate that this receptor plays an important role in the immune-inflammatory response. In fact, h4 receptor antagonists have been used in peritonitis (Thurmond RL et al, J Pharmacol Exp Ther 2004, 309: 404-13), pleurisy (Takeshita K et al, J Pharmacol Exp Ther 2003, 3 07:1 072- 8) and scratches (Bell JK et al, Br J 'Pharmacol 2004, 142: 374-80) showed in vivo activity in a murine model. In addition, H4 receptor antagonists have been demonstrated in allergic asthma (Dunford PJ et al., 2006), inflammatory bowel disease (Varga C et al, Eur J ❹ Pharmacol 2005, 522: 1 30-8), pruritus (Dunford PJ) Et al, J Allergy Clin Immunol 2007, 119: 176-83), atopic dermatitis " (Cowden JM et al, J Allergy Clin Immunol 2 0 0 7; 119 (1): S 2 3 9 (Ab s 93 5), American Academy of Allergy,

Asthma and Immunology 2 0 0 7 A AAAI Annual Meeting, San Diego, USA), eye 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 nerve 200936570 disease pain (Cowart MD et al, J Med Chem. 2008; 5 1 (20): 6547-57) showed an in vivo model active. It is therefore expected that H4 receptor antagonists can be used to treat or prevent allergic, immune and inflammatory diseases, and pain. Therefore, it is desirable to provide novel compounds having H4 receptor antagonistic activity, and these compounds are good drug candidates. In particular, preferred compounds should bind strongly to the histamine H4 receptor without exhibiting affinity for other receptors. In addition to binding to the H4 receptor, the compound should exhibit good pharmaceutical activity in an in vivo model of immune inflammation. Moreover, the compound should reach the target tissue or organ when administered via the selected route of administration and have preferred pharmacokinetic properties. In addition, it should be non-toxic and demonstrate little side effects. The compound 4-(4-ethyl-piped-1-yl)-6-propyl-pyrimidin-2-amine has been described in the literature, in detail, described in S_ Ohno et al.; chem. Pharm. Bull 1 986, 34(10), 4150. This article describes the synthesis and hypoglycemic activity of a series of 7,8-dihydro-6H-thiopyrano[3,2-d]. Such a compound is simply described as a compound produced by the reaction of a 7,8-dihydro-6h_thiopyrano[3,2-d]pyrimidine derivative with Ni/Raney, and its therapeutic use is not described. SUMMARY OF THE INVENTION One aspect of the present invention relates to a compound of formula I 200936570

Wherein: R 丨 is not C 2 · 8 alkyl or CP cycloalkyl _Cq 4 alkyl, wherein the C 3-7 ring-based group may optionally pass - or a plurality of substituents independently selected from alkyl, phenyl and fluorine Substituted; R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group which may be a 4- to 7-membered monocyclic ring, a 7- to 8-membered bridged double ring or a 8 to 12 member. a fused bicyclic ring wherein the heterocyclic group may contain up to two N atoms and does not contain any other hetero atom, and may be optionally substituted with one or more substituents independently selected from Ci4 alkyl and NRaBb. The heterocyclic group either contains 2 N atoms and is not substituted by the NRaRb group, or contains 1 n atom and is substituted by one NRaRb group; or R2 represents Η or C 1.4 alkyl ' and R 3 represents a nitrogen sulfonyl group a pyrrolidinyl, piperidinyl or aziridine group, which may be optionally substituted by a plurality of Cl 4 alkyl groups;

Ra is a Η or 0^4 yard base;

Rb represents an anthracene or a Cu alkyl group; or Ra and Rb together with the N atom to which they are bonded form a nitrogen group, a sloppy base, a piperylene group or a nitrogen group, which may optionally pass one or more C! -4 alkyl substituted; the restriction is that the compound of formula I is not 4-(4-ethyl-piperidin-1-yl-9-200936570)-6-propyl-pyrimidin-2-amine. The invention also relates to salts and solvates of the compounds of formula I. Certain compounds of formula I may have a palmitic center which produces a variety of stereoisomers. The present invention is directed to each of these stereoisomers and to mixtures thereof. The compounds of formula I show high affinity for the h4 histamine receptor. Thus another aspect of the invention relates to a compound of formula I ό nh2

N^N

Nr2r3 where:

The Ri system represents a c2-8 alkyl group or a c3-7 cycloalkyl-c〇-4 alkyl group, wherein the c: 3-7 ring-based group may be optionally subjected to - or a plurality of independently selected from the group consisting of Ci4 alkyl, phenyl and fluorine. Substituted by a substituent; R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group' which may be a 4- to 7-membered monocyclic ring, a 7- to 8-membered bridged bicyclic ring or 8- to I2- A fused bicyclic ring wherein the heterocyclic group may contain up to two N atoms and does not contain any other hetero atom' and may be optionally substituted with one or more substituents independently selected from the group consisting of Cl4 alkyl and NRaRb, with limitations Is a heterocyclic group or contains 2 N atoms and is not substituted by an NRaRb group, or contains 1 n atom and is substituted by one NRaRb group; or R2 represents an anthracene or a Cu alkyl group, and R3 represents a nitrogen group , pyr-10-0 200936570 pyridyl, piperidinyl or aziridine, which may be optionally substituted by one or more Ci-4 alkyl;

Ra is a hydrazine or a C, .4 alkyl group;

Rb represents hydrazine or C^.4 alkyl; or Ra and Rb together with the N atom to which they are bonded form a nitrogen-based, pyrrolidinyl, piperidinyl or aziridine group, which may optionally be passed through one or Multiple mountain-4 alkyl substitutions; 0 with the proviso that the compound of formula I is not 4_(4-ethyl-piperidin-1-yl)-6-propyl-pyrimidin-2-amine; . Another aspect of the invention relates to a pharmaceutical composition comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease mediated by H4 histamine receptors. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of an allergic, immunological or inflammatory disease or pain. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of an allergic, immunological or inflammatory disease. More preferably, the allergic, immune or inflammatory disease is selected from the group consisting of respiratory diseases, eye diseases, skin diseases, inflammatory bowel diseases, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic red-11 - 200936570 Lupus and transplant rejection. Even more preferably, the allergic, immune or inflammatory disease is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataract, dermatitis (eg atopic Dermatitis), psoriasis, urticaria, itching, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of pain. More preferably, the pain is selected from the group consisting of inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-operative pain, migraine, cancer pain, visceral pain, osteoarthritis pain, and neuropathic pain. Another aspect of the invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of a condition mediated by the H4 histamine receptor. Another aspect of the invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of an allergic, immune or inflammatory disease or pain. Another aspect of the invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of an allergic, immunological or inflammatory disease. More preferably, the allergic, immune or inflammatory disease is selected from the group consisting of respiratory diseases, eye diseases, skin diseases, inflammatory bowel diseases, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and Transplant rejection. More preferably, the allergic, immune or inflammatory disease is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis 200936570, dry eye, cataract, dermatitis (eg, ectopic Sexual dermatitis), psoriasis, urticaria, itching, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection. Another aspect of the invention pertains 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 the group consisting of inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-operative pain, partial headache, cancer pain, visceral pain, osteoarthritis pain, and neuropathic pain. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of a condition mediated by a Η4 histamine receptor. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of allergic, immunological or inflammatory diseases or pain. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of an allergic, immunological or inflammatory disease. More preferably, the allergic, immunological or inflammatory disease is selected from the group consisting of respiratory diseases, eye diseases, skin diseases, inflammatory bowel diseases, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and Transplant rejection. Even better - the allergic, immune or inflammatory disease is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataract, dermatitis (eg atopic Dermatitis), psoriasis, ricin, itching, ulcerative colitis, Crohn's disease, s-13-200936570 disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus systemic lupus erythematosus Transplant rejection. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of pain. More preferably, the pain is selected from the group consisting of inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-operative pain, migraine, cancer pain, visceral pain, osteoarthritis pain, and neuropathic pain. Another aspect of the invention relates to a method of treating a disease mediated by a histamine H4 receptor in an individual in need thereof, in particular a human, comprising administering to the individual a compound of formula I or a pharmaceutically acceptable compound thereof salt. Another aspect of the invention relates to a method of treating an allergic, immunological or inflammatory disease or pain in an individual in need thereof, in particular a human, comprising administering to the individual a compound of formula I or a pharmaceutically acceptable compound thereof Salt. A further aspect of the invention relates to a method of treating an allergic, immunological or inflammatory disease in an individual in need thereof, in particular a human, comprising administering to the individual a compound of formula I or a pharmaceutically acceptable compound thereof salt. More preferably, the allergic, immune or inflammatory disease is selected from the group consisting of respiratory diseases, eye diseases, skin diseases, inflammatory bowel diseases, rheumatoid arthritis, multiple-sclerosis, cutaneous lupus, systemic erythema Lupus and transplant rejection. Even more preferably, the allergic, immune or inflammatory disease is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataract, dermatitis (eg, atopic Dermatitis), psoriasis, urticaria, itching, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic erythema-14-200936570 Lupus and transplant rejection. Another aspect of the invention relates to a method of treating pain in an individual in need thereof, particularly a human, which comprises administering to the individual a compound of formula I or a pharmaceutically acceptable salt thereof. More preferably, the pain is selected from the group consisting of inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-operative pain, migraine, cancer, pain, visceral pain, osteoarthritis pain, and neuropathic pain. A further aspect of the invention relates to a process for the preparation of a compound of formula I as hereinbefore defined, which comprises: reacting a compound of formula II with a compound of formula III

Hnr2r3

III

Wherein Ri, R2 and R3 have the aforementioned meanings; or (b) reacting a compound of the formula IIB with a compound of the formula nnh2

IIB HNR2R3

Wherein R4 represents a leaving group and 1^, 2 and R3 have the aforementioned meanings -15-200936570; or (C) when the Ri system represents Rr-CHyd- in the compound of formula I, the compound of formula VI is treated with a suitable reducing agent

Wherein R1' represents a Ci-6 alkyl group or a c3_7 cycloalkyl-CG-2 alkyl group, wherein the C3_7 cycloalkyl group is optionally substituted by one or more independently selected from the group consisting of a C.4 alkyl group, a phenyl group and a fluorine group. Substituting 'and R2 and R3 have the aforementioned meanings; or (d) converting a compound of formula I into another compound of formula I in one or several steps. A novel compound of formula VI which can be used as an intermediate in the preparation of a compound of formula I constitutes another aspect of the invention. Thus, another aspect of the invention pertains to a compound of formula VI

-16- 200936570 wherein: RT is a Cm alkyl group or a C3-7 cycloalkyl-Cg_2 alkyl group, wherein the C3-7 ring-based group is optionally substituted with one or more substituents independently selected from the group consisting of C:. 4 alkyl, phenyl and fluorine;

Ri and R3 have the meanings indicated for the compounds of formula I. The invention also relates to salts and solvates of the compounds of formula VI. Certain compounds of formula VI may have a palmitic center that produces several stereoisomers. The present invention is directed to each of these stereoisomers and to mixtures thereof. Compounds of formula VI have also been found to have η4 receptor antagonistic activity. Thus, another aspect of the invention pertains to a compound of formula VI

Wherein: R"l' is not a Cl.6 yard base or a C3-7 ring yard base_C〇-2 yard base' wherein the C 3-7 cycloalkyl group is optionally independently selected from one or more of the following Substituents substituted: h-4 alkyl, phenyl and fluoro; and R2 and R3 have the meanings indicated for the compounds of formula I; they are used in therapy. Another aspect of the invention relates to a pharmaceutical composition comprising a compound of formula VI of -17-200936570, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Another aspect of the invention is the use of a compound of formula VI or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease mediated by the h4 histamine receptor. Another aspect of the invention pertains to a compound of formula VI or a pharmaceutically acceptable salt thereof for use in the treatment of a condition mediated by the H4 histamine receptor. β Another aspect of the invention is the use of a compound of formula VI or a pharmaceutically acceptable salt thereof for the treatment of a disease mediated by a Η4 histamine receptor. Another aspect of the invention relates to a method of treating a disease mediated by a histamine 114 receptor in an individual (especially a human) in need thereof, comprising: administering to the individual a compound of formula VI or a pharmaceutically acceptable compound thereof salt.

In the previous definition, the term Cx.yalkyl means a straight or branched alkyl chain having from X to y carbon atoms. For example, Ci-4-alkyl includes the groups methyl Q, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl and tert-butyl. The term Coalkyl means that the alkyl group is absent. The term c3-7 cycloalkyl- -

The Co-4 alkyl group thus includes a C3.7 cycloalkyl group and a C3.7 cycloalkyl-Cm alkyl group. The term C3.7 cycloalkyl' as a group or as part of a group denotes a saturated carbocyclic ring having from 3 to 7 carbon atoms which may be monocyclic or bridged bicyclic. Examples include, in particular, the groups cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and bicyclo [2.2.1] heptyl. As described above, the c3_7 cycloalkyl group (in R! and in RT) may be optionally substituted with one or more substituents independently selected from the group consisting of -18-200936570 alkyl, phenyl and fluoro. The substituents may be on any of the available carbon atoms of the C3-7 cycloalkyl group, including the carbon that bridges the ring to the remainder of the molecule. The C3-7 cycloalkyl-<^-4 alkyl group means a C3-7 cycloalkyl group as defined above, which is substituted with a hydrogen atom of a C, -4 alkyl group. Examples of C3-7 cycloalkyl-C!-4 Institute* include, in particular, the group cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, 2-cyclopropane Ethyl ethyl, 2-cyclobutylmethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 3-cyclopropylpropyl, 3-cyclobutylpropyl, 3-cyclopentyl a 3-cyclohexylpropyl group, a 4-cyclopropylbutyl group, a 4-cyclobutylbutyl group, a 4-cyclopentylbutyl group, and a 4-cyclohexylbutyl group, wherein the cycloalkyl ring can be as defined above Replaced as usual. The term "saturated" means a group that does not contain any double or para-bonds. 'Bridged bicyclic' group means having two shared atoms (bridge ends) connecting three chains (bridges) such that two bridges with a higher atomic number form the main ring, while bridges with a lower atomic number are "bridge". ❺ In the definition of NR2R3, 112 and R3 together with the N atom to which they are bonded may form a saturated 4- to 7-membered monocyclic heterocyclic ring containing up to 2 N atoms and no other heteroatoms. Examples include, in particular, a nitrogen-based group, a pyrrolidinyl group, a piperidinyl group, a piperene group, and a high piperene group. In the definition of NR2R3, the core and r3 together with the n atom to which they are bonded may form a bridged bicyclic group having 7 to 8 atoms. The bridged bicyclic group can contain up to two N atoms and does not contain any other heteroatoms. Examples include, in particular, 2,5-diaza-bicyclo[2.2.1]heptyl and 2,5-diaza-bicyclo[2.2.2]octyl. -19- 200936570 The term "fused bicyclic" group, in the definition of nr2r3, means an 8- to 12-membered bicyclic system consisting of two adjacent rings sharing two atoms. The fused bicyclic group can contain up to two N atoms at any effective position and does not contain any other heteroatoms. Examples include, in particular, octahydropyrrolo[3,4-b]pyridinyl, octahydropyrrolo[3,2-c]pyridinyl, octahydro-pyrrolo[1,2-a]pyrrino and octahydropyrrole And [3,4-c]pyrrolyl. As defined in the definition of the compound of formula I above, for the term NR2R3, the first three types of saturated heterocyclic rings (monocyclic, bridged bicyclic and fused bicyclic _

Any one or more groups independently selected from the group consisting of C^4 alkyl and NRaRb, optionally having a heterocyclic group or containing 2 N atoms and not substituted by an NRaRb group, or containing 1 N The atom is substituted with a NRaRb group. Thus, if the heterocyclic ring contains only one N atom, the ring must be substituted with an NRaRb group and may be optionally substituted with one or more Cl-4 hospital groups. If the ring contains 2 N atoms, it may be optionally substituted with one or more c 1 -4, but it may not be substituted by any of the N R a R b groups. The substituent (if present) can be located at any effective position of the ring and is included on the N atom when it is a Cl_4 hospital Q group. The phrase "optionally substituted by one or more" means that the group may be substituted by one or more, - preferably 1, 2, 3 or 4 substituents, more preferably 1 or 2 substituents, The restriction is that the group has sufficient standing to be substituted. These substituents may be the same or different and may be located at any effective position. Throughout the specification, the statement "treating" a disease, "treating a treatment," a disease, and the like refers to both a therapeutic treatment and a soothing treatment or prophylactic treatment of the disease. For the purposes of the present invention, beneficial or desired Clinical Outcomes-20- 200936570 Includes, but is not limited to, mitigating or ameliorating one or more symptoms, reducing the extent of the disease, stabilizing (ie, not worsening) the disease state, preventing a disease that is prone to or not showing symptoms of the disease, causing disease, delaying or slowing the disease Deteriorating, ameliorating or alleviating the condition and alleviation (whether partial or complete). The subject in need of treatment includes those who have a disease or condition and those who are susceptible to the disease or condition or who need to prevent the disease or condition. The present invention therefore relates to the definition above. Compound I. In another embodiment, the invention relates to a compound of formula I, wherein R1 represents a group selected from the group consisting of C2-5 alkyl and C3-7 cycloalkyl-C〇-l alkyl. In a specific embodiment, the invention relates to a compound of formula I, wherein Ri is selected from the group consisting of a third butyl group, an isopropyl group, a propyl group, a 2,2-dimethyl-propyl group, a butyl group, a group of a butyl group, a cyclopropylmethyl group, and a cyclopropyl group. In another embodiment, the invention relates to a compound of formula I, wherein R1 represents a compound selected from the group consisting of a third butyl group, an isopropyl group, and a propyl group. a group of isobutyl, indole cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclopropyl. In another embodiment, the invention relates to a compound of formula I, wherein - Ri is selected a group derived from a tributyl group, an isopropyl group, a propyl group, an isobutyl group, a cyclopropylmethyl group, and a cyclopropyl group. In another embodiment, the present invention relates to a compound of the formula, wherein the Ri system A group selected from the group consisting of propyl, isobutyl, cyclobutyl, cyclopentyl and cyclopropylmethyl. In another embodiment, the invention relates to a compound of formula I, wherein Ri is selected from a group of a C2-5 alkyl group and a c3-7 cycloalkyl group, and more preferably a group selected from the group consisting of a tert-butyl group, an isopropyl group and a cyclopropyl group, in the range of from 21 to 200936570. In another embodiment, The present invention relates to a compound of formula I, wherein Ri represents a group selected from the group consisting of C2.5 alkyl and c3-7 cycloalkyl-Ci alkyl, and is preferably selected from the group consisting of propyl, isobutyl and cyclic. A propylmethyl group. In another embodiment, the invention relates to a compound of formula I, wherein Ri represents C2.8 alkyl ' preferably c2-5 alkyl, and more preferably selected from a group of a third butyl group, an isopropyl group, a propyl group, a 2,2-dimethyl-propyl group, a butyl group, and an isobutyl group. In another embodiment, the present invention relates to a compound of formula I. Wherein R represents a group selected from the group consisting of a tributyl group, an isopropyl group, a propyl group, and an isobutyl group. In another embodiment, the invention relates to a compound of formula I, wherein the A group of a third butyl group and an isopropyl group. In another embodiment, the invention relates to a compound of formula I, wherein h represents a group selected from the group consisting of a propyl group and an isobutyl group. In one aspect, the invention is a compound of the formula: wherein Ri represents C3-7 cycloalkyl-Cm alkyl, preferably c3.7 cycloalkanyl-indenyl- and more preferably cyclopropane. Methyl group. - In another embodiment, the compound of the invention is related to the formula, wherein Ri represents C3-7 cycloalkyl' and is preferably cyclopentyl, cyclobutyl or cyclopropyl. In another embodiment, the invention is directed to a compound of the formula wherein R is a cyclopropyl group. In another embodiment, the invention is a compound of the formula, -22-200936570 wherein R2 and R3 have the meaning of the compound of the above formula I, with the proviso that when R2 and R3 together with the N atom to which they are bonded This non-piperage group is formed when a saturated heterocyclic group is formed. In another embodiment, the invention relates to a compound of formula I, wherein R.sup.2 and R.sup.3 together with the N atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of: (i) containing two n atoms And a heterocyclic group which does not contain any other hetero atom, wherein the heterocyclic group is optionally substituted by one or more Cu alkyl groups; and (ii) a heterocyclic group containing 1 N atom and no other hetero atom Wherein the heterocyclic group is substituted with one NRaRb group and optionally substituted with one or more Ci-4 substituent groups; wherein the heterocyclic group (i) and (ii) may be a 4- to 7-membered single ring a 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic ring; or R2 represents 11 or a C alkyl group, and R3 represents a nitrogen sulfonyl group, a pyrrolidinyl group, a piperidinyl group or a hydrazinyl group. 'It may be optionally substituted by one or more (^-4 alkylindoles. In another embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group which may be a 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic ring wherein the heterocyclic group may contain up to two N atoms and Without Other heteroatoms, and optionally substituted by one or more substituents independently selected from the group consisting of Cl-4 alkyl and NRaRb, with the proviso that the heterocyclic group or containing 2 N atoms and not substituted by the NRaRb group, Or containing 1 n atom and substituted by one NRaRb group. -23- 200936570 wherein saturated among them, a plurality of 8-members, among which one of them is in another specific embodiment, the present invention relates to formula I The compound, R2 and R.sup.3 together with the N atom to which they are bonded, form a heterocyclic group selected from the group consisting of: (i) a heterocyclic group containing 2 N atoms and no other hetero atom. Optionally substituted by one or more C!-4 alkyl groups; and (ii) heterocyclic group containing 1 N atom and no other hetero atom

Wherein the heterocyclic group is substituted by a NRaRb group and may be optionally substituted by one or c 1 . 4 yard bases. · a medium heterozygous base (i) and (ii) may be a 4_ to 7 member monocyclic ring, 7- to bridged double ring or 8_ to It fused double ring. In another specific embodiment, the present invention is a compound of the formula, and Ra and Rb independently represent hydrazine or Ci 4 alkyl. In another specific embodiment, the invention relates to compounds of formula I, and Ra and Rb independently represent H, methyl or ethyl.

In another embodiment, the invention relates to a compound of formula I, and Ra and Rb independently represent η or methyl. In another specific embodiment, the invention relates to a compound of formula I, Ra represents hydrazine and Rb represents hydrazine or Ci 4 alkyl. In another specific embodiment, the invention relates to a compound of formula I, Ra is a quinone and Rb represents H, methyl or ethyl. In another specific embodiment, the invention relates to a compound of formula I, Ra is an indole and Rb represents indole or methyl. In another specific embodiment, the invention relates to a compound of formula I, Ra is a quinone and Rb represents a c 1 alkyl group. -24- 200936570 In another embodiment, the invention relates to a compound of formula I, wherein the Ra system represents η and the Rb represents methyl or ethyl. In another embodiment, the invention is a compound of formula I, wherein Ra is Η and Rb is methyl. In another embodiment, the invention is a compound of formula I, wherein Ra and Rb represent H. In another embodiment, the invention relates to a compound of formula I, Φ wherein 112 and R3 together with the argon atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of:

Wherein Ra and Rb have the meaning of the compound of the above formula I, R. It means Η or Cl-4 ’ base ' and preferably Re means Η. In another embodiment, the invention relates to a compound of formula I, -25-200936570 wherein R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group selected from (a) to (h), Further, Ra, Rb and Re each independently represent an anthracene or a Cm alkyl group, and preferably Ra, Rb and Rc each independently represent an anthracene or a methyl group, and more preferably a Ra system represents H, Rb represents a methyl group and a Re system represents a Hey. In another embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with the N atom to which they are bonded form a choice of (a), (b), (c), (d), ( f), a saturated heterocyclic group of (g) and (h), wherein Ra and Rb have the meanings previously expressed for the compound of formula I and Rc φ means fluorene or Cu alkyl, and preferably Rc represents hydrazine. In another embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with the ruthenium atom to which they are bonded are formed from (a), (b), (c), (d), ( f), a saturated heterocyclic group of (g) and (h), and Ra, Rb and Re each independently represent H or Cm alkyl, and preferably - are Ra, Rb and R. The oxime or methyl group is independently indicated, and it is more preferred that the Ra system represents Η, the Rb represents a methyl group and the Re system represents Η. In another embodiment, the invention relates to a compound of formula I, wherein 112 and R3 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group selected from (a) to (f), wherein Ra & Rb has the meaning previously expressed for the formula I and Re represents Η or (^-4 alkyl, and preferably R. represents Η. In another embodiment, the invention relates to Formula I a compound wherein R 2 and R 3 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group selected from (a) to (f), and Ra, Rb and Re each independently represent Η or C, -4 alkyl, Preferably, Ra, Rb and Re each independently represent a hydrazine or a methyl group, -26-200936570 and more preferably a Ra system represents Η 'Rb represents a methyl group and R represents a η. In another embodiment, The present invention relates to a compound of formula I, wherein R2 and R3 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group selected from (a) to (d) wherein Ra& Rb has the meaning previously for the compound of formula I And R. is taken from the oxime or Ci.4 fen, and preferably R. represents Η. In another embodiment, the invention relates to a compound of formula I, D wherein R 2 and R 3 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group selected from (a) to (d), and Ra, Rb and Re each independently represent Η or Cm alkyl, and preferably Ra Rb and Re each independently represent an anthracene or a methyl group, and more preferably a Ra system represents H, Rb represents a methyl group, and a Re represents a hydrazine. In another specific embodiment, the invention relates to a compound of formula I, ' Wherein R 2 and R 3 together with the N atom to which they are bonded form a saturated heterocyclic group selected from (a) and (b), wherein 113 and Rb have the meanings previously expressed for the compound of formula I and R represents hydrazine or Ci. 4 alkyl, and preferably R. is shown in the drawings. In another embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with the ruthenium atom to which they are bonded are selected from The saturated heterocyclic group of (a) and (b), and Ra, Rb and R each independently represent an anthracene or a Cm alkyl group, and preferably Ra, Rb and Rc each independently represent a hydrazine or a methyl group. In one aspect, the invention relates to a compound of formula I, wherein R2 and R3 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group selected from (a) and (b), and Ra represents H, Rb Indicates 11 or Cm alkyl and R. represents hydrazine. -27- 200936570 In another embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with the N atom to which they are bonded are selected from (a) and (b) a saturated heterocyclic group, wherein Ra represents H, Rb represents hydrazine or methyl and R represents hydrazine. In another embodiment, the present invention relates to a compound of formula I, wherein R2 and R3 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group selected from (a) and (b), Ra represents H, and Rb represents methyl and *

The Rc system indicates Η. In another embodiment, the invention relates to a compound of formula I, wherein 112 and R3 together with the argon atom to which they are bonded form a saturated heterocyclic group of formula (a)

Ra\ /Rb Ν 〇 (a) ' wherein Ra and Rb have the meanings previously given for the compound of formula I, and RC represents Ci-4 alkyl, and preferably R. Indicates H. In another embodiment, the invention is directed to a compound of formula I, wherein R2 and R3 are bonded together; The atoms together form a saturated heterocyclic group of the formula (a), and Ra, Rb and Re each independently represent hydrazine or Cm alkyl group and preferably Ra, Rb and independently represent hydrazine or methyl group. -28-200936570 In another embodiment, the invention is related to the formula wherein R2 and R3 together with the N atom to which they are bonded are saturated with a heterocyclic group, Ra is a fluorene, and Rb is a fluorene or fluorene. In another embodiment, the invention relates to a formula wherein R2 and R3 together with a helium atom to which they are bonded saturate a heterocyclic group, Ra is a fluorene, and Rb is fluorene or fluorene. In another embodiment, the invention relates to a formula wherein R2 and R3 together with a helium atom to which they are bonded saturate a heterocyclic group, Ra represents hydrazine, and Rb represents a methyl group or a methyl group. In another embodiment, the invention relates to a formula wherein R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group, Ra represents hydrazine, and Rb represents a methyl group and a fluorenyl group. In another embodiment, the invention is related to the formula: wherein R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group, Ra is a fluorene, Rb is a methyl group and hydrazine is another embodiment. In one aspect, the present invention relates to a compound wherein R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group I, > a compound of the formula (a) of -4 alkyl and Rc I, j is a compound of the formula (a) and Re is a compound of the formula I, and the Re of the formula (a) represents a compound of Η I, and the Rc of the formula (a) represents a compound of the formula I, ^ (a) is a compound representing Η I, and -29-200936570 of formula (b)

N

c

(b) wherein Ra and Rb have the meanings previously expressed for the compound of formula I, and Rc represents hydrazine or Cm alkyl, and preferably Re represents hydrazine. In another embodiment, the invention is a compound of formula I, wherein R2 and R3 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group of formula (b), and Ra, Rb and R. It is independently represented by hydrazine or Cm alkyl group, preferably Ra, Rb and Re each independently represent hydrazine or methyl group, and more preferably, Ra means H, Rb represents methic group and Rc represents hydrazine. In another embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group of formula (b), Ra represents η, and Rb represents Η Or C^-4 alkyl and Rc Q represents hydrazine. In another embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (b), and Ra represents Η'Rb Indicates Η or methyl ' and Re represents Η. In another embodiment, the invention relates to a compound of formula 1 wherein R2 and R3 together with the argon atom to which they are bonded form a saturated heterocyclic group of formula (f) -30-200936570

Ra

(0) wherein Ra is a group of 11 or Cu, and or a methyl group. In another embodiment, the present invention has a center and R3 together with a N atom-saturated heterocyclic group bonded thereto is preferably a Ra system. a compound of formula I which forms a formula (h)

Ra/ 3

Among them, Ra is not listed or C1-4, and _ or methyl. In another embodiment, the present invention is wherein | R2 represents η or Ci-4 alkyl and R3 is epi-, piperidinyl or aziridine, which may optionally be passed through one or: Zhijia is Ra A compound of the formula I, which is a nitrogen-based group, a pyrrolidinium, a Ci-4, and a group of -31 - 200936570, and preferably R2 represents Η and R3 represents 1-methyl-pyrrolidine- 3- base. In another embodiment, the invention relates to a compound of formula I, wherein Ri represents a group selected from the group consisting of C2-5 alkyl and c3-7 cycloalkyl-(:^alkyl) and is preferably selected from the third a group of a group, an isopropyl group, a propyl group, a 2,2-dimethyl-propyl group, a butyl group, an isobutyl group, a cyclopropylmethyl group, and a cyclopropyl group; and R2 and R3 together with the group bonded thereto The N atoms together form a saturated heterocyclic group which may be a 4- to 7-membered monocyclic ring, a 7- to 8-membered bridged bicyclic ring or an 8- to 12-membered fused bicyclic ring, wherein the heterocyclic group may be Containing up to two N atoms and containing no other heteroatoms, and optionally substituted by one or more substituents independently selected from C..4 alkyl and NRaRb, with the proviso that the heterocyclic group or contains 2 One N atom and not substituted by an NRaRb group, or containing 1 N atom and substituted by one NRaRb group. - In another specific embodiment, the invention relates to a compound of formula I, wherein Ri represents a group selected from C2 -5 alkyl and C3_7 cycloalkyl-(: alkyl group ' and preferably selected from the group consisting of tert-butyl, isopropyl, propyl, 2,2-dimethyl--propyl, butyl Base, isobutyl, cyclopropylmethyl and cyclopropyl a group; and · and R3 together with the N atom to which they are bonded form a saturated hetero-cyclic group selected from the group consisting of: (i) a heterocyclic group containing 2 N atoms and no other hetero atom, wherein The heterocyclic group may be optionally substituted by one or more (^-4 alkyl groups; and (ii) a heterocyclic group containing 1 N atom and containing no other hetero atom, wherein the heterocyclic group is substituted by an NRaRb group And optionally substituted by one or more Ci-4 alkyl groups; -32- 200936570 wherein the heterocyclic groups (i) and (ii) may be 4- to 7-membered monocyclic, 7- to 8-membered bridges Bicyclic or 8- to 12-membered fused bicyclic ring. In another embodiment, the invention relates to a compound of formula I, wherein Ri is selected from C2-5 alkyl and C3-7 cycloalkyl-(:^alkyl The group 'and is preferably selected from the group consisting of a third butyl group, an isopropyl group, a propyl group, a 2,2-dimethyl-propyl group, a butyl group, an isobutyl group, a cyclopropylmethyl group and a cyclopropyl group. R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group selected from (a) to (h) wherein Ra, Rb and Re have the aforementioned meanings, and preferably Ra, Rb and R Is independent of Η or Cm alkyl, and more preferably Ra, Rb and R<= are independent of hydrazine or methyl. In another embodiment, the invention relates to a compound of formula I, wherein Ri represents a group selected from C2-5 alkyl and C3.7 cycloalkyl. -Co. Alkyl group, and preferably selected from the group consisting of a third butyl group, an isopropyl group, a propyl group, a 2,2-dimethyl-propyl group, a butyl group, an isobutyl group, a cyclopropyl group And a group of a cyclopropyl group; and R 2 and R 3 together with the N atom to which they are bonded form a saturated heterocyclic group selected from (a) to (f) fluorene, wherein Ra, Rb and Re have the aforementioned meanings, and Preferably, Ra, Rb and Re are independently represented by 1^ or Cu alkyl group, and more preferably Ra?, Rb and Re are independently represented by hydrazine or methyl group. In another specific embodiment, 'the present invention relates to the compound of the formula 1' wherein Ri represents a group selected from the group consisting of C2-5 alkyl and C3-7 cycloalkyl-(: alkyl), and is preferably selected from the group consisting of a group of tributyl, isopropyl, propyl, 2,2-dimethyl-propyl, butyl, isobutyl, cyclopropylmethyl and cyclopropyl; and R2 and R3 together with the bond thereof The N atoms of the knot together form a saturated heterocyclic group selected from (a) to (d), wherein Ra, Rb and Rc have the aforementioned meanings ', and preferably -33 to 200936570 are Ra, Rb and R. Cu alkyl, and more preferably Ra, Rb and Rc, independently represent hydrazine or methyl. In another embodiment, the invention relates to a compound of formula I, wherein Ri is selected from C2-5 alkyl and a C3_7 cycloalkyl-(:alkyl group' and is preferably selected from the group consisting of a third butyl group, an isopropyl group, a propyl group, a 2,2-dimethyl-propyl group, a butyl group, an isobutyl group, a group of a cyclopropylmethyl group and a cyclopropyl group; R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group selected from (a) and (b), wherein Ra, Rb and R have the foregoing Meaning, and preferably Ra, Rb and Re independently represent Η or C丨_4 alkyl More preferably, Ra, Rb and Re are independently represented by hydrazine or methyl. In another embodiment, the invention relates to a compound of formula I, wherein Ri represents a group selected from C2-5 alkyl and C3-7 cycloalkyl- (^-, a group of an alkyl group' and preferably selected from the group consisting of a third butyl group, an isopropyl group, a propyl group, a 2,2-dimethyl-propyl group, a butyl group, an isobutyl group, a cyclopropyl group And a group of a cyclopropyl group; and R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group of the formula (a), wherein Ra, Rb and Re each independently represent an anthracene or a Cu alkyl group, and Preferably, Ra, Rb and Rc are independently represented by hydrazine or methyl. In another embodiment, the invention relates to a compound of formula I, wherein R1 represents a group selected from C2.5 alkyl and C3-7 cycloalkyl. - (: alkyl group ' and preferably selected from the group consisting of a third butyl group, an isopropyl group, a propyl group, a 2,2-dimethyl-propyl group, a butyl group, an isobutyl group, a cyclopropyl group And a group of a cyclopropyl group; and R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group of the formula (b), wherein Ra, Rb and Rc each independently represent an anthracene or a Cu alkyl group, and Preferably, Ra, Rb and R are independently represented by hydrazine or methyl group, and more preferably Ra And Rb-34-200936570 stands for Η or methyl and Rc represents η. In another embodiment, the invention relates to a compound of formula I, wherein Ri represents a selected from the group consisting of a third butyl group and an isopropyl group. a group of a propyl group, an isobutyl group, a cyclopropylmethyl group, a cyclobutyl group, a cyclopentyl group, and a cyclopropyl group; and R and 3 together with the N atom to which they are bonded form a saturated heterocyclic group, It may be a 4- to 7-membered monocyclic ring, a 7- to 8-membered bridged bicyclic ring or an 8 to 12-membered fused bicyclic ring wherein the heterocyclic group may contain up to two N atoms and does not contain any other impurities. The atom 'and optionally substituted with one or more substituents independently selected from the group consisting of Cu alkyl and NRaRb' is limited to the heterocyclic group or containing 2 N atoms and not substituted by the NRaRb group' or contains 1 The n atom is substituted with one NRaRb group. In another embodiment, the invention relates to a compound of formula I, wherein Ri is selected from the group consisting of a third butyl group, an isopropyl group, a propyl group, an isobutyl group, a cyclopropylmethyl group, a cyclobutyl group, a ring. a group of a pentyl group and a cyclopropyl group; and r2 and R·3 together with the N atom to which they are bonded form a saturated heterocyclic G group selected from the group consisting of: (i) containing 2 N atoms and not containing any other impurities a heterocyclic group of an atom, wherein 'the heterocyclic group is optionally substituted by one or more Ci -4 alkyl groups; and (ii) a heterocyclic group containing 1 N atom and free of any other hetero atom The ring group is substituted with an NRaRb group and optionally substituted with one or more Ch4 alkyl groups; wherein the heterocyclic groups (i) and (ii) may be 4- to 7-membered monocyclic, 7- to 8- Bridge double ring or 8- to 12-member fused double ring. In another embodiment, the invention relates to a compound of formula I, -35-200936570 wherein Ri is selected from the group consisting of a third butyl group, an isopropyl group, a propyl group, an isobutyl group, a cyclopropylmethyl group, and a ring. a group of a butyl group, a cyclopentyl group and a cyclopropyl group; and r2 and r3 together with the N atom to which they are bonded form a saturated heterocyclic group selected from (a) to (h), and Ra, Rb and R. It is independently represented by hydrazine or Cm alkyl group, and preferably Ra, Rb and R. It is independently represented by hydrazine or a methyl group, and more preferably, the Ra system represents H, Rb represents a methyl group and the Re system represents H. In another embodiment, the invention relates to a compound of formula I, wherein 'Ri' is selected from the group consisting of a third butyl group, an isopropyl group, a propyl group, an isobutyl group, a cyclopropylmethyl group, a cyclobutyl group. a group of a cyclopentyl group and a cyclopropyl group; R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group selected from (a) to (f), and Ra, Rb and R. Preferably, it is a hydrazine or a Cm alkyl group, and preferably Ra, Rb and Re each independently represent a hydrazine or a methyl group, and more preferably a Ra system represents H, Rb represents a methyl group and Re represents a hydrazine. In another embodiment, the invention relates to a compound of formula I, wherein R! is selected from the group consisting of a third butyl group, an isopropyl group, a propyl group, an isobutyl group, a cyclopropylmethyl group, a cyclobutyl group. a group of a cyclopentyl group and a cyclopropyl group; R2 and r3 Q together with the N atom to which they are bonded form a saturated 'heterocyclic group selected from (a) to (d), and Ra, Rb and R. It is independently represented by 11 or 4 alkyl, and more preferably - Ra, Rb and R. It is independently represented by hydrazine or a methyl group, and more preferably, the Ra system represents H, Rb represents a methyl group and Rc represents H. In another embodiment, the invention relates to a compound of formula 1, wherein Ri is selected from the group consisting of a third butyl group, an isopropyl group, a propyl group, an isobutyl group, a cyclopropylmethyl group, a cyclobutyl group, and a ring. a group of a pentyl group and a cyclopropyl group; r2 and R3 together with the N atom to which they are bonded form a saturated -36-200936570 heterocyclic group selected from (a) and (b), and Ra, Rb and Rc are independently It represents 1{ or a Cu alkyl group, and it is preferable that Ra, Rb, and Re each independently represent a hydrazine or a methyl group, and more preferably, a Ra system means that H' Rb represents a methyl group and Rc represents η. In another embodiment, the invention relates to a compound of formula I, which is selected from the group consisting of tert-butyl, isopropyl, propyl, isobutyl, cyclopropylmethyl, cyclobutyl, cyclopentane. And a group of a cyclopropyl group; r2 and r3 together with the N atom to which they are bonded form a saturated heterocyclic group of the formula (a), and D and, 趴 and Re independently represent 11 or (^-4 alkyl) Preferably, Ra, Rb and Rc each independently represent a hydrazine or a methyl group, and more preferably a Ra system represents η, Rb represents a methyl group and Rc represents hydrazine. In another specific embodiment, the invention relates to a compound of formula I, wherein Ri represents a group selected from the group consisting of a third butyl group, an isopropyl group, a propyl group, an isobutyl group, a cyclopropylmethyl group, a cyclobutyl 'cyclopentyl group, and a cyclopropyl group; R3 together with the N atom to which it is bonded form a saturated heterocyclic group of the formula (b), and Ra, Rb and R independently represent a fluorene or Cm alkyl group, and preferably Ra O , Rb and Rc are independently represented Η or methyl, and more preferably Ra represents Η, 'Rb represents methyl and represents Η. * In another embodiment, the invention relates to a compound of formula I, wherein R! represents Ο- Octaalkyl , preferably a c2-5 alkyl group, and more preferably a group selected from the group consisting of a tributyl group, an isopropyl group, a propyl group, a 2,2-dimethyl-propyl group, a butyl group, and an isobutyl group; R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group which may be a 4- to 7-membered monocyclic ring, a 7- to 8-membered bridged bicyclic ring or an 8- to 12-membered fused bicyclic ring. Wherein the heterocyclic group may contain up to two N atoms and does not contain any other hetero atom, and may be optionally substituted by one or more substituents independently selected from Ct-4 and NRaRb, which are limited by -37-200936570 The condition is that the heterocyclic group either contains 2 N atoms and is not substituted by the NRaRb group, or contains 1 N atom and is substituted by one NRaRb group. In another embodiment, the present invention relates to a compound of the formula Wherein Ri is not more than 2·8, and preferably is 〇2_5 fluorenyl, and more preferably selected from the group consisting of a tert-butyl group, an isopropyl group, a propyl group, a 2,2-dimethyl-propyl group, a group of butyl and isobutyl; and R2 and R3 together with the N atom to which they are bonded - a saturated heterocyclic group selected from: @ (i) contains 2 N atoms and does not contain any other hetero atom Heterocyclic group, wherein the hetero The cyclic group may be optionally substituted by one or more mountain-4 alkyl groups; and (ii) a heterocyclic group containing 1 N atom and free of any other hetero atom, wherein the heterocyclic group is substituted with an NRaRb group and Optionally substituted by one or more Ch alkyl groups; wherein the heterocyclic groups (i) and (ii) may be 4- to 7-membered monocyclic, 7- to 8-bei bridged bicyclic or 8- to 12 - In another embodiment, the present invention relates to a compound of formula I, wherein R represents C2-8 alkyl, preferably c2-5 alkyl, and more preferably selected from the third a group of butyl, isopropyl, propyl, 2,2-dimethyl-propyl, butyl and iso-butyl; Rz and r3 together with the N atom to which they are bonded form a (a) a saturated heterocyclic group to (h), wherein Ra, Rb and R. It has the aforementioned meaning 'and preferably Ra, Rb and Re are independently represented by ^! or Ci-4 alkyl, and more preferably Ra, Rb and Rc independently represent an anthracene or a methyl group. In another embodiment, the invention relates to a compound of formula I, wherein Ri represents C2.8 alkyl, preferably C2-5 alkyl, and more preferably -38-200936570 from tributyl, iso a group of propyl, propyl, 2,2-dimethyl-propyl, butylbutyl; and R2 and R3 together with the N atom to which they are bonded are selected from the saturated impurities of (a) to (f) A cyclic group wherein Ra, Rb and Rc have the aforementioned meanings, and preferably Ra, Rb and Re each independently represent a fluorene or a C group, and more preferably Ra, Rb and Re each independently represent a hydrazine or a methyl group. In another specific embodiment, the present invention relates to a compound of the formula wherein the R1 group represents a C2-8 yard group, preferably a C2_5 yard group, and more preferably φ from a tributyl group, an isopropyl group, or a propyl group. a group of 2,2-dimethyl-propyl, butylbutyl; and R2 and R3 together with the N atom to which they are bonded are selected from the saturated heterocyclic groups of (a) to (d), wherein Ra And Rc have the above meanings, and it is preferred that Ra, Rb and Re independently represent Η or C groups, and more preferably Ra, Rb and Re independently represent Η or methyl. In another embodiment, The present invention relates to a compound of formula I wherein R! represents C2_8 alkyl, preferably C2.5 alkyl, and more preferably from tert-butyl, isopropyl, propyl, 2,2-dimethyl- a group of a propyl group, a butyl group and a butyl group; R~2 and Κ·3 together with the N atom to which they are bonded are formed from the saturated heterocyclic group of (a) and (b), wherein Ra, Rb and Re Meaning, and preferably Ra, Rb and Rc independently represent 11 or Ci-4, and more preferably Ra, Rb and Rc independently represent hydrazine or methyl. In another embodiment, the invention relates A compound of formula I wherein R1 represents C2-8 alkyl, preferably C2-5 alkyl, More preferably from the group consisting of a tributyl group, an isopropyl group, a propyl group, a 2,2-dimethyl-propyl group, and a butyl group; and R2 and R3 together with the N atom to which they are bonded ( a) a saturated heterocyclic group, wherein Ra, Rb and 1^ are independently formed and have different formations, and have 1 - 4 yards for selection and heterogeneity, and are selected and selected - I__ _·&gt /. There is an alkyl group, which is selected and formed to form -39-200936570 or Ci-4 alkyl, and preferably Ra, Rb and Re are independently represented by hydrazine or methyl 0. Another specific embodiment The present invention relates to a compound of formula I, wherein R1 represents C2.8 alkyl, preferably C2-5 alkyl, and more preferably selected from the group consisting of tert-butyl, isopropyl, propyl, 2, a group of 2-dimethyl-propylbutyl and isobutyl; and R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (b) wherein Ra, Rb and Rc are independently Η or C! -4 alkyl, and preferably Ra, Rb and Re independently represent hydrazine or methyl, @ and more preferably Ra and Rb independently represent hydrazine or methyl, and Re represents Η 〇 In a specific embodiment, the invention relates to a compound of formula I Wherein R! represents a group selected from the group consisting of a tributyl group, an isopropyl group, a propyl group, and an isobutyl group; and R2 and R3 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group, which may be 4 a 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic ring wherein the heterocyclic group may contain up to two N atoms and no other heteroatoms, and Optionally substituted with one or more substituents independently selected from the group consisting of Ci-4 decyl and NRaRb, with the proviso that the heterocyclic group or contains 2 N atoms and is not substituted by the NRaRb group, or contains 1 N ' atom and substituted by a NRaRb group. In another embodiment, the invention relates to a compound of formula I, wherein Ri represents a group selected from the group consisting of a third butyl group, an isopropyl group, a propyl group and an isobutyl group; and R2 and R3 together The bonded N atoms together form a saturated heterocyclic group selected from the group consisting of: (i) a heterocyclic group containing 2 N atoms and containing no other hetero atom, -40-200936570 wherein the heterocyclic group is optionally subjected to one or a plurality of Cl.4 substituents; and (11) a heterocyclic group containing 1 N atom and no other hetero atom, wherein the heterocyclic group is substituted by one NRaRb group and optionally passed through - or more The C i _4 substituent is substituted; wherein the heterocyclic group (i) and (ii) may be a 4- to 7-membered monocyclic ring, a 7- to 8-membered bridged bicyclic ring or an 8- to 12-membered fused bicyclic ring. In another embodiment, the invention relates to a compound of formula I, wherein R represents a group selected from the group consisting of a tert-butyl group, an isopropyl group, a propyl group and an isobutyl group; and R2 and R_3 together with the bond thereof The N atoms of the knot together form a saturated heterocyclic group selected from (a) to (h), and Ra, Rb & Re independently represent η or Cm alkyl ' and preferably Ra, Rb and Re independently represent η or Methyl, and more preferably Ra is a fluorene, and Rb is a methyl group and R. The system indicates Η. In another embodiment, the invention relates to a compound of formula I, wherein is a group selected from the group consisting of a tert-butyl group, an isopropyl group, a propyl group and an isobutyl group; and R2 and R3 together with the linkage thereof The rhodium atoms together form a saturated heterocyclic group selected from (a) to (f), and Ra, Rb and Rc each independently represent η or Ci-4 alkyl, and preferably Ra, Rb and R. It is η or a methyl group independently, and it is more preferable that Ra is a fluorene, Rb is a methyl group, and Re is a hydrazine. In another embodiment, the invention relates to a compound of formula I, wherein Ri represents a group selected from the group consisting of a tert-butyl group, an isopropyl group, a propyl group and an isobutyl group; and R2 and R3 together with the linkage thereof The N atoms together form a saturated heterocyclic group selected from (a) to (d), and Ra, Rb and Rc each independently represent hydrazine or C!_4 alkyl, and preferably Ra, Rb and Re are independently represented. Or a methyl group, and it is more preferable that the Ra system represents H, Rb represents a methyl group, and Re represents a hydrazine. -41 - 200936570 In another embodiment, the invention relates to a compound of formula I, wherein Ri represents a group selected from the group consisting of a tert-butyl group, an isopropyl group, a propyl group and an isobutyl group; and R2 and R3 together The N atoms bonded thereto form a saturated heterocyclic group selected from (a) and (b), and Ra, Rb & Re independently represent η or Cm alkyl ' and preferably Ra, Rb and R. It is η or a methyl group independently, and it is more preferable that the Ra system represents H, Rb represents a methyl group, and Re represents a hydrazine. In another embodiment, the invention relates to a compound of formula I, wherein Ri represents a group selected from the group consisting of a tert-butyl group, an isopropyl group, a propyl group and an isobutyl group; and R2 and R3 together with the linkage thereof The N atoms together form a saturated heterocyclic group of the formula (a) and Ra, Rb and Re each independently represent a fluorene or a Cm alkyl group, and preferably Ra, Rb and Rc each independently represent a hydrazine or a methyl group, and more preferably For the Ra system, the H' Rb system is not methyl and the Rc system is η. In another embodiment, the invention relates to a compound of formula I, wherein Ri represents a group selected from the group consisting of a tert-butyl group, an isopropyl group, a propyl group and an isobutyl group; and R2 and R3 together with the linkage thereof The N atoms together form a saturated heterocyclic group of the formula (b), and Ra, Rb and Re each independently represent 11 or (^-4 alkyl ' and preferably Ra, Rb and R. More preferably, the Ra system represents hydrazine, Rb represents a methyl group and Rc represents hydrazine. In another specific embodiment, the invention relates to a compound of formula I, wherein Ri represents C3_7 cycloalkyl-Cm alkyl. , preferably C3_7 cycloalkyl-<^alkyl' and more preferably cyclopropylmethyl; and r2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group which may be 4 - to a 7-membered monocyclic ring, a 7- to 8-membered bridged bicyclic ring or an 8 to 12-membered fused bicyclic ring wherein the heterocyclic group may contain up to two N atoms and does not contain any other hetero atom, and may be -42 - 200936570 optionally substituted by one or more substituents independently selected from C|_4 alkyl and NRaRb' with the proviso that the heterocyclic group contains 2 N atoms and is not substituted by the NRaRb group, or contains 1 n And substituted by a NRaRb group. In another specific embodiment, the present invention relates to a compound of the formula ,, wherein 1^1 is represented by (^3.7 环院基-(1; 1.4 院基' is preferably 〇3_7 ring-based-Ci alkyl, and more preferably cyclopropylmethyl; and R2 and R3 together with the ruthenium atom bonded thereto form a saturated heterocyclic group selected from the group consisting of: (i) 曰2 a heterocyclic group having a halogen atom and containing no other hetero atom, wherein the heterocyclic group is optionally substituted by one or more Ci-4 alkyl groups; and (H) contains 1 N atom and does not contain any other hetero atom a heterocyclic group wherein the heterocyclic group is substituted by an NRaRb group and optionally substituted by one or more CL4 alkyl groups; wherein the heterocyclic group (i) and (ii) may be 4- to 7-membered Monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic. In another embodiment, 'the invention relates to a compound of formula I, wherein Ri is C3_7 cycloalkyl- Cw alkyl, preferably C3.7 cycloalkane "yl-Cl alkyl' and more preferably cyclopropylmethyl; 1 and R3 together with the N atom to which they are bonded form a choice from (a) to ( h) a saturated heterocyclic group, and Ra, Rb and R each independently represent an anthracene or an alkyl group, preferably Ra, Rb and R. They independently represent a hydrazine or a methyl group, and more preferably a Ra system represents hydrazine, Rb represents a methyl group and Rc represents hydrazine. In a specific embodiment, the invention relates to a compound of formula I, wherein Ri represents C3_7 cycloalkyl-Cm alkyl, preferably C3-7 cycloalkane-43-200936570 base-Cl, and more preferably Is a cyclopropylmethyl group; R2 and β·3 together with the N atom to which they are bonded form a saturated heterocyclic group selected from (a) to (f), and Ra, Rb and R. It is independently represented by hydrazine or C^.4 alkyl group, preferably Ra, Rb and Rc each independently represent hydrazine or methyl group, and more preferably Ra is a fluorene, Rb is a methyl group and Rc is a hydrazine. In another embodiment, the invention relates to a compound of formula I, wherein R! represents C3.7 cycloalkyl-Cm alkyl, preferably C3-7 cycloalkyl-C! alkyl, and more preferably Cyclopropylmethyl; 1 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group selected from (a) to (d), and Ra, Rb and R. It is independently represented by hydrazine or (^_4 alkyl group, preferably Ra, Rb and R. It is independently represented by hydrazine or methyl group, and more preferably, Ra is a fluorene, Rb is a methyl group and R is a hydrazine. In a specific embodiment, the invention relates to a compound of formula I, wherein R represents C3-7 cycloalkyl-Cm alkyl, preferably C3-7 cycloalkyl-C, alkyl, and more preferably cyclopropyl. a methyl group; R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group selected from (a) and (b), and

Ra, Rb and Rc each independently represent a ^1 or Cm alkyl group, preferably Ra, Rb and R. It is independently represented by hydrazine or a methyl group, and more preferably, the Ra system represents hydrazine, the Rb system ' represents a methyl group, and the Rc system represents hydrazine. In another embodiment, the invention relates to a compound of formula I, wherein R represents a c3-7 cycloalkyl-Ch alkyl group, preferably a C3-7 cycloalkyl-C, alkyl group, and more preferably Cyclopropylmethyl; R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (a), and Ra, Rb and Rc are independently represented or CU4 alkyl, preferably Ra, Rb And Re is independent of the table -44-200936570 Η or methyl ' and more preferably Ra is H, Rb is methyl and Rc is Η. In another embodiment, the invention relates to a compound of formula I, wherein I represents C3-7 cycloalkyl-Cm alkyl, preferably C3-7 cycloalkylalkyl and more preferably cyclopropyl The group; r2 and r3 together with the N atom to which they are bonded form a saturated heterocyclic group of the formula (b), and Ra, Rb and Rc each independently represent a fluorene or Cm alkyl group, preferably Ra, Rb and Re are independently 0 represents Η or methyl, and more preferably Ra represents η, Rb represents a methyl group and Rc represents Η. In another embodiment, the invention relates to a compound of formula I, wherein R! represents a C3-7 cycloalkyl group, preferably a cyclopropyl group; and 112 and r3 together with the N atom to which they are bonded form a saturated heterocyclic group which may be a 4- to 7-membered monocyclic ring, a 7- to 8-membered bridged bicyclic ring or an 8- to 12-membered fused bicyclic ring wherein the heterocyclic group may contain up to two N atoms and Without any other hetero atom' and optionally substituted by one or more substituents selected from (^-4 alkyl and NRaRb, the restriction is that the heterocyclic group or contains 2 N atoms and is not The NRaRb group is substituted or contains 1 N atom and is substituted with a NRaRb ' group. In another embodiment, the invention relates to a compound of formula I, wherein Ri represents c3-7 cycloalkyl, preferably Is a cyclopropyl group; and R 2 and r 3 together with the N atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of: (i) a heterocyclic group containing 2 N atoms and no other hetero atom, wherein The heterocyclic group may be optionally substituted by one or more CL4 alkyl groups; and (i) a heterocyclic group containing 1 N atom and containing no other hetero atom -45-200936570 The heterocyclic group is substituted by one NRaRb group and optionally substituted by one or more alkyl groups; wherein the heterocyclic groups (i) and (ii) may be 4- to 7-membered monocyclic, 7- to 8 - A bridged bicyclic or 8- to 12-membered fused bicyclic ring. In another embodiment, the invention relates to a compound of formula I, wherein Ri represents C3_7 cycloalkyl, preferably cyclopropyl; r2 And r3 together with the N atom to which it is bonded together form a saturated heterocyclic group selected from (a) to (h), and 1^, 1^ and Re independently represent only a Cm alkyl group, preferably ◎

Ra, Rb and R. It is independently represented by hydrazine or a methyl group, and more preferably, the Ra system represents hydrazine, Rb represents a methyl group, and Rc represents hydrazine. In another embodiment, the invention relates to a compound of formula I, wherein Ri represents C3-7 cycloalkyl, preferably cyclopropyl; and r2 and r3 together with the N atom to which they are bonded are selected from The saturated heterocyclic group ' of (a) to (f) and Ra, Rb and Rc each independently represent an anthracene or a Cm alkyl group, preferably Ra, Rb and independently represent an anthracene or a methyl group, and more preferably a Ra system. Η , Rb is not methyl and Rc is not. In another embodiment, the invention relates to a compound of formula I, wherein R! represents C3.7 cycloalkyl' preferably cyclopropyl; and R2 and R3 together with - the N atom to which they are bonded A saturated heterocyclic group selected from (a) to (d) is formed, and Ra, Rb and R are formed. It is independently represented by η or Cu alkyl, preferably Ra, Rb and R. The oxime or methyl group is independently indicated, and more preferably the Ra system indicates that Η ' Rb is benzyl and Rc is not. In another embodiment, the invention relates to a compound of formula I, wherein Ri represents C3-7 cycloalkyl' preferably cyclopropyl; R2 and r3 together with -46 - 200936570 bonded N atom The saturated heterocyclic group selected from (a) and (b) is formed together, and Ra, Rb, and Re are independently represented by a group or a Ci_4, preferably Ra, Rb, and R. It is independently represented by hydrazine or a methyl group, and more preferably, the Ra system represents hydrazine, Rb represents a methyl group, and Rc represents hydrazine. In another embodiment, the invention relates to a compound of formula I, wherein Ri represents C3_7 cycloalkyl, preferably cyclopropyl; and r2 and r3 together with the N atom to which they are bonded form formula (a) a saturated heterocyclic group, and Ra 0 ' Rb and Re independently represent hydrazine or a Ci. 4 alkyl group, preferably Ra, Rb and

Rc represents hydrazine or methyl group independently, and more preferably, Ra system represents H, Rb represents methyl group and Re system represents hydrazine. In another embodiment, the invention relates to a compound of formula I, wherein Ri represents C3-7 cycloalkyl, preferably cyclopropyl; 1^2 and r3 together with the N atom to which they are bonded form a saturated heterocyclic group of the formula (b), and Ra, Rb and Re each independently represent an anthracene or a Cu alkyl group, preferably Ra, Rb and Rc each independently represent an anthracene or a methyl group and more preferably a Ra system represents H, The Rb is not methyl and the Re is not H. In another embodiment, the invention relates to a compound of formula I, wherein R1 represents C2-8 or C3.7 ring-based - C〇.4, and R2 and R3 together with The N atoms together form a saturated heterocyclic group of the formula (a): and the Ra system represents hydrazine, the Rb group represents a methyl group and the rc system represents hydrazine. In another embodiment, the invention relates to a compound of formula I, wherein Ri represents a group selected from the group consisting of C2-5 alkyl and C3-7 cycloalkyl-(: alkyl), preferably selected from the group consisting of a third butyl group. a group of isopropyl, propyl, isobutyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclopropyl; 112 and r3 together with the N atom bonded thereto -47-200936570 A saturated heterocyclic group of the formula (a); and a Ra system represents Η 'Rb represents a methyl group and Rc represents a hydrazine. In another specific embodiment, the invention relates to a compound of the formula I, wherein the R! a group derived from a tributyl group, an isopropyl group, a propyl group, an isobutyl group, a cyclopropylmethyl group and a cyclopropyl group; and R2 together with the ruthenium atom to which it is bonded form a saturated heterocyclic ring of the formula (a) And Ra is a hydrazine, Rb is a methyl group and Re is a hydrazine. In another specific embodiment, the present invention is a compound of the formula, wherein 0 is a group selected from a propyl group and an isobutyl group. a group of a cyclobutyl group, a cyclopentyl group and a cyclopropylmethyl group; R2 and R3 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group of the formula (a); and the Ra system represents η, Rb Methyl is represented and Re represents hydrazine. In another embodiment, the invention relates to a compound of formula I, wherein R represents a group selected from the group consisting of a tributyl group, an isopropyl group and a cyclopropyl group; And R3 together with the N atom to which it is bonded form a saturated heterocyclic group of the formula (a); and Ra represents Η, Rb represents a methyl group and Re represents Η. 另一 In another specific embodiment, the present invention A compound of formula I, wherein R represents a group selected from the group consisting of propyl, isobutyl and cyclopropylmethyl; - R2 and R3 together with the N atom to which they are bonded form a saturation of formula (a) a heterocyclic group; and a Ra system represents a fluorene, Rb represents a methyl group and a Re represents a hydrazine. In another embodiment, the invention relates to a compound of formula I, wherein R1 represents a C2-8 fenyl group. Is a C2-5 yard group, and more preferably a group selected from the group consisting of a tributyl group, an isopropyl group, a propyl group and an isobutyl group; and R2 and R3 together with the N atom to which they are bonded form a formula (a) Saturated heterocyclic group; and -48- 200936570

The Ra system represents hydrazine, Rb represents a methyl group and Rc represents hydrazine. In another embodiment, the invention relates to a compound of formula I, wherein R! represents C3_7 cycloalkyl-Cm alkyl, preferably C3.7 cycloalkyl-C!, and more preferably cyclopropyl. The methyl group; R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group of the formula (a); and the Ra system represents Η and the Rb represents methyl and R. The system indicates Η. In another embodiment, the present invention relates to a compound of the formula: wherein Ri represents a c3-7 cycloalkyl group, and preferably a cyclopentyl group, a cyclobutyl group and a cyclopropyl group; and R2 and R3 together with the bond thereof The N atoms of the knot together form a saturated heterocyclic group of the formula (a); and the Ra system represents hydrazine, the Rb group represents a methyl group and the Re system represents hydrazine. Moreover, the present invention encompasses all possible combinations of the particular and preferred embodiments described above for the compounds of formula I. In a further embodiment, the invention relates to a compound of formula I selected from the group consisting of: Ο 4-(cyclopropylmethyl)-6-((3R)-3-(methylamino)pyrrolidine-1- 4-pyrimidin-2-amine; • 4-cyclopropylmethyl-6-(3-(methylamino)nitroso-oxime-pyrimidine-2-amine; 4-cyclopropylmethyl-6 -((3R)-3-aminopyrrolidin-1-yl)pyrimidin-2-amine; 4-cyclopropylmethyl-6-(piperidinyl)purine-2-amine; 4-ring Propylmethyl-6-(3-methyl-3-(methylamino)azol-1-yl)pyrimidine-2-amine; -49- 200936570 4- (3-Amino nitrogen-n-yl-yl) - 6-cyclopropylmethylpyrimidin-2-amine; 4-cyclopropylmethyl-6-(1,4-diazepin-1-yl)pyrimidine-2-amine; 4- (4-amine 5-piperidin-1-yl)-6-cyclopropylmethylpyrimidin-2-amine; 4-cyclopropylmethyl-6-((4aR,7aR)-octahydropyrrolo[3,4-b] Pyridyl-6-yl)pyrimidin-2-amine; 4-cyclopropylmethyl-6-((3S)-3-(methylamino) succinyl D-l-yl)pyrimidin-2-amine; R) -4-cyclopropylmethyl-6-[(N-methylpyrrolidin-3-yl)amine]pyrimidine-2-amine; (S) -4 -cyclopropylmethyl-6- (3 -Methylindolo-l-yl) Chew--2 - amine; (R) - 4 -cyclopropylmethyl-6- (3 - Base Π and -1 -yl) chews - 2 - amine; 4-cyclopropylmethyl-6- [3-(disc)-1-yl)azin-1-yl]II D疋_2-amine; 4-(cyclopropylmethyl)-6-(six-gas batches of [l,2-a]H than indole-2(1H)-yl)pyrimidin-2-amine (S) -4-(cyclopropylmethyl)-6-(hexaaminopyrene-pyrolo[l,2-a] phage-2 (1H)-yl)pyrimidin-2-amine; 4- Isopropyl-6-(3-(methylamino)azol-1-yl)pyrimidine-2-amine» 4-isopropyl-6-((3R)-3-(methylamino)pyrrole Pyridin-1-yl)pyrimidine-2-amine; 4-tert-butyl-6-(3-(methylamino)nitrol-1-yl)pyrimidine-2- 2-50- 200936570 Amine; 4- Tributyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidine-2-amine; 4-(3-(methylamino)nitrol-l-yl) -6-propylpyrimidin-2-amine; 4-((3R)-3-(methylamino)pyrrolidin-1-yl)-6-propylsulfudidine-2-amine; 4-cyclopropyl -6-(3-(Methylamino)-blocker-1-yl) ketidine-2-amine 0 4 -cyclopropyl-6-((3R)-3-(methylamino)indole比略Β-1-yl)pyrimidin-2-amine; 4-ethyl-6-(3-(methylamino)azin-1-yl) chelate D疋-2-amine; 4-ethyl - 6-( (3R) -3- (Methylamino)pyrrolidin-1-yl)pyrimidine-2-amine; 4-butyl-6-(3-(methylamino)azol-1-yl)pyrimidine-2-amine; 4-butyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidine D-but-2-amine; '4-cyclopentylmethyl-6-(3- (Methylamino)nitrol-l-yl)pyrimidine- "2-amine; 4-cyclopentylmethyl-6-((3R)-3-(methylamino)D ratio slightly steeper-1_ 4-pyrimidin-2-amine; 4-isobutyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine; 4-isobutyl-6- (3-(Methylamino)nitrol-l-yl)pyrimidin-2-amine-51 - 200936570 4-(2,2-Dimethylpropyl)-6-( (3R) -3-(A Amino)pyrrolidin-1-ylpyrimidin-2-amine; 4-(2,2-dimethylpropyl)-6-(3-(methylamino)azepine-1-yl)pyrimidine -2-amine; trans-4-(2-phenylcyclopropyl)-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyrimidin-2-amine; (R) 4-tert-butyl-6-[(N-methylpyrrolidin-3-yl)amine]pyrimidine-2-amine; 4-(2-cyclopentylethyl)-6-((3R)- 3-(methylamino)pyrrolidin-1 -yl)pyrimidin-2-amine; 4-(2-cyclopentylethyl)-6-(3-(methylamino)methane-1-yl Pyrimidine-2-amine; 4-(2-cyclopropylethyl)-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyrimidin-2-amine; 4-( (311)-3-(methylamino)[1 to slightly 11疋-1-yl)-6-(4-methylpentyl)pyrimidin-2-amine; 4-(3-(methylamino) Nitrozol-1-yl)-6-(4-methylpentyl)pyrimidine-2-amine; 4-(3-cyclopentylpropyl)-6-((3R)-3-(A) Amino)pyrrolidin-1 -ylpyrimidin-2-amine; 4-(4-cyclohexylbutyl)-6-((3R)-3-(methylamino)pyrrolidine-1 yl) Pyrimidine-2-amine; 4-(4-cyclohexylbutyl)-6-(3-(methylamino)azol-1-yl)pyrimidine-2-amine; -52- 200936570 (S) -4 -(2-cyclopropylethyl)-6-(3-methylpiperazin-1-yl)pyrimidin-2-amine; 4-(3-Amino-nitrol-l-yl)-6-( Cyclopentylmethyl)pyrimidine-2-amine> 4-(3-(methylamino)nitrol-l-yl)-6-(2,2,3,3-tetramethylcyclopropyl) Pyrimidine-2-amine; 4-cyclobutyl-6-(3-(methylamino)azepin-1-yl)pyrimidine-2-amine oxime 4-cyclopentyl-6-(3-(methyl Amino)nitrol-l-yl)pyrimidin-2-amine 4-((3R)-3-(methylamino)indole succinimide-1-butyl)-6-( 2,2,3, 3-tetramethylcyclopropyl)pyrimidin-2-amine 4- 4-Isobutyl-6-(3-methyl-3-(methylamino)azol-1-yl)pyrimidine-2-amine; 4-(3-methyl-3-(methylamine) (N)-ytyl-1-yl)-6-neopentyl pyrimidine-2-amine; '(S)-4-(3-methylpiperazin-1-yl)-6-neopentylpyrimidine -2 -amine; '4-(3-(methylamino)azol-l-yl)-6-(1-methylcyclopropyl)pyrimidin-2-amine; (R)-4-(cyclo) Propylmethyl)-6-(hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl)pyrimidin-2-amine; 4-cyclopentyl-6-(3-methyl- 3-(methylamino)nitrol-l-yl)pyrimidine-2-amine; 4-cyclobutyl-6-(3-methyl-3-(methylamino)nitrol-1-yl) Pyrimidine-2-amine; 4-(3-methyl-3-(methylamino)azol-1-yl)-6-(2,2,3,3-tetramethylcyclo) Propyl)pyrimidine-2-amine; (S)-4-(3-methylpiperidino-1-yl)-6-(2,2,3,3-tetramethylcyclopropyl)pyrimidine-2 -amine; 4-(3-(methylamino)azol-1-yl)-6-(pentan-3-yl)pyrimidin-2-amine; _ 4-((3R)-3-(A Amino)pyrrolidin-1-yl)-6-(pentane-3-oxa)pyrimidine-2-amine; 4-((1S,2S,4S)-bicyclo[2.2.1]heptane-2 -yl)-6-(3.(methylamino)nitrol-l-yl)pyrimidine -2-amine; and 4-((1S,2R,4S)-bicyclo[2.2.1]heptan-2-yl)-6-(3-(methylamino)azol-1-yl)pyrimidine 2-amine. In additional embodiments, the present invention provides for histamine Η4 receptor activity at 1 〇μΜ, more preferably 1 μΜ and more preferably 0.1 μΜ in an H4 receptor binding assay (such as described in Example 64). 50% inhibited compound of formula I. In another embodiment, the invention relates to a compound of formula VI, wherein Rr represents Ci-6 alkyl' and is preferably isobutyl. In another embodiment, the invention relates to a compound of formula VI, wherein RV represents C3-7 cycloalkyl-Cualkyl. In another embodiment, the invention relates to a compound of formula VI wherein R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group which may be a 4- to 7-membered monocyclic ring, 7- To 8-membered bridged bicyclic or 8- to 12--54-200936570 shelled bicyclic ring, wherein the heterocyclic group may contain up to two N atoms and does not contain any other heteroatoms, and may optionally pass one or more Substituents independently selected from d-4 alkyl and NR a R b are substituted by the restriction that the heterocyclic group contains 2 N atoms and is not substituted by an NRaRb group, or contains 1 n atom and Substituted by the NRaRb group. In another embodiment, the invention relates to a compound of formula VI, wherein Ra and Rb independently represent hydrazine or (^_4 alkyl. 0 In another embodiment, the invention relates to a compound of formula VI, wherein Ra And Rb represents independently hydrazine or methyl. In another embodiment, the invention relates to a compound of formula VI, wherein R2 and R3 together with the hydrazine atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of:

-55- 200936570 wherein Ra and Rb have the meanings of the above compounds of formula I, and Rc represents hydrazine or Ci.4 alkyl. In another embodiment, the invention relates to a compound of formula VI, wherein R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group selected from (a) and (b). In another embodiment, the invention relates to a compound of formula VI, wherein R 2 and R 3 together with the N atom to which they are bonded form a saturated heterocyclic group selected from (a) and (b), and Ra, Rb and Re is independently represented by hydrazine or Cm alkyl, and is preferably Ra, Rb and Re independently represents hydrazine or methyl. In another embodiment, the invention relates to a compound of formula VI, wherein R2 and R3 together with the argon atom to which they are bonded form a saturated heterocyclic group of formula (a)

(8) wherein Ra and Rb have the meanings of the compounds of the above formula I and the Re represents 11 or C^-4 alkyl groups, and preferably Ra, Rb and R. It is independently represented by hydrazine or Cm alkyl group and more preferably Ra, Rb & Re is independently represented by hydrazine or methyl group. In another embodiment, the invention relates to a compound of formula VI, wherein R2 and R3 together with the hydrazine atom to which they are bonded form a saturated heterocyclic group of formula (b) -56-200936570

(b) ό wherein Ra and Rb have the meaning of the compound of the above formula I, and R. It means Η or Cm alkyl, and preferably Ra, Rb and Re each independently represent hydrazine or C!-4 alkyl, and more preferably Ra, Rb and Rc independently represent hydrazine or methyl, and more preferably Ra and Rb independently represent hydrazine or methyl and R. It is η. In another embodiment, the invention relates to a compound of formula VI, wherein R2 represents hydrazine or 0-4 alkyl and R3 represents a hydrazinyl, pyrrolidinyl, piperidinyl or aziridine group, It may be optionally substituted by one or more Ci-4 alkyl groups, and preferably R2 represents hydrazine and R3 represents 1-methyl-pyrrolidole-3-yl. In another embodiment, the invention relates to a compound of formula VI, wherein RT represents 1.6 alkyl, preferably isobutyl; and R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group It may be a 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic ring wherein the heterocyclic group may contain up to two N atoms and does not contain any other a hetero atom, and optionally substituted by one or more substituents independently selected from the group consisting of Ci.4 alkyl and NRab, with the proviso that the heterocyclic group or containing 2 N atoms and not -57-200936570 via NRaRb The group is substituted with 'or contains 1 n atom and is substituted with one NRaRb group. In another embodiment, the invention relates to a compound of formula VI, wherein Ri' represents a Cu alkyl group, preferably an isobutyl group; Together with the N atom to which it is bonded, a saturated heterocyclic group selected from (a) to (h) wherein Ra, Rb and Re have the aforementioned meanings, and preferably Ra, Rb and Re independently represent 11 or Cm The alkyl group, and more preferably Ra, Rb and Rc, independently represents a hydrazine or a methyl group.另一 In another embodiment, the invention relates to a compound of formula VI, wherein Ri' represents ci-6 alkyl, preferably isobutyl; and R2 and R3 together with the N atom to which they are bonded are selected From the saturated heterocyclic groups of (a) and (b), wherein Ra, Rb and R. In the above sense, it is preferred that Ra, Rb and Re independently represent H or a home base and more preferably Ra, Rb and RC independently represent fluorene or methyl. In another embodiment, the invention relates to a compound of formula VI, wherein R1 ' represents ¢-6 alkyl, preferably isobutyl; and R2 and R3 are attached together with the N atom to which they are bonded A saturated heterocyclic group 'of the formula (a)' wherein Ra, Rb and R are formed. It is independently indicated that H or ci-4 alkyl' and preferably Ra _ , Rb and Rc independently represent H or methyl. In another embodiment, 'the present invention relates to a compound of formula VI' wherein Ri' means that Ci.6 is preferably an isobutyl group; and R.2 and R.3 together with the N atom to which it is bonded Together, a saturated heterocyclic group of the formula (b) is formed, wherein Ra, Rb and R are. It is independently represented by H or Ci-4 alkyl' and preferably Ra, Rb and R. It is independent of H or methyl group and more preferably Ra and Rb is -58-200936570 stands for hydrazine or methyl group and Rc stands for hydrazine. Moreover, the invention includes all possible combinations of the specific and preferred embodiments described above for the compounds of formula VI. In a further embodiment, the invention relates to a compound of formula VI selected from the group consisting of 4-(2-cyclopentylethynyl)-6-(3-(R)-3-(methylamino)pyrrolidine -1-yl)pyrimidin-2-amine; 0 4-(2-cyclopentylethynyl)-6-(3-(methylamino)azol-1-yl)pyrimidine-2-amine; 4- (2-cyclopropylethynyl)-6-(3-(R)-3-(methylamino)pyrrolidin-1 -yl)pyrimidin-2-amine; 4-(2-isobutylethynyl) -6-(3-(R)-3-(methylamino) 'pyrrolidin-1 -yl)pyrimidin-2-amine; 4-(2-isobutylethynyl)-6- (3- (methylamino)azin-1-ylpyrimidin-2-amine; Φ 4-(4-cyclohexyl-1-butynyl)-6-(3-(11)-3-(methylamine) Pyrrolidin-1-ylpyrimidin-2-amine; • 4-(4-cyclohexyl-1-butynyl)-6-(3-(methylamino)nitroso-l-yl)pyrimidine 2-amine; 4-(3-cyclopentyl-1-propynyl)-6-(3-(R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine And (s) -4-(2-cyclopropylethynyl)-6-(3-methylpiped-1-yl)pyrimidine-2-amine. In additional embodiments, the invention is directed to H4 receptor binding assays (such as described in Example 64)! 〇 μΜ, more preferably 1 μΜ and yet -59- 200936570 more preferably 0·1 μΜ of a compound of formula VI which provides 50% inhibition of histamine H4 receptor activity. The compounds of the present invention contain one or more basic nitrogens and thus form salts with organic or inorganic acids. Examples of such salts include, inter alia, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; and organic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, B. Alkane sulfonic acid, benzene acid expansion, p-toluene acid expansion, butyl succinic acid, oxalic acid, acetic acid, cis-succinic acid, ascorbic acid, citric acid, lactic acid, tartaric acid, malonic acid, ethanolic acid, succinic acid and Salt of propionic acid. There are no restrictions on the salts that can be used, as long as they are pharmaceutically acceptable for therapeutic purposes. The term pharmaceutically acceptable salt means that it is applied in accordance with medical judgment for contact with tissues of humans and other animals without undue toxicity, irritation, allergic reactions, and the like. Pharmaceutically acceptable salts are well known in the art. Salts of the compounds of formula I may be prepared during the final isolation and purification of the compounds of the invention, or may be prepared in a conventional manner by a sufficient amount of the desired acid treatment of the compound. The salt of the compound of formula I can be converted to another salt of the compound of formula I by ion-exchange using an ion exchange resin. - The compounds of the formula I and their salts may differ somewhat in their 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. 化合物 The compounds of the invention may form complexes with solvents which are reacted in or precipitated or crystallized from the solvent. These complexes are referred to as solvates. The term solvate as used in the present invention denotes a complex stoichiometric complex formed from a solute (compound of formula I -60-200936570 or a salt thereof) and a solvent. Examples of the solvent include pharmaceutically acceptable solvents such as water, ethanol, and the like. The complex with water is called a hydrate. The solvate ', including hydrates, of the compound of the present invention (or a salt thereof) is included in the scope of the present invention. The compounds of formula I may exist in different physical forms, i.e., amorphous and crystalline. Moreover, the compounds of the invention may have the ability to crystallize in more than one form, a feature known as polymorphism. Polymorphs can be distinguished by various physical properties well known in the art, such as X-ray diffraction patterns, melting points or solubility. All physical forms of the compounds of formula I, including all polymorph forms ("polymorphs"), are included within the scope of the invention. Certain compounds of the invention may exist in several optical isomers and/or in several non-image isomer forms. The non-image isomers can be separated by conventional techniques such as chromatography or partial crystallization. Optical isomers can be segregated by conventional techniques of optical resolution to produce optically pure isomers. Such isolation can be carried out on any of the palm-forming synthetic intermediates or the products of formula I. Optically pure isomers can also be prepared by mirror-specific synthesis. The present invention encompasses all individual isomers and mixtures thereof (e.g., mixtures of racemic or non-image areomers), whether by synthesis or by physical mixing. Compounds of formula I can be prepared by following the methods described below. As will be apparent to those skilled in the art, the exact method used to prepare a particular compound may vary depending on its chemical structure. Moreover, in some of the following methods, it may be desirable or desirable to protect the reactive or unsettled groups with conventional protecting groups. The nature of such protection groups and their methods of introduction or removal are well known to the art (see, for example, Greene T.W. and Wuts P.G.M, "Protective Groups in 200936570

Organic Synthesis", John Wiley & Sons, 3rd edition '1999). Unless otherwise stated, in the following methods, the meaning of the different substituents is as previously described for the compound of formula I. Typically, Formula I The compound can be obtained by reacting a compound of the formula 11 with a hydrazine compound as shown in the following scheme.

Wherein R!, R2 and R3 have the meanings previously described for the compound of formula I. b represents a leaving group such as a halogen atom or a triflate. A reaction between the compounds of formula II and III can be carried out using a coupling agent such as, for example

PyB〇p (benzotriazol-1-yl-oxytripyrrole rust)) suitable solvent (such as I,4-dioxane, tetrahydrofuran, dichloromethane, N'N~A) Mercaptoamine or acetonitrile, preferably in acetonitrile) in the presence of a base (such as hydrazine, hydrazine-diisopropylethylamine, dimethylaniline, diethylaniline or monoethylamine) preferably triethyl The amine is carried out. The reaction can be carried out at a temperature comprised between room temperature and reflux at a temperature between -62 and 200936570. Alternatively, a compound of formula I can be prepared by reacting a hydrazine compound with a reactive derivative (IIB) of a compound of formula II by converting a hydroxy group present in the compound of formula II to a cleavage group (such as It is obtained by a halogen atom or a triflate, preferably chlorine. The -OH group derived from the compound of formula II can be reacted with a halogenating agent such as POC13 in the presence of a random appropriate solvent, or in a suitable solvent such as 0 1,4-dioxane or 1,2-dichloroethane. In the presence of a mixture with P0C13/PC15 or N,N-dimethylformamide/grass chloride, it is converted to a leaving group such as a halogen atom, preferably chlorine. The reaction is carried out by heating preferably at a temperature between 100 ° C and 140 ° C. Similarly, the hydroxyl group of the compound of formula II can be converted to the trifluoro 'methanesulfonate group by reaction with trifluoromethanesulfonic anhydride in the presence of pyridine. The resulting reactive derivative (IIB) of the compound of formula II is then reacted with a compound of formula III to yield a compound of formula I. The reaction is carried out in a suitable solvent such as ethanol, methanol, butanol, hydrazine, hydrazine-dimethylformamide, dimethyl 'arylene, tetrahydrofuran or toluene, preferably ethanol. Including the presence of a mechanamine, especially such as triethylamine, hydrazine, hydrazine-diisopropylethylamine, dimethylaniline and diethylaniline, preferably comprised between 50 and 100 °C. Execution by heating at a temperature. Heating may be carried out by heating or by microwave irradiation at a wattage which allows the temperature mentioned above. Generally, the amine substituent of the compound of formula III is first protected against the formation of by-products prior to the reaction between formula II and III or the compound of IIB and III. Similarly, the amines of the compounds of formula II and IIB can be protected, if desired, from the amines -63 to 200936570. Any suitable protecting group can be used, such as, for example, a third butoxycarbonyl (Boc) group. When an amine substituent of the formula / and/or III and/or IIB compounds is protected, a subsequent deprotection step may be required, which is carried out under standard conditions. When the protecting group is Boc, the deprotection can be carried out by adding a strong acid such as HCl in a suitable solvent such as 1,4-dioxane, diethyl ether or methanol or a solution of trifluoroacetic acid in dichloromethane. It is carried out directly on the obtained crude product. The compound of formula III is commercially available or can be prepared by methods described in the literature. The compound of formula II can be prepared by reacting a compound of formula IV with a phosphonium salt, preferably a hydrochloride salt, as shown in the following scheme:

Where Ri has the meaning described in Formula I. The reaction is carried out in the presence of a base such as potassium carbonate, sodium butoxide or sodium ethoxide, preferably sodium methoxide, in a suitable solvent, preferably ethanol. The reaction can be carried out by heating at a suitable temperature usually between room temperature and reflux temperature, preferably under reflux. The compound of the formula IV is commercially available or can be easily obtained from a commercially available compound by a known method (see, for example, Journal of Organic Chemistry 2000, 8402 and Tetrahedron Letters 1991, 773 1 ). Or a compound of formula I wherein Ri represents R1, _CH2-CH2 (-64-200936570, a compound of formula I') can be prepared by reduction of a compound of formula VI, as shown in the following scheme =

Nr2r3

Wherein RV represents a Cu alkyl group or a C3_7 cycloalkyl-C〇-2 alkyl group, wherein the c3.7 cycloalkyl group is optionally independently selected from one or more selected from the group consisting of (:, -4 alkyl, phenyl and Substituted by a fluorine substituent; and R2 and R3 have the meaning of the above compound of formula I. ' The reaction is preferably from a hydrogen source (preferably in gaseous form (H2)) and a metal catalyst (preferably homogeneous or The reducing medium consisting of a heterogeneous form of palladium, and more preferably Pd/C), is carried out in a suitable solvent such as, for example, methanol or hydrazine ethanol. The reaction can be carried out usually at room temperature and reflux temperature. This is preferably carried out by heating at a suitable temperature, preferably at room temperature. • Typically, a compound of formula VI can be prepared by reacting a compound of formula V with a compound of formula III as shown in the following scheme:

-65- 200936570 wherein Rl' has the aforementioned meaning and R2 and R3 have the meanings as defined for the compound of formula 1. The reaction can be carried out in the presence of a base (including organic amines such as, in particular, pyridine, triethylamine, ν, ν-diisopropylethylamine, dimethylaniline and diethylaniline) in a suitable solvent (such as ethanol, This is carried out by heating in methanol or butanol, preferably at reflux temperature. In the same manner as previously described for the synthesis of the compound of formula I, the amino substituent of the compound of formula III is protected to avoid the formation of by-products, followed by the reaction between the compounds of formula V and III (reaction between the compounds of formula II and III above) . Similarly, the amine group of the compound of formula V can also be protected if desired. When the amine substituent of the compound of formula III and/or V is protected, a subsequent deprotection step may be required, which is carried out under standard conditions. The formula ν can be obtained by a coupling reaction of an alkyne of the formula VII with a commercially available 2-amino-4,6-dichloropyrimidine, as shown in the following scheme:

Where RT has the aforementioned meaning. The reaction can be carried out under conditions of Sonogashira in triphenylphosphine, a copper catalyst (I) such as Cul as a secondary catalyst, and a base such as, for example, N,N_200936570 such as, for example, tetrakis(triphenylphosphine)palladium(0) ( Pd(PPh3)4) or bis(triphenylphosphine)dichloropalladium(Π) (Pd(Ph3P)2Cl2)) is carried out. The reaction is usually carried out under anhydrous and anaerobic conditions. The reaction can be carried out by heating in a solvent such as dioxane, N,N-dimethylformamide, toluene, preferably in tetrahydrofuran, and at a temperature usually comprised between 60 ° C and 100 ° C. The compound of formula VII is commercially available or can be prepared from commercially available compounds using standard methods. Further, some of the compounds of formula I or VII can be prepared from other compounds of formula I or VI by standard reaction conditions, under appropriate standard conditions, by one or more suitable functional group conversion reactions. As mentioned above, the compounds of the invention exhibit potent histamine 受4 receptor antagonistic activity. Thus, the compounds of the invention are expected to be useful in the treatment of diseases mediated by the Η4 receptor in mammals, including humans. Diseases which can be treated using the compounds of the formula I and VI of the invention include, inter alia, allergic, immunological or inflammatory diseases or pain. Examples of allergic, immunological or inflammatory diseases which may be treated with a compound of the invention include, without limitation: respiratory diseases such as asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD); ocular diseases such as Allergic rhinoconjunctivitis, dry eye and cataract; skin diseases such as dermatitis (eg atopic dermatitis), psoriasis, urticaria and itching; inflammatory bowel disease, such as ulcerative colitis and Crohn's disease; rheumatoid Arthritis; multiple sclerosis; cutaneous lupus; systemic lupus erythematosus; and transplant rejection. Examples of pain conditions that can be treated using the compounds of the invention include, inter alia, inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-operative pain, -67-200936570 migraine, cancer pain, visceral pain, osteoarthritic pain, and neuropathic pain . In a preferred embodiment, the compounds of the invention are used to treat allergic, immunological or inflammatory diseases. In a more preferred embodiment, the compound of the present invention is for the treatment of an allergic, immunological or inflammatory disease selected from the group consisting of respiratory diseases, eye diseases, skin diseases, inflammatory bowel diseases, rheumatoid arthritis. , multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection. In still further preferred embodiments, the allergic, immunological or inflammatory disease is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataract, skin. Inflammation (eg atopic dermatitis), psoriasis, urticaria, itching, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection . In another preferred embodiment, the compounds of the invention are used to treat pain, preferably inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-operative pain, migraine, cancer pain, visceral pain, bone and joint Inflammatory pain or neuropathic pain. * Detection of the ability of a compound to interact with histamine H4 receptors is well known in the art. For example, H4 receptor binding assays can be used, such as those detailed in Example 64. Another test that can be used is the binding assay of GTP[Y-35S] to membranes exhibiting H4 receptors. Functional assays of H4 receptor-expressing cells can also be used, for example in systems that measure the activity of any kind of cell mediated by a second messenger associated with the H4 receptor, such as intracellular cAMP levels or Ca2+ activity. effect. Another function that can be used -68-200936570 is a selective controlled spontaneous fluorescence forward scatter detection (GAFS) for eosinophils (eg, human eosinophils), such as described in detail in Example 65; It is well known to the skilled artisan (see, for example, the method disclosed by Buckland KF et al., 2003, previously incorporated herein by reference in its entirety). In vivo assays which can be used to test the activity of the compounds of the invention are also well known in the art (see, for example, various literature references listed in the in vivo animal models of the prior art section, especially regarding n peritonitis, pleurisy, allergic asthma, inflammatory bowel disease). In vivo models of atopic dermatitis and itching, all references are incorporated herein by reference. When the active compound is selected, the 10 μΜ test must produce an activity that inhibits more than 50% of the Η4 receptor activity in the test provided in Example 64. More preferably, the compound should exhibit greater than 50% inhibition at 1 μ ,, more preferably 〇 1 μΜ. The invention also relates to a pharmaceutical composition comprising a Formula I or VI compound (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients. The excipient must be "acceptable" in its ability to be compatible with the other ingredients of the composition and to not harm the subject. The compounds of the present invention can be administered in the form of any pharmaceutical formulation, the properties of which are well known, depending on the nature of the active compound and the route of administration. Any route of administration can be used, such as oral, parenteral, nasal, ocular, topical, and rectal administration. Solid compositions for oral administration include medicinal preparations, granules and capsules. In either case, the method of manufacture is based on the simple mixing of the active compound with the excipient - 69-200936570, dry granulation or wet granulation. Such excipients may be, for example, diluents such as lactose, microcrystalline cellulose, mannitol or dibasic calcium phosphate; binders such as, for example, starch, gelatin or putopurine; disintegrants such as sodium carboxymethyl starch Or croscarmellose sodium; and a lubricant such as, for example, magnesium stearate, stearic acid or talc. Tablets may be additionally coated with suitable excipients by known techniques to delay their disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time, or simply improving their organoleptic properties or their stability. ^ The active compound can also be incorporated by application of a natural or synthetic film coating to the inert sheet n particles. It may also be a soft gelatin capsule in which the active compound is mixed with a water or oily vehicle such as coconut oil, mineral oil or olive oil. Powders and granules for preparing an oral suspension by adding water can be prepared by mixing the active compound with a dispersing or wetting agent, suspension and preservative. Other excipients such as sweeteners, flavoring agents, and coloring agents may also be added in liquid form for oral administration including inert diluents generally used (such as pure water, ethanol, sorbitol, glycerin, polyethylene glycol). (乳液macrogols) and propylene glycol) emulsions, solutions, suspensions, syrups and mashes. These compositions may also contain adjuvants such as wetting agents, suspending agents, sweetening agents, flavoring agents, preservatives, and buffering agents. The injectable preparation for parenteral administration of the present invention comprises a sterile solution, suspension or emulsion in an aqueous or nonaqueous solvent such as propylene glycol, polyethylene glycol or vegetable oil. These compositions may also contain adjuvants such as wetting agents, emulsifying agents, dispersing agents and preservatives. It can be sterilized by any known method or prepared as a sterile solid composition which is dissolved in water or any other sterile injectable medium -70-200936570 immediately prior to use. It can also be started from sterile materials and maintained under these conditions throughout the process. The compounds of the invention may also be formulated for topical administration to treat conditions such as the eye, skin and gastrointestinal tract that occur in areas or organs accessible through the path. Formulations include creams, lotions, gels, powders, solutions and dressings in which the compound is dispersed or dissolved in a suitable vehicle. When administered nasally or by inhalation, the compound can be formulated into an aerosol so that the compound can be easily released from it with a suitable propellant. Among other factors, the dosage and frequency of administration depend, inter alia, on the nature and severity of the condition to be treated, the age, general condition and weight of the patient, as well as the particular compound being administered and the route of administration. For example, a suitable dosage range will range from about 0.01 mg/kg to about 100 mg/kg per day, and can be administered in single or divided doses. [Embodiment] The present invention will be described by way of the following examples. EXAMPLES The following abbreviations were used in the examples: AcN: acetonitrile EtOAc: ethyl acetate n-BuOH: 1-butanol c ο n c : concentrate DIEA: hydrazine, hydrazine-diisopropylethylamine -71 - 200936570

EtOH : ethanol g : gas MeOH : methanol

PyBOP: hexafluorophosphate (benzotriazol-1-yloxy)tripyrrolidinium scale TEA: triethylamine tR: residence time LC/MS: liquid chromatography-mass spectrometry 6 LC-MS was determined using one of the following methods Spectrum: Method 1: X-T erra MSC 1 8 5 μ m (1 0 0 mm X 2.1 mm) column, temperature: 30 ° C, flow rate: 0.35 mL/min, eluent: A = AcN, B = NH4HC03 10 mM, gradient: 0 min A is 10%; 10 min A is 90%; 15 min A is 90%. · Method 2 : Ac quity UPLC BEH C 1 8 1,7 μιη (2.1x50 mm) column, temperature: 40 ° C, flow rate: 0.50 mL / min, dissolving agent: A =

AcN, B = NH4HC03 10 mM, gradient: 〇 min A is 10%; 0.25 〇 m i n A is 10%; 3 · 0 0 m i n A is 90%; 3 · 7 5 m i n A is 90%.

Reference Example 1 A methyl [(3R)-pyrrolidin-3-yl]carbamic acid tert-butyl ester [(3R)-1-benzylpyrrolidin-3-yl]methylaminocarbamic acid tert-butyl ester Di-tert-butyl dicarbonate (11.6 g, 53.07 mmol) dissolved in 15 mL of CH2C12 was added to (3R)-1-pyryl-N-methyl-U-pyrrol-3-amine (10 g, 52.55 mmol) dissolved in 115 mL CH2CI2 at 0 ° C in a solution of 72-200936570. The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated, and the crude product was purified from silica gel using EtOAc/EtOAc EtOAc (EtOAc) LC-MS (method 1): tR = 9.55 min; m/z = 291 (MH + (b)

^ Compound obtained in the previous step (14.5 g, 50.14 mmol), Pd/C (10%, 50% in water) (3 g) and ammonium formate (1 2.7 g, 2 0 0.5 mmol) in MeOH (390 The mixture in mL) and water (45 mL) was heated under reflux for 5 h. The reaction was filtered through celite <RTI ID=0.0></RTI> and the residue was washed with EtOAc and MeOH. The solvent was evaporated to dryness to give the title compound (yield: 100%). *H NMR (3 00 MHz, CDC13) 6 : 1 · 3 8 (s, 9 Η), 1 · 72 (m, 1H), 1.96 (m, 1H), 2.53 (s, NH), 2.80 (s, 3H), 2.87 (m, 1H), ❹ 2.93 (m, 1H), 3.1 l (m, 2H), 4.58 (m, 1H).

• Reference Example 1 B-Methyl [(3S )-pyrrolidin-3-yl]carbamic acid tert-butyl ester The title compound was prepared in a manner similar to that described in Reference Example 1 A, but using the corresponding (S) mirror image. The isomer is used as the starting material. *H NMR (3 00 MHz, CD C13) δ : 1.4 6 (s, 9H), 1.71 (m, 1H), 1.77 (s, NH), 1.96 (m, 1H), 2.76 (m, 1H), 2.78 (s, 3H), 2.89 (m, 1H), 3.06 (m, 2H), 4.61 (m, 1H). -73- 200936570 Reference Example 2 T-butyl 3-methyl 3-methyl (meth) carbazate [1-( benzylmethyl) nitro-l-yl] methyl carbamic acid tert-butyl ester Replacing (3R) benzyl-N-methylpyrrolidin-3- with 1-(diphenylmethyl)-N-methylazide-3-amine according to the procedure described in section a) of Example 1A Amine, the desired compound was obtained in a yield of 73%. LC-MS (method!): tR = w. 14 min; m/z = 3 5 3 ( MH - (b) Compound of the previous compound (6.18 g, 17.53 mmol) in 60 mL MeOH and 15 mL The solution in EtOAc was ventilated with argon. Pd/C (10% in water, 50%) (929 mg) was added and the solution was then ventilated with argon and stirred in H2 atmosphere for 18 hours. The soil was filtered and the residue was washed with EtOAc EtOAc EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj (s, 9 Η), 2 · 8 8 (s, 3H), 3.56 (m, 2H), 3.71 (m, 2H), 4_75 (m, 1H). Reference Example 3 (4aR, 7aR)-octahydro- 1 H-pyrrolo[3,4-b]pyridine-1 -carboxylic acid tert-butyl ester (4aR, 7aR-6-benzyl octahydro-1 Η-pyrrole [3.4-b]pyridine-1 -carboxylic acid tert-butyl 200936570 The ester will be dissolved in CH2C12 (2 mL) in triethylamine (0.95 mmol) and di-tert-butyl dicarbonate (0.75 3.42 mmol) R,R) -6-benzyloctahydropyrrolo[3.4-b Pyridine (0.9@,3· in CH2C12 (9 mL) in a solution. Chromatography, using a polar gradient / EtOAc mixture as the eluent to provide 0.79 g of 詈Q yield: 72%). LC-MS (Method 2): tR = 2.94 min; m/z = (b) The compound obtained in the compound portion (0.79 g, 2.49 mmol) in MeOH was ventilated with argon. Pd/C (10%, y) (157 mg) was added and the solution was ventilated with argon and hydrated overnight. The reaction was filtered through celite 2.0 and the residue was evaporated to dryness eluting with MeOH &quot; solvent to afford the desired compound of 0.61, the maximum mass of the piano ' LC-MS (method 2): tR = 1.29 min; m/z = reference Example 4 3_Methylazol-3-yl(methyl)aminocarbamic acid tert-butyl ester [1-(diphenylmethyl)-3-methylazpor-3-yl]methylamino ester mL, 6.84 Add to (1 mmol) and mix overnight. Add hexane compound (3 1 7 (MH + in 50% water in 10 0 %, stir in the mixture. Will: 0 227 (MH + acid third) -75- 200936570 The method described in section a) of Example 1A, but substituted with (1-R)-N,3-dimethylazetid-3-amine (3R)-1-benzyl -N-methylpyrrolidine-3-amine to give the desired compound in maximum yield. lU NMR (3 00 MHz, CDC13) 6 : 1.53 (s, 12H), 2.59 (s, 3H), 2.89 (m, 2H), 3.16 (m, 2H), 4.30 (s, 1H), 7.17 (m, 1H), 7.26 (m, 2H), 7.42 (m, 1H). (b) The title compound (6.06 g, 16.5 mmol). Pd/C (10%) (8 14 mg) was added and the mixture was ventilated with argon and stirred overnight in H.sub.2 atmosphere. The reaction was filtered through celite <RTI ID=0.0></RTI> and the residue was washed with EtOAc and MeOH. The solvent was evaporated to dryness to give a mixture of 4.55 g of the title compound and the same equivalent of diphenylmethane, which was used in the next step. 4 NMR (300 MHz, CDC13) S: 1.45 (s, 12H), 2.67 (s, 3H), 3.28 (m, 1H), 3.61 (m, 1H), 3.87 (m, 1H), 4.00 (m, 1H) ❹ Reference Example 5 (R)-1-methylpyrrolidine-3-amine dihydrochloride (R) 1-methylpyrrolidin-3-ylaminocarbamic acid tert-butyl ester formaldehyde 37% aqueous solution ( 1.19 mL, 14.6 mmol) and (subsequent and gradually) sodium borohydride (0.61 g, 16.1 mmol) added to (R)-pyrrolidin-3-ylaminocarbamic acid tert-butyl ester (1·〇g, 5.34 mmol) ) in a solution of 23-76-200936570 mL MeOH. The resulting mixture was stirred at room temperature under argon overnight. The solvent was evaporated and the crude product was dissolved in CH.sub.3, washed with saturated aqueous NaCI and then sat. The organic phase was dried over Na.sub.2.sub.4, and concentrated to dryness to afford the desired compound (yield: 7 9%). !H NMR (3 00 MHz, CDC13) 6 : 1.43 (s, 9H), 1.58 (m, 1H), 2.25 (m, 2H), 2.33 (s, 3H), 2.52 (m, 2H), 2.77 (m) , 1H), φ 4.16 (m, 1H), 4.86 (m, NH). (b) a mixture of the title compound (〇·85 g, 4.25 mmol), 4 Μ HC1 in 1,4-dioxane (40 mL) and MeOH (1 mL). Stir for 1 hour. It is then evaporated to dryness. The crude product is soluble

MeOH and concentrating again to dryness afforded 0.77 g of the title compound. φ *H NMR (300 MHz, CD3〇D) 2.15 (m, 1H), 2.55 (m, 1H), 2.91 (s, 3H), 3.15 (m, 1H), 3.3-3.85 (m, 3H), 4.10 (m, 1H). Reference Example 6 2-Amino-6-cyclopropylmethylpyrimidin-4-ol Toluene hydrochloride (0.46 g, 4.8 mmol) and sodium methoxide (0.26 g, 4-8 mmol) were added to 4-cyclopropyl- A solution of ethyl 3- oxybutyrate (〇· 71 g, 4.2 mmol) in dry ethyl acetate (40 mL) The solvent was evaporated to dryness. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj LC-MS (method 2): tR = 0.85 min; m/z = 166 (MH + NMR </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Ethyl propyl 3- oxybutyrate: Reference example name Starting material method (LC-MS) tR (min) m/z (MH+) 7 2-Amino-6-isopropyl chelate 4. - alcohol 4-methyl-3-oxoxypentanoate 2 0.71 154 8 2-amino-6-tert-butylpyrimidin-4-ol 4,4-dimethyl-3-oxyl Methyl ester 2 1.04 168 9 2-Amino-6-propylpyrimidin-4-ol 3-oxyhexanoic acid ethyl ester 2 0.73 154 10 2-Amino-6-cyclopropylpyrimidin-4-ol 3 - cyclopropyl-3-oxopropionic acid ethyl ester 2 0.63 152 11 2-amino-6-ethylpyrimidin-4-ol 3-oxy valerate methyl ester 2 0.42 140 12 2-amino group- 6-Butylpyrimidin-4-ol 3-oxyheptanoate ethyl ester 2 1.08 168 13 2-Amino-6-cyclopentylmethylpyrimidin-4-ol 4-cyclopentyl-3-oxyl Ethyl butyrate 2 1.32 194 14 trans-2-amino-6-(2-phenylcyclopropyl)pyrimidin-4-ol trans-3-oxy-3-(2-phenylcyclopropyl) Ethyl propionate 2 1.57 228 200936570 15 2-Amino-6-isobutylpyrimidin-4-ol 5-methyl-3-oxyl Ethyl hexanoate 2 1.03 168 16 2-Amino-6-(2,2-dimethylpropyl)pyrimidin-4-ol 5,5-Methyl-3-oxyhexanoic acid ethyl ester 2. 1.18 182 Reference Example 1 7 4-(2-Cyclopentylethynyl)-6-chloropyrimidin-2-amine 4,6-Dichloropyrimidin-2-amine (0.5 g, 3.05 mmol), triphenylphosphine (16) Mg, 0.06 mmol), bis(triphenylphosphine)dichloropalladium(II) (21 mg, 0.03 mmol) and copper telluride (11 mg, 0.06 mmol) were placed in a flask. Add THF-triethylamine 2: 3 The mixture (5.6 mL), the system was inerted in a vacuum/argon cycle (3 times). Finally, cyclopentyl b was added (0.38 mL, 3.35 mmol), and the resulting mixture was heated at 60 ° C for 1 Η. The resulting crude product was purified by chromatography eluting elut elut elut elut elut elut elut elut elut tR = 2.36 min; m/z = 222/224 (MH+). Reference Example 1 8 to 2 1 The following compound was obtained by a method similar to that described in Reference Example P, except that a cyclohexylacetylene was substituted with a suitable starting material: -79- 200936570 Reference Example Starting Material Method (LC-MS) tR (min) m/z (MH^ 18 4-(2-cyclopropylethynyl)-6-chloropyrimidin-2-aminecyclopropylacetylene 2 1.87 194/196 19 4-(3-cyclopentyl-1 -propynyl)-6-chloropyrimidin-2-amine 3-cyclopentyl-1-propyne 2 2.57 236/238 20 4-(4-cyclohexyl-1-butynyl)-6-chloropyrimidine- 2-amine 4-cyclohexyl-1-butyne 2 2.96 264/266 21 4-chloro-6-(4-methyl-1-pentynyl)pyrimidine-2-amine 4-methyl-1-pentyne 2 2.29 210/212 Reference Example 22 4-(2-Cyclopentylethynyl)-6-((3R)-3-(methylamino)-triazin-1-yl)pyrimidin-2-amine (R -1- (2-Amino-6-(2-cyclopentylethynyl)pyrimidin-4-yl)-yt-bromodin-3-yl(methyl)aminocarbamic acid tert-butyl ester. Reference Example 1A The compound (0.18 g, 0.9 mmol) was added to a mixture of the compound obtained in Reference 17 (0.2 g, 0.9 mmol) and DIEA (0.16 g, 0.9 mmol) in EtOH (4 mL). Heat at 1 ° ° C for 24 hours. Make it cold The solvent was evaporated to dryness. The obtained crude product was purified by chromatography eluting with EtOAc (EtOAc) LC-MS (Method 2): m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m The mixture was stirred at room temperature for 3 hours in anhydrous dichloromethane (19.4 mL). The solvent was evaporated to dryness. The pH was adjusted to 9 and the phases were separated. The aqueous phase was re-extracted with chloroform. The combined organic phase was dried over Na 2 SO 4 and concentrated to dryness to afford 0.13 g of the desired compound (yield: 91%). LC-MS (Method 2) : tR = 1.64 min ; m/z = 2 86 (MH + References 23 to 29 The following compounds were obtained in a similar manner to that described in Reference Example 22, but using the appropriate starting materials: Reference Example Name Starting Material Method (LC -MS) tR (min) m/z (MH+) 23 4-(2-cyclopentylethynyl)-6-(3-(methylamino)azol-1-yl)pyrimidin-2-amine Test Example 17 and Reference Example 2 2 1.64 272 24 4-(2-Cyclopropylethynyl)-6-((3R)-3-(methylamino)pyrrole-d-yl) 啼deep-2- Amine Reference Example 18 and Reference Example 1A 2 1.28 258 25 4-((3R)-3-(Methylamino)pyrrolidin-1-yl)-6-(4-methyl-1-pentynyl Pyrimidine-2-amine Reference Example 21 and Reference Example 1A 2 1.59 274 -81 - 200936570 26 4-(3-(Methylamino)nitrol-1-yl)-6-(4-methyl-1- Pentynyl)pyrimidin-2-amine Reference Example 21 and Reference Example 2 2 1.59 260 27 4-(4-Cyclohexyl-1-butynyl)-6-((3R)-3-(methylamino) Pyrrolidin-1-ylpyrimidin-2-amine Reference Example 20 and Reference Example 1A 2 2.17 328 28 4-(4-Cyclohexyl-1-butynyl)-6-(3-(methylamino)nitrogen岨-l-yl)pyrimidin-2-amine Reference Example 20 and Reference Example 2 2 2.18 314 29 4-(3-Cyclopentyl-1-propynyl)-6-((3R)-3-(methyl Amino)pyrrolidinylpyrimidin-2-amine Reference Example 19 and Reference Example 1A 2 1.82 300 Reference Example 3 0 (S) -4-(2-cyclopropylethynyl)-6-(3-methyl The title compound of the peptidin-1-ylpyrimidine-2-amine was prepared according to the method described in part a) of Reference Example 22, but using Reference Example 18 and (S)-2-methylpiped as a starting point. Substance 〇LC -MS (Method 2): tR = 1.29 min; m/z = 2 5 8 (MH + ) ° Reference Example 31 3_(1_methylcyclopropyl)-3-oxyoxypropionate 1-methyl Base cyclopropane carbonyl chloride Add oxalyl chloride (6.7 mL, 77_0 mmol) slowly to 1-methylcyclopropanecarboxylic acid (7.0 g, 70 mmol) in anhydrous dichloromethane (30 mL) at 0 °C In the cooled suspension, 'finally add two drops of DMF ° mixture to room at 200936570 and stir overnight. The solvent was evaporated to dryness, and then evaporated to dryness, and then evaporated to dryness to afford 7.6 g of the desired compound (yield: 92%) which was used in the subsequent synthetic step. (b) title compound butyllithium (152 mL, 1.6 EtOAc in hexanes, 245 mmol) was slowly added to ethyl monomalonate (14.5 mL, φ 122.5 mmol) in anhydrous THF. 306 mL) was taken from a solution of acetone-C 2 in a cooled solution at -78 °C. The bath was removed and the internal temperature was raised to -5 °C. The reaction mixture was then cooled again to -65 °C, then a portion of the obtained compound ( 7.61 g, 64.2 mmol) in THF (10 mL) was added and then stirred at -6 5 ° C for one hour. The temperature is raised slightly and the reaction crude is diluted with water*. The THF was evaporated to dryness. The combined organic phase is dried over Na 2 SO 4 and concentrated to dryness to give the title compound as a crude material. *H NMR (300 MHz, CDC13) 5 : 0.80 (m, 2H), 1.20- • 1.30 (m, 2H + 3H), 1.35 (s, 3H), 3.43 (s, 2H), 4.16 (q, 2H) . Reference Example 3 2 3-Hydroxy-3-(2,2,3,3-tetramethylcyclopropyl)propanoic acid ethyl ester The desired compound was obtained in a procedure similar to that described in Reference 31, but using 2 2,3,3-Tetramethylcyclopropanecarboxylic acid was used as the starting material. *H NMR (300 MHz, CDC13) 6:1 .1 5 -1.3 5 (m, 1H + 3H + -83- 200936570 12H), 3.42 (s, 2H), 4_22 (q, 2H). Reference Example 3 3 Ethyl 4-ethyl-3-oxohexanoate The desired compound was obtained by the method described in part b of the same referenced Example 3, but using 2-ethylbutylphosphonium chloride as a starting point. substance. LC-MS (method 2): tR = 2.28 min; m/z = 185 ( ΜΗ ) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Ethyl propyl-3- oxybutyrate: Reference example name Starting material method (LC-MS) tR (min) m/z (MH+) 34 2-Amino-6-cyclopentylpyrimidine-4- Ethyl 3-cyclopentyl-3-indolyl propionate ethyl ester 2. 1. 180 180 35 2-Amino-6-cyclobutylpyrimidin-4-ol 3-cyclobutyl-3-oxopropoxylate 2 0.89 166 36 2-Amino-6-(bicyclo[2.2.1]hept-5-en-2-yl)pyrimidin-4-ol (mixture of exo and endo isomers) 3-(bicyclo[ 2.2.1] Gh-5-hydroxy-2-propionate ethyl ester (mixture of exo and endo isomers) 2 1.17 + 1.25 204 37 2-Amino-6-( 1-Methylcyclopropyl)pyrimust-4-ol Reference Example 31 2 1.03 166 38 2-Amino-6-(2,2,3,3-tetramethylcyclopropandin-4-ol Reference Example 32 2 1.41 208 -84- 200936570 39 L-amino-6-(pentane pyrimidine-4-reference example 33 alcohol oxime 2.22 182 Reference Example 4 0 and 4 1 1-(2-Amino-6-(( 1 ft, 28,48)-bicyclo[2.2.1]hept-5-en-2-yl)pyrimidin-4-yl)nitrogen-l-yl (A) Tertiary butyl methacrylate and smectomer (exo isomer) (Reference Example 40) and 1-(2-Amino-6-((111,211,48)-bicyclo[2.2. 1]hept-5-en-2-ylpyrimidin-4-yl)aza D-butyl-3-yl(methyl)aminocarbamic acid tert-butyl ester and mirror image isomer (endo-isomer) (Reference) Example 41) The compound obtained in Reference Example 36 (0·30 g, 1.48 mmol), the amine obtained in Reference Example 2 (〇·88 g, equivalent to 0.44 g 100%, 2.3 mmol) and

A mixture of PyBOP (1.0 g, 1 · 92 mmol) in a mixture of TEA (9 mL) and acetonitrile (15 mL) was stirred overnight at 85 °C. The reaction mixture was evaporated to dryness. A 1 N NaOH aqueous solution was added until the pH was alkaline, the phases were separated, and the organic phase was washed again with a 1 N NaOH solution. The organic phase was dried over anhydrous Na 2 SO 4 and concentrated to dryness. The crude product containing the mixture of exo/endo isomers was purified by preparative HPLC (method: X-Bridge Prep C18 OBD 5 μηι (100 mm x l9 mm) column, temperature: 30 ° C, flow rate: 20.0 mL/min, Eluent: A = AcN, B = NH4HCO3 75 mM> : OminA^ 30%; 1 minA^ 30%; 9.50 min A is 90%; 10 min A is 90%), and the product-containing fraction is evaporated to dryness. The peak of higher polarity corresponds to the exo isomer, providing 261 mg of the racemic mixture of Reference 40 (yield: 47%). The lower pole -85-200936570 peak corresponds to the endo-isomer, providing 280 mg of the racemic mixture of Reference 41 (yield: 51%). Reference Example 40 LC-MS (method 2): tR = 2.29 min; m/z 372 (MH+). Reference Example 41 LC-MS (method 2): tR = 2.39 min; m/z 372 (MH+). Example 1 4-(Cyclopropylmethyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine(R)-1-(2-amine 3- 6-(cyclopropylmethyl)pyrimidin-4-yl)pyrrolidin-3-yl(methyl)aminocarbamic acid tert-butyl ester Reference compound 6 (1.0 g, 6.06 mmol), Reference Example 1A The mixture of the obtained amine (1.95 g, 9·7 mmol) and PyBOP (4.1 g, 7.9 mmol) in a mixture of TEA (37 mL) and 1,4-dioxane (63 mL) was stirred at room temperature for 4 days. 'After adding more reference compound 1A (I·95 g, 9·7 mmo1), PyBOP*^4·1 g, 7·9 mmol) and TEA (19 mL), and stirring at room temperature for one day . The reaction mixture was evaporated to dryness. The residue was diluted with water and chloroform, and 2N Na? The phases were separated and the aqueous phase was extracted twice with chloroform. The combined organic phase was dried with anhydrous Na2S〇4 and concentrated to dryness. The crude product obtained was purified by chromatography on a silica gel using EtOAc/EtOAc mixture eluting to afford 2.5 g of the desired compound. LC-MS (method 2): tR = 2.17 min; m/z 348 ( MH+) -86 - 200936570 b) Compound of the title compound was dissolved in MeOH (12 mL). A solution of 4 Μ in methane, 45 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated to dryness. The residue was dissolved in water and washed twice with EtOAc EtOAc. The 2 N NaOH solution was added to the acidic aqueous phase D until basic pH and extracted twice with EtOAc. The combined organic phases were dried over anhydrous Na2SO4 and concentrated to dryness. The obtained crude product was purified by chromatography eluting with EtOAc (EtOAc) LC-MS (method 2): tR = 1.20 min; m/z 248 (MH+). Examples 2 to 10 The following compounds were prepared by following the procedure similar to that described in Example 1, except that the appropriate amine was substituted for methyl [(3R)-pyrrolidin-3-yl]carbamic acid • tert-butyl ester. : Example name Amine method (LC-MS) tR (min) m/z (MH+) 2 4-cyclopropylmethyl-6-(3-(methylamino)nitrol. 2-Amine Reference Example 2 2 1.23 234 3 4-Cyclopropylmethyl-6-((3R)-3-aminopyrrolidine-1-pyrimidine-2-amine [(3R)-卩比咯D定- 3_yl] tert-butyl carbamic acid 2 1.10 234 -87- 200936570

4- 4-cyclopropylmethyl-6-(piperazin-1-yl) pyrimidine-2-amine pepamine ~1_carboxylic acid tert-butyl ester (*) 2 1.03 234 5 4-cyclopropyl A -6-(3-methyl-3-(methylamino)nitrol-l-yl)pyrimidin-2-amine Reference Example 4(*) 2 1.34 248 6 4-(3-Amine Nitrogen Tsui - 1-yl)-6-cyclopropylmethylpyrimidin-2-amineazin-3-ylaminocarbamic acid tert-butyl ester (*) 2 1.07 220 7 4-cyclopropylmethyl-6-(1, 4-diazepin-1-yl)pyrimidine-2-amine U4-diazepine carboxylic acid tert-butyl ester 2 1.13 248 8 4-(4-Aminopiperidin-1-yl)-6-cyclopropyl Methylpyrimidine-2-aminepiperidin-4-ylaminocarbamic acid tert-butyl ester (*) 2 1.02 248 9 4-cyclopropylmethyl-6-((4aR,7aR)-octahydropyrrolo[3 , 4-b]pteridine-6-ylpyrimidin-2-amine Reference Example 3 (" 2 1.34 274 10 4-Cyclopropylmethyl-6-((3S)-3-(methylamino)pyrrole Pyridin-1-ylpyrimidin-2-amine Reference Example 1B(*) 2 1.21 248 (*) The reaction was carried out in acetonitrile at 80 ° C to carry out the compounds of Examples 1 to 16 by following Example 1 Prepared by the method described in part a), but substituted with a suitable amine for the methyl [(3R) pyrrolidin-3-yl]carbamic acid tert-butyl ester, acetonitrile as a solvent and at 80 ° C Heat: Example name Amine method (LC-MS) tR (min) m/z (MH+) 11 (R)-4-cyclopropylmethyl-6-[(N-methylpyrrolidin-3-yl) Amino]pyrimidin-2-amine Reference Example 5 2 1.17 248 -88- 200936570 12 (SM-cyclopropylmethyl-6-(3-methyl WM-yl)pyrimidin-2-amine(S)-2- Methyl _ 2 1.21 248 13 (R)-4-cyclopropylmethyl-6-(3-methyl-l-yl)pyrimidin-2-amine (R)-2-methyl_ 2 1.22 248 14 4-cyclopropylmethyl-6-[3-(preferably steep_1 que) nitrogen oxime]pyrimidin-2-amine 1-(azepin-3-yl)pyrrole steep 2 1.59 274 15 4-(ring Propylmethyl)-6-(hexahydropyrrolo[l,2-a]pyrrole B|f&gt;2(lH)-yl)pyrimidine-2-amine 1,4-diazabicyclo[4.3.0]壬 2 2 1.60 274 16 (S)-4-(cyclopropylmethyl)-6-(hexahydropyrrolo[l,2-a)] (l is Π--2(1H.)-yl)pyrimidine 2-Amine (S)-l,4_: azabicyclo[4.3.0]nonane 2 1.58 274 Example 1 7 to 3 5 The following compounds were prepared by following the procedure described in Example 1, but The corresponding starting materials are used in each case: Example name Starting material method (LC-MS) tR (min) m/z 17 4-isopropyl-6-(3-(methylamino)nitrogen -1-yl)pyrimidin-2-amine Reference Example 7 Test Example 2 2 1.17 222 18 4-Isopropyl-6-((3R)-3-(methylamino)pyrrole-stampyl-1-yl)pyridin-2-amine Reference Example 7 and Reference Example 1A 2 1.16 236 19 4-Ter Butyl-6-(3-(methylamino)azol-1-yl)pyrimidine-2-amine Reference Example 8 and Reference Example 2 2 1.38 236 20 4-Terbutyl group- 6-((3R)-3-(methylamino)pyrrolidine-1-®pyrimidine-2-amine Reference Example 8 and Reference Example 1A 2 1.33 250 -89 - 200936570 21 4-(3-(methylamine) Base)N-nitro-1-yl)-6-propylpyrimidin-2-amine Reference Example 9 and Reference Example 2 2 1.19 222 22 4-((3R)-3-(methylamino)pyrrolidine-1- ))-6-propylpyrimidin-2-amine Reference Example 9 and Reference Example 1A 2 1.18 236 23 4-Cyclopropyl-6-(3-(methylamino)nitrol-l-yl)pyrimidine-2 -Amine Reference Example 10 and Reference Example 2 2 1.11 220 24 4-Cyclopropyl-6-((3R)-3-(methylamino)pyrrole-d-yl)pyrimidin-2-amine Reference Example 10 Reference Example 1A 2 1.10 234 25 4-Ethyl-6-(3-(methylamino)azol-1-yl)pyrimidine-2-amine Reference Example 11 and Reference Example 2 2 1.01 208 26 4-ethyl -6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidine-2-amine Reference Example 11 and Reference Example 1A 2 1.03 222 27 4-butyl-6-(3-( Methylamino)nitrogen Phen-1-yl pyrimidine-2-amine Reference Example 12 and Reference Example 2 2 1.39 236 28 4-butyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidine 2-Amine Reference Example 12 and Reference Example 1A 2 1.41 250 29 4-Cyclopentylmethyl-6-(3-(methylamino)-pyrimidinylpyrimidine-2-amine Reference Example 13 and Reference Example 2 2 1.57 262 30 4-Cyclopentylmethyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidine-2-amine Reference Example 13 and Reference Example 1A 2 1.60 276 31 4-Isobutyl-6-((3R)-3-(methylamino)pyrrole-d-yl)pyrimidin-2-amine Reference Example 15 and Reference Example 1A(*) 2 1.30 250 32 4-Different Butyl-6-(3-(methylamino)azol-l-ylpyridin-2-amine Reference Example 15 and Reference Example 2 (, 2 1.34 236 200936570 33 4-(2,2-dimethyl Propyl)-6-((3R)-3_(methylamino)pyrrole-d-yl)pyrimidin-2-amine Reference Example 16 and Reference Example 1A(*) 2 1.43 264 34 4-(2,2 - dimethylpropyl)-6-(3-(methylamine guanidin-1-yl)pyrimidine-2-amine Reference Example 16 and Reference Example 2 (*) 2 1.47 250 35 Anti-4-(2 -Phenylcyclopropyl)-6-((3R)-3-(methylamino)pyrrole-th-yl)pyrimidin-2-amine Reference Example 14 and Reference Example 1A 2 1.74 310 (*) Reaction system In acetonitrile at 80 C heating to 0 Example 3 6 The following compounds were prepared by following the procedure described in part a) of Example 1 but using the appropriate starting material, acetonitrile as solvent and heating at 8 ° C: Example name Starting material method (LC-MS) tR (min) m/z (MI^) 36 (R)-4-tert-butyl-6-[(N-methylpyrrolidin-3-yl)amino] Pyrimidine-2-amine Reference Example 8 and Reference Example 5 2 1.30 250 Example 3 7 4-(2-Cyclopentylethyl)-6-((3R)-3-(methylamino)pyrrolidine-1 -Pyryl-2-amine A reference solution of Example 22 (80.0 mg, 0.28 mmol) in 1.6 mL MeOH was ventilated with argon. Pd/C (5% 5% in water) (24 mg) was added and the mixture was then ventilated with argon and stirred overnight in H.sub.2 atmosphere. Reaction -91 - 200936570 The mixture was filtered through celite® and the residue was washed with MeOH. The solvent was evaporated to dryness. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj LC-MS (method 2): tR = 1.72 min; m/z 290 (MH+) </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Starting material: Example name Starting material method (LC-MS) tR (min) m/z (MH+) 38 4-(2-cyclopentylethyl)-6-(3-(methylamino) Nitrol-l-yl)pyrimidin-2-amine Reference Example 23 2 1.75 276 39 4-(2-cyclopropylethyl)-6-((3R)-3-(methylamino)pyrrolidine small group Pyrimidine-2-amine Reference Example 24 2 1.39 262 40 4-((3R)-3-(Methylamino)pyrrolidin-1-yl)-6-(4-methylpentyl)pyrimidin-2- Amine Reference Example 25 2 1.67 278 41 4-(3-(Methylamino)azin-1-yl)-6-(4-methylpentyl)pyrimidine-2-amine Reference Example 26 2 1.69 264 42 4 -(3-cyclopentylpropyl)-6-((3R)-3-(methylamino-based slightly-deep _1-ylpyridin-2-amine Reference Example 29 2 1.90 304 43 4-(4- Cyclohexylbutyl)-6-((3R)-3-(methylamino)pyrrolidinyl)pyrimidin-2-amine Reference Example 27 2 2.30 332 44 4-(4-cyclohexylbutyl)-6 -(3-(Methylamino)azetidyl)pyrimidin-2-amine Reference Example 28 2 2.29 318 200936570 45 (S)-4-(2-cyclopropylethyl)-6-(3-A Kisperidone Μ_yl)pyrimidin-2-amine Reference Example 30 2 1.38 262 Example 4 6 to 6 1 The following compound was obtained by following the procedure similar to that described in Example 1, but using the appropriate starting material 'acetonitrile as solvent and Heating at 80 ° C: Example name Starting material method (LC-MS) tR (min) m/z (ΜΗ.) 46 4-(3-Amino-nitrol-l-yl)-6-( Amylmethyl)pyrimidine-2-amine Reference Example 13 and N-butyl 3-carbamido-3-ylcarbamate 2 1.43 248 47 4-(3-(Methylamino)nitrol-l-yl)- 6-(2,2,3,3-tetramethylcyclopropyl)pyrimidin-2-amine Reference Example 38 and Reference Example 2 2 1.69 276 48 4-Cyclobutyl-6-(3-(methylamino) Indole-1-yl) Chewy-2-amine Reference Example 35 and Reference Example 2 2 1.25 234 49 4-Cyclopentyl-6-(3-(methylamino)nitropyridin-1-yl)pyrimidine- 2-Amine Reference Example 34 and Reference Example 2 2 1.41 248 50 4-((3R)-3-(Methylamino)pyrrolidinyl)-6-(2,2,3,3-tetramethylcyclo) Propyl)pyrimidin-2-amine Reference Example 38 and Reference Example 1A 2 1.67 290 51 4-Isobutyl-6-(3-methyl-3-(methylamino)nitropyridin-1-yl)pyrimidine- 2-Amine Reference Example 15 and Reference Example 4 2 1.44 250 52 4-(3-Methyl-3-(methylamino) thiazepine-1-yl)-6·New Kean steep 2 -amine Reference Example 16 and Reference Example 4 2 1.57 264 53 (S)-4-(3-methylpiperazinyl)-6-neopentylpyrimidin-2-amine Reference Example 16 and S)-2-methylpiper trap (" 2 1.44 264 -93- 200936570 54 4-(3-(methylamino)nitrol-l-yl)-6-(1-methylcyclopropyl) Strepin-2-amine Reference Example 37 and Reference Example 2 2 1.31 234 55 (R)-4-(cyclopropylmethyl)-6-(hexahydropyrrolo[1,2-a]pyrazine-2 ( 1Η&gt;ylpyrimidin-2-amine Reference Example 6 and (R)-l,4-diazabicyclo[4.3.0]nonane (" 2 1.58 274 56 4-cyclopentyl-6-(3-A) Base-3-(methylamino)azol-1-yl)pyrimidine-2-amine Reference Example 34 and Reference Example 4 2 1.48 262 57 4-Cyclobutyl-6-(3-methyl-3-( Methylamino)azin-1-ylpyrimidin-2-amine Reference Example 35 and Reference Example 4 2 1.33 248 58 4-(3-Methyl-3-(methylamino)azane small group)- 6-(2,2,3,3-Tetramethylcyclopropyl)pyrimidin-2-amine Reference Example 38 and Reference Example 4 2 1.78 290 59 (S)-4-(3-methylpiperazin-1 -yl)-6-(2,2,3,3-tetramethylcyclopropyl)pyrimidin-2-amine Reference Example 38 and (S)-2-methyl- and (" 2 1.66 290 60 4-( 3-(Methylamino)nitrol-l-yl)-6-(pentan-3-yl)pyrimidin-2-amine Reference Example 39 and Reference Example 2 2 1.47 250 61 4-((3R)-3-(methylamino)pyrrolidine H-l-yl)-6-(penten-3-yl)pyrimidine-2-limb reference example 39 and reference examples 1A 2 1.46 264 (*) The HC1 treatment described in part b) of Example 1 is dispensed with. Example 62 4-((1S,2S,4S)-Bicyclo[2.2.1]heptan-2-yl)-6-(3-(methylamino)nitrol-l-yl)pyrimidin-2- Amine and mirror image isomers (exo isomers, in the form of racemic mixtures) Reference Example 40 (261 mg, 0.70 mmol) in MeOH 0.5 Μ The solution was hydrogenated in H-CubeTM system using the following conditions: 10% Pd /C column 200936570 匣, flow rate 1 mL/min, temperature 25 ° C and pressure 1 bar H2. The solvent was evaporated, and the residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The solvent was evaporated to dryness. The residue was dissolved in water, washed twice with EtOAc and EtOAc. The 2 N NaOH solution was added to the acidic aqueous phase until basic pH and extracted twice with chloroform. The combined organic phases were dried with EtOAc (EtOAc m. LC-MS (Method 2): m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m -(3-(Methyl 'amino)azin-1-yl)pyrimidin-2-amine and mirror image isomer (endo isomer, racemic mixture) The title compound was followed by analogous example 62 The method was prepared by using Reference Example 41 as a starting material in the form of a racemic mixture. LC-MS (Method 2): tR = 1.62 min; m/z 274 (MH+) Example 64 [3H]-Histamine A competitive binding assay for human histamine H4 receptor for performing binding assays, using self-expression Cell membrane extracts prepared from human histamine H4 receptor stabilized CHO recombinant cell lines (

Euroscreen/Perkin-Elmer ) 〇-95- 200936570 Compounds to be tested at 10 nM [3H]-histamine and 15 pg cell membrane extract at the desired concentration in total volume 2 50 μί 2 50 mM Tris-HC1, pH 7.4, 1.25 mM ED 培育 Incubate in duplicate at 25 °C for 60 minutes. Non-specific binding was defined in the presence of 100 μΜ unlabeled histamine. The reaction was terminated by using a vacuum collector (Multiscreen Millipore) in a 96-well plate (Multiscreen HTS Millipore) which had been previously immersed in 0.5% polyethylenimine for 2 hours at 〇 °C. The plate was then washed with 50 mM Tris (pH 7.4), 1.25 mM EDTA, and dried at 50 to 60 ° C for 1 hour, after which a scintillation counting liquid was added to measure the combined radiation by a 5 plate scintillation counter. active. The compounds of Examples 1 to 63 were tested in this test to exhibit greater than 50% inhibition of the binding of histamine to the human histamine Η4 receptor at 1 μ. Similarly, the compounds of formula VI described in Reference Examples 22, 23, 25, 26, 28 and 29 exhibited greater than 50% inhibition of the binding of histamine to the human histamine Η4 receptor. Example 6 5 histamine-induced shape change detection of human eosinophils (selective control spontaneous fluorescence forward scattering detection, GAFS) In this test, human eosinophils induced by histamine were measured by flow cytometry. The shape changes and is detected by an increase in cell size (forward scattering, FSC). Polymorphonuclear leukocytes (PMNL, containing neutrophils and eosinophils 200936570 white blood cells) are made from whole blood of healthy human volunteers, prepared by sedimentation in 1.2% dextrin (SIGMA). In the presence of -Paque® (Biochrom), the white blood-rich fraction (PMNL) is isolated from the top layer at 450 g. l. lxlO6 cells / ml / tube concentration was resuspended in PBS at 37 ° C with different concentrations of test compound (dissolved in PBS for 30 minutes, then stimulated with 300 nM histamine (Fluka) 50, added Paraformaldehyde (final concentration 1% in PBS) to maintain cell shape. Cell shape changes were analyzed by flow cytometry (FACS BD Biosystems). The blood cell line in PMNL is based on its higher relative to neutrophils Spontaneous firefly (Fluorescent channel FL2). Cell shape change is detected by forward dispersion 'FSC'. The results are expressed as a percentage change in histamine-induced shape change at each test compound. The compounds of Examples 1 to 63 were tested in this test, J 于 in the shape change of human eosinophils induced by histamine * 50% inhibition. Ready. Briefly, the blood cells, by the heart of the 20 points PMNL in the granules, ) pretreatment minutes. The most terminated reaction Cali bur, eosinophilic white light to select the control signal (a concentration of 1 μ Μ pairs produced greater than -97-

Claims (1)

200936570 X. Patent application scope 1. A compound of formula I R! represents a C2.8 alkyl group or a c3_7 cycloalkyl group -C().4 alkyl group wherein the C3-7 ring-based group is optionally independently selected from one or more selected from the group consisting of Cl4 alkyl, phenyl and fluorine. Substituted by a substituent; R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group' which may be a 4- to 7-membered monocyclic ring, a 7- to 8-membered bridged double ring or an 8- to 12- A fused bicyclic ring wherein the heterocyclic group may contain up to two N atoms and does not contain any other hetero atom 'and may be optionally substituted with or substituted with a plurality of substituents independently selected from d_4 alkyl and NRaBb'. The heterocyclic group contains 2 N atoms and is not substituted by the NRaRb group, or contains 1 n atom and is substituted by one NRaRb group; or R2 represents Η or C! _4 alkyl, and r3 represents nitrogen a pyrrole group, a pyridyl group, a piperidinyl group or a hydrazinyl group which may be optionally substituted by one or more Ci4 alkyl groups: Ra system represents a Cm alkyl group; Rb represents an indica or Ci_4 yard group; or Ra and Rb together with The N atoms bonded together form a nitrogen group, -98-200936570 pyrrolidinyl, piperidinyl or aziridine, which may be optionally substituted by one or more c,-4 alkyl groups; I Compound is not 4- (4-ethyl - l tillage -; _ yl!) -6-propyl - pyrimidin-2-amine; or a salt thereof. 2. A compound according to claim 1, wherein Ri represents a C2.8 alkyl group. 0. A compound according to claim 2, wherein Ri represents a group selected from the group consisting of a tributyl group, an isopropyl group, a propyl group and an isobutyl group. 4. A compound of claim 2, wherein 1 is a group selected from the group consisting of a tributyl group and an isopropyl group. 5. For the compound of claim 2, wherein 1 is a group selected from the group consisting of propyl and isobutyl. 6- The compound of claim 1 wherein L is a C3-7 ring-based base - Ci. 4 hospital base. Ο 7. A compound according to claim 6 wherein R! represents ^cyclopropylmethyl. &quot; 8 • A compound of claim 1 wherein R1 represents a C3-7 cycloalkyl group. 9. A compound according to claim 8 wherein R! represents cyclobutyl, cyclopentyl or cyclopropyl. 10. The compound 'in the '8' of the scope of the patent application, which is represented by cyclopropyl. 11. For example, the compound of the scope of the patent application, in which the Ri series -99-200936570 is not selected from the C2-5 yard base and the C3_7 ring yard base _C〇.i. 12. The compound of claim 11, wherein Ri is selected from the group consisting of a third butyl group, an isopropyl group, a propyl group, an isobutyl group, a cyclopropylmethyl group, a cyclobutyl group, a cyclopentyl group, and a ring. a group of propyl groups. A compound according to claim 11 wherein R! represents a group selected from the group consisting of a tributyl group, an isopropyl group, a propyl group, an isobutyl group, a cyclopropylmethyl group, and a cyclopropyl group. 14- The compound of claim 11, wherein L represents a group selected from the group consisting of propyl, isobutyl, cyclobutyl, cyclopentyl and cyclopropylmethyl. 15. The compound of claim 11, wherein R1 represents a group selected from the group consisting of a tributyl group, an isopropyl group, and a cyclopropyl group. 16. The compound of claim 11, wherein R1 represents a group selected from the group consisting of propyl, isobutyl and cyclopropylmethyl. 17. - Compound of formula VI Wherein: RT is a C..6 alkyl or c37 cycloalkyl-C()_2 alkyl group, wherein the C3_7 cycloalkyl group is optionally independently selected from one or more selected from the group consisting of d-4 alkyl, phenyl and 100-200936570 Substituted by a fluorine substituent; R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group' which may be a 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic ring or 8- to 12-membered fused bicyclic ring wherein the heterocyclic group may contain up to two N atoms and does not contain any other hetero atom, and may optionally be subjected to - or a plurality of substituents independently selected from Ci 4 alkyl and NRaRb Substituted 'with the proviso that the heterocyclic group contains 2 N atoms and is not substituted by the NRaRb group, or contains 1 n atom and is substituted by one NRaRb group; or R2 represents Η or C, -4 An alkyl group, and R3 represents a nitrogen block, a pyridyl group, a pulse n-group or a nitrogen group, which may be optionally substituted by one or more Ci4 alkyl groups; and a Ra system represents a hydrazine or a Cw alkyl group; Η or (^.4 alkyl; or Ra and Rb together with the ruthenium atom to which they are bonded form a nitrogen sulfonyl group, a hydrazino group or a hydrazinyl group, which may optionally pass one or more Base substitution The compound of claim 17, wherein R1 is a Cu alkyl group. ' 19. The compound of claim 1, wherein R1 is isobutyl. The compound of any one of claims 1 to 19 wherein R 2 and R 3 together with the N atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of: -101 - 200936570 (i) containing 2 N a heterocyclic group which is atomic and does not contain any other hetero atom, wherein the heterocyclic group is optionally substituted by one or more mountain alkyl groups; and (ii) contains 1 N atom and does not contain any other hetero atom. a cyclic group wherein the heterocyclic group is substituted with one NRaRb group and optionally substituted with one or more C!-4 alkyl groups; wherein the heterocyclic groups (i) and (ii) may be 4- to 7- a single ring, a 7- to 8-membered bridged bicyclic ring or an 8- to 12-membered fused bicyclic ring. 2 1. A compound of claim 20, wherein R2 and R3 together with the N atom to which they are bonded Forming a saturated heterocyclic group selected from the group consisting of: Where R. Represents Cw alkyl. 22. A compound as claimed in claim 21, wherein R. The system shows Η. A compound according to claim 21 or 22, wherein R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group selected from (a) and (b). 24. The compound of claim 21 or 22, wherein R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (a). 2. A compound according to claim 21 or 22, wherein R2 Q and 113 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (b). 2. A compound according to claim 21, wherein R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (d). 2. A compound according to claim 21, wherein R2 and R3' together with the N atom to which they are bonded form a saturated heterocyclic group of formula (f). The compound of any one of claims 1 to 25, wherein Ra and Rb independently represent 11 or a Ci.4 alkyl group. 〇 2 9. The compound of claim 28, wherein Ra and Rb' independently represent hydrazine or methyl. A compound of claim 29, wherein the Ra line represents hydrazine and the Rb line represents hydrazine or a methyl group. 3 1. A compound according to claim 30, wherein the Ra group represents Η and the Rb represents a methyl group. 32. A compound according to claim 1 which is selected from the group consisting of: 4-(cyclopropylmethyl)-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyrimidine -2 -amine; -103- 200936570 4-cyclopropylmethyl-6-(3-(methylamino)azol-1-yl)pyrimidine-2-amine; 4-cyclopropylmethyl-6 -((3R)-3-aminopyrrolidin-1-yl)pyrimidine-2-amine; 4-cyclopropylmethyl_6_(pipedino-1-yl)pyrimidine-2-amine; 4-cyclopropene Methyl-6-(3-methyl-3-(methylamino)nitrol-l-yl)pyrimidin-2-amine; 4-(3-Aminonitropyran-1-yl)-6- Cyclopropylmethylpyrimidin-2-amine; 4-cyclopropylmethyl-6-(1,4-diazepine-1-yl)pyrimidine-2-amine; 4-(4-Aminopiperidine- 1-yl)-6-cyclopropylmethylpyrimidin-2-amine; 4-cyclopropylmethyl-6-((4aR,7aR)-octahydropyrrolo[3,4-b]pyridine-6 Pyrimidine-2-amine; 4-cyclopropylmethyl-6-((3S)-3-(methylamino)pyrrolidin-1-yl)pyrimidine-2-amine; (R) -4- Cyclopropylmethyl-6-[(N-methylpyrrolidin-3-yl)amine]pyrimidine-2-amine; (S)-4-cyclopropylmethyl-6-(3-methyl Piper D-l-yl)pyrimidin-2-amine; (R) _4_cyclopropylmethyl-6_(3·methylpiperidine D And-1-yl)pyrimidine_2·amine; 4-cyclopropylmethyl-6-[3-(pyrrolidin-1-yl)azol-1-yl]pyrimidin-2-amine; 4-(ring Propylmethyl)_6_(hexahydropyrrolo[l,2_a]pyrazine-2(1H)-yl)pyrimidine-2-amine; -104- 200936570 (s) -4-(cyclopropylmethyl)- 6-(hexahydropyrrolo[1,2-a)]-2(1H)-yl)pyrimidin-2-amine; 4-isopropyl-6-(3-(methylamino)nitroso-l-1 -yl)pyrimidin-2-amine « 4 -isopropyl-6-((3R)-3-(methylamino)P ratio slightly steep-1-yl)pyrimidine-2-amine; 4_third _6_(3_(Methylamino)nitrol-l-yl)pyrimidin-2- decylamine; 4-t-butyl-6-((3R)-3-(methylamino)pyrrolidine -1-yl)pyrimidin-2-amine; 4-(3-(methylamino)methane-1-yl)-6-propylpyran-D-amine; 4-((3R)-3 -(methylamino)pyrrolidin-1-yl)-6-propylpyrimidin-2-amine; 4-cyclopropyl-6-(3-(methylamino)azol-1-yl)pyrimidine 2-Amine 赘〇4-cyclopropyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl) 'pyrimidin-2-amine; 4-ethyl- 6-( 3 -(Methylamino)methane-1-yl)dark-2-amine; 4-ethyl-6-((3R)-3-(methylamino)pyridinium L-pyridin-1 -yl)pyrimust-2-amine; 4-butyl-6-(3-(methylamino)azol-1-yl)pyrimidine-2-amine; 4-butyl-6- ((3R)-3-(Methylamino)pyrrolidin-1-yl)pyrimidine D-II-amine; 4-cyclopentylmethyl-6-(3-(methylamino)nitrogen-resistance- 1-yl)pyrimidine-105- 200936570 2-amine; 4-cyclopentylmethyl-6-((3R)-3-(methylamino)pyrrolidin-1-ylpyrimidin-2-amine; 4 -isobutyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine; 4-isobutyl-6-(3-(methylamino) Nitrogen-1-yl)pyrimidine-2-amine» 4-(2,2-dimethylpropyl)-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyrimidine -2 -amine; 4-(2,2-dimethylpropyl)-6-(3-(methylamino)azol-1-yl)pyrimidine-2-amine; anti- 4-(2- Phenylcyclopropyl)-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyrimidin-2-amine; (R)-4-tert-butyl-6-[( N-methylpyrrolidin-3-yl)amine]pyrimidine-2-amine; 4-(2-cyclopentylethyl)-6-((3R)-3-(methylamino)pyrrolidine-1 -yl)pyrimidine-2-amine; 4-(2-cyclopentylethyl)-6-(3-(methylamino)azol-1-yl)pyrimidin-2-amine 4-(2-cyclopropylethyl)-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyrimidine-2-amine; 4-((3R)-3- (Methylamino)pyrrolidin-1-yl)-6-(4-methylpentyl)pyrimidine-2-amine; 4-(3-(methylamino)azepine-1-yl)-6 -(4-methylpentyl)pyrimidine-106- 200936570 Π定-2-amine; 4-(3-cyclopentylpropyl)-6-((3R)-3-(methylamino)pyrrolidine -1 -yl)pyrimidine-2-amine; 4-(4-cyclohexylbutyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine; 4-(4-cyclohexylbutyl)-6-(3-(methylamino)nitrol-l-yl)pyrimidin-2-amine; 0 (S) -4-(2-cyclopropylethyl - 6-(3-methylpiperidino-1-yl)pyrimidine-2-amine; 4-(3-Amino-nitrol-l-yl)-6-(cyclopentylmethyl)pyrimidine-2 -Amine 4-(3-(methylamino)azol-l-yl)-6-(2,2,3,3-tetramethyl^cyclopropyl)pyrimidin-2-amine; 4-cyclobutene -6-(3-(methylamino)nitrol-l-yl)pyrimidin-2-amine» 〇4-cyclopentyl-6-(3-(methylamino)nitrol-l-yl Pyrimidine-2-amine&gt; • 4 - (( 3 R ) - 3 -(methylamino)pyrrolidin-1 -yl)-6 -( 2,2,3,3-tetramethyl Propyl)pyrimidine-2-amine; 4-isobutyl-6-(3-methyl-3-(methylamino)nitrol-l-yl)pyrimidin-2-amine; 4-(3-A 3-(methylamino)azol-1-yl-6-neopentylpyrimidin-2-amine; (S)-4-(3-methylpiperazin-1-yl)-6 - neopentylpyrimidin-2-amine; -107- 200936570 4-(3-(methylamino)azol-1-yl)-6-(1-methylcyclopropyl)pyrimidin-2-amine; (R) -4-(cyclopropylmethyl)-6-(hexachloropyrene than succinyl[l,2-a]shama-2(1H)-yl)pyrimidin-2-amine; 4-cyclopentyl 5--6-(3-methyl-3-(methylamino)azol-l-yl)pyrimidine-2-amine; 4-cyclobutyl-6-(3-methyl-3-(methyl) Amino)nitrol-1-ylpyrimidin-2-amine; 4-(3-methyl-3-(methylamino)gaso-l-yl)-6- (2,2,3,3_ Tetramethylcyclopropyl)pyrimidine-2-amine; (S) _4_(3-methylpiped-1-yl)-6-(2,2,3,3-tetramethylcyclopropyl)pyrimidine- 2-amine (4-(methylamino)-blocker-1-yl)-6-(pentene-3-yl)dark-2-amine; 4-((3R)-3-( Methylamino) lysyl-1-yl)-6-(pentene-3-yl)pyrimidine-2-amine; 4-((18,28,48)-bicyclo[2.2.1]heptane- 2-yl)-6-(3-(methylamino) Nitrothyl-1-ylpyrimidin-2-amine; and 4-((13,211,43)-bicyclo[2.2.1]heptan-2-yl)-6-(3-(methylamino)nitrogen -1 -yl)pyrimidine-2-amine; or a salt thereof. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. A compound of the formula 1 according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, for use in therapy. 35. Use of a compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a disease mediated by histamine H4 receptor Pharmaceutical products. 36. The use of claim 35, wherein the disease mediated by the histamine receptor is an allergic, immunological or inflammatory disease or pain. 3. A method of preparing a compound of formula I as claimed in claim 1 which comprises: (a) reacting a compound of formula II with a compound of formula III Nh2 Hnr2r3 III wherein Ri, R2 and r3 have the definitions as defined in claim 1; or (b) reacting a compound of formula IIB with a hydrazine compound -109- 200936570 wherein R4 represents a leaving group and R!, R2 and R3 have the definitions as set forth in claim 1; or (c) when Ri in the compound of formula I represents Rr-CH2-CH2- Treatment of a compound of formula VI with a suitable reducing agent Wherein 1' represents (:1.6 alkyl or (:3_7 cycloalkyl-(:().2 alkyl), wherein the C3_7 cycloalkyl group is optionally independently selected from one or more (^-4 alkyl, benzene) Substituting a substituent with a fluoro group; and R2 and R3 have the definitions as defined in claim 1; or (d) converting the compound of formula I to another compound of formula I in one or several steps. - 200936570 VII. Designated representative circle: (1) The designated representative circle of this case is: None (2), the representative symbol of the representative figure is simple: No 8. If there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention: Formula I -4-