TW200940529A - 2-amino-pyrimidine derivatives - Google Patents

Abstract

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

Description

200940529 IX. INSTRUCTIONS OF THE INVENTION [Technical Fields of the Invention] The present invention relates to a series of novel 2-amino-pyrimidine derivatives, methods of preparing the same, pharmaceutical compositions comprising the same, and therapeutic treatment of such compounds Use. [Prior Art] 0 One of the most effective transmitters for tissue-based allergic reactions. Although the effects of histone on smooth muscle cell contraction, vascular permeability, and gastric acid secretion are known, the effects of histamine on the immune system are now gradually revealed. A few years ago, a novel histamine receptor named H4 was cloned by several independent research teams (see Oda T et al, J Biol Chem 2000, 2 7 5: 3 678 1 -6; Nguyen T et al, Mol Pharmacol 200 1, 5 9: 427-33). Like other members of the H4 receptor family, the Q H4 is regulated by a G protein-coupled receptor (GPCR) containing seven transmembrane segments. However, the H4 receptor is less homologous to the other three histamine receptors (see Oda T et al); it is noted that the H4 receptor shares only 35% homogeneity with the H3 receptor. The H3 receptor is only expressed in the cells of the central nervous system (CNS), but it has been observed that the H4 receptor system is expressed in cells of the hematopoietic system, especially eosinophils, mast cells, alkalophilic leukocytes, dendritic cells. And T cells (see literature Oda T et al). The fact that the H4 receptor is highly distributed in cells of the immune system suggests that the tU receptor is involved in an immunoinflammatory response. Furthermore, this hypothesis is reinforced by the fact that the H4 receptor gene 200940529 is regulated by inflammatory stimuli such as interferon, TNFcx and IL-6. Nonetheless, the H4 receptor is also expressed in other types of cells (such as human synovial cells from patients with rheumatoid arthritis (see Wojtecka-Lukasik E et al, Ann Rheum Dis 2006, 65 (Suppl) II): 12 9; Ikawa Y et al, Biol Pharm Bull 2005, 28: 20 1 6-8) and human synovial cells from patients with osteoarthritis (see literature Grzybowska-Kowalczyk A et al, European) Histamine Research Society XXXVI Annual Meeting, ❹

Florence, Italy, 2007, P-11)) and human intestinal tract (see Sander LE et al, Gut 2006, 5 5: 498-504). It has also been reported that the performance of the H4 receptor in nasal polyps is increased compared to that in healthy human nasal mucosa (see J0kiiti A et al, Cell Biol Int 2007, 31: 1367-70). Studies of specific ligands for this H4 receptor have helped to define the pharmacological properties of this H4 receptor. These studies have demonstrated that several histamine-induced responses to eosinophils (such as chemotaxis, conformational changes, and upregulation of CD1 lb and CD54) are specifically mediated by the H4 receptor. (See literature by Ling P et al, Br J Pharmacol 2004, 142:161-71; B uc k1 an d KF et al, Br J Pharmacol 2003, 1 40:1 1 1 7-27). This H4 receptor has been shown to affect the maturation, cytokine production and movement of dendritic cells (see Jelinek I et al, 1st Joint Meeting of European National Societies of Immunology, Paris, France, 2006, PA-1255). Furthermore, the role of the H4 receptor in mast cells has been studied. Although the activation of the H4 receptor did not induce granulation of -6-200940529 mast cells, it released histamine and other pro-inflammatory transmitters. Furthermore, the H4 receptor has been shown to mediate the chemotaxis of mast cells. Sex and 15 transfer (see literature by Hofstra CL et al, J Pharmacol Exp Ther 2003, 305: 1 2 1 2-2 1 ). For T lymphocytes, the H4 has been shown

Activation of the receptor induces T cell migration and differentially attracts lymphocyte populations with inhibitory genes/regulatory phenotypes and functions (see Morgan RK et al, American Thoracic Society Conference, San Diego, USA, 2006, P). -536) and modulate activation of CD4+ T cells (see Dunford PJ et al, J Immunol 2006, 176: 7062-70). For the intestine, the distribution of this H4 receptor suggests that the H4 receptor may play a role in the control of peristalsis and gastric acid secretion (see literature by Morini G et al, European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, OR) -10). The various functions of the H4 receptor observed on eosinophils, mast cells and T cells suggest that the H4 receptor may play an important role in the immune inflammatory response. In fact, H4 receptor antagonists have been used in murine peritonitis (see Thurmond RL et al, J Pharmacol Exp Ther 2004, 309: 404-13), murine pleurisy (see the paper Takeshita K et al, J Pharmacol Exp Ther 2 003, 3 07: 1 072-8) and sputum sputum (see literature Jell JK et al, Br J Pharmacol 2004, 1 42: 3 74-80) showed in vivo activity in the model. In addition, by allergic asthma (see Dunford PJ et al, 2006), intestinal inflammatory disease (see Virga C et al, Eur J Pharmacol 2005, 522:1 3 0-8), support (see Dunford) PJ et al, J Allergy Clin Immunol 2007, 1 1 9: 200940529 176-83), atopic dermatitis (see Cowden JM et al, J Allergy Clin Immunol 2007; 119 (1): S239 (Abs 935),

American Academy of Allergy, Asthma and Immunology 2007 AAAAI Annual Meeting, S an D i e g o, U S A), eye inflammation (see Zampeli E et al, European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007,

OR-36), 7jc swelling and hyperalgesia (see Coruzzi G et al, Eur J Pharmacol 2007, 563: 240-4) and neuropathic pain (see Q

The experimental mode of Cowart MD et al., J Med Chem. 2008; 5 1 (20): 6547-57) has demonstrated the in vivo activity of H4 receptor antagonists. Therefore, H4 receptor antagonists are expected to be useful in the treatment or prevention of allergic, immune and inflammatory diseases and pain. Thus, what we desire is a novel compound which provides H4 receptor antagonist activity and which is a good drug. In general, preferred compounds should bind strongly to the histamine H4 receptor and at the same time exhibit low affinity to other receptors. In addition to binding to the H4 receptor, the compound should further exhibit good pharmacological activity in the in vivo disease pattern. Furthermore, when administered by a selected route of administration, the compound should be able to reach the target tissue or organ and have beneficial pharmacokinetic properties. In addition, the compound should be non-toxic and has been shown to have only a few side effects. Furthermore, when administered for peripheral treatment, the compound should exhibit reduced CNS penetration. SUMMARY OF THE INVENTION 8-200940529 One aspect of the present invention relates to a compound of formula

I 〇 where

Ri represents a base selected from (i) or (ii):

(·0 (ϋ); R·2 and R3 together with their bonded nitrogen atoms form a saturated heterocyclic ring of 4 to 7 members, 7 to 8 members of bridged double rings or 8 to 12 members of fused double rings. a cycloalkyl group wherein the heterocyclic group may contain up to 2 nitrogen atoms and does not contain any other hetero atom 'and optionally substituted with one or more substituents independently selected from a C4 alkyl group or NRaBb' The heterocyclic group contains 2 nitrogen atoms and is not substituted by NRaRb group or contains 1 nitrogen atom and is substituted by NRaRb group; or R2 represents HS Ci-4 alkyl group, and R3 represents tetrahydroindenyl group, pyrrole steep group, piperidine a pyridyl or azamidyl group, which may be optionally substituted with one or more Cl.4 alkyl groups;

Ra stands for hydrazine or C!.4 alkyl;

Rb represents hydrazine or (^-4 alkyl; -9- 200940529 or 1 and Rb together with the nitrogen atom to which they are bonded to form a tetrahydroindenyl group, a pyrrolidinyl group, a piperidinyl group or a nitrogen amide group, The group may be optionally substituted by one or more Cj-4 alkyl groups; R4 and Rs are each independently selected from fluorene or Cm alkyl, and additionally R4 or R5 may represent aryl or C3-8 cycloalkyl-C〇 -6 alkyl, and additionally both R4 and R5 groups on the same carbon atom may be bonded to the carbon atom to form a C3_8 cycloalkyl group; R6 represents a group selected from Cu alkyl, c3-8 cycloalkylalkyl Or an An-Co-4 0 alkyl group, wherein any alkyl group is optionally substituted with one or more halo groups and the c3_8 cycloalkyl group is optionally independently selected from one or more independently selected from c!- Substituted by a substituent of a 4 alkyl, halo or aryl group; R 7 represents a saturated monocyclic 4 to 7 membered heterocyclic ring containing one oxygen atom and no other additional hetero atom, wherein the ring may be via any available carbon atom The remainder of the molecule is bonded, and wherein R7 is optionally substituted with one or more substituents independently selected from the group consisting of Ci. 4 alkyl or halo;

η represents 1, 2 or 3; Q ρ represents 〇, 1 or 2; ΑΓ1 represents a phenyl group optionally substituted by one or more groups independently selected from C丨-4 alkyl, halogen, C丨-4 alkoxy, C _ 4-haloalkyl, C丨-4 haloalkoxy, cyano, hydroxy-C〇-6 alkyl, R8C02-CG-6 alkyl, R8SO2NHCO-C0-6 alkane , (1H-tetrazol-5-yl)-C〇-6 alkyl, -CONR8R8 ' -S〇2NRgR-8 ' S〇2R8, ' -NR8S02R85 ' -NRsCONRsRg ' -NRsCORs or -NRsRs ; 118 stands for , (: 1-6 alkyl, (: 3-8 cycloalkyl-(:()-6 alkyl or aryl-(:0-4 -10- 200940529 alkyl; ruler 8' stands for <:1_6 An alkyl group, (: 3-8 cycloalkyl-(: «^6 alkyl or aryl-(:().4 alkyl and the other two R8 or one R8 and one r8' may be bonded to each other to form -C2-5alkylene; and aryl represents phenyl optionally substituted by one or more groups independently selected from C^-4 alkyl, halo, Ci.4 alkoxy, Ci .4 haloalkyl, Cl 4 Tetraalkoxy, cyano or amine. The invention also relates to salts and solvates of the compounds of formula I. Certain compounds of formula I may contain a chiral center which may result in Various stereoisomers are produced. The invention relates to each such stereoisomer and mixtures thereof. The compounds of formula I exhibit high affinity for histamine H4 receptors. Thus, another aspect of the invention relates to Compound of formula I for treatment

among them

Ri represents a base selected from (1) or (ii): -11 - 200940529

(i) (8) R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic ring which may be a 4 to 7 membered monocyclic '7 to 8 membered bridged bicyclic ring or 8 to 12 membered fused bicyclic ring' A heterocyclic group may contain up to 2 nitrogen atoms and does not contain any of its heteroatoms' and is optionally substituted with one or more substituents independently selected from a C4 alkyl group or NRaBb, except that the heterocyclic group contains 2 nitrogen atoms and not substituted by NRaRb group or containing 1 nitrogen atom and substituted by NRaRb group; or R2 represents hydrazine or Ci-4 alkyl group, and R3 represents tetrahydroindenyl group, pyrrole steep group, piperidinyl group or a nitrogen group, which may be optionally substituted with - or a plurality of C1_4 alkyl groups;

Ra represents hydrazine or Cl_4 alkyl;

Rb represents a hydrazine or a Cm alkyl group; $Ra and Rb together with the nitrogen atom to which they are bonded form a tetrahydroindenyl group, a phenanthrenyl group, a piperidinyl group or a nitrogen azo group, which may optionally be One or more C 1 -4 substituents; R 4 and R 5 are each independently selected from η or Cl 4 alkyl, and additionally r 4 or r 5 may represent aryl or C 3.8 cycloalkyl-C 6 alkyl, And additionally at the same carbon atom i: both R4 and 1 group may be bonded to the carbon atom to form a c3_8 ring-based group; R6 represents a group selected from the group consisting of Cl-8 alkyl, C3-8 cycloalkyl-CD_6 alkyl Or Ari-C〇-4 院基基', any one of which may be optionally substituted by one or more halo groups and the C3_8 cycloalkyl group may be optionally independently selected from one or more (^^ Alkyl-12-200940529 substituted with a substituent of a 'halo or aryl group; R7 represents a saturated monocyclic 4 to 7 membered heterocyclic ring containing one oxygen atom and no other additional hetero atom, wherein the ring may be via any available carbon An atom is bonded to the remainder of the molecule, and wherein R7 is optionally substituted with one or more groups independently selected from G-4 alkyl or halo; η represents 1, 2 or 3; Ρ represents 〇, 1 or 2 ; φ An stands for optional a phenyl group substituted with one or more groups independently selected from C 丨 -4 alkyl, halo, C 4 alkoxy, C 丨 4 haloalkyl, C 丨 4 halo Oxy, cyano, hydroxy-C〇-6 alkyl, RSC02-CG-6 alkyl, R8S02NHCO-Cg.6 alkyl, (1H-tetrazol-5-yl)-C〇.6 alkyl, -CONR8R8 , -so2nr8r8, -so2r8, -nr8so2r8, -nr8conr8r8, -nr8cor8 or -nr8r8; R8 represents H'Cm alkyl, C3.8 cycloalkyl-CG_6 alkyl or aryl-C〇-4 alkyl; Κ·8' stands for Ci-6 yard base, C3-8 ring yard base _C〇-6 yard base or square base 4 ()-4 yard base and the other two R8 or one R8 and one R8' can be mutually interlocked To form -c2_5 alkylene; and aryl represents phenyl optionally substituted with one or more groups independently selected from Ci-4 alkyl, halo, Ci.4 alkoxy, Cu Haloalkyl, Ci-4 haloalkoxy, cyano or 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 Accepted from -13 to 200940529 Excipients. Another aspect of the invention pertains to a compound of formula I or a pharmaceutically acceptable salt thereof A pharmaceutical use for the treatment of a disease mediated by histamine H4 receptor. Another aspect of the invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of allergic, immune or inflammatory diseases or pain Uses of the invention. Another aspect of the invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of an allergic, immune or inflammatory disease. More preferably, the allergic, immune or inflammatory disease is selected from the group consisting of respiratory diseases, eye diseases, skin diseases, intestinal inflammation diseases, rheumatoid arthritis, multiple atherosclerosis, cutaneous lupus, systemic lupus erythematosus or transplant rejection. Still 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, urticaria, jatropha, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus or transplant rejection. Another aspect of the invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of pain. More preferably, the pain is selected from the group consisting of inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-operative pain, migraine, cancer pain, visceral pain, osteoarthritis pain or 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 intermediate to histamine H4 receptor. -14- 200940529 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 pertains to a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of an allergic, immune or inflammatory disease. More preferably, the allergic, immune or inflammatory disease is selected from the group consisting of respiratory diseases, eye diseases, skin diseases, intestinal inflammatory diseases, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus or transplant rejection. Still 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, urticaria, jatropha, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus or 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, migraine, cancer pain, visceral pain, osteoarthritis pain, or neuropathic pain. Another aspect of the invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of a disease mediated by histamine H4 receptor. Another aspect of the invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of allergic, immune or inflammatory diseases or pain. Another aspect of the invention pertains to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of an allergic, immune or inflammatory disease. More preferably, the allergic, immune or inflammatory disease is selected from the group consisting of respiratory diseases, eye diseases, skin diseases, intestinal inflammation diseases, rheumatoid arthritis, multiple sclerosis, skin wolf -15-200940529 sores, systemic lupus erythematosus or Transplant rejection. Still 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, castor pain, jatropha, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus or transplant rejection. Another aspect of the invention pertains to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of pain. More preferably, the pain is selected from the group consisting of inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-operative pain, migraine, cancer pain, visceral pain, osteoarthritis pain, or neuropathic pain. Another aspect of the invention relates to a method of treating a disease mediated by histamine H4 receptor in an individual in need of treatment, particularly a human, comprising administering to the subject a compound of formula I or a pharmaceutically acceptable salt thereof. Another aspect of the invention relates to a method of treating an allergic, immune or inflammatory disease or pain in an individual in need of treatment, particularly a human, comprising administering to the individual a compound of formula I or a pharmaceutically acceptable salt thereof. Another aspect of the invention relates to a method of treating an allergic, immune or inflammatory disease in an individual in need of treatment, particularly a human, comprising administering to the individual a compound of formula I or a pharmaceutically acceptable salt thereof. More preferably, the allergic, immune or inflammatory disease is selected from the group consisting of respiratory diseases, eye diseases, skin diseases, intestinal inflammation diseases, rheumatoid arthritis, multiple sclerosis, skin burs, systemic lupus erythematosus or transplant rejection. Still 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 200940529 eg atopic) Dermatitis), psoriasis, measles, jatropha, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus or transplant rejection. Another aspect of the invention relates to a method of treating pain in an individual in need of treatment, particularly a human body, 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 sputum, cancer pain, visceral pain, osteoarthritis pain, or neuropathic pain. Another aspect of the invention pertains to a process for the preparation of a compound of formula I above, which comprises: (a) reacting a compound of formula II with a compound of formula III (or an amine protected form thereof)

❹ wherein Ri, R.2 and R3 are as defined above, and if necessary, remove any protecting groups which may be present; or (b) a compound of formula IIB and a compound of formula III (or an amine protected form thereof) Reaction-17- 200940529

R1^^L IIB 1,1 wherein L represents a leaving group and R!, R2 and R3 are as defined above, followed by removal of any protecting groups which may be present; or (C) via one or several steps Converting a compound of formula I to another compound of formula I

In the above definition, the Cx_y alkyl group means a saturated linear or branched alkyl chain having X to y carbon atoms. Thus, alkyl refers to a straight or branched alkyl chain containing from 1 to 8 carbon atoms. The alkyl group means a straight or branched alkyl chain having 1 to 4 carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, butyl and tert-butyl groups. C. The alkyl group means that the alkyl group is not present.

The Ci-4 halogen base table does not have one or more hydrogen atoms of the Ci-4 building group formed by one or more substitutions of the same or different halogen atoms (i.e., fluorine, chlorine, bromine or iodine). Examples include, in particular, trifluoromethyl, fluoromethyl, 1-chloroethyl, 2-chloroethyl, 1-fluoroethyl, 2-fluoroethyl, 2-bromoethyl, 2-iodoethyl, 2 , 2,2-trifluoroethyl, pentafluoropropyl, 3-chloropropyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, seven Fluoropropyl, 4-fluorobutyl and nonafluorobutyl.

The Cid alkoxy group represents a group of the formula <^.4 alkyl-0- wherein the alkyl moiety is as defined above. Thus, the Ci-4 alkoxy group includes a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a butyl group - 200940529 oxy group and a tert-butoxy group.

The acyl group of Ci-4 is not a group of one or more hydrogen atoms of Ci_4, or a group of one or more hydrogen atoms which may be substituted by the same or different _ atoms (ie, fluorine, chlorine, bromine or iodine). . Examples include, in particular, trifluoromethoxy 'fluoromethoxy, K chloroethoxy, 2-chloroethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2-ethoxyethoxy, 2 -iodoethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 3-fluoropropoxy, 3-chloropropoxy, 2,2,3,3-tetrafluoropropoxy Base, Q 2,2,3,3,3-pentafluoropropoxy, heptafluoropropoxy, 4-fluorobutoxy and nonafluorobutoxy. The C3-8 cycloalkyl group as a group or as a part of a C3-8 cycloalkyl-CQ-6 alkyl group means a saturated carbocyclic ring containing 3 to 8 carbon atoms which may be a monocyclic or bridged bicyclic group. Examples include, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl and bicyclo [2.2.2] octyl. Preferred (: 3-8 cycloalkyl monocyclic ring (: 3-6 cycloalkyl group. C3_8 cycloalkyl-CG-6 alkyl group includes (: 3-8 cycloalkyl group and C3_8 cycloalkyl-fluorene). The C3-8 cycloalkylalkyl group means a group in which one or more hydrogen atoms of (^-6 alkyl group are substituted by one or more C3_8 cycloalkyl groups which may be the same or different. Preferably, the Ci The -6 alkyl group is substituted by one or two C3.8 cycloalkyl groups and more preferably by a C3_8 cycloalkyl group. The C3_8 cycloalkyl group may be substituted for one hydrogen atom on one carbon atom of the alkyl group or Two hydrogen atoms on one of the same carbon atoms of the alkyl group (for this: (the 3.8 cycloalkyl group is a carbon atom together with the alkyl group), such as the following group as an example: -19- 200940529

One of the carbon atoms in 2-cyclopropylbutyl butyl is substituted by cyclopropyl

(1·Ethyl·cyclopropyl)methyl butyl two hydrogen atoms on the same carbon atom are substituted by cyclopropyl

The c3-8 cycloalkyl-CL6 alkyl group includes, in particular, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, bicyclo [2.2. 1] heptylmethyl, dicyclopropylmethyl, (1-methyl-cyclopropyl)methyl, (1-ethyl-cyclopropyl)methyl, (1-cyclopentylmethyl-cyclo) Propyl)methyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 2,2-dicyclopropyl-ethyl, 2 -cyclohexyl-2-cyclopropyl-ethyl, 2-(1-methyl-cyclopropyl)ethyl, 1-cyclopropyl-1-methylethyl, 1-cyclopropylethyl, 1 -cyclobutylethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 3-cyclopropylpropyl, 3-cyclobutylpropyl, 3-cyclopentylpropyl, 3-cyclohexyl Propyl, 1-cyclopropyl-2-methylpropyl, 4-cyclopropylbutyl, 3-cyclopropylbutyl, 2-cyclopropylbutyl, 1-cyclopropylbutyl, 4- Cyclobutylbutyl, 4-cyclopentylbutyl, 4-cyclohexylbutyl, 5-cyclopropylpentyl and 6-cyclopropylhexyl. As defined in the above R6, the C3_8 cycloalkyl group as a group or as a part of a C3-8 cycloalkyl-Cualkyl group may be optionally substituted with one or more groups. The temple substrate is independently selected from Ci-4. House base, _ or aryl. The groups may be the same or different and may be located on any of the available carbon atoms of the c3-8 cycloalkyl group, including the carbon atoms that bond the ring to the remainder of the molecule. The An-Cw base in the definition of R6 includes Ari and An-Ci.4. -20- 200940529 ◊An-Ci-4 alkyl represents a group formed by substituting a hydrogen atom of a Cu alkyl group with an Ari group. Examples of the An-c!-4 alkyl group include, in particular, a benzyl group, a 1-phenylethyl group, a 2-phenylethyl group, a 1-phenyl-1-methylethyl group, a 3-phenylpropyl group, and 2 Phenyl-1-methylpropyl, wherein the phenyl groups are optionally substituted as defined above for Ari. Similarly, the aryl-C〇.4 alkyl group in the definition of R8 includes an aryl group and an aryl-C.4 alkyl group. The aryl-Ci-4alkyl group represents a group formed by substituting a hydrogen atom of a CL4 alkyl group with an aryl group. In the definition of φ ΑΓι2, two quaternary 8 groups or one R8 group and one Rs' group on the same atom or different atoms may be bonded to each other to form a -C2-5 alkylene group. The -C2.5 alkylene group means a linear alkylene chain having 2 to 5 carbon atoms, i.e., a group of the formula -(CH2)2.5. Examples of the two groups or one R8 group and one R8' group forming a -C2.5 alkyl group include, inter alia:

The hydroxy-CG-6 alkyl group includes a hydroxyl group and a hydroxy-Cw alkyl group. The hydroxy-Ci.6 alkyl group represents a group in which one or more hydrogen atoms of the Cu alkyl group are substituted by one or more hydroxyl groups. Preferably, the C -6 alkyl group is substituted with ~ hydroxy groups. Examples include, in particular, hydroxymethyl, 1-hydroxyethyl, -21 - 200940529 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl 2,3-Dihydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 2-hydroxybutyl and 1-hydroxybutyl. R8C02-C〇.6 Alkyl includes -(: 02118 and RsCOz-Cm alkyl.

The RsCOrCu alkyl group represents a group in which one or more hydrogen atoms of a Cu alkyl group are substituted by one or more -C02R8 groups. Preferably, the (^-6 alkyl group is substituted with a -co2R8 group. The r8so2nhco-c0-6 alkyl group includes -conhso2r8 and r8so2nhco- ❿ C 1.6.

The RjjSOzNHCO-Cm building group represents a group formed by substitution of one or more hydrogen atoms of a Cm alkyl group with one or more -conhso2r8 groups. Preferably, the Cu alkyl group is substituted with a -conhso2r8 group. (1H-tetrazol-5-yl)-CQ.6 alkyl includes (1H-tetrazol-5-yl)- and (1H-tetrazol-5-ylalkyl. (1H-tetrazol-5-yl) )-(:!.6 alkyl represents a group formed by substitution of one or more hydrogen atoms of a Cu alkyl group with one or more (1H-tetrazol-5-yl)- groups. Preferably, the Cu The alkyl group is substituted with one (1H-tetrazol-5-yl)- group. As defined by R6, any alkyl group may be optionally substituted with one or more halo groups. a C〇-6-yard group which is a part of a C3-8 cycloalkyl-CG-6 alkyl group and a C〇-4 alkyl group which is a part of the Ari-C〇-4 yard group. As described above, R7 represents a saturated monocyclic heterocyclic ring of 4 to 7 ring atoms and containing 1 oxygen atom and no other hetero atom. The heterocyclic ring may be bonded to the rest of the molecule via any available carbon atom. Example of the R7 ring-22- 200940529 includes especially:

Any R7 ring is optionally substituted with one or more groups. The groups are independently selected from the above C!.4 alkyl or halo, and the substituents may be located at any available position in the ring. Halo (or halogen for short) means fluorine, chlorine, bromine or iodine. Preferred halo groups are fluorine and chlorine and more preferably fluorine. The amine group in the definition of aryl represents nh2. "Saturated" means a group that does not contain any double or triple bonds. ❹ “Bridged bicyclic” system refers to a bicyclic system containing two common atoms (bridgeheads) connecting three non-cyclic chains (bridges), such that two bridges with a larger number of atoms form the main ring and have fewer atoms. The bridge is the "bridge." In the definition of NR2R3, 112 and R3 and the nitrogen atom to which they are bonded may together form a saturated 4 to 7 membered monocyclic heterocyclic ring containing up to 2 nitrogen atoms and no other heteroatoms. Examples include, in particular, tetrahydroindenyl, pyrrolidinyl, piperidinyl, piperazinyl and piperazinyl. In the definition of NR2R3, R2 and R3 and the nitrogen atom to which they are bonded may together form a bridged bicyclic group having 7 to 8 atoms. The bridged bicyclic -23- 200940529 base can contain up to 2 nitrogen atoms and does not contain any other heteroatoms. Examples include especially 2,5-diaza-bicyclo[2.2.1]heptyl and 2,5-diaza-bicyclo[2.2.2]octyl. In the definition of NR2R3, a "fused bicyclic" group refers to an 8- to 12-membered bicyclic system consisting of two adjacent rings sharing two common atoms. The fused bicyclic group may contain up to 2 nitrogen atoms at any available position and does not contain any other heteroatoms. Examples include, in particular, octahydropyrrolo[3,4-b]pyridyl, octahydropyrrolo[3,2-c]pyridyl, octahydropyrolo[l,2-a]pyrazinyl and eight Hydropyrrolo[3,4_c]pyrroline.

As the NR2R3 in the definition of the compound of the above formula I, the above three types of saturated heterocyclic rings (monocyclic, bridged bicyclic and fused bicyclic) are optionally substituted by one or more groups, and the groups are independently selected from the group consisting of Cu alkyl or NRaRb, except that the heterocyclic group contains 2 nitrogen atoms and is not substituted by the NRaRb group or contains 1 nitrogen atom and is substituted by the NRaRb group. Thus, if the heterocyclic ring contains 1 nitrogen atom, the ring must be substituted with an N RaRb group and may alternatively be substituted with one or more alkyl groups. If the heterocyclic ring contains 2 nitrogen atoms, shellfish! | Q The ring is optionally substituted with one or more Ch4 alkyl groups and the ring cannot be substituted with any NRaRb group. The substituents, if present, may be located at any available position of the ring, including the substituents which may be on the nitrogen atom if the alkyl group is an alkyl group. When η represents 2 or 3 or p represents 2 in the compound of formula I and thus more than one R4 group and more than one R5 group are present in the compound of formula I, each R4 and each Rs are independently selected from the above compounds of formula I The possible meanings of such substituents in the definitions are and thus the radicals may be the same or different. -24- 200940529 "Optionally substituted by one or more" means that a radical may be substituted by one or more (preferably 1, 2, 3 or 4, more preferably 1 or 2) substituents, Its base contains a usable position that is easily replaced. These substituents may be the same or different and may be located at any available position. Throughout the specification, 'treatment of a disease, 'treatment', and the like refers to the treatment of the disease and palliative or prophylactic treatment. For the purposes of the present invention, beneficial or desirable clinical results include, but are not limited to, φ to alleviate or ameliorate one or more symptoms, reduce the extent of the disease, stabilize the disease state (ie, not worsen), and prevent the disease from predisposed to the disease. Or in patients who do not show symptoms of the disease, delay or slow the progression of the disease, improve or palliative state of the disease and alleviate the pain (either in part or in whole). Those in need of treatment include those who are already suffering from a disease or condition and those who are predisposed to or susceptible to the disease or condition. The "amino group-protected form" relating to the compound of the formula HNR2R3 (III) means any form of the compound oxime in which the amine-type nitrogen atom is protected by a protecting group. Accordingly, the invention relates to compounds of formula I as defined above. In another preferred embodiment, the invention is directed to a compound of formula I, wherein L represents (i). In another preferred embodiment, the invention is directed to a compound of formula I, wherein R! represents (Π). In another preferred embodiment, the invention relates to a compound of formula I, wherein R4 and R5 are each independently selected from fluorene or C^-4 alkyl and additionally R4 or r5, which may represent an aryl or C3-8 ring. Alkyl-CG-6 alkyl. In another preferred embodiment, the invention is directed to a compound of formula I, wherein R4 and R5 are each independently selected from the group consisting of hydrazine or Cu alkyl and the other R4 or R5 group may represent an aryl group. In another preferred embodiment, the invention is directed to a compound of formula I, wherein R4 and R5 are each independently selected from hydrazine or C!-4 alkyl. In another preferred embodiment, the invention is directed to a compound of formula I, wherein R4 and R5 are each independently selected from the group consisting of hydrazine or methyl. In another preferred embodiment, the invention is directed to a compound of formula I, wherein R4 and R5 represent hydrazine. In another preferred embodiment, the invention relates to compounds of formula I, wherein η represents 1 or 2. In another preferred embodiment, the invention is directed to a compound of formula I wherein η is 1. In another preferred embodiment, the invention is directed to a compound of formula I wherein η is 2. In another preferred embodiment, the invention is directed to a compound of formula I, wherein Ρ represents hydrazine or 1. In another preferred embodiment, the invention is directed to a compound of formula I, wherein ρ is 0. In another preferred embodiment, the invention is directed to a compound of formula I wherein lanthanide 1 is used. In another preferred embodiment, the invention is directed to a compound of formula I wherein in group (i) η represents 1 or 2 and in group (ii) ρ represents 0 or 1. In another preferred embodiment, the invention is directed to a compound of formula I, wherein -26-200940529 R! represents (〇 and n represents 1. In another preferred system, the invention relates to formula I, Ri represents (i), η represents 1 and R4 and R5 are each independently selected alkyl. In another preferred system, the present invention relates to Formula I

Ri represents (i), η represents 1 and R4 and R5 are independently selected 〇Q in another preferred system.

Ri represents (i), η represents 1 and IU and R5 represent Η. In another preferred embodiment, the invention relates to a phenyl group of the formula I, optionally substituted by one or more groups, selected from the group consisting of alkyl, halo, (^-4 alkoxy, Cl-4 halogenated alkoxy In another preferred system, the invention relates to a phenyl group substituted by a group selected from the group consisting of hydroxyindole, .R8C02-C〇.6, R8S02NHCO-C〇.6 yard base,

Base)-C〇_6, s-C, s, s, s, s, s, s, s, s, s, s, Oxygen.

In another preferred embodiment, the invention relates to a phenyl group substituted by a group selected from the group consisting of hydroxy^, -conr8r8, _s〇2R8' or -Nr8C〇R8, and the group is a substituent which is selected from a Ci4 alkyl group, a B compound, wherein a compound or a C..4 compound, wherein a compound or a methyl compound thereof, wherein the group is a mono group, c1 a compound of the formula - wherein the group -C〇.6 alkyl (1H-tetrazole-δ-βΟζΚν, _ 8 R 8 ^ and the group is a C 1 -4 compound, wherein g -C〇.6 The alkyl group is optionally substituted into a _ or Ci. 4 -27-200940529 oxy group. In another preferred system, the invention relates to a compound of formula I, wherein An represents a phenyl group substituted at the meta position with a group, the group Selected from hydroxy-c〇-6 alkyl, r8co2-c〇.6 alkyl, R8S〇2NHC〇_c. 6 alkyl, (1H-tetrakis-5-yl)-C〇.6 alkyl, { (10) 尺山' _s〇2NR8R8, _S02R8, -NI^SO山, ' _NR8C〇NR8R8, NR8c〇R8 or NRSR8, and the group is optionally substituted with a base selected from the group consisting of cuane Base, halogen or Cl-4 alkoxy. In another preferred system, the invention relates to a compound wherein Ari represents a phenyl group substituted with a group at the meta position selected from the group consisting of a thiol-C〇-6 alkyl group, -CONR8R8, -S〇2R8, or _Nr8C〇r8, and the group is optionally selected Further substituted with a group selected from a c14 alkyl group, a halogen or a CL4 alkoxy group. In another preferred system, the invention is directed to a compound of the formula wherein An represents a meta group substituted with a group. Phenyl, the group being selected from the group consisting of hydroxy-C〇-6, -CONR8R8, -S02Rs, or -NR8COR8. In another preferred embodiment, the invention relates to a compound of the formula wherein R6 represents a C4-8 alkyl group. a group of c3_8 cycloalkyl-C()-6 alkyl or Ari_Co-4 alkyl, wherein any alkyl group is optionally substituted with - or a plurality of halo groups (preferably fluorine) and the C3-8 ring The alkyl group is optionally substituted with one or more substituents which are selected solely from the group consisting of Cl. 4, Illustrative (preferably fluoro) or aryl. In another preferred system, the invention is A compound of formula I, wherein R6 represents one selected from Ci-8 alkyl, c3-8 cycloalkyl-Co-!alkyl or Ar"-28 - 200940529

a group of a Co-2 alkyl group, wherein any alkyl group is optionally substituted with one or more halo groups (preferably fluorine) and the C3.8 cycloalkyl group is optionally substituted with one or more substituents, The substituents are independently selected from the group consisting of Ci-4 alkyl, halo (preferably fluorine) or aryl. In another preferred embodiment, the invention is directed to a compound of formula I, wherein Κ·6 represents a group selected from the group consisting of Ci_8, C3_8 ring-based Cj-ι or Ari_C〇-2 alkyl. In another preferred embodiment, the invention relates to a compound of formula I, wherein R6 represents a group selected from the group consisting of C4.5 alkyl, C3_6 ring-homo-co-i alkyl or Απ-C 0 -2. In another preferred embodiment, the invention relates to a compound of formula I, wherein Κ·6 represents a group selected from the group consisting of Ci.5, C3-8 ring-based, C〇-i, or Απ-Cod alkyl. Any one of the alkyl groups may be optionally substituted with one or more halo groups (preferably fluorine) and the C3.S cycloalkyl group may be optionally substituted with one or more substituents which are independently selected From ciΜ alkyl, halo (preferably fluorine) ruthenium or aryl. In another preferred embodiment, the invention relates to a compound of formula I, wherein R6 represents a group selected from the group consisting of Cu alkyl, c3.8 cycloalkyl-Cod alkyl or An-Co-i alkyl. In another preferred embodiment, the invention relates to a compound of formula I, wherein R6 represents a group selected from the group consisting of Cu alkyl or C3-8 cycloalkyl-CG.6 alkyl, wherein any alkyl group optionally passes through one or more Substituted halo (preferably fluoro) and optionally substituted by one or more substituents independently selected from Ci_4, halo (preferably fluoro) or aryl . -29-200940529 In another preferred embodiment, the invention relates to a compound of formula I, wherein R6 represents a group selected from the group consisting of Cu alkyl or C3-8 cycloalkyl-Cw alkyl, wherein any alkyl group optionally passes through - Or a plurality of halo groups (preferably fluorine) substituted and the c3_8 cycloalkyl group optionally substituted by one or more substituents independently selected from the group consisting of 1-4 alkyl groups, halogens (preferably fluorine) ) or aryl. In another preferred embodiment, the invention relates to a compound of formula I, wherein R6 represents a group selected from the group consisting of Cu alkyl or C3-8 cycloalkyl-Cod alkyl. In another preferred embodiment, the invention relates to a compound of formula I, wherein Re represents a group selected from C4-5 alkyl or C3-8 cycloalkyl-Cm alkyl. In another preferred embodiment, the invention relates to a compound of formula I, wherein R6 represents a group selected from the group consisting of Ci8 or 〇3_6 ring-based-Co-, wherein any alkyl group optionally One or more halo groups (preferably fluorine) are substituted and the C3_6 cycloalkyl group is optionally substituted by one or more substituents independently selected from Ci-4 alkyl, halo (preferably fluorine) Or aryl. In another preferred embodiment, the invention relates to a compound of formula I, wherein R.sup.6 represents a group selected from the group consisting of Cl.8 or C3.6 ring-based-Co-! fluorenyl. In another preferred embodiment, the invention is directed to a compound of formula I, wherein R·6 represents an is from a C4.5 or a C3-6 ring-based base. In another preferred embodiment, the invention relates to a compound of formula I, wherein R6 represents a group derived from a Ci-s sulfhydryl or a C3-6 ring-based-Ci compound. In another preferred embodiment, the invention relates to a compound of formula I, wherein R.sup.6 represents a group selected from the group consisting of C4.5 or C3_6. In another preferred embodiment, the invention relates to compounds of formula I, wherein r6 represents isobutyl or cyclopropylmethyl. -30- 200940529 In another preferred embodiment, the invention relates to a compound of formula I, wherein R6 represents a group selected from C3-8 cycloalkyl-CQ-6 alkyl or An-Co-4 alkyl, wherein any alkane The substituent is optionally substituted with one or more halo groups (preferably fluorine) and the C3_8 cycloalkyl group is optionally substituted with one or more substituents independently selected from (^-4 alkyl, Halogen (preferably fluorine) or aryl. In another preferred system, the invention relates to compounds of formula I, wherein R6 represents one selected from C3-8 cycloalkyl-Co.i alkyl or Ari-CG-2 a Q group of an alkyl group, wherein any alkyl group is optionally substituted with one or more halo groups (preferably fluorine) and the C3_8 cycloalkyl group is optionally substituted with one or more substituents, such substituents Is independently selected from the group consisting of Ci-4 alkyl, halo (preferably fluorine) or aryl. In another preferred system, the invention relates to a compound of formula I, wherein R6 represents one selected from C3.8 cycloalkyl-Cw Alkyl or Ari-CQ.2 alkyl group. In another preferred system, the invention relates to a compound of formula I, wherein R6 represents one selected from C3-8 cycloalkyl-Cm alkyl or An-Co-i Alkyl group of an alkyl group. In another preferred embodiment, the invention relates to a compound of formula I, wherein R6 represents a group selected from C3-8 cycloalkyl-CU6 alkyl or An-Co-4 alkyl, wherein any alkyl group optionally One or more halo groups (preferably fluorine) are substituted and the C3_8 cycloalkyl group is optionally substituted by one or more substituents independently selected from the group consisting of Ci.4 alkyl, halo (preferably Fluoro) or aryl. In another preferred embodiment, the invention relates to a compound of formula I, wherein IU represents a group selected from C3-8 cycloalkyl-Cw alkyl or Ari-CG-2 alkyl, wherein The monoalkyl group may be optionally substituted with one or more halo groups (preferably fluorine) from -31 to 200940529 and the C3-8 cycloalkyl group may be optionally substituted with one or more substituents which are Independently selected from the group consisting of a mountain alkyl group, a halogen (preferably fluorine) or an aryl group. In another preferred system, the invention relates to a compound of formula I, wherein R6 represents a compound selected from the group consisting of C3-8 cycloalkyl-Ci alkane a group of an alkyl group or an An-Ci alkyl group, wherein any alkyl group is optionally substituted with one or more halo groups (preferably fluorine) and the c3-8 cycloalkyl group is optionally substituted with one or more substituents, Such Based substituents independently selected ¢ ^ -4 alkyl, halo (preferably fluoro) or aryl.

In another preferred embodiment, the invention relates to a compound of formula I, wherein Q R6 represents a group selected from the group consisting of c3-8 cycloalkyl-Ci alkyl or Απ-Cl alkyl, in another preferred system, the invention A compound of formula I, wherein R6 represents a group selected from the group consisting of a c3-6 cycloalkyl-Ci alkyl group or an Ari-Ci alkyl group, in another preferred system, the invention is directed to a compound of formula I, wherein R6 represents optionally one Or a halogen alkyl group (preferably fluorine) substituted with a Cu alkyl group. In another preferred embodiment, the invention relates to compounds of formula I, wherein R6 represents an alkyl group optionally substituted with one or more halo groups, preferably fluoro. In another preferred embodiment, the invention relates to compounds of formula I, wherein Re represents a Cu alkyl group. In another preferred embodiment, the invention is directed to compounds of formula I, wherein Re represents a c4-5 alkyl group optionally substituted with one or more halo groups, preferably fluoro. -32- 200940529 In another preferred embodiment, the invention relates to compounds of formula I, wherein R6 represents a C4-5 yard group. In another preferred embodiment, the invention relates to compounds of formula I, wherein R6 represents isobutyl. In another preferred embodiment, the invention relates to a compound of formula I, wherein Re represents Cs_8 ring-yard-CQ.6 alkyl, wherein the alkyl group is optionally substituted by one or more halo groups, preferably fluoro. And the c38 cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of Ci.4 alkyl, halo (preferably fluorine) or aryl. In another preferred embodiment, the invention relates to a compound of formula I, wherein R6 represents C3_8 cycloalkyl-CD-1 alkyl, wherein the alkyl group is optionally substituted with one or more halo groups, preferably fluoro, and The C3-8 cycloalkyl group is optionally substituted with one or more substituents which are independently selected from the group consisting of ct-4 alkyl, halo (preferably fluorine) or aryl. In another preferred embodiment, the invention relates to compounds of formula I, wherein 〇 R6 represents C3_8 cycloalkyl-Co-ialkyl. In another preferred embodiment, the invention relates to compounds of formula I, wherein R6 represents c3_6 cycloalkyl-Co-ialkyl, wherein the alkyl group is optionally substituted by one or more halo groups, preferably fluoro And the c3.8 cycloalkyl group is optionally substituted with one or more substituents independently selected from G-4 alkyl, halo (preferably fluorine) or aryl. In another preferred embodiment, the invention relates to compounds of formula I, wherein R6 represents C3-6 cycloalkyl-Co.i alkyl. In another preferred embodiment, the invention relates to compounds of formula I, wherein -33-200940529 r6 represents c3.8 cycloalkyl-C.6 alkyl, wherein the alkyl group is optionally substituted with one or more halo groups ( Preferably, the fluoro) is substituted and the c3-8 cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of -4 alkyl, halo (preferably fluoro) or aryl.

In another preferred embodiment, the invention relates to the compound of formula I wherein r6 represents c3-8 cycloalkyl-C, alkyl, wherein the alkyl group is optionally substituted by one or more halo groups (preferably fluorine) Substituted and the <:3.8 cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of q.4 alkyl, halo (Q preferably fluoro) or aryl. In another preferred embodiment, the invention is directed to compounds of formula I wherein R6 represents a C3-8 cycloalkyl-Ci alkyl group. In another preferred embodiment, the invention is directed to compounds of formula I wherein R6 represents c3-6 cycloalkyl-C, alkyl. In another preferred embodiment, the invention is directed to a compound of formula I wherein R6 represents a cyclopropylmethyl group.

In another preferred embodiment, the invention is directed to a compound of formula I wherein U R6 represents an Ari-CG 4 alkyl group, wherein the alkyl group is optionally substituted with one or more halo groups, preferably fluoro. In another preferred embodiment, the invention is directed to a compound of formula I, wherein Rfi represents an An-Co-2 alkyl group, wherein the alkyl group is optionally substituted with one or more halo groups, preferably fluoro. In another preferred embodiment, the invention is directed to a compound of formula I, wherein R6 represents An-c. ^院基. In another preferred embodiment, the invention is directed to the compound of formula I wherein -34-200940529 Κ·6 represents Ar 1 -Cq^alkyl. In another preferred embodiment, the invention relates to compounds of formula I, wherein R6 represents An-q alkyl. In another preferred embodiment, the invention relates to a compound of formula I, wherein R6 represents an Ah-Cu alkyl group, wherein Ari represents a phenyl group substituted with a group selected from the group consisting of hydroxy-C〇.6 alkyl, r8c〇 2-C〇-6 alkyl, R8S02NHCO-C〇_6 alkyl, (1H-tetrazol-5-yl)-C〇-6 alkyl, -0CONR8R8, -SO2NR8R8, -SO2R8', -NR8SO2R8, —NR 8 — — — — — — — — — — — — — — — — — — — — a group selected from the group consisting of hydroxy-C〇-6 alkyl, -CONR8R8, -S02R8' or -NR8COR8, and the group is optionally further substituted with a group selected from the group consisting of Cl-4 alkyl, halogen or C 1 - 4 hospitaloxy. In another preferred embodiment, the invention relates to a compound of formula I, wherein 〇R6 represents an Ari-CQ-2 alkyl group, wherein Ari represents a phenyl group substituted at the meta position with a group selected from hydroxy-Co- 6 alkyl, R8C02-C〇_6 alkyl, R8S02NHC0-CQ.6 alkyl, (1H-tetrazol-5-yl)-CQ.6 alkyl, _ CONRgRs, -S02NR8R8, -S02R8, , -NR8S02R8 , NR8CONR8R8, -NR8COR8 or -NR8R8, and the group is optionally substituted with a group selected from C, 4 alkyl, halogen or Cl_4 alkoxy; and preferably Ar, Representing a phenyl group substituted with a group at a meta position selected from hydroxy-C〇-6 alkyl, _CONR8R8, -S〇2r8, or _NR8COR8, and the group is optionally further substituted with a group, Substituting -35- 200940529 is selected from the group consisting of Cl-4, halogen or d.4. In another preferred embodiment, the invention relates to a compound of formula I, wherein R6 represents An-c^alkyl, wherein Ari represents a phenyl substituted with a radical - the radical is selected from hydroxy-CG.6 alkyl, R8c 〇2_C()_6 alkyl, R8S02NHCO-C〇-6 alkyl, (1H_tetrazole_5_yl)-C〇6 alkyl, · CONRgRg, _S02NR8R8, _s〇2r8, _nr8S02R8, -NR8CONR8R8, -NR8COR And NR8R8, and the group is optionally further substituted with a group selected from the group consisting of a c14 alkyl group, a halogen or a c14 alkoxy group; and preferably An represents a phenyl group substituted with a group selected from the group consisting of Or a base further optionally substituted with a group selected from the group consisting of a c14 alkyl group, a halogen or a C 1 -4 group, optionally a further group substituted with a group of -C〇-6, _c〇NR8R8, -S〇2R8, or -NR8COR8 Alkoxy. In another preferred embodiment, the invention relates to a compound of formula I, wherein R6 represents An-C!alkyl' wherein Ari represents a phenyl group substituted at the meta position by a radical selected from the group consisting of hydroxy-C〇- 6 alkyl, r8co2-c〇.6 alkyl, R8SO2NHCO-C0_6, (1H-tetradec-5-yl)-C0.6, _ CONR8R8, -S02NR8R8, -S02R8, -nr8so2r8, ' NR8CONR8R8, -\!^8 (: 〇118 or -\118118, and the group is optionally substituted with a substituent selected from the group consisting of C1_4 alkyl, halogen or C1 4 alkoxy; and preferably Ar, represented by a phenyl group substituted by a radical at a meta position selected from hydroxy-CG.6 alkyl, -C0NRsR8, _s〇2R8, or NR8COR8' and optionally substituted by a radical The substituent is selected from the group consisting of Ci. 4 alkyl, halo or Cl 4 alkoxy. In another preferred system, the invention relates to a compound of formula I, wherein -36-200940529 R 6 represents A r ! In the preferred system, the present invention relates to the compound of formula 1 Ri represents (i); η represents 1; R4 and R5 represent Η; and represents one selected from Cm alkyl, C3.8 cycloalkyl-C< An-Co-2 alkane Based on the base, any alkyl group can be selected Φ by a group (preferably fluorine) and the C3-8 cycloalkyl group optionally substituted by a substituent, such substituent is independently selected from a C i _4 alkyl, | fluoro) or aryl. In another preferred embodiment, the invention relates to the compound of formula I, Ri, which represents (i); η represents 1; R4 and R5 represent Η; and IU represents one selected from the group consisting of Cu alkyl, c3-8 cycloalkyl-Cc ❹ Ari-C 〇-2 base of the hospital. In another preferred embodiment, the present invention relates to the compound of formula I, Ri, which represents (1); η represents 1; R4 and R5 represent Η; and R6 represents one selected from C4-5 alkyl, c3.6 cycloalkyl-C() An- The base of the Co-2 hospital. In another preferred embodiment, the present invention relates to the compound of formula I, wherein R represents (i); wherein I _ 1 or a plurality of halogens or a plurality of _ (preferably 'where decyl or 'where Ί Alkyl or 'where -37- 200940529 η represents 1; R4 and R5 represent Η;

Κ·6 represents a base selected from the group consisting of Ci.8 or C3-6 ring-based bases, and any of the bases may optionally pass one or more halo groups (preferably fluorine). Substituted and the c3_6 cycloalkyl is optionally substituted by one or more substituents independently selected from the group consisting of Ci-4, halo (preferably fluoro) or aryl. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents (i); η represents 1; R4 and R5 represent oxime; and R6 represents a group selected from a Cu alkyl group or a c3-6 cycloalkylalkyl group. . In another preferred embodiment the invention relates to a compound of formula I, wherein R I represents (i); η represents 1;

R4 and R5 represent Η; and R6 represents a group selected from C4·5 alkyl or c3-6 cycloalkyl-Cgi alkyl. In another preferred embodiment, the invention is directed to compounds of formula I, wherein R1 represents (i); η represents 1; R4 and Rs represent oxime; and L represents isobutyl or cyclopropylmethyl. In another preferred embodiment, the invention is directed to a compound of the formula wherein -38-200940529 Μ represents (i); n represents 1; and R5 represents Η;

Re represents a group selected from a C3-8 cycloalkyl-CQ-6 alkyl group or an Ari-CQ-4 alkyl group, wherein any alkyl group is optionally substituted with one or more halo groups (preferably fluorine) and the C3- 8-cycloalkyl optionally substituted with one or more substituents

'The substituents are independently selected from C!-4 alkyl, halo (preferably fluoro) or aryl oxime in another preferred system, and the invention relates to compounds of formula I, wherein Ri represents (i); n represents 1 ; R 4 and R 5 represent an anthracene, and h represents a group selected from a C 3-8 cycloalkyl-Cm alkyl group or an Ari-CG 2 alkyl group. In another preferred embodiment, the invention is directed to a compound of formula I, wherein Ri represents (1); η represents 1; 尺 4 and R5 represent Η; and 尺6 represents a 'selected from 匚3-8 ring-based-〇^ 1.6 院基基或八1"1-€()-4 院基基基, any of which may be optionally substituted by one or more halo groups (preferably _) and the c3.8 cycloalkyl group may be Optionally substituted with one or more substituents, wherein the substituents are independently selected from the group consisting of Cu4 alkyl, halo (preferably fluoro) or aryl, based on another preferred system, the invention is directed to a compound of formula I, wherein -39 - 200940529

Ri represents (i); n represents 1; R4 and R5 represent Η; and represents a group selected from the group consisting of C3-6 ring-based-Cl-based or Ar!. In another preferred embodiment, the invention is directed to a compound of formula I, Ri represents (i); η represents 1; R4 and R5 represent oxime; and R6 represents optionally one or more halo groups (preferably fluorine C) 1 - 8 院基。 In another preferred system, the invention relates to a compound of formula I, Ri represents (i); η represents 1; R4 and R5 represent oxime; and R 6 represents C.. 5 alkyl, preferably C 4 _ 5 alkyl. In another preferred system, the invention relates to a compound of formula I, R! represents (i); η represents 1; R4 and R5 represent Η; and r6 represents isobutyl. In a preferred system, the invention is directed to a compound of formula I, Ri represents (i); η represents 1; -C!alkyl wherein β is substituted by ❹ wherein 40-200940529 R4 and R5 represent Η; and R6 represents C3 a -8 cycloalkyl-C^alkyl group, wherein the alkyl group is optionally substituted with one or more halo groups (preferably fluorine) and the C3_8 cycloalkyl group is optionally substituted with one or more substituents, The substituents are independently selected from (^-4), halo (preferably fluoro) or aryl. In another preferred embodiment, the invention is directed to a compound of formula I, wherein R! represents (i); f) 11 represents 1; R4 and R5 Table [eta]; and R6 represents a cycloalkyl group -Co c3.6 group.!. In another preferred system, the invention relates to a compound of formula I, wherein

Ri represents (i); η represents 1; R4 and R5 represent Η; and R6 represents cyclopropylmethyl. G In another preferred system, the invention relates to a compound of formula I, wherein

Ri represents (i); η represents 1; R4 and R5 represent Η; and R6 represents C3_8 cycloalkylalkyl, wherein the alkyl group is optionally substituted by one or more halo groups (preferably fluorine) and the C3_8 The cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of a mountain-4 alkyl group, a halogen (preferably fluorine) or an aryl group. In another preferred embodiment, the invention relates to compounds of formula I, wherein -41 - 200940529 R 1 represents (i); n represents 1; R4 and R5 represent Η; and R6 represents C3.8 cycloalkyl-C! base. In another preferred embodiment, the invention relates to a compound of the formula ,, wherein Ri represents (i); η represents 1; R4 and R5 represent Η; and ❿ R 6 represents A r 1 - C 〇 · 2 院. In another preferred embodiment, the invention relates to compounds of formula I, wherein Ri represents (i); η represents 1; R4 and R5 represent oxime;

Re stands for An-C. -2 alkyl 'where Ari represents a group substituted by a group'. The group is selected from the group consisting of hydroxy-C〇-6 alkyl, r8C〇2_Cg_6 alkyl, R8S02NHC0-C().6 alkyl, (1H-four Azul-5-yl)_c"alkyl, - ❹ C ONRsRs, -s〇2NR8Rs, -S02R8, _nr8S02R8', _NR8CONR8R8, -NR8COR8 or -NR8R8, and the group is optionally further substituted with a base, The substituent is selected from a C1_4 alkyl group, a halogen or a. "Alkoxy, and preferably ΑΓ represents a phenyl substituted with a radical selected from the group consisting of thio-C〇-6, -CONR8R8, _s〇2r8, or _NR8C〇R8, and the group Optionally, further substituted with a group selected from C14 alkyl, halo or decyloxy. In another preferred system, the invention is directed to a compound of formula Z, wherein -42- 200940529

Ri represents (i); n represents 1; R4 and R5 represent Η; and R·6 represents Ari-C. -2alkyl' wherein 八 represents a radical substituted with a benzyl group at the meta position. The group is selected from the group consisting of hydroxy-C〇_6 alkyl, R^COyCo.6 alkyl, R8S02NHCO-C〇-6 alkane a group, (1H-tetrazol-5-yl)_C()_6 alkyl, CONRgRs, -S Ο2NR8Rg, -S 02R8, -NR8 S 〇2 Re ', ❹ NR8CONR8R8, -NR8C〇R8 or -NR8R8, The group may be optionally substituted with a group selected from the group consisting of a mountain alkyl group, a halogen group or a c14 prismoxy group; and preferably ΑΓι represents a phenyl group substituted with a group at the meta position. The group is selected from the group consisting of a thio-C -6-6, -C Ο NR 8 R 8 , _ § r 2 r 8, or NR 8COR 8 , and the group is optionally further substituted with a group selected from C !-4 alkyl, halo or d-4 alkoxy. In another preferred embodiment, the invention is directed to a compound of formula I, wherein R1 represents (i); ❾ η represents 1; R4 and R5 represent Η; and Κ·6 represents An-C: a hospital base. In another preferred system, the invention relates to a compound of formula I, wherein

Ri represents (i); η represents 1; R4 and R5 represent Η; and R·6 represents Au-Ci alkyl 'where Ari represents a radical substituted by a radical'. The radical is selected from the group -C 0 . Affiliation, R 8 C 〇2 - C 〇6 院, -43- 200940529 R8S〇2NHC〇-C〇_6 alkyl, (1H-tetrazol-5-yl)-C()_6 alkyl,- CONRgRg, -S02NR8R8, -s〇2r8, _NR8S〇2r8, -NR8CONR8R8, -NR8COR8 or -NR8R8, and the group is optionally further substituted with a group selected from the group consisting of C1_4 alkyl, halogen or C1- 4 alkoxy; and preferably An represents a phenyl group substituted by a group selected from the group -Cq-6, -CONR8R8, _s〇2R8, or _nr8COR8, and the group optionally further Substituted by a radical selected from the group consisting of c14 alkyl, halo or CL4 alkoxy. In another preferred embodiment, the invention relates to compounds of formula I, wherein R! represents (i); η represents 1; R4 and R5 represent Η; and R6 represents Ari-Ci alkyl' wherein Ari represents meta-position a group-substituted phenyl group which is selected from the group consisting of hydroxy-CM alkyl, R8C〇2_Cg_6 alkyl 'R8S02NHC〇-C〇.6 alkyl, (1H-tetrazol-5-yl)-C〇_6 alkyl , _ CONR8R8, -S02NR8R8, -S〇2R8, -NR8S02R8, _NR8CONR8R8, -NR8COR8 or -NR8R8, and the group is optionally substituted with a substituent selected from the group consisting of Ci_4, halogen Or C^-4 alkoxy; and preferably An represents a phenyl group substituted at the meta position with a group selected from the group consisting of hydroxy-CG.6 alkyl, _c〇NR8R8, -S〇2R8, or. NR8COR8' and the group is optionally substituted with a radical selected from the group consisting of Ci.4 alkyl, halo or Cl_4 alkoxy. In another preferred embodiment, the invention relates to a compound of formula I, wherein R.sup.2 and R.sup.3, together with the nitrogen atom to which they are bonded, form a saturated -44-200940529 heterocyclic group selected from: a heterocyclic group containing 2 nitrogen atoms and no other hetero atom, wherein the heterocyclic group is optionally substituted by one or more (^-4 alkyl groups; and (ii) contains 1 nitrogen atom and is not a heterocyclic group containing any other hetero atom, wherein the heterocyclic group is substituted with an NRaRb group and optionally substituted with one or more mountain-4 alkyl groups; wherein the heterocyclic groups (i) and (ii) are It is a 4- to 7-membered single ring, a 7 to 80 member bridged double ring or an 8 to 12 member fused double ring; or R2 represents a hydrazine or a <^-4 alkyl group, and R3 represents a tetrahydroindenyl group, and a D ratio is slightly a steep, piperidinyl or azamidyl group optionally substituted by a plurality of Cl 4 alkyl groups. In another preferred system, the invention is directed to a compound of the formula wherein R 2 and R 3 and The bonded nitrogen 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 contain up to 2 nitrogen atoms And does not contain Any other hetero atom and optionally substituted by one or more substituents independently selected from C..4 alkyl or NRaBb, except that the heterocyclic group contains two nitrogen atoms and is not substituted or contained by the NRaRb group i nitrogen atoms and substituted by NRaRb groups. In another preferred system, the invention relates to compounds of formula I, wherein R2 and R3 together with the nitrogen atoms to which they are bonded form a saturated heterocyclic group selected from: (heterocyclic group containing 2 nitrogen atoms and containing no other hetero atom, wherein the heterocyclic group is optionally substituted by one or more Cl 4 alkyl groups; and (11) contains 1 nitrogen atom and does not contain any a heterocyclic group of another hetero atom, -45- 200940529 wherein the heterocyclic group is substituted with an NRaRb group and optionally substituted with one or more Cu alkyl groups; wherein the heterocyclic groups (i) and (ii) are 4 to 7 membered monocyclic, 7 to 8 membered bridged bicyclic or 8 to 12 membered fused bicyclic. In another preferred system, the invention is directed to a compound of formula I wherein Ra and Rb each represent hydrazine or cumane In another preferred embodiment, the invention relates to compounds of formula I, wherein each of Ra and Rb represents hydrazine, methyl or ethyl. In a preferred system, the invention relates to a compound of formula I, wherein each of Ra and Rb represents a hydrazine or a methyl group. In another preferred system, the invention relates to a compound of formula I, wherein Ra represents hydrazine and Rb represents hydrazine or Cu In another preferred embodiment, the invention relates to a compound of formula I, wherein Ra represents hydrazine and Rb represents hydrazine, methyl or ethyl. In another preferred system, the invention relates to a compound of formula I, wherein Ra Representative of hydrazine and Rb represents hydrazine or methyl. In another preferred embodiment, the invention relates to compounds of formula I, wherein Ra represents hydrazine and Rb represents a Cu alkyl group. In another preferred system, the invention relates to a compound of formula I Wherein Ra represents Η and Rb represents methyl or ethyl. In another preferred embodiment, the invention relates to compounds of formula I, wherein Ra represents deuterium and Rb represents methyl. In another preferred embodiment, the invention is directed to a compound of formula I, wherein Ra and Rb represent hydrazine. In another preferred embodiment, the invention is directed to a compound of formula I wherein r2 and r3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of:

Wherein Ra and Rb are as defined in the above formula I compounds and Re represents Η or Cu alkyl, and preferably Re represents Η. In another preferred embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) to (h), and Ra, Rb and Re each represents hydrazine or a C1 _4 alkyl group, and preferably Ra, Rb and Rc each represent a hydrazine or a methyl group. In another preferred embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) or (b) wherein Ra and Rb are As defined above in the compound of formula I, -47 to 200940529 and Re represents hydrazine or Ci 4 alkyl, and preferably Re represents hydrazine. In another preferred embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) or (b) and Ra, Rb and Re each represents η or Cm alkyl' and preferably Ra, Rb and Re each represent hydrazine or methyl. In another preferred embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) or (b) 'Ra stands for Η, Rb Represents Η or Cm alkyl and Re stands for © Η. In another preferred embodiment, the invention relates to a compound of formula I, wherein R2 and R.sup.3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (3) or (b) 'Ra stands for H Rb represents hydrazine or methyl and Re represents H. In another preferred embodiment, the invention relates to a compound of formula I, wherein R2 and R3 and the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) or (b) 'Ra stands for H' Rb represents a methyl group and rc represents η. In another preferred embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic ring of formula (a)

Ra

Rb

Rc (8) -48 - 200940529 wherein Ra and Rb are as defined above for the compound of formula I and Re represents Η or Ci-4, and preferably Rc represents Η. In another preferred embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (a), and Ra, Rb and Re each represent Η Or Cm alkyl, and preferably Ra, Rb and R. Each represents Η or methyl. In another preferred embodiment, the invention relates to a compound of formula I, wherein R 2 and R 3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (a), Ra represents deuterium, and R b represents deuterium or Cm alkane. And Rc stands for Η. In another preferred embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with the nitrogen atom bonded to the temple form a saturated heterocyclic group of formula (a), and Ra represents Η 'Rb represents Η or methyl And rc stands for Η. In another preferred embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (a), Ra represents hydrazine, Rb represents methyl and Rc Represents η or methyl. In another preferred embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (a), Ra represents deuterium, and Rb represents methyl and Rc stands for methyl. In another preferred embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (a), and Ra represents Η 'Rb represents methyl and Re Represents η. In another preferred embodiment, the invention relates to compounds of formula I, wherein R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (b) -49- 200940529

Ra\ /Rb

(b) wherein Ra and Rb are as defined in the above formula I compounds and Re represents H or Cu alkyl, and preferably represents hydrazine. In another preferred embodiment, the invention relates to a compound of formula I wherein _R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (b) and Ra, Rb and Rc each represent Anthracene or Cm alkyl, preferably Ra, Rb and R. Each represents a hydrazine or a methyl group, and more preferably, Ra and Rb each represent a hydrazine or a methyl group and Rc represents η. In another preferred embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (b) 'Ra represents Η, and Rb represents η or Cm Alkyl and R. Representative Η. In another preferred embodiment, the invention relates to a compound of formula I, wherein 〇R2 and RS together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (b) 'Ra represents H' Rb represents Η or A Base and Re represents H. In another preferred embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (b) 'Ra represents Η, Rb represents methyl and Rc Represents η. In another preferred embodiment, the invention relates to compounds of formula I, wherein R 2 represents ^ or c, .4 alkyl and where 3 represents tetrahydroindenyl, pyrrolidinyl, piperidinyl or azamidin' The group is optionally substituted by one or more Ci4 alkyl-50-200940529, and preferably R2 represents hydrazine and R3 represents 1-methyl-pyrrolidin-3-yl hydrazine in another preferred system The invention relates to the compound of formula 1 wherein I represents a group selected from (1) or (U); R2 and R3 together with the nitrogen atom to which they are bonded may form a 4 to 7 membered monocyclic ring, a 7 to 8 membered bridged double ring or 8 to 12 member-fused bicyclic saturated heterocyclic group, wherein the heterocyclic group may contain up to 2 nitrogen atoms and does not contain any other hetero atom and optionally one or more independently selected from C^- Substituted with a substituent of 4 alkyl or NRaRb, except that the heterocyclic group contains 2 nitrogen atoms and is not substituted by NRaRb group or contains 1 nitrogen atom and is substituted by NRaRb group: and R6 represents one selected from the group consisting of -8 alkyl Or a C3_8 cycloalkyl-CG-6 alkyl group, wherein any alkyl group is optionally substituted with one or more halo groups (preferably fluorine) and the C3_8 cycloalkyl group is optionally one or more Replace Substituent, the other substituent is independently selected from Ci.4 alkyl, halo (preferably fluoro) or aryl. Q In another preferred system, the invention relates to a compound of formula I, wherein

Ri represents a group selected from (〇 or (ii); R2 and R3 together with the nitrogen atom to which they are bonded may form a 4 to 7 membered single ring '7 to 8 member bridged double ring or 8 to 12 member fused a bicyclic saturated heterocyclic group wherein the heterocyclic group may contain up to 2 nitrogen atoms and does not contain any other hetero atom and may be optionally substituted by one or more substituents independently selected from Ci4 alkyl or NRaBb, The heterocyclic group has 2 nitrogen atoms and is not substituted by the NRaRb group or contains 1 nitrogen atom and is substituted by the NRaRb group. 200940529 厌6 represents one selected from the group consisting of Cl-8 or C3-8 ring _C〇- a group of 6 substituents, wherein any alkyl group is optionally substituted with one or more halo groups (preferably fluorine) and the C3 cycloalkyl group is optionally substituted with one or more substituents. Is independently selected from the group consisting of 0-4 alkyl, halo (preferably fluorine) or aryl; η represents 1 or 2; and Ρ represents 0 or 1. In another preferred system, the invention relates to a compound of formula I, wherein R! represents a group selected from (i) or (ii); R2 and R3 together with the nitrogen atom to which they are bonded form a single ring of 4 to 7 members, a bridged double ring of 7 to 8 members, or 8 to 12 members Fused double ring a heterocyclic group, wherein the heterocyclic group may contain up to 2 nitrogen atoms and does not contain any other hetero atom and is optionally substituted with one or more substituents independently selected from Ci-4 alkyl or NRaBb, The heterocyclic group contains 2 nitrogen atoms and is not substituted by the NRaRb group or contains 1 nitrogen atom and is substituted by the NRaRb group. t R6 represents a group selected from a Cm alkyl group or a C3-8 cycloalkyl group-CG.6 alkyl group. Any alkyl group may be optionally substituted with one or more halo groups (preferably fluorine) and the C8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci-4 An alkyl group, a halogen (preferably fluorine) or an aryl group; R. 4 and R. 5 are each independently selected from Cm alkyl; n represents 1 or 2; and P represents deuterium or 1. Another preferred system The invention relates to a compound of formula I, wherein Ri represents a group selected from (i) or (ii); 200940529 R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from: 1) a heterocyclic group containing 2 nitrogen atoms and containing no other hetero atom, wherein the heterocyclic group is optionally substituted by one or more C 4 alkyl groups; and (Π) contains 1 a heterocyclic group which does not contain any other hetero atom, wherein the heterocyclic group is substituted with an NRaRb group and optionally substituted with one or more C!-4 alkyl groups; 0 wherein the heterocyclic groups (1) and Ii) may be a 4- to 7-membered single-ring '7 to 8 member bridged double ring or 8 to 12 member fused double ring; and R6 represents one selected from C!.8 yard base or C3-8 ring yard base - c〇_ The base of the group 6 is optionally substituted by one or more halo groups (preferably fluorine) and the C3_8 cycloalkyl group is optionally substituted with one or more substituents, such substituents They are independently selected from the group consisting of CN4 alkyl, halo (preferably fluorine) or aryl. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents a group selected from (1) or (ii); Q R2 and R3 together with the nitrogen atom to which they are bonded form a saturated impurity selected from the group consisting of Cyclic group: (i) a heterocyclic group containing 2 nitrogen atoms and no other hetero atom, wherein the heterocyclic group is optionally substituted by one or more C 4 alkyl groups; and (Π) contains 1 nitrogen atom And a heterocyclic group which does not contain any other hetero atom, wherein the heterocyclic group is substituted with an NRaRb group and optionally substituted with one or more C!-4 alkyl groups; wherein the heterocyclic groups (i) and (ii) It may be a 4 to 7 membered monocyclic ring, a 7 to 8 member bridged double ring or an 8 to 12 membered fused bicyclic ring; -53- 200940529 R6 represents one selected from a Cu alkyl group or a c3_8 cycloalkyl-cG.6 alkyl group. Any one of the alkyl groups may be optionally substituted with one or more halo groups (preferably fluorine) and the c3-8 cycloalkyl group may be optionally substituted with one or more substituents selected independently from the group consisting of C^-4 alkyl, halo (preferably fluorine) or aryl; η represents 1 or 2; and Ρ represents 0 or 1. In another preferred system, the invention relates to a compound of formula I, wherein

Ri represents a group selected from (i) or (ii); U R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of: (i) containing two nitrogen atoms and not containing a heterocyclic group of any other hetero atom, wherein the heterocyclic group is optionally substituted by one or more C!-4 alkyl groups; and (Π) a heterocyclic group containing 1 nitrogen atom and no other hetero atom Wherein the heterocyclic group is substituted with an NRaRb group and optionally substituted with one or more C!-4 alkyl groups;

Wherein the heterocyclic groups (i) and (Π) may be a 4- to 7-membered monocyclic ring, a 7 to 8 Q-membered bridged bicyclic ring or an 8- to 12-membered fused bicyclic ring; and R6 represents one selected from the group consisting of Cu alkyl or C3. Any of the alkyl groups of the 8-cycloalkyl-CQ.6 alkyl group may be optionally substituted with one or more halo groups (preferably fluorine) and the C3-8 cycloalkyl group may be optionally substituted by one or more Substituted, the substituents are independently selected from C^-4 alkyl, halo (preferably fluoro) or aryl; h and R5 are each independently selected from hydrazine or Cu alkyl; η represents 1 or 2; And Ρ represents 0 or 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein I represents a group selected from (1) or (ii); R2 and R3 together with the nitrogen atom to which they are bonded are selected from (a) a saturated heterocyclic group to (h), wherein Ra, Rb and R. Preferably, Ra, Rb and Re each represent an anthracene or a Cu alkyl group, and more preferably Ra, Rb and Rc each represent a hydrazine or a methyl group; and R6 represents a group selected from a Cu alkyl group, as defined above. Or a U group of a C3-8 cycloalkyl-CG.6 alkyl group, wherein any alkyl group is optionally substituted with one or more halo groups (preferably fluorine) and the C3_8 cycloalkyl group is optionally passed through a Or a plurality of substituents which are independently selected from the group consisting of Ci-4, halogen (preferably fluorine) or aryl. In another preferred embodiment, the invention relates to a compound of formula I, wherein R! represents a group selected from (1) or (ii); and R3 and together with the nitrogen atom to which they are bonded, are selected from (a) to (h) a saturated heterocyclic group 'wherein Ra, Rb and R. Preferably, Ra, Rb and Re each represent hydrazine or Cm alkyl, and more preferably 〇Ra, Rb and Rc each represent hydrazine or methyl; R6 represents one selected from Cu alkyl. Or a C3_8 cycloalkyl-Co-6 alkyl group, wherein any alkyl group is optionally substituted with one or more halo groups (preferably fluorine) and the c3_8 cycloalkyl group is optionally one or more Substituent substitution, the substituents are independently selected from the group consisting of Ci_4, halo (preferably fluorine) or aryl; η represents 1 or 2; and Ρ represents 〇 or 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein a group selected from (1) or (ii); -55-200940529 R2 and R3, together with the nitrogen atom to which they are bonded, are selected from (a) To a saturated heterocyclic group of (h), wherein Ra, Rb and Re are as defined above, preferably Ra, Rb and R. Each represents a hydrazine or a Cw alkyl group, and more preferably, Ra, Rb and Rc each represent a hydrazine or a methyl group; and R6 represents a group selected from a Ci-8 alkyl group or a C3-8 cycloalkyl-C〇-6 alkyl group. Any one of the alkyl groups may be optionally substituted with one or more halo groups (preferably fluorine) and the C3_8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from C !-4 alkyl, halo (preferably fluorine) or aryl; 0 R4 and R5 are each independently selected from hydrazine or <^.4 alkyl; η represents 1 or 2; and Ρ represents 0 or 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein a group selected from (1) or (ii); R2 and R3, together with the nitrogen atom to which they are bonded, are selected from (a) or (b) A saturated heterocyclic group, wherein Ra, Rb and Re are as defined above, and preferably Ra, Rb and R. Each represents Η or Cm alkyl, and more preferably @Ra, Rb and Re each represent Η or methyl, and still more preferably Ra stands for Η 'Rb stands for methyl and Rc stands for η; and R6 stands for one choice Any one of the alkyl groups of the Cm alkyl or C3_8 cycloalkyl-C〇-6 alkyl group may be optionally substituted with one or more halo groups (preferably fluorine) and the C3.8 cycloalkyl group may be Optionally substituted with one or more substituents independently selected from the group consisting of a C4 alkyl group, a halogen (preferably fluorine) or an aryl group. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents a group selected from (1) or (ii); -56-200940529 R2 and R3 together with the nitrogen atom to which they are bonded form a (a) Or a saturated heterocyclic group of (b) wherein Ra, Rb and Re are as defined above, and preferably Ra, Rb and Re each represent an anthracene or a Ci-4 alkyl group, and more preferably Ra, Rb and Re each represent a hydrazine or a methyl group, and still more preferably, Ra represents hydrazine, Rb represents a methyl group and Rc represents hydrazine; R6 represents one selected from a Cu alkyl group or a c3.8 cycloalkyl-CG-6 alkyl group. Any one of which may optionally be substituted with one or more halo groups (preferably fluorine) and the C 3-8 ring moieties may be optionally substituted with one or more substituents, such The substituent is independently selected from C!-4 alkyl, halo (preferably fluorine) or aryl; η represents 1 or 2; and Ρ represents 〇 or 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein R! represents a group selected from (i) or (ii); R2 and & 3 and together with the nitrogen atom to which they are bonded are selected ( a saturated heterocyclic group of a) or (b), wherein Ra, Rb and Re are as defined above, Q and preferably Ra, Rb and Rc each represent an anthracene or a Cu alkyl group, and more preferably Ra, Rb and Re each represent a hydrazine or a methyl group, and still more preferably, Ra represents hydrazine, Rb represents a methyl group and Rc represents hydrazine; and R6 represents a group selected from a Cu alkyl group or a c3-8 cycloalkyl-cG-6 alkyl group. Any one of the alkyl groups may be optionally substituted with one or more halo groups (preferably fluorine) and the C3-8 cycloalkyl group may be optionally substituted with one or more substituents. From C!_4 alkyl, halo (preferably fluoro) or aryl R4 and R5 are each independently selected from fluorene or C,-4 alkyl; η represents 1 or 2; and -57- 200940529 P represents 0 or 1. In another preferred embodiment, the invention relates to a compound of formula I, which represents a group selected from (1) or (Π); R2 and R3, together with the nitrogen atom to which they are bonded, form a saturated heterocyclic group of formula (a) Wherein Ra, Rb and Rc each represent a hydrazine or a Cm alkyl group, and preferably Ra, Rb and R. Each represents a hydrazine or a methyl group, and still more preferably Ra represents H, Rb represents a methyl group and Rc represents hydrazine;

Re represents a Q group selected from a C alkyl group or a c3.8 cycloalkyl-cG.6 alkyl group, wherein any alkyl group is optionally substituted with one or more halo groups (preferably fluorine) and the C3_8 The cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of Ci.4 alkyl, halo (preferably fluorine) or aryl. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents a group selected from (1) or (ii);

R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (a) wherein Ra, Rb and Re each represent a fluorene or Cm alkyl group, and preferably Ra, Rb and Re are each Represents hydrazine or methyl, and still more preferably Ra Q represents Η 'Rb represents a methyl group and Rc represents η; R·6 represents a group selected from a Cu alkyl group or a C3-8 cycloalkyl-CG-6 alkyl group. 'any of the alkyl groups may be optionally substituted with one or more halo groups (preferably fluorine) and the C3-8 cycloalkyl group may be optionally substituted with one or more substituents, which are independently selected From CL4 alkyl, halo (preferably fluorine) or aryl; η represents 1 or 2; and Ρ represents 0 or 1. In another preferred system, the invention relates to compounds of formula I, wherein -58- 200940529

Ri represents a group selected from (1) or (ii); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of the formula (a) wherein Ra, Rb and Re each represent Η or Cl_4 alkyl And preferably Ra, Rb and Re each represent η or methyl, and still more preferably Ra represents Η, Rb represents methyl and Rc represents η; R6 represents one selected from Cu alkyl or c3-8 naphthenic Any of the alkyl groups of the group -C〇-6 alkyl group may be optionally substituted by one or more halo groups (preferably fluorine) and the C3·8 cycloalkyl group may optionally be subjected to one or more Substituted substituents, each of which is independently selected from the group consisting of Ci-4 alkyl, halo (preferably fluoro) or aryl; R.4 and R5 are each independently selected from the group consisting of hydrazine or Ci-4; η Represents 1 or 2; and Ρ represents 〇 or 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents a group selected from (1) or (ii); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated impurity of formula (b) a ring group, wherein Ra, Rb and R. Each represents hydrazine or Cl_4 alkyl, and preferably Ra, Rb and Re each represent hydrazine or methyl, and more preferably Ra and Rb each represent hydrazine or methyl and Re represents hydrazine, and still more preferably Ra represents Η 'Rb represents a methyl group and Rc represents Η; and IU represents a group selected from C!-8 alkyl or C3-8 cycloalkyl-Co-6 alkyl, wherein any alkyl group optionally One or more halo groups (preferably fluorine) are substituted and the c3-8 cycloalkyl group is optionally substituted by one or more substituents independently selected from Ci-4 alkyl, halo (preferably Fluorine) or aryl. In another preferred embodiment, the invention relates to compounds of formula I, wherein -59- 200940529

Ri represents a group selected from (1) or (Π); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of the formula (b), wherein Ra, Rb and R. Each represents hydrazine or Cm alkyl, and preferably Ra, Rb and Rc each represent hydrazine or methyl, and more preferably Ra and Rb each represent hydrazine or methyl and Rc represents hydrazine, and still more preferably Ra represents Η, Rb represents a methyl group and Re represents Η; R6 represents a group selected from a Ci-8 alkyl group or a C3-8 cycloalkyl-CG-6 alkyl group, wherein any one of the alkyl groups may optionally be subjected to one or more a halo group (preferably fluorine) substituted and the c3-8 cycloalkyl group optionally substituted by one or more substituents independently selected from Cid alkyl, halo (preferably fluorine) or aryl; η represents 1 or 2; and Ρ represents 0 or is in another preferred system, the invention relates to a compound of formula I, wherein Ri represents a group selected from (i) or (ii); R2 and R3 and the same The nitrogen atoms of the knot together form a saturated heterocyclic group of formula (b) wherein Ra, Rb and Re each represent a fluorene or Cm alkyl group, and preferably Ra, Rb and R. Each represents a hydrazine or a methyl group, and more preferably, Ra and Rb each represent fluorene or methyl and Re represents hydrazine, and still more preferably Ra represents Η 'Rb represents a methyl group and Re represents Η; R6 represents a selected one Any of the alkyl groups optionally substituted by one or more halo groups (preferably a gas) and the C3_8 cycloalkyl group may be optionally substituted with one or more halo groups (preferably a gas). Optionally substituted with one or more substituents independently selected from C,.4 alkyl, halo (preferably fluoro) or aryl; R4 and R5 are each independently selected from hydrazine or Cb4 alkane. ;; -60- 200940529 η represents 1 or 2; and ρ represents 0 or 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein R represents represents (i); and R2 and R3 together with the nitrogen atom to which they are bonded may form a 4 to 7 membered monocyclic ring, 7 to 8 a bridged bicyclic or 8 to 12 membered fused bicyclic saturated heterocyclic group wherein the heterocyclic group may contain up to 2 nitrogen atoms and does not contain any other heteroatoms and optionally one or more independent Substituted with a substituent selected from (^-4 alkyl or NRaRb, except that the heterocyclic group contains 2 nitrogen atoms and is not substituted by the NRaRb group or contains 1 nitrogen atom and is substituted by the NRaRb group to another preferred system. The present invention relates to a compound of formula I, wherein R 1 represents (i); and R 2 and R 3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of: Ο (1) containing 2 nitrogens a heterocyclic group which does not contain any other hetero atom, wherein the heterocyclic group is optionally substituted by one or more Cl-4 alkyl groups; and (11) contains one nitrogen atom and does not contain any other hetero atom. a heterocyclic group, wherein the heterocyclic group is substituted with an NRaRb group and optionally substituted with one or more C!-4 alkyl groups; wherein the heterocyclic groups (i) and Ii) may be a 4 to 7 membered monocyclic ring, a 7 to 8 member bridged bicyclic ring or a 8 to 12 membered fused bicyclic ring. In another preferred system, the invention relates to a compound of formula I, wherein R1 represents (i); And -61 - 200940529 尺 2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) to (h), wherein Ra, Rb and R are as defined above. Preferably, Ra, Rb and Re each represent a hydrazine or a Ci-4 alkyl group, and more preferably Ra, Rb and Rc each represent a hydrazine or a methyl group. In another preferred system, the invention relates to a compound of formula I Wherein R represents represents (i); and R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) or (b), wherein Ra, Rb and R are as defined above Defining, q and preferably Ra, Rb and Rc each represent Η or Cm alkyl, and more preferably Ra, Rb and Re each represent Η or methyl, and still more preferably Ra represents Η, Rb represents Methyl and Re represents hydrazine. In another preferred system, the invention relates to compounds of formula I, wherein R! represents (i); and R2 and R3 together with the nitrogen atom to which they are bonded form (a) Saturated heterocyclic group 'where Ra, Rb and Re each represent Η Cu alkyl, and preferably Ra, Rb and Re each represent a hydrazine or a methyl group, and still more preferably Ra 0 represents hydrazine, Rb represents a methyl group and Rc represents hydrazine. In another preferred system, the invention Regarding the compound of formula I, wherein

Ri represents (i); and R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (b) wherein Ra, Rb and Rc each represent a hydrazine or a Ci-4 alkyl group, and Preferably, Ra, Rb and Re each represent a hydrazine or a methyl group, and more preferably, Ra and Rb each represent a hydrazine or a methyl group and Re represents hydrazine, and still more preferably, Ra represents hydrazine, and Rb represents a methyl group and rc Representative Η. -62- 200940529 In another preferred embodiment, the invention relates to compounds of formula I, wherein R! represents (i); R2 and R3 together with the nitrogen atom to which they are bonded may form a single ring of 4 to 7 members, a 7 to 8 membered bridged bicyclic or 8 to 12 membered fused bicyclic saturated heterocyclic group wherein the heterocyclic group may contain up to 2 nitrogen atoms and does not contain any other hetero atom and optionally one or more Substituted independently from the substituent of the mountain-4 alkyl or NRaRb, the heterocyclic group contains 2 nitrogen atoms and 0 is not substituted by the NRaRb group or contains 1 nitrogen atom and is substituted by the NRaRb group: and R6 represents an alternative From Cu alkyl or C3_8 cycloalkyl-c core 6 alkyl (preferably selected from Cu alkyl or C3-6 cycloalkyl-alkyl, more preferably selected from Cu alkyl or C3-6 cycloalkyl-Ci An alkyl group, and still more preferably selected from the group consisting of a C4-5 alkyl group or a C3-6 cycloalkyl-C! alkyl group, wherein any alkyl group is optionally substituted with one or more halo groups (preferably fluorine) Substituted and any cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of Cl-4 alkyl Q, halo (preferably fluorine) or aryl. In another preferred system, the invention relates to a compound of formula I, wherein

Ri represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of: (0) a heterocyclic group containing 2 nitrogen atoms and containing no other hetero atom, wherein The heterocyclic group is optionally substituted by one or more C!-4 alkyl groups; and (ii) a heterocyclic group containing 1 nitrogen atom and no other hetero atom, wherein the heterocyclic group is via NRaRb group Substituted and optionally one or more -63- 200940529

Ci-4 alkyl substituted; wherein the heterocyclic groups (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.

Re represents one selected from a Cu alkyl group or a C3.8 cycloalkyl-CG-6 alkyl group (preferably selected from the group consisting of a mountain -8 alkyl group or a C3-6 cycloalkyl-Cm alkyl group, more preferably selected from the mountain -8). An alkyl group or a C3-6 cycloalkyl-Ci alkyl group, and still more preferably selected from the group consisting of a C4-5 alkyl group or a C3-6 cycloalkyl-Cl alkyl group, wherein any alkyl group is optionally subjected to one or a plurality of halo groups (preferably fluorine) are substituted and any cycloalkyl group is optionally substituted with 0 or more substituents independently selected from C, .4 alkyl, halo (preferably fluorine) ) or aryl. In another preferred embodiment, the invention relates to compounds of formula I, wherein R 1 represents (i); R 2 and R 3 together with the nitrogen atom to which they are bonded may form a 4 to 7 membered single ring, 7 to 8 members A bridged bicyclic or 8- to 12-membered fused bicyclic saturated heterocyclic group wherein the heterocyclic group may contain up to 2 nitrogen atoms and no other heteroatoms and optionally one or more independently selected from Cl_4 The substituent of the alkyl hydrazine or NRaRb is substituted, except that the heterocyclic group contains two nitrogen atoms and is not substituted or contained by the NRaRb group! And a nitrogen atom and substituted by the NRaRb group represents one selected from the group consisting of Cu alkyl or c3-8 cycloalkyl-cG-6 alkyl (preferably selected from q.8 alkyl or C3-6 cycloalkyl-Cm alkyl, More preferably selected from the group consisting of Cu or C6 cycloalkyl-C! alkyl, and still more preferably selected from the group consisting of c4-5 alkyl or cycloalkyl-Ci alkyl, any of which may be selected Substituted by one or more halo groups (preferably fluorine) and any cycloalkyl group optionally substituted by one or more substituents from 64 to 200940529, the substituents being independently selected from the group consisting of Cl_4, halo ( Preferably, fluoro) or aryl; and η represents 1 or 2, and preferably η is 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents (i); R.2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of: 0 ( i) a heterocyclic group containing 2 nitrogen atoms and no other hetero atom, wherein the heterocyclic group is optionally substituted by one or more Ci.4 alkyl groups; and (Π) contains 1 nitrogen atom and is not a heterocyclic group containing any other hetero atom, wherein the heterocyclic group is substituted with an NRaRb group and optionally substituted with one or more Q-4 alkyl groups; wherein the heterocyclic groups (i) and (ii) are It is a 4- to 7-membered monocyclic ring, a 7- to 8-membered bridged bicyclic ring or a 8 to 12-membered fused bicyclic ring; and R6 represents one selected from a Cu alkyl group or a C3_8 cycloalkyl-(:〇.6 alkyl group (〇 preferably Either selected from Cl 8 alkyl or c 3.6 cycloalkyl-cm alkyl, more preferably selected from Cu alkyl or c 3.6 cycloalkyl-CW alkyl, and still more preferably selected from C 4-5 alkyl or a C3_6 cycloalkyl-c!alkyl group, wherein any alkyl group is optionally substituted with one or more halo groups (preferably fluorine) and any cycloalkyl group optionally has one or more substituents Substituted, the substituents are independently selected from C^-4 alkyl Halogen (preferably fluorine) or aryl; and η represents 1 or 2, and preferably n is 1. In another preferred system, the invention relates to a compound of formula I, wherein R 1 represents (i); 65- 200940529 R.2 and R.3 and the nitrogen atom bonded to them 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 8 membered fused bicyclic ring. Wherein the heterocyclic group may contain up to 2 nitrogen atoms and does not contain any other hetero atom and may be optionally substituted by one or more substituents independently selected from the group consisting of (^_4 or NRab), the heterocyclic ring The group contains 2 nitrogen atoms and is not substituted by the NRaRb group or contains 1 nitrogen atom and is substituted by the NRaRb group. » R6 represents one selected from Cu alkyl or C3 8 cycloalkyl-C〇-6 alkyl (© preferably It is selected from C..8 alkyl or c3_6 cycloalkyl-Cm alkyl, more preferably selected from Cu alkyl or C3-6 cycloalkyl-Ci alkyl, and still more preferably selected from C4-5 alkyl. Or a C3_6 cycloalkyl-Ci alkyl group, wherein any alkyl group is optionally substituted with one or more halo groups (preferably fluorine) and any cycloalkyl group optionally has one or more substituents Substituted, the substituents are independently selected from Ci. 4 alkane And a halogen (preferably fluorine) or an aryl group; R4 and R5 are each independently selected from fluorene or a C4 alkyl group, and preferably R4 and R5 represent Η; and 〇η represents 1 or 2, and preferably η In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from: i) a heterocyclic group containing 2 nitrogen atoms and no other hetero atom, wherein the heterocyclic group is optionally substituted by one or more (:, .4 alkyl groups; and (Π) contains 1 nitrogen atom And a heterocyclic group which does not contain any other hetero atom, -66- 200940529 wherein the heterocyclic group is substituted by the NRaRb group and optionally substituted by - or a plurality of tetraalkyl groups: wherein the heterocyclic groups (i And (ii) may be a 4 to 7 membered monocyclic ring, a 7 to 8 shelled bridged bicyclic ring or an 8 to 12 membered fused bicyclic ring; R6 represents one selected from (^-8 alkyl or c38 cycloalkyl-C()_6 An alkyl group (preferably selected from C 8 alkyl or c 3-6 cycloalkylalkyl, more preferably selected from Cu or CM cycloalkyl-Ci alkyl, and still more preferably selected from c4_5 〇 a base of a hospital or C3·6 cycloalkyl-Cl alkyl group, wherein The monoalkyl group may be optionally substituted with one or more halo groups (preferably fluorine) and any cycloalkyl group may be optionally substituted with one or more substituents independently selected from C1_4 alkyl groups, halo. (preferably fluorine) or aryl; R4 and R5 are each independently selected from hydrazine or Ci-4 alkyl, and preferably R4 and R5 represent hydrazine; and η represents 1 or 2, and preferably η 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein 〇Ri represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic ring selected from (a) to (h) a group, wherein Ra, Rb and Re are as defined above, and preferably Ra, Rb and Re each represent a hydrazine or a Ci-4 alkyl group, and more preferably Ra, Rb and Re each represent Η or A And R6 represents one selected from Cu alkyl or C3-8 cycloalkyl-CG-6 alkyl (preferably selected from Cu alkyl or C3-6 cycloalkyl-alkyl, more preferably selected from alkyl or C3- a 6 cycloalkyl-C! alkyl group, and still more preferably selected from the group consisting of a C4-5 alkyl group or a C3-6 cycloalkyl-C! alkyl group, wherein any alkyl group is optionally -67-200940529 Or a plurality of halo groups (preferably fluorine) substituted and any cycloalkyl group optionally substituted by one or more substituents independently selected from Ci-4 alkyl, halo (preferably fluorine) Or aryl. In another preferred embodiment, the invention relates to a compound of formula I, wherein L represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) to (h) Where Ra, Rb and Re are as defined above,

And preferably Ra, Rb and Re each represent hydrazine or C, _4 alkyl, and more preferably, Q, Ra, Rb and Rc each represent hydrazine or methyl; R6 represents one selected from Ci-8 alkyl or C3 .8 cycloalkyl-C〇.6 alkyl (preferably selected from d.8 alkyl or C3-6 cycloalkyl-Co-!alkyl, more preferably selected from Cu alkyl or C3-6 ring An alkyl-Ci alkyl group, and still more preferably selected from the group consisting of a C4-5 alkyl group or a c3-6 cycloalkyl-Ci alkyl group, wherein any alkyl group is optionally substituted with one or more halo groups (preferably And the cycloalkyl group is optionally substituted by one or more substituents independently selected from the group consisting of Ci-4 alkyl, halo (preferably fluorine) or aryl; 1 or 2, and preferably η is 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein R! represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic ring selected from (a) to (h) Base, where Ra, Rb and R. It is as defined above, and preferably Ra, Rb and Re each represent Η or (^_4 alkyl, and more preferably Ra, Rb and Rc each represent Η or methyl; Κ·6 represents an election From Ci-8 yard base or C3-8 ring yard base - C〇_6 yard base (-68- 200940529 is preferably selected from C!-8 alkyl or C3-6 cycloalkyl-Co.i alkyl, More preferably selected from the group consisting of a Cu alkyl group or a c3-6 cycloalkyl-Ci alkyl group, and still more preferably selected from a C4.5 alkyl group or a c3-6 cycloalkyl-Ci alkyl group, any of The alkyl group is optionally substituted with one or more halo groups (preferably fluorine) and any cycloalkyl group is optionally substituted with one or more substituents independently selected from C^4 alkyl groups, Halogen (preferably fluorine) or aryl; R4 and R5 are each independently selected from hydrazine or (^-4 alkyl, and preferably R4 and represents hydrazine; and η represents 1 or 2, and preferably η 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated impurity selected from (a) or (b) a cyclic group, wherein Ra, Rb and R are as defined above, and preferably Ra, Rb and R. Each represents a hydrazine or a Cm alkyl group, More preferably, Ra, Rb and Rc each represent a hydrazine or a methyl group, and still more preferably, Ra represents hydrazine, Rb represents a methyl group and Rc represents hydrazine; and R6 represents one selected from Cm alkyl group or C3_8 cycloalkyl-C. Indole-6 alkyl (preferably selected from the group consisting of s-8 alkyl or C3-6 cycloalkyl-Cm alkyl, more preferably selected from alkyl or C3-6 cycloalkyl-C! alkyl, and still more preferably selected a group derived from a C4-5 alkyl group or a C3_6 cycloalkyl-Ci alkyl group, wherein any alkyl group is optionally substituted with one or more halo groups (preferably fluorine) and optionally any cycloalkyl group Substituted by one or more substituents, each of which is independently selected from the group consisting of h. 4 alkyl, halo (preferably fluoro) or aryl. In another preferred system, the invention is directed to a compound of formula I wherein - 69- 200940529

Ri represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) or (b), wherein Ra, Rb and R. It is as defined above and preferably Ra, Rb and Re each represent hydrazine or a Cu4 alkyl group, and more preferably Ra, Rb and R. Each represents a hydrazine or a methyl group, and still more preferably, Ra represents H, Rb represents a methyl group and Rc represents H; R6 represents a group selected from Ci-8 alkyl or c3-8 cycloalkyl-CQ.6 alkyl (preferably It is selected from the group consisting of -8 alkyl or C3-6 cycloalkyl-Co-! alkyl, more preferably selected from Cu alkyl or C3.6 cycloalkyl-Ci alkyl, and still more preferably selected from a group of c4.5 alkyl or C3.6 cycloalkyl-C! alkyl), wherein any alkyl group is optionally substituted with one or more halo groups (preferably fluoro) and any cycloalkyl group may be selected Substituted by one or more substituents, each of which is independently selected from -alkyl, halo (preferably fluoro) or aryl; and η represents 1 or 2, and preferably η is 1.

In another preferred embodiment, the invention relates to a compound of formula I, wherein R! represents (i); Q R2 and R3 together with the nitrogen atom to which they are bonded form a saturated impurity selected from (a) or (b) a ring group, wherein Ra, Rb and R. Is as defined above, and preferably Ra, Rb and Rc each represent 11 or C!-4 alkyl, and more preferably Ra, Rb and Rc each represent a hydrazine or a methyl group, and still more preferably Ra represents hydrazine, Rb represents a methyl group and Re represents hydrazine; R6 represents one selected from a Cu alkyl group or a C3.8 cycloalkyl-CG-6 alkyl group (preferably selected from a Cl-8 alkyl group or a C3-6 cycloalkylalkyl group). More preferably selected from the group consisting of C!-8 alkyl or C3_6 cycloalkyl-Ci alkyl, and still more preferably selected from the group consisting of c4_5-70-200940529 alkyl or C3_6 cycloalkyl-c! alkyl), Any one of the alkyl groups may be optionally substituted with one or more halo groups (preferably fluorine) and any cycloalkyl group may be optionally substituted with one or more substituents independently selected from Ci-4. An alkyl group, a halogen (preferably fluorine) or an aryl group; R4 and R5 are each independently selected from fluorene or CU4 alkyl, preferably R4 and R5 represent η; and η represents 1 or 2, and preferably η Department 1. φ In another preferred system, the invention relates to a compound of formula I, wherein

Rt represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (a), wherein Ra, Rb and Re each represent a fluorene or Cm alkyl group, and preferably Ra , Rb and Rc each represent a hydrazine or a methyl group, and still more preferably Ra represents hydrazine, Rb represents a methyl group and Re represents hydrazine;

Re represents one selected from C, -8 alkyl or C3_8 cycloalkyl-C〇-6 alkyl (preferably selected from Cu alkyl or C34 cycloalkyl-Cw alkyl, more preferably Q from Cu alkane) Or a c3-6 cycloalkyl-c, alkyl group, and still more preferably selected from the group consisting of a C4-5 or a C3-6 ring-based group - Cl, which may optionally be One or more halo groups (preferably fluorine) are substituted and any cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of behen-4-alkyl, halo (preferably fluorine) ) or aryl. In another preferred embodiment, the invention relates to a compound of formula I wherein (i); r2 and r3 together with the nitrogen atom to which they are bonded form a heterocyclic ring of formula (a) wherein Ra, Rb and Rc are each Do not represent η or Ci-4 alkyl ' and preferably -71 - 200940529

Ra, Rb, and Re each represent Η or methyl, and still better Ra stands for Η,

Rb represents a methyl group and represents η; R6 represents a group selected from a C1-6 alkyl group or a C3-8 cycloalkyl-C()-6 alkyl group (preferably selected from (^-8 alkyl or C3-6 cycloalkyl-CQ_1 alkyl) More preferably selected from the group consisting of Cu or a C36 cycloalkyl-C1 alkyl group, and still more preferably selected from the group consisting of c4.5 or C3.6 cycloalkyl-Ci alkyl, wherein The substituent is optionally substituted with one or more halo groups (preferably fluorine) and any cycloalkyl group is optionally substituted with one or more substituents independently selected from C1.4 alkyl group 0, Halogen (preferably fluorine) or aryl; and η represents 1 or 2, and preferably n is 1. In another preferred system, the invention relates to a compound of formula I, wherein R 1 represents (i); R2 And R3 and a nitrogen atom bonded thereto form a saturated heterocyclic group of formula (a) wherein Ra, Rb and Rc each represent fluorene or C, -4 alkyl, and preferably Ra, Rb and Rc Each represents a hydrazine or a methyl group, and still more preferably, Ra represents hydrazine, Rb represents a methyl group and Rc represents η; 〇R6 represents a group selected from a Cu alkyl group or a C3_8 cycloalkyl-C〇-6 alkyl group (preferably Selected from CL8 alkyl or C3_6 cycloalkyl-Co.! alkyl, more preferably selected from alkyl or C3.6 naphthenes a -Ci alkyl group, and still more preferably selected from the group consisting of a C4-5 alkyl group or a C3.6 cycloalkyl-Ci alkyl group, wherein any alkyl group is optionally substituted with one or more halo groups (preferably And the cycloalkyl group is optionally substituted by one or more substituents independently selected from the group consisting of h-4 alkyl, halo (preferably fluoro) or aryl; R4 and R5 Each is independently selected from hydrazine or Cm alkyl, preferably & -72-200940529 and Κ·5 represent Η; and η represents 1 or 2, and preferably η is i. In another preferred system, The present invention relates to compounds of formula I, wherein

Ri represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of the formula (b)' wherein Ra, Rb and R. Each represents a fluorene or a tetraalkyl group, and preferably Ra, Rb and Re each represent a hydrazine or a methyl group, and more preferably Ra and 〇 Rb each represent H or a methyl group and R. Representing Η, and still better, Ra stands for ’ ’ Rb for methyl and Re for Η;

Rfi represents one selected from (^-8 alkyl or c3-8 cycloalkyl-cG-6 alkyl (preferably selected from Cu alkyl or c3-6 cycloalkylalkyl, more preferably selected from G.8 or C36). a cycloalkyl-Ci alkyl group, and still more preferably selected from the group consisting of a C4-5 or C3-6 cycloalkyl-C-alkyl group, wherein any alkyl group is optionally substituted with one or more halo groups (preferably fluorine) substituted and any cycloalkyl group optionally substituted by - or a plurality of substituents independently selected from C14 alkyl hydrazine, halogen (preferably fluorine) or aryl. In a preferred system, the invention relates to a compound of formula I, wherein R1 represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (b) wherein Ra ' Rb and Rc Each represents hydrazine or C,-4 alkyl, and preferably Ra, Rb and Re each represent hydrazine or methyl, and more preferably Ra and Rb each represent η or methyl and Re represents hydrazine, and still More preferably, Ra represents Η 'Rb represents a methyl group and Re represents Η; R6 represents one selected from a C. 8 alkyl group or a C3_8 cycloalkyl group - CQ.6 alkyl group (-73-200940529 is preferably selected from Cl-8) Alkyl or C^6 cycloalkyl-Co-i alkyl, more preferably selected from Cu alkyl or C3-6 cycloalkane a group of -C, alkyl, and still more preferably selected from C4-5 alkyl or c3-6 cycloalkyl-Cialkyl, wherein any alkyl group is optionally via one or more halo groups (preferably Fluorine substituted and optionally substituted with one or more substituents, each independently selected from C!-4 alkyl, halo (preferably fluoro) or aryl; and η represents 1 Or 2, and preferably η is 1. In another preferred system, the invention relates to a compound of formula I, wherein R 1 represents (i); R 2 and R 3 are taken together with the nitrogen atom to which they are bonded (b) a saturated heterocyclic group, wherein Ra, Rb and Re each represent an anthracene or a Cm alkyl group, and preferably Ra, Rb and Re each represent a hydrazine or a methyl group, and more preferably Ra and Rb are each Represents hydrazine or methyl and Rc represents hydrazine, and still more preferably Ra stands for Η, Rb stands for methyl and Rc stands for Η; ruler 6 stands for one from Ci_8 or C3-8 ring - C〇-6 a base (preferably selected from C!-8 alkyl or C3_6 cycloalkyl-Cm alkyl, more preferably from Cu alkyl or c3.6 cycloalkyl-C, alkyl, and still more preferably a group selected from a C4-5 alkyl group or a C3_6 cycloalkyl-C! alkyl group, wherein any one of the alkyl groups is optionally subjected to a Or a plurality of halo groups (preferably fluorine) substituted and any cycloalkyl group optionally substituted by one or more substituents independently selected from Ci-4 alkyl, halo (preferably fluorine) Or aryl; R4 and R5 are each independently selected from fluorene or Cu alkyl, preferably R4 and R5 represent Η; and η represents 1 or 2, and preferably η is 1. -74- 200940529 In a preferred system, the invention relates to the compound of formula 1 wherein I represents (i); R2 and R3 together with the nitrogen atom to which they are bonded may form a 4 to 7 membered monocyclic ring, a 7 to 8 membered bridged bicyclic ring or 8 to 12 membered fused bicyclic saturated heterocyclic group wherein the heterocyclic group may contain up to 2 nitrogen atoms and does not contain any other hetero atom and optionally one or more independently selected from C^-4 alkane Substituted with a substituent of NRaRb, wherein the heterocyclic group contains 2 nitrogen atoms and is not substituted by NRaRb group or contains 1 nitrogen atom and is substituted by NRaRb group. f R6 represents isobutyl or cyclopropylmethyl; R4 And R5 are each independently selected from hydrazine or Cm alkyl, preferably R4 and R5 represent hydrazine; and η represents 1 or 2, and preferably η is 1. In another preferred embodiment, the invention relates to compounds of formula I, wherein R! represents (i); ❹ R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from: a heterocyclic group containing 2 nitrogen atoms and not containing any other hetero atom, wherein the heterocyclic group is optionally substituted by one or more ¢:,-4 alkyl groups; and (ii) contains 1 nitrogen atom and a heterocyclic group which does not contain any other hetero atom, wherein the heterocyclic group is substituted with an NRaRb group and optionally substituted with or a plurality of C 1 _ 4 fluorenyl groups; wherein the heterocyclic groups (i) and (ii) It can be 4 to 7 membered single ring, 7 to 8 member bridged double ring or 8 to 12 member fused double ring; -75- 200940529 R6 stands for isobutyl or cyclopropylmethyl; R4 and R5 are independently selected From the oxime or Cu alkyl group, preferably R4 and R5 represent Η; and η represents 1 or 2, and preferably η is 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) to (h) , where Ra, Rb and R. As defined above, _ and preferably Ra, Rb and Re each represent hydrazine or Cu alkyl, and more preferably Ra, Rb and Re each represent hydrazine or methyl; R6 represents isobutyl or hydrazine The propylmethyl group; the R4 and R5 groups are each independently selected from the group consisting of fluorene or s-alkylene, preferably R4 and R5 represent hydrazine; and η represents 1 or 2, and preferably η is 1. In another preferred system, the invention relates to a compound of formula I, wherein

Representing (i); Q R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) or (b), wherein Ra, Rb and Re are as defined above, and Preferably, Ra, Rb and Re each represent η or Cu alkyl, and more preferably Ra, Rb and R. Each represents hydrazine or methyl, and still more preferably, Ra represents hydrazine, Rb represents methyl and Rc represents hydrazine; R6 represents isobutyl or cyclopropylmethyl; R4 and R5 are each independently selected from hydrazine or hydrazine. ^-4 alkyl, preferably R4 and R5 represent Η; and -76-200940529 η represents 1 or 2, and preferably η is 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein R1 represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (a), wherein Ra, Rb And Rc each represents hydrazine or Cm alkyl, and preferably Ra, Rb and Re each represent fluorene or methyl, and still more preferably Ra represents Η'^ represents methyl and Re represents Η; 0 R6 represents different Butyl or cyclopropylmethyl; R4 and R5 are each independently selected from hydrazine or Cb4 alkyl, preferably R4 and R5 represent hydrazine; and η represents 1 or 2, and preferably η is 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (b) wherein Ra, Rb And Rc each represents hydrazine or a Cl. 4 alkyl group, and 〇 preferably Ra, Rb and Re each represent a hydrazine or a methyl group, and more preferably, Ra and Rb each represent a hydrazine or a methyl group and R. Representing η, and still more preferably Ra represents Η, Rb represents a methyl group and Re represents Η; IU represents an isobutyl or cyclopropylmethyl group; and R4 and R5 are each independently selected from hydrazine or Cm alkyl, preferably. The grounds R4 and R5 represent Η; and π represents 1 or 2' and preferably η is 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents (i); -77- 200940529 R2 and R3 together with the nitrogen atom to which they are bonded may form a 4 to 7 membered single ring, 7 a saturated heterocyclic group having up to 8 membered bicyclic or 8 to 12 membered fused bicyclic rings wherein the heterocyclic group may contain up to 2 nitrogen atoms and does not contain any other hetero atom and optionally one or more independent Substituted with a substituent selected from 匕.4 alkyl or NRaRb, except that the heterocyclic group contains 2 nitrogen atoms and is not substituted by the NRaRb group or contains 1 nitrogen atom and is substituted by the NRaRb group. t R6 represents a mountain-8 alkyl group. Preferably, Cm alkyl, more preferably C4-5 alkyl and still more preferably isobutyl; R4 and R5 are each independently selected from hydrazine or Cm alkyl, preferably R4 and R5 represent hydrazine; and η represents 1 Or 2, and preferably η is 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from: (i) a heterocyclic group having 2 nitrogen atoms and containing no other hetero atom, wherein the heterocyclic group is optionally substituted by one or more Ci-4 alkyl groups; and (ii) contains 1 nitrogen atom and does not contain any other a heterocyclic group of a hetero atom, wherein the heterocyclic group is substituted with an NRaRb group and optionally substituted with one or more G-4 alkyl groups; wherein the heterocyclic groups (i) and (ii) may be 4 to 7 membered single ring, 7 to 8 membered bridged bicyclic or 8 to 12 membered fused bicyclic ring; R6 represents Cm alkyl 'preferably d_5 alkyl, more preferably C4_5 alkane-78-200940529 and still more preferably isoindene R4 and Rs are each independently selected from fluorene or CU4 alkyl, preferably R4 and R5 represent hydrazine; and η represents 1 or 2, and preferably η is 1. In another preferred embodiment, the invention relates to a compound of the formula wherein (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) to 〇(h). , where Ra, Rb and R. It is as defined above, and preferably Ra, Rb and R. Each represents hydrazine or a Cw alkyl group, and more preferably Ra, Rb and R. Each represents hydrazine or methyl; R 6 represents C -8 alkyl, preferably ci /5 alkyl, more preferably C 4 -5 alkyl and still more preferably isobutyl; R4 and R5 are each Independently selected from hydrazine or Cm alkyl, preferably R4 and R5 represent hydrazine; and η represents 1 or 2, and preferably η is 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein I represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic ring selected from (a) or (b) And wherein Ra, Rh and Re are as defined above, and preferably Ra, Rb and Rc each represent Η or (^-4 alkyl, and more preferably Ra, Rb and R. Each represents Η Or methyl, and still more preferably Ra represents hydrazine, Rb represents methyl and Re represents hydrazine; R6 represents Cm alkyl, preferably Cm alkyl, more preferably C4-5 alkyl and still more preferably isobutyl -79- 200940529 R4 and R5 are each independently selected from hydrazine or Ci-4 alkyl, preferably R4 and R5 represent Η; and η represents 1 or 2, and preferably η is 1. In a preferred system, the invention relates to a compound of formula I

Ri represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of the formula U), wherein Ra, Rb and R. Each represents hydrazine or Cu alkyl ' and preferably Ra, Rb and Re each represent hydrazine or methyl, and still more preferably Ra 0 represents hydrazine, Rb represents methyl and Rc represents hydrazine; R6 represents C" a group, preferably a Cm alkyl group, more preferably (: 4-5 alkyl group and still more preferably isobutyl group; R4 and R5 systems are each independently selected from hydrazine or Cm alkyl group, preferably R4 and R5 represent hydrazine; η represents 1 or 2, and preferably η is 1. In another preferred system, the invention relates to a compound of formula I, wherein

Ri represents (i); Q and r3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of the formula (b), wherein Ra, Rb and Rc each represent a fluorene or Cm alkyl group, and preferably Ra , Rb and R. Each represents hydrazine or methyl, and more preferably, Ra and Rb each represent fluorene or methyl and Re represents hydrazine, and still more preferably Ra represents Η, Rb represents methyl and Re represents Η; R·6 represents Cm Alkyl, preferably Cm alkyl, more preferably c4.5 alkyl and still more preferably isobutyl; R. 4 and R5 are each independently selected from hydrazine or Ci-4 alkyl, preferably R4 - 80-200940529 and R5 represent Η; and η represents 1 or 2, and preferably η is in another preferred system, the invention relates to a compound of formula I, wherein R! represents (i); R2 and R3 and The nitrogen atoms bonded thereto 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 2 a nitrogen atom and which does not contain any other hetero atom and optionally is substituted with one or more substituents independently selected from C..4 alkyl or NRaBb, except that the heterocyclic group contains 2 nitrogen atoms and is not NRaRb group substituted or contains 1 nitrogen atom and substituted by NRaRb group

I Κ·6 represents C3-8 ring yard base - C〇.6 yard base, preferably C3-6 ring yard base _ Coq alkyl group, more preferably C3.6 cycloalkyl-(^ alkyl group and still more Preferably, the cyclopropylmethyl group; R4 and R5 are each independently selected from the group consisting of hydrazine or Ci. 4 alkyl, preferably r4 〇 and R5 represent Η; and η represents 1 or 2, and preferably η is 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein R! represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from: (i) a heterocyclic group containing 2 nitrogen atoms and no other hetero atom, wherein the heterocyclic group is optionally substituted by one or more C 4 alkyl groups; and (Π) contains 1 nitrogen atom and does not contain any a heterocyclic group of another hetero atom, -81 - 200940529 wherein the heterocyclic group is substituted with an NRaRb group and optionally substituted with one or more C!-4 alkyl groups; wherein the heterocyclic groups (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; R6 represents a C3_8 cycloalkyl-CQ_6 alkyl group, preferably a C3_6 cycloalkyl-Co"alkyl group. More preferably, C3_6 cycloalkyl-Ci alkyl and still more preferably cyclopropylmethyl; R4 and R5 Also independently selected from Η or C^.4 alkyl, preferably R4 φ and R5 represent Η; and η represents 1 or 2, and preferably η is 1. In another preferred system, the invention relates to A compound, wherein Ri represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) to (h), wherein Ra, Rb and R are as defined above Definitions, and preferably Ra, Rb and each represent a hydrazine or a Ch alkyl group, and more preferably Ra, Rb and Rc each represent a hydrazine or a methyl group; ❹ r6 represents a c3-8 cycloalkyl-c〇. 6 alkyl, preferably c3.6 cycloalkyl-Co.i alkyl, more preferably C34 cycloalkyl-Ci alkyl and still more preferably cyclopropylmethyl; R4 and R5 are independently selected From the oxime or Cm alkyl group, preferably R4 and R5 represent Η; and η represents 1 or 2, and preferably η is 1. In another preferred system, the invention relates to a compound of formula I, wherein h represents ( i); -82- 200940529 R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) or (b), wherein Ra, Rb and Re are as defined above, and Preferably, Ra, Rb and R each represent Η or Cm alkyl, and more preferably Ra, Rb and Rc each represent Or methyl, and still more preferably Ra represents Η, Rb represents methyl and Re represents Η; Κ·6 represents C3-8 cycloalkyl-CG-6 alkyl, preferably C3.6 cycloalkyl-Co" More preferably, C3_6 cycloalkyl-(^ alkyl and still more preferably cyclopropylmethyl R4 and R5 are each independently selected from the group consisting of fluorene or Cm, preferably R4 and Rs represent Η; and η Represents 1 or 2, and preferably η is 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein R 1 represents (i); R 2 and R 3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (a) wherein Ra, Rb and Rc each represent an anthracene or a Cu alkyl group, and 〇 preferably Ra, Rb and each represent a fluorene or a methyl group, and still more preferably Ra represents Η, Rb represents a methyl group and Re represents η; R6 represents C3 -8 ring yard base _C〇_6 fluorenyl group, preferably C3.6 ring yard base-Co-i alkyl group, more preferably c3-6 cycloalkyl-Ci alkyl group and still more preferably cyclopropyl group Methyl; R4 and R5 are each independently selected from fluorene or Cm alkyl, preferably R4 and Κ5 represent Η; and η represents 1 or 2, and preferably η is 1. In another preferred system, the invention relates to a compound of formula 1, wherein -83- 200940529

Ri represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of the formula (b), wherein Ra, Rb and Re each represent a hydrazine or a Cl 4 alkyl group, and preferably Ra Rb and Re each represent hydrazine or methyl, and more preferably, Ra and Rb each represent fluorene or methyl and Re represents hydrazine, and still more preferably Ra represents Η, Rb represents methyl and Rc represents Η; R6 Represents a C3_8 cycloalkyl-C〇_6 alkyl group, preferably a C3-6 cycloalkyl-Co-i alkyl group, more preferably a c3-6 cycloalkyl-Ci alkyl group and still more preferably a cyclopropylmethyl group. R4 and R5 are each independently selected from fluorene or Cm alkyl, preferably R4 and R5 represent Η; and η represents 1 or 2, and preferably η is 1. In another preferred system, the invention relates to a compound of formula I, wherein

Ri represents (i); R2 and R3 together with the nitrogen 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 a 8 to 12 membered fused bicyclic ring. Wherein the heterocyclic group may contain up to 2 nitrogen atoms and does not contain any other hetero atom and may be optionally substituted by one or more substituents independently selected from C..4 or NRab, except The group contains 2 nitrogen atoms and is not substituted by the NRaRb group or contains 1 nitrogen atom and is substituted by the NRaRb group: and R6 represents an alkyl group (wherein the alkyl group optionally passes through one or more halogen groups (preferably fluorine) Substituting), and preferably represents an Au-Cw alkyl group and more preferably an An-Ci alkyl group. -84- 200940529 In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from: (i) a heterocyclic group containing 2 nitrogen atoms and no other hetero atom, wherein the heterocyclic group is optionally substituted by one or more Cl.4 alkyl groups; and (ii) contains 1 nitrogen atom and a heterocyclic group which does not contain any other hetero atom, wherein the heterocyclic group is substituted with an NRaRb group and optionally one or more

Cj-4 alkyl substituted; wherein the heterocyclic groups (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; and R6 represents Ari- C〇-4 alkyl (wherein the alkyl group is optionally substituted by one or more halo groups (preferably fluorine)), and preferably represents an An-Co-2 alkyl group and more preferably An-Clane base. In another preferred embodiment, the invention is directed to a compound of formula I wherein 0 Ri represents (i); R2 and R3 together with the nitrogen atom to which they are bonded may form a 4 to 7 membered single ring, 7 to 8 members a bridged bicyclic or 8- to 12-membered fused bicyclic saturated heterocyclic group wherein the heterocyclic group can contain up to 2 nitrogen atoms and does not contain any other heteroatoms and optionally one or more independently selected from Ch4 Substituting a substituent of an alkyl group or NRaRb, except that the heterocyclic group contains 2 nitrogen atoms and is not substituted with an NRaRb group or contains 1 nitrogen atom and is substituted by an NRaRb group. t R6 represents an Ari-CG.4 alkyl group (wherein The alkyl group is optionally substituted by one or more -85 to 200940529 halo groups (preferably fluorine), and preferably represents an An-Co-2 alkyl group and more preferably Απ-Cl alkyl group; and η represents 1 or 2, and preferably η is 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents (i); R2 and r3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from: (i) a heterocyclic group having 2 nitrogen atoms and containing no other hetero atom, wherein the heterocyclic group is optionally substituted by one or more Ci-4 alkyl groups; and (ii) contains 1 nitrogen atom and does not contain any other a heterocyclic group of a hetero atom, wherein the heterocyclic group is substituted with an NRaRb group and optionally substituted with one or more Cj-4 alkyl groups; wherein the heterocyclic groups (i) and (ii) may be 4 to 7 membered single ring, 7 to 8 membered bridged bicyclic or 8 to 12 membered fused bicyclic ring; represents An-Co-4 alkyl (wherein the alkyl group optionally passes through one or more halo groups (preferably fluorine) Substituting), and preferably representing a human alkyl group and more preferably An-c alkyl group; and η represents 1 or 2, and preferably η system 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a 4 to 7 membered single ring, 7 to 8 member bridge A bicyclic or 8 to 12 membered fused bicyclic saturated heterocyclic group wherein the heterocyclic group may contain up to 2 nitrogen atoms and does not contain any other hetero atom and optionally is independently selected from C by one or more! -4 alkyl-86- 200940529 or a substituent of NRaRb, except that the heterocyclic group contains 2 nitrogen atoms and is not substituted or contained by the NRaRb group! a nitrogen atom and substituted by the NRaRb group R6 represents an An-Co-4 alkyl group (wherein the alkyl group is optionally substituted by one or more halo groups (preferably fluorine)), and preferably represents Ari-cG- 2 alkyl and more preferably A r! - C ! alkyl; R 4 and R 5 are each independently selected from fluorene or mountain-4 alkyl, preferably r 4 0 and R 5 represent Η; and η represents 1 or 2, And preferably η is 1. In another preferred embodiment, the invention relates to compounds of formula I, wherein R 1 represents (i); R 2 and R 3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from: (i) a heterocyclic group containing 2 nitrogen atoms and no other hetero atom, wherein the heterocyclic group is optionally substituted by one or more Ci-4 alkyl groups; and φ (ii) contains 1 nitrogen atom and does not contain a heterocyclic group of any other hetero atom, wherein the heterocyclic group is substituted with an NRaRb group and optionally substituted with one or more Q-4 alkyl groups; wherein the heterocyclic groups (i) and (ii) may be 4 to 7 membered single ring, 7 to 8 member bridged double ring or 8 to 12 member fused double ring; R·6 stands for Ari-Co-4 yard base (where the yard base is optionally via one or more halo groups ( Preferably, fluoro) is substituted, and preferably represents Ari-CQ-2 alkyl and more preferably An-C! alkyl; R4 and Rs are each independently selected from hydrazine or Cm alkyl, preferably r4 -87- 200940529 and R 5 represent Η, and η represents 1 or 2, and preferably η is 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein R! represents (0; R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) to (h) Wherein Ra, Rb and R are as defined above, and preferably Ra, Rb and Rc each represent Η or C, _4 alkyl, and more preferably Ra, Rb and Re each represent Η or A And R 6 represents Ari-C〇_4 alkyl (wherein the alkyl group is optionally substituted by one or more halo groups (preferably fluorine)), and preferably represents Ari-CQ-2 alkyl group and More preferably An-Ci alkyl. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents (i); R2 and R3 together with the nitrogen atom to which they are bonded are selected from (a) a saturated heterocyclic group to (h), wherein Ra, Rb and Re are as defined above, and preferably Ra, Rb and Re each represent an anthracene or a Ci-4 alkyl group, and more preferably Ra, Rb And R. each represents hydrazine or methyl; R6 represents Ari-CG_4 alkyl (wherein the alkyl group is optionally substituted by one or more halo groups (preferably fluorine)), and preferably represents Αη-Cod An alkyl group and more preferably an An-Ci alkyl group; and η represents 1 or 2, and Preferably, in another preferred system, the invention is directed to a compound of formula I, wherein Ri represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form from (a) to -88 -

200940529 (h) a saturated heterocyclic group, wherein Ra, Rb and Re are as described above, and preferably Ra, Rb and Re each represent Η or Cl 4 alkyl, Ra, Rb and each represent Η or methyl R6 represents Ar丨-CG.4 alkyl (wherein the alkyl group may be optionally substituted with a halo group (preferably fluorine)), and preferably represents An-Co-: preferably an An-Ci alkyl group; R4 And R5 are each independently selected from fluorene or mountain-4 alkyl, and R5 represents hydrazine; and η represents 1 or 2, and preferably η is 1. In another preferred embodiment, the invention relates to the compound of formula I, Ri, which represents (i); R2 and R3, together with the nitrogen atom to which they are bonded, form a saturated heterocyclic group of (b) wherein Ra, Rb and Re are As described above and preferably, Ra, Rb and Re each represent Η or Cm alkyl, and Ra, Rb and Rc each represent an anthracene or a methyl group, and still more preferably, Rb represents a fluorenyl group and Rc represents hydrazine; R6 represents an An-Co-4 alkyl group (wherein the alkyl group may be optionally substituted with a halo group (preferably fluorine)), and preferably represents an An-Co-2 subunit Ari-Ci. In another preferred embodiment, the present invention relates to the compound of formula I, Ri, which represents (i); 112 and r3, together with the nitrogen atom to which they are bonded, form a saturated heterocyclic group of (b) wherein Ra, Rb and Rc are As above and preferably, Ra, Rb and Rc each represent a Η or C!-4 院基f definition, and, more preferably, one or more! alkyl groups and more preferably r4, selected from (a) or: definer, and more preferably also Ra, via one or more alkyl groups and more, selected from (a) or a definition, and more preferably -89-200940529, Ra, Rb and R . Each represents a hydrazine or a methyl group, and still more preferably, Ra represents hydrazine, Rb represents a methyl group and Rc represents hydrazine; represents an Ari-CG-4 alkyl group (wherein the alkyl group optionally passes through one or more halo groups ( Preferably, fluoro) is substituted, and preferably represents An-Co. 2 alkyl and more preferably Ari-Ci; and η represents 1 or 2, and preferably η is 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein R! represents (i); 0 R2 and R3 together with the nitrogen atom to which they are bonded form a saturated impurity selected from (a) or (b) a cyclic group wherein Ra, Rb and Re are as defined above, and preferably Ra, Rb and Re each represent a fluorene or Cm alkyl group, and more preferably Ra, Rb and Re each represent a hydrazine or a methyl group. And still more preferably, Ra represents Η, Rb represents methyl and Rc represents Η; R6 represents Ari-CQ-4 alkyl (wherein the alkyl group is optionally substituted by one or more halo groups (preferably fluorine) And preferably represents an Ari-CG-2 alkyl group and more preferably an An-C! alkyl group; 0 R4 and R5 are each independently selected from the group consisting of hydrazine or Ci. 4, preferably Κ·4 and R5 represents Η; and η represents 1 or 2, and preferably! ! Department i. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (a) wherein Ra, Rb And Rc each represents an anthracene or a Cu alkyl group, and preferably Ra, Rb and R. Each represents a hydrazine or a methyl group, and still more preferably Ra-90-200940529 represents hydrazine, Rb represents a methyl group and Rc represents hydrazine; and R6 represents an An-Co-4 alkyl group (wherein the alkyl group optionally passes through a Or a plurality of halo groups (preferably fluorine), and preferably represents an An-CQ 2 alkyl group and more preferably an An-Ci alkyl group. In another preferred system, the invention relates to a compound of formula I, wherein

Ri represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a heterocyclic ring of formula U) wherein Ra, Rb and Rc each represent hydrazine or C!-4 alkyl, and preferably

Ra, Rb and Re each represent a hydrazine or a methyl group, and still more preferably Ra represents hydrazine, Rb represents a methyl group and Re represents hydrazine; R6 represents an An-Co^ alkyl group (wherein the alkyl group optionally passes through one or A plurality of halo groups (preferably fluorine) are substituted, and preferably represent an An-Co-2 alkyl group and more preferably an An alkyl group; and η represents 1 or 2, and preferably η is 1. In another preferred embodiment, the invention relates to a compound of formula I wherein Q represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (a), wherein Ra, Rb And R. Each represents Η or Cu 院基' and preferably Ra, Rb and Re each represent Η or methyl, and still more preferably Ra represents Η, Rb represents methyl and Rc represents Η; R6 represents Ari-CQ_4 alkane a group (wherein the alkyl group is optionally substituted by one or more halo groups (preferably fluorine)), and preferably represents a Απ-Co-2 theater group and more preferably an An-Ci alkyl group; R4 and R5 Each is independently selected from the group consisting of hydrazine or Cm alkyl group, preferably -91 to 200940529, and R5 represents Η; and η represents 1 or 2, and preferably η is 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (b), wherein Ra, Rb And each represents Η or Cm alkyl, and preferably Ra, Rb and Re each represent hydrazine or methyl, and more preferably Ra and Rb each represent hydrazine or methyl and Re represents hydrazine and is still better The ground Ra represents Η, Rb represents a methyl group and Rc represents Η;

Re represents an Ari-CG-4 alkyl group (wherein the alkyl group is optionally substituted by one or more halo groups (preferably fluorine)), and preferably represents an Ari-Co-2 deutero group and more preferably An -Ci alkyl. In another preferred embodiment, the invention relates to a compound of formula I, wherein R 1 represents (i); R 2 and R 3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (b), wherein Ra, Rb and Re each represent an anthracene or a Cu alkyl group, and preferably Ra, Rb and Re each represent an anthracene or a methyl group, and more preferably Ra and Rb each represent an anthracene or a methyl group and Re represents a deuterium and still More preferably, Ra represents Η, Rb represents a methyl group and Rc represents Η;

Re represents an An-Co-4 alkyl group (wherein the alkyl group is optionally substituted by one or more halo groups (preferably fluorine)), and preferably represents an inlet alkyl group and more preferably Αη-Ci Alkyl; and η represents 1 or 2, and preferably n is 1. In another preferred embodiment, the invention relates to compounds of formula I, wherein -92-200940529 R1 represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (b), Among them Ra, Rb and R. Each represents η or Cu alkyl, and preferably Ra, Rb and R. Each represents a hydrazine or a methyl group, and more preferably, Ra and Rb each represent a hydrazine or a methyl group and Re represents hydrazine, and still more preferably, Ra represents hydrazine, and Rb represents a methyl group and R. Represents Η; R6 represents an An-Co-4 alkyl group (wherein the alkyl group is optionally substituted by one or more halo groups (preferably fluorine)), and preferably represents an An-Co-2 alkyl group and More preferably, an alkyl group; R4 and R5 are each independently selected from fluorene or Cm alkyl, preferably R4 and R5 represent hydrazine; and η represents 1 or 2, and preferably η is 1. In another preferred embodiment, the invention is directed to a compound of formula I, wherein Ri represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a 4 to 7 ® member single ring, 7 to 8 members A bridged bicyclic or 8 to 12 membered fused bicyclic saturated heterocyclic group wherein the heterocyclic group may contain up to 2 nitrogen atoms and does not contain any other hetero atom and optionally one or more independently selected from Ci Substituted with a substituent of .4 alkyl or NRaRb, except that the heterocyclic group contains 2 nitrogen atoms and is not substituted by NRaRb group or contains i nitrogen atoms and is substituted by NRaRb group » R6 represents An-Co-2 alkyl group and Preferably, An-c, alkyl; ΑΓι represents a phenyl group substituted by a group selected from the group consisting of hydroxy-C()-6 alkyl, r8co2-Cg-6 alkyl, r8so2nhco-c〇-6 alkyl, 1H-tetrazole--93- 200940529 5-base)-C〇.6 hospital base, -CONRsRs, -S02NR8R8, _s〇2r8, _ NR8S02R8', -NR8CONR8R8, -NR8C〇R^_NR8R8, and the base Optionally further substituted with a group selected from the group consisting of a C14, a ring or a Ci_4 alkoxy group, and 'preferably Ari represents a phenyl group substituted with a ~ group" which is selected from the group consisting of a thio-C- 6 yard base, -C〇 NR8R8, _§〇2 尺8, or _NReCORs' and the group is optionally further substituted with a 'substituent selected from Ci-4 alkyl, halo or mountain-4 alkoxy; R4 and RS Each is independently selected from hydrazine or Cl_4 alkyl, preferably R4 and R5 represent hydrazine; and η is 1. In another preferred embodiment, the invention relates to compounds of formula I, wherein Ri represents (i); R.sup.2 and R.sup.3, together with the nitrogen atoms to which they are bonded, form a saturated heterocyclic group selected from: (i) a heterocyclic group containing 2 nitrogen atoms and containing no other hetero atom, wherein the heterocyclic group is optionally substituted by one or more (^.4 alkyl groups; and (Π) contains 1 nitrogen atom And a heterocyclic group which does not contain any other hetero atom, wherein the heterocyclic group is substituted by an NRaRb group and optionally substituted by a plurality of alkyl groups; wherein the heterocyclic groups (i) and (ii) may be 4 to 7 membered monocyclic, 7 to 8 membered bridged bicyclic or 8 to 12 membered fused bicyclic ring; R6 represents An-Co.2 alkyl and preferably Ar]-Ci alkyl; and An represents a base substitution Phenyl group, the group is selected from the group consisting of hydroxy-Cg-6 alkyl 'R 8 C Ο 2 - C 0 - 6 , R 8 S Ο 2 NHC Ο - CG _ 6 yard base, (1 Η - 四哗· -94- 200940529 5-base)-C〇-6 院基, -CONRsRs, -S〇2NR8r8, _s〇2r8, 'nr8so2r8, -NR8CONR8R8, -NR8COR8 or · Take the mountain, and the base may optionally further a base substituted, the substituent is selected from the group consisting of Ci4 fluorenyl, halogen Or Ci. 4 oxime 'and 'preferably Ar' represents a phenyl group substituted with a group selected from the group consisting of hydroxy-cQ-6 alkyl, -conr8r8, _8〇2 ft. 8, or _NR8COR8, And optionally further substituted by a group selected from Ct.4 alkyl, halo or Ci-4 alkoxy, and U R4 and R5 are each independently selected from hydrazine or Cu alkyl. Preferably, R4 and R5 represent Η; and η is 1. In another preferred system, the invention relates to a compound of formula I, wherein Ri represents (i); R2 and R3 together with the nitrogen atom to which they are bonded may form a 4 to 7 membered monocyclic ring, a 7 to 8 membered bridged bicyclic ring or a 8 to 12 membered fused bicyclic saturated heterocyclic group, wherein the heterocyclic group may contain up to 2 nitrogen atoms and does not contain any D The atom is optionally substituted by one or more substituents independently selected from Ci.4 alkyl or NRaBb, except that the heterocyclic group contains 2 nitrogen atoms and is not substituted by the NRaRb group or contains 1 nitrogen atom and NRaRb radical substitutions » R6 represents An-C〇 2 alkyl group and preferably An-Ci alkyl group;

An represents a phenyl group substituted by a group at a meta position selected from the group consisting of hydroxy-C〇-6 alkyl, r8co2-c〇.6 alkyl, r8so2nhco-c〇_6 alkyl, (1H-tetrazole) -5-yl)-C〇-6 alkyl, -CONR8R8, -S〇2NR8R8, -SO2R8, -NR8S02R8, -NRgCONRgRg '-NR8COR8 or -95-200940529 nr8r8, and the group optionally further a substituent which is selected from G. 4 alkyl, halo or C!-4 alkoxy; and, preferably, Ari represents a phenyl group substituted at the meta position with a group selected from hydroxy-C. 〇6 alkyl, -CONR8R8, -s〇2R8' or -nr8cor8, and the group is optionally further substituted with a group selected from C^-4 alkyl, halo or CL4 alkoxy R4 and R5 are each independently selected from hydrazine or Ci-4 alkyl, preferably R4 and R5 represent hydrazine; and η is 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents (i); 112 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from: (i) a heterocyclic group having 2 nitrogen atoms and containing no other hetero atom, wherein the heterocyclic group is optionally substituted by one or more Ci-4 alkyl groups; and (Π) contains 1 nitrogen atom and does not contain any other a heterocyclic group of a hetero atom, wherein the heterocyclic group is substituted with an NRaRb group and optionally substituted with one or more Cj-4 alkyl groups; wherein the heterocyclic groups (i) and (ii) may be 4 to 7 membered monocyclic, 7 to 8 membered bridged bicyclic or 8 to 12 membered fused bicyclic ring; R6 represents An-Co-2 alkyl and preferably An-Ci alkyl;

Ari represents a phenyl group substituted by a group at a meta position selected from the group consisting of hydroxy-C 〇 6 alkyl, R 8 C Ο 2 - C 〇 - 6 alkyl, R 8 S Ο 2 NHC Ο - C 〇 _ 6 alkyl, (1Η-tetrazole·5-yl)-C〇.6 alkyl, -C〇NR8R8, -S02NR8R8, - 200940529 S〇2R8,, -NR8S02R8,, NR8CONR8R8, -nr8cor8 or -NR8R8 And the group is optionally further substituted with a group selected from a Cm alkyl group, a halogen or a -4 alkoxy group; and 'preferably, 八 represents a phenyl group substituted with a group at the meta position, The group is selected from the group consisting of hydroxy-Co.6 alkyl, -CONR8R8, -S〇2RV or -NR8COR8, and the group is optionally further substituted with a group selected from alkyl, halo or Cl-4 alkoxy; 0 R4 and R5 are each independently selected from hydrazine or Ci. 4 alkyl, preferably r4 and R5 represent η; and η is 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein I represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) to (h) 'wherein Ra, Rb and Re are as defined above, and preferably Ra, Rb and R. Each represents Η or Cm alkyl, and more preferably, Q, Ra, Rb and Rc each represent hydrazine or methyl; R6 represents Ar丨-C〇·2 alkyl and preferably Ar-Ci alkyl;

An represents a phenyl group substituted by a group selected from the group consisting of hydroxy-(: 〇_6 alkyl, R 8 C 〇 2 - c 〇 6 院, R 8 S Ο 2 NHC 0 - C. _ 6院Base, (1 Η -tetrakis-5-yl)-C〇-6, base -CONR8R8, -S02NR8R8, -S〇2R8, -NR8S02R8', -NR8CONR8R8' _NR8COR8 or -NR8R8, and the base can be selected Further substituted with a group selected from d-4 alkyl, halo or C!-4 alkoxy; and, preferably, Ar! represents a phenyl group substituted with a group selected from the group consisting of - C〇_6, _c〇nr8r8, -SO2R8, or -97-200940529 NRgCORs ' and the group is optionally substituted with a radical selected from the group consisting of C!·4 alkyl, Halogen or Q-4 alkoxy; R4 and RS are each independently selected from hydrazine or Cm alkyl, preferably Han and Rs represent hydrazine; and 4 η is 1. In another preferred system, the invention relates to A compound of formula I, wherein Ri represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (&) to (h) wherein Ra, Rb and R are as defined. As defined above, and preferably Ra, Rb and Re each represent Η or Cm alkyl, and preferably Ra , Rb and Rc each represent a hydrazine or a methyl group; Κ·6 represents an Ari-Co-2 hospital base and preferably an Ar!-Ci hospital base;

Ari represents a phenyl group substituted by a radical at a meta position selected from the group consisting of a radical -CQ.6 alkyl 'R8C02-C〇.6 alkyl, R8S02NHC〇-C〇_6 alkyl, (1H-four Zin-5-yl)-C〇.6 alkyl, -CONR8R8, -S02NR8R8, _so2r8', -nr8so2r8, -nr8conr8r8'-nr8cor8 or _NR8R8, and the group is optionally further substituted with a base, The substituent is selected from the group consisting of Ci_4, halogen or Ci-4 alkoxy; and, preferably, Ar! represents a phenyl group substituted at the meta position with a group selected from the group consisting of hydroxy-CG_6, -CONR8Rs, -so2R8' or -NR8COR8, and the group is optionally substituted with a group selected from the group consisting of a s-alkyl, a halogen or a clM-oxyl group; the R4 and Rs are each independently selected from hydrazine or Cm alkyl, preferably r4 and R5 represent Η; and -98- 200940529 η is 1. In another preferred embodiment, the invention relates to a compound of formula I wherein L represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from U) or (b), Wherein, Ra, Rb and Re are as defined above, and preferably Ra, Rb and Re each represent Η or C, -4 alkyl, and more preferably Ra, Rb and Rc each represent Η or methyl And still more preferably, Ra represents @Η, Rb represents a methyl group and Rc represents a fluorene; R6 represents an Ari-C〇-2 yard base and preferably an Ari-Ci yard group; Αι^ represents a phenyl group substituted with a base The group is selected from the group consisting of a base group of _c〇_6 and R 8 C Ο 2 - C. - 6 yard base, R 8 S Ο 2 N H C Ο - C. . 6 fluorenyl, (1 η -tetradecyl 5-yl)-C〇.6 yard, -C0NR8R8, -S02NR8R8, _S02R8, _ NR8S02R8, -NR8CONR8R8, -NR8COR8 or -nr8r8, and the base Optionally further substituted with a group selected from the group consisting of C1 4, halo or Ci-4 alkoxy; and 'preferably An represents a phenyl group substituted with a radical selected from the group consisting of -C〇-6 fluorenyl, -C〇NR8R8, nr8cor8, and the group is optionally further substituted with S groups selected from C..4 alkyl, halo or Ci.4 alkoxy; R4 And R5 are each independently selected from hydrazine or Cl. 4 alkyl, preferably ^ and R5 represent hydrazine; and η is 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic ring selected from or -99-200940529 (b) Base, where Ra, Rb and R. It is as defined above, and preferably Ra, Rb and R. Each represents a hydrazine or a Cu alkyl group, and more preferably Ra, Rb and Re each represent a hydrazine or a methyl group, and still more preferably Ra represents Η 'Rb represents a methyl group and Rc represents Η; R6 represents Ari-C〇 -2 alkyl and preferably An-Ci alkyl;

Ari represents a phenyl group substituted by a radical at a meta position selected from the group consisting of a thio- CG-6 alkyl group, a R8C02-CG.6 alkyl group, a r8so2nhco-c〇.6 alkyl group, (1H-tetrazole- 5-yl)-Co-6 alkyl, -CONR8R8, -S02NR8R8, _so2r8', -nr8so2r8, -nr8conr8r8, -nr8cor8 or _nr8r8, and the group is optionally further substituted with a radical, the substituent Or a base selected from the group consisting of Cl. 4, halogen or Ci-4; and, preferably, Ar! represents a phenyl group substituted at the meta position with a group selected from the group consisting of hydroxy-C〇-6 alkyl groups, -CONR8R8, -S02R8' or -NR8COR8, and the group is optionally further substituted with a group selected from a C 4 alkyl group, a halogen or an alkoxy group; the R 4 and R s are each independently selected from η or Cu alkyl, preferably R4 and R5 represent Η; and η is 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (a) wherein Ra, Rb And Re each represents η or Cm alkyl, and preferably Ra, Rb and Re each represent fluorene or methyl, and still more preferably Ra represents Η 'Rb represents a methyl group and Re represents η; -100- 200940529 Ruler 6 represents the Ari-C〇-2 yard base and preferably the Aq-Ci yard base;

Ari represents a phenyl group substituted by a group selected from the group consisting of keto-cq_6, R 8 C 0 2 C 〇. 6 院, R 8 S Ο 2 NHC Ο - C 〇 · 6 Η-tetrakis-7-yl)-C〇.6 alkyl, _CONr8R8, _s〇2NR8R8, _s〇2R8, -NRsS〇2R8, -NRgCONRgRs, -NR8COR8; ^_NR8R8, and the group optionally further a radical substitution, the substituent being selected from the group consisting of Ci-4 alkyl, halogen or C 4 alkoxy; and, preferably, Ar 2 represents a phenyl group substituted by a group - the group is selected from hydroxy-cG-6 alkane a group, -conr8r8, -S〇2R8, or NR8COR8, and the group is optionally further substituted with a group selected from the group consisting of cU4 alkyl, halo or alkoxy; R4 and Rs are each Independently selected from η or Ci-4 alkyl, preferably R4 and R5 represent oxime; and η is 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein R1 represents (i); 〇R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (a) wherein Ra, Rb and Rc each represent η or Cl_4 alkyl, and preferably Ra, Rb and Re each represent a fluorene or a methyl group, and still more preferably Ra represents Η 'Rb represents a methyl group and Re represents η; R6 represents An a Cw alkyl group and preferably an An-Ci alkyl group; a phenyl group substituted by a group at a meta position selected from the group consisting of hydroxy-cQ.6, R8c〇2_C()_6 alkyl, R8S〇 2nhco-c〇.6 alkyl, (1H-tetradec-5-yl)-C〇.6 alkyl, -(:(^118118, -80:^118118, -S02R8', _NR8S02R8,, -NR8C〇 NR8R8, -NR8COR8 or -101 - 200940529 nr8r8, and the group is optionally further substituted with a group selected from C!-4 alkyl, halogen or C,4 alkoxy; and, preferably Ari represents a phenyl group substituted with a group at a meta position selected from the group consisting of hydroxy-C〇.6 alkyl, -CONR8R8, -S02R8' or -NR8COR8, and the group is optionally further substituted with a group, The substituent is selected from the group consisting of Ci. 4 alkyl, halogen or Ci-4 decyloxy R4 and R5 are each independently selected from the group consisting of anthracene or behen-4-alkyl, preferably r4 and R5 represent anthracene; and η is 1. In another preferred system, the invention relates to a compound of formula I, wherein R1 represents (i); R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of the formula (b), wherein Ra, Rb and Rc each represent a fluorene or a Ch4 alkyl group, and preferably Ra, Rb And Re each represents hydrazine or methyl, and more preferably Ra and Rb each represent fluorene or methyl and Rc represents hydrazine, and still more preferably Ra represents η ' Rb represents a methyl group and Rc represents Η; R6 represents An -Co-2 alkyl and preferably Αγ, -C, alkyl;

An represents a phenyl group substituted by a group selected from a hydroxyalkyl group, R8C〇2-C〇.6 alkyl group, R8S〇2NHCO-C〇.6 alkyl group, (1H-tetrazol-5-yl group) )-C〇.6 院, _c〇NR8R8, -S02NR8R8, -S02Rs, -NR8S02R8', _NR8CONR8R8, -80: 〇118 or _hard 8118, and the group is optionally further substituted by a base The group is selected from a C14 alkyl group, a halogen or a ci_4 alkoxy group; and 'preferably A Γ ! represents a phenyl group substituted with a group selected from a hydroxy-c" alkyl group, _c〇NR8R8, -S〇 2R8, or -102-200940529 NR8COR8, and the group is optionally further substituted with a group selected from c, -4 alkyl, halogen or Ci-4 alkoxy; R4 and R5 are independently selected From hydrazine or Cm alkyl, preferably r4 and R5 represent hydrazine; and η is 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein R 1 represents (i); R 2 and R 3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (b), wherein Ra, Rb and Rc each represent an anthracene or an alkyl group, and preferably Ra, Rb and Re each represent an anthracene or a methyl group, and more preferably Ra and Rb each represent a fluorene or a methyl group and Re represents a hydrazine, and still more Preferably, Ra represents η, Rb represents methyl and Rc represents Η; R6 represents Ari_C〇-2, and preferably Ari-Ci; A ri represents a phenyl substituted with a radical at the meta position. It is selected from the group consisting of hydroxy-C 0 - 6 , R 8 C Ο 2 - C 〇 - 6 , R 8 S Ο 2 NHC Ο - c 〇. 6 院, 〇 (1Η-tetrazol-5-yl) -C〇.6 alkyl '-(:0\118118, -8〇2]^118118, -S02R8', -NR8S02R8, -NR8CONR8R8 '-NR8COR8 or -nr8r8, and the group optionally further passes through a group Substituted, the substituent is selected from a Ci-4 hospital, a halogen or a Ci-4 alkoxy; and, preferably, Ari represents a phenyl group substituted at the meta position with a group selected from a hydroxyl group -C() _6 alkyl, -CONR8R8, -s〇2R8' or -NR8COR8' and the group optionally enters - a substituent substituted from CL4 alkyl, halo or C|_4 alkoxy; R4 and R5 are each independently selected from hydrazine or Ci.4 alkyl, preferably R4-103-200940529 and R5 represent And η is 1. In another preferred embodiment, the invention relates to a compound of the formula wherein Ri represents oxime (ii); and p represents oxime or 1. In another preferred embodiment, the invention relates to formula I a compound wherein R1 represents (ii); and R2 and, together with the nitrogen atom to which they are bonded, form a saturated heteroatom which may be a 4 to 7 membered monocyclic ring, a 7 to 8 membered bridged bicyclic ring or a 8 to 12 membered fused bicyclic ring. a cyclic group wherein the heterocyclic group may contain up to 2 nitrogen atoms and does not contain any other hetero atom and is optionally substituted by one or more substituents independently selected from Ci4 alkyl or NRaBb, the heterocyclic ring The present invention relates to a compound of formula I, wherein Ri represents (ii); R2 and R3, and wherein the radical contains 2 nitrogen atoms and is not substituted by the NRaRb group or contains 1 nitrogen atom and is substituted by the NRaRb group in another preferred system. Together with the nitrogen atom to which they are bonded, 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 The cyclic group may contain up to 2 nitrogen 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 Cl_4 alkyl or NRaB, except that the heterocyclic group contains 2 nitrogen atoms. And is not substituted by the NRaRb group or contains 1 nitrogen atom and is substituted by the NRaRb group: and P represents 〇 or 1. -104 - 200940529 In another preferred system, the invention relates to a compound of formula I, wherein

Ri represents (ii); R2 and R3 together with the nitrogen 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 a 8 to 12 membered fused bicyclic ring. Wherein the heterocyclic group may contain up to 2 nitrogen 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 Cl_4 alkyl or NRaRb, except that the heterocyclic group contains 2 a nitrogen atom and which is not substituted by the NRaRb group or contains 1 nitrogen atom and is substituted by the NRaRb group. » R4 and R5 are each independently selected from the group consisting of anthracene or alkylene-4alkyl; and P represents deuterium or 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein R! represents (ii); and R2 and R3 together with the nitrogen atom to which they are bonded form a saturated impurity selected from (a) to (h) The ring group 'wherein Ra, Rb and Re are as defined above, and preferably Ra, Rb and Rc each represent a fluorene or Cm alkyl group, and more preferably Ra, Rb and each represent a hydrazine or a methyl group. In another preferred embodiment, the invention relates to a compound of the formula wherein R 1 represents (ii); R 2 and R 3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic ring selected from (a) to (h) Wherein Ra, Rb and Re are as defined above, and preferably Ra, Rb and Re each represent a hydrazine or a Cl 4 alkyl group, and more preferably Ra, Rb and each represent a hydrazine or a methyl group; ρ stands for 〇 or 1. In another preferred embodiment, the invention relates to a compound of formula I, wherein R1 represents (ii); R2 and R3 together with the nitrogen atom to which they are bonded form a choice of (a) to (h) a saturated heterocyclic group, wherein Ra, Rb and Re are as defined above, and preferably Ra, Rb and Rc each represent an anthracene or a C!-4 alkyl group, and more preferably Ra, Rb and Rc each represent Η or methyl; R4 and R5 are each independently selected from hydrazine or Ci-4 alkyl; and P represents hydrazine or 1. In another preferred system, the invention relates to a compound of formula I, wherein

Ri represents (Π); and R 2 and R 3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) or (b), wherein Ra, Rb and Re are as defined above, and Preferably, Ra, Rb and Re each represent a hydrazine or a Cm alkyl group, more preferably Ra, Rb and Rc each represent a hydrazine or a methyl group, and still more preferably Ra represents hydrazine, Rb represents a methyl group and Rc represents hydrazine. . In another preferred embodiment, the invention relates to a compound of formula I, wherein (R) and R3, together with the nitrogen atom to which they are bonded, form a saturated heterocyclic group selected from (a) or (b), Among them Ra, Rb and R. It is as defined above, and preferably Ra, Rb and R. Each represents a hydrazine or a Cm alkyl group. More preferably, Ra, Rb and Rc each represent a hydrazine or a methyl group, and still more preferably, Ra represents hydrazine, Rb represents a methyl group and Rc represents hydrazine; and Ρ represents hydrazine or 1. In another preferred embodiment, the invention is directed to a compound of formula I, wherein -106- 200940529

Ri represents (ii); R2 and R3 and a saturated heterocyclic group bonded to the nitrogen (b) thereof, wherein Ra, Rb; g and preferably Ra, Rb and Re each represent Ra, Rb and Rc Do not represent hydrazine or methyl, Rb represents methyl and Rc represents hydrazine; R4 and R5 are each independently selected from Η φ φ Ρ represents 〇 or 1.

In another preferred system, the invention I

Ri represents (ii); and R2 and R3 and the nitrogen H heterocyclic group bonded thereto, wherein Ra, Rb and Re are each preferably Ra, Rb and R. Each represents Η or Table H, Rb represents a methyl group and rc represents η. In another preferred embodiment, the invention 〇 Ri represents (ii); R2 and R3 and the nitrogen-topped heterocyclic group bonded to them, wherein Ra, Rb and R. Each is better than Ra, Rb and R. Each represents Η or ’ ' Rb stands for methyl and Rc stands for Η; Ρ stands for 0 or 1. In another preferred system, the invention is

Ri represents (ii); R2 and R3 and their bonded nitrogen levees, together with atoms formed from (a) or l are as defined above, Η or Ci_4 院基's better and still better Ra represents an alkyl group of hydrazine; and I is a compound of formula I wherein the yttrium forms a compound of formula (a) which represents a hydrazine or a Ci_4 valence group which is more methyl, and still more preferably Ra s S to a compound of formula I, Wherein the hazelnuts together form a saturated formula of formula (a) which represents a hydrazine or an alkyl group, is more methyl, and still more preferably Ra and is a compound of formula I, wherein the ε together form a saturated formula (a) -107- 200940529 Heterocyclic group 'wherein Ra, Rb and R. Each represents Η or Cl_4 alkyl, preferably Ra, Rb and Re each represent hydrazine or methyl, and still more preferably Ra represents H' Rb represents methyl and Re represents η; R·4 and Rs are each It is independently selected from hydrazine or Ci-4 alkyl; and P represents 0 or 1. In another preferred system, the invention relates to a compound of formula I, wherein

Ri represents (ii); and R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of the formula (b)' wherein Ra, Rb and R. Each represents hydrazine or C!-4 alkyl, and preferably Ra, Rb and R. Each represents a hydrazine or a methyl group, and more preferably, Ra and Rb each represent a hydrazine or a methyl group and R. Representing Η, and still better Ra stands for Η, Rb stands for methyl and Re stands for Η. In another preferred embodiment, the invention relates to a compound of formula I, wherein R 1 represents (ii); R 2 and R 3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (b), wherein Ra, Rb and Rc each represent Η or (^_4 alkyl, and preferably Ra, Rb and each represent Η or methyl, and more preferably Ra and Rb each represent Η or methyl and Re represents Η, and Still more preferably, Ra represents Η 'Rb represents a methyl group and Re represents Η; and ρ represents 〇 or 1. In another preferred system, the invention relates to a compound of the formula I in which (Π); r2 and r3 and The nitrogen atoms bonded thereto form a saturated heterocyclic group of the formula (b), wherein Ra, Rb and Rc each represent a fluorene or a Ci-4 courtyard group and -108 - 200940529 preferably Ra, Rb and Rc Do not represent hydrazine or methyl, and more preferably Ra and Rb each represent fluorene or methyl and Rc represents H, and still more preferably Ra represents Η, Rb represents methyl and Rc represents Η; R4 and R5 are each Independently selected from hydrazine or C, _4 alkyl; and Ρ represents hydrazine or 1. Furthermore, the invention includes all possible combinations of the specific and preferred systems of the above compounds of formula I. 另一 In another preferred system, the invention turn off a compound of formula I selected from the group consisting of 4-cyclohexyloxymethyl-6-(3-(methylamino)tetrahydroindenyl)pyrimidine-2-amine; 4-cyclohexyloxymethyl ^-(^".-(Methylaminopyrrolidinium-fluorenyl)pyrimidine-2-amine; 4-(cyclopropylmethoxymethyl)-6-(3-(methylamino)tetrahydrol吖唉-^yl)pyrimidine-2-amine; Ο 4_(cyclopropylmethoxymethyl)-6-((3 R)-3-(methylamino)pyrrolidine·1-yl)pyrimidine- 2-amine; 4-cyclobutoxymethyl-6-(3-(methylamino)tetrahydroindole-buyl) pyrimidine-2-amine; 4-cyclobutoxymethyl_6_( (3R)_3_(methylamino)pyrrolidine-fluorenyl-pyrimidin-2-amine; 4-cyclopentyloxymethyl-6-(3-(methylamino)tetrahydroindole-; • pyrimidine-2-amine; 4-cyclopentyloxymethyl-6-((3R)-3-(methylamino)pyrrolidinyl-fluorenyl)-109- 200940529 pyrimidine-2-amine; 4-isopropoxymethyl-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidine-2-amine; 4-isopropoxymethyl-6-((3 R -3-(methylamino)pyrrolidin-1-yl)pyrimidine-2-amine; 4-isobutoxymethyl-6-(3-(methylamino)tetrahydroinden-1-yl Pyrimidine-2-amine; 4-iso Oxymethyl-6-((3 R)-3-(methylamino)pyrrolidin-1-yl)pyrimidine-2-amine; 4-(2,2-dimethylpropoxymethyl) -6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidine-2-amine; 4-(2,2-dimethylpropoxymethyl)-6-((3R) -3-(Methylamino)pyrrolidin-1-yl)pyrimidine-2-amine; 4-tertoxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyrimidin-2-amine; 4-(cyclopentylmethoxymethyl)-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidine-2-amine; 4_( Cyclopentylmethoxymethyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine; 4-(((lS,2R,4R)- Bicyclo[2.2.1]hept-2-yloxy)methyl)-6-(3-(methylamino)tetrahydroindol-1-ylpyrimidin-2-amine; 4-(((lS, 2R,4R)-bicyclo[2.2.1]hept-2-yloxy)methyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidine-2-amine; 4-benzyloxymethyl-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidine - 200940529 2-amine; 4-benzyloxymethyl-6-((3R)- 3-(methylamino)pyrrolidin-1-ylpyrimidin-2-amine; 6-methoxymethyl-4-((3R)-3-(methylamino)pyrrolidin-1-yl ) Pyridin-2-amine; 6-methoxymethyl-4-(3-(methylamino)tetrahydroindol-1-yl)pyrimidine-2-amine; 0 4-(3-(methylamine) Tetrahydroindol-1-yl)-6-phenoxymethylpyrimidine-2-amine; 6-(2-methoxyethyl)4-(3-(methylamino)tetrahydroindole唉-1-yl)pyrimidine-2-amine; 4-(4-fluorophenoxymethyl)-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-2-amine 4-(2,4-difluorophenoxymethyl)-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidine-2-amine; ❹ 4-(3,4 -difluorophenoxymethyl)_6-(3-(methylamino)tetrahydroindol-1-ylpyrimidine-2-amine; 4-(2,4-difluorophenoxymethyl) -6-((3 R)-3-(methylamino)pyrrolidin-1-yl)pyrimidine-2-amine; 4-(3,4-difluorophenoxymethyl)-6-(( 3 R)_3-(Methylamino)pyrrolidin-1 -yl)pyrimidine-2-amine; 4-(3-Aminotetrahydroindol-1-yl)-6-isopropoxymethylpyrimidine 2-Amine» 4-((3R)-3-Amino-U-pyrrolidine-1-yl)-6-isopropoxymethyl wall 卩疋2- 2-111 - 200940529 Amine; 4-( 3-(methylamino)tetrahydroindole-buyl)·6-(tetrahydrofuran-4)-spray-2-amine; 4-(3-(methylamino)tetrahydroindole唉-Buji)-6_((S)_tetrahydrofuran_2.yl)pyrimidin-2-amine; 4-((3R)-3-(methylamino)pyrrolidinyl-1-yl)_6-(( S)_tetrahydrofuran-2-yl)pyrimidine-2-amine; 4-(3-(methylamino)tetrahydroindole-buyl)_6_((R)_tetrahydrofuran-2-yl)pyrimidin-2- Amine; 4-((3R)-3-(methylamino)pyrrolidinyl-1-yl)-6-((R)-tetrahydrofuran-2-yl)pyrimidine-2-amine; 4-(2-(4- Chlorophenoxy)propan-2-yl)-6-(3-(methylamino)tetrahydroindol-1-ylpyrimidin-2-amine; 4-(2-(4-chlorophenoxy) Prop-2-yl)-6-((3R)-3-(methylamino)pyrrolidinyl-pyridyl-2-pyrimidine-2-amine; 6-((R)-l-methoxyethyl)- 4-(3-(methylamino)tetrahydroindol-1-yl)pyrimidine-2-amine; 4-(3-(methylamino)tetrahydroindol-1-yl)-6-( (R)-phenyl(methoxy)methyl)pyrimidine-2-amine; 4-((311)-3-(methylamino)pyrrolidin-1-yl)-6-((11)- Phenyl(methoxy)methyl)pyrimidine-2-amine; 4-(3-(methylamino)tetrahydroindol-1-yl)-6-((S)-phenyl(methoxy) )methyl)pyrimidin-2-amine; 4-cyclohexyloxymethyl-6-[3-methyl-3-(methylamino)tetrahydroindole-1-112- 200940529-pyrimidine- 2-amine; 4-isobutoxymethyl-6-[3-methyl-3-(methylamino)tetrahydroindol-1-yl]pyrimidin-2-amine; 4-isopropoxy Methyl-6-[3-methyl-3-(methylamino)tetrahydroindole-pyl]pyrimidin-2-amine; 4-(1,1-dimethyl-2-methoxy 6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidine-2-amine; ❹ 4-(2-isopropoxyethyl)-6-(3-(A Aminoamino)tetrahydroindole-1_yl)pyrimidin-2-amine; 4-(1-(methoxymethyl)cyclopentyl)-6-((3R)-3-(methylamino)pyrrole Pyridin-1-yl)pyrimidine-2-amine; 4-[3-methyl-3-(methylamino)tetrahydroindole-1_yl]_6_[(2S)_tetrahydrofuran-2-yl]pyrimidine -2-amine; 4-[(dicyclopropylmethoxy)methyl]_6_(3-(methylamino)tetrahydroindol-1-yl)pyrimidine-2-amine; O 4-(1- (methoxymethyl)cyclopentyl)_6_(3-(methylamino)tetrahydroindole-1-yl)pyrimidine-2-amine; 3-(((2-amino-6-(3-) (methylamino)tetrahydroindole-indole-yl)pyrimidin-4-yl)methoxy)methyl)benzoic acid methyl ester; 4-(((2-amino-6-(3-(methyl)) Amino)tetrahydroindole-indole-yl)pyrimidine-4-yl)methoxy)methyl)benzoic acid methyl ester; 2-(((2- Amino-6-(3-(methylamino)tetrahydroindole-]-yl)pyrimidin-4-yl)methoxy)methyl)benzoic acid methyl vinegar; 4-(3-(methylamino)tetra Hydroquinone_丨_yl)_6_((4_(methylsulfonyl)-113- 200940529 benzyloxy)methyl)pyrimidine-2-amine; 4-(3-(methylamino)tetrahydroindole唉-1-yl)-6-((3-(methylsulfonyl)benzyloxy)methyl)pyrimidine-2-amine; 2- [3-(((2-amino-6-(3) -(methylamino)tetrahydroindol-1-yl)pyrimidin-4-yl)methoxy)methyl)phenyl]propan-2-ol; [3-(((2-amino-6) -(3-(Methylamino)tetrahydroindol-1-yl)pyrimidin-4-yl)methoxy)methyl)phenyl]methanol; [4-(((2-amino-6--6-) (3-(Methylamino)tetrahydroindole-buyl)pyrimidin-4-yl)methoxy)methyl)phenyl]methanol; [2-(((2-amino-6-(3) -(methylamino)tetrahydroindole-bupyridin-4-yl)methoxy)methyl)phenyl]methanol; 3-[((2-amino-6-(3-) Aminoamino)tetrahydroindol-1-yl)pyrimidin-4-yl)methoxy)methyl]benzoic acid; 3-[((2-amino-6-(3-(methylamino))) Tetrahydroindol-1-yl)pyrimidin-4-yl)methoxy)methyl]benzamide: and 3-[((2-Amino-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-4-yl)methoxy)methyl]-N-butylbenzamide , or their salt. In another preferred embodiment, the invention is directed to a compound of formula I which is capable of determining the H4 receptor at 10 μΜ (more preferably 1 μΜ and particularly preferably 1 μΜ) (such as Example 6 5 or 6 6 Inhibitors provide inhibition of histamine H4 receptor activity by more than 50%. The compounds of the invention contain one or more basic nitrogens and are therefore capable of forming salts with organic or inorganic acids. Examples of such salts include, inter alia, with inorganic acids (-114-200940529 such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid) and organic acids (such as methanesulfonic acid, trifluoro) Methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trans-butenedioic acid, oxalic acid, acetic acid, maleic acid, ascorbic acid, citric acid, lactic acid, tartaric acid, malonic acid, glycolic acid , succinic acid and propionic acid) salts. There is no limitation on the type of salt that can be used, provided that the salt is pharmaceutically acceptable for therapeutic purposes. A pharmaceutically acceptable salt means a salt which is applied to tissues of the human body and other mammals in accordance with medical judgment without causing excessive toxicity, irritation, allergic reaction and the like. Pharmaceutically acceptable salts are well known in the art. Salts of the compounds of formula I can be prepared by reacting a salt of a compound of formula I during the final isolation and purification of a compound of the invention or by reacting a compound of formula I with a sufficient amount of the desired acid in a conventional manner. The salt of the compound of formula I can be converted to other salts of the compound of formula I by ion exchange using an ion exchange resin. The compound of formula I and its salts may differ in certain physical properties, but for the purposes of the present invention All are equivalent. The scope of the invention includes all salts of the compounds of formula I. The compound of the present invention may form a complex with a solvent capable of reacting therewith or with a solvent in which precipitation or crystallization can be precipitated. These complexes are referred to as solvates. As used herein, a solvate refers to a complex formed by a solute (a compound of formula I or a salt thereof) and a solvent in a variable stoichiometry. Examples of the solvent include pharmaceutically acceptable solvents such as water, ethanol and the like. The complex formed with water is called a hydrate. The scope of the present invention contains -115-200940529 a solvate comprising a compound of the present invention (or a salt thereof), which includes a hydrate. The compounds of formula I may exist in different physical forms (i.e., amorphous or crystalline). Furthermore, the compounds of the invention can be crystallized in more than one type (i.e., polymorphic). Polymorphs can be distinguished by the different physical properties known in the art, such as X-ray diffraction patterns, melting points or solubility. The scope of the present invention encompasses all physical forms of the compounds of formula I, including all polymorphic forms ("polymorphs"). Certain compounds of the invention may exist in the form of several optical isomers and/or several non-image areomers. The non-image isomers can be separated by conventional techniques such as chromatography or fractional crystallization. The optical isomers can be resolved by conventional optical resolution techniques to form optically pure isomers. This resolution can be carried out by using any chiral synthetic intermediate or the product of formula I. Optically pure isomers can also be obtained separately by mirror-specific synthesis. The present invention encompasses all individual isomers and their mixtures (e.g., mixtures of racemic or non-mirror isomers) obtained by synthesis or by physical mixing of such isomers. The compound of formula I can be obtained by following the methods described below. It will be apparent to those skilled in the art that the precise method for preparing a given compound can vary depending on the chemical structure of the given compound. Further, in some of the following methods, it may be necessary or recommended to protect the reactive group or the unstable group using a conventional protecting group. The nature of such protecting groups and methods of introducing or removing such protecting groups are well known in the art (see, for example, the literature Greene TW and Wuts PG, "Protective Groups in Organic Synthesis", John Wiley & Sons, 3rd edition, 1999). -116- 200940529 Unless otherwise stated, the meaning of the different substituents for the compounds of formula I in the methods described below are as described above. In general, a compound of formula I can be obtained by reacting a compound of formula II with a compound of formula III as shown in the reaction scheme below:

L wherein Rt, R2 and R3 are as defined above for the compound of formula I and L represents a leaving group such as a halogen, triflate or tosylate. In a suitable solvent (such as 1,4 - dioxins, tetrahydrofuran, dichloromethane, N,N-dimethylformamide or acetonitrile, preferably acetonitrile) and in a base (such as N, N-diiso) In the presence of propylethylamine, dimethylaniline, diethylaniline or triethylamine, preferably triethylamine, a coupling agent such as, for example,

PyBOP (benzotriazol-1-yl-oxygen trisodium sulphate hexafluorophosphate) is reacted with a compound of formula II and a compound of formula III. The reaction can be carried out at a temperature ranging from room temperature to reflux temperature, preferably under reflux. -117- 200940529 Alternatively, by reacting a compound of formula III with a reactive derivative of a compound of formula II (i.e., a compound of formula IIB, which is prepared by converting a hydroxyl group on a compound of formula II to a leaving group (such as a halogen or The compound of formula I can be obtained by reacting a triflate, preferably chloro)). Thus, it may optionally be borrowed in the presence of a suitable solvent by reaction with a halogenating agent such as POC13 or in the presence of a suitable solvent such as 1,4-dioxane or 1,2-dichloroethane. The hydroxyl group of the compound of formula II can be converted to a leaving group (such as a halogen, preferably by reaction with a halogenating agent 卩0 (:13/? (:15 or N,N-dimethylformamide/grass chloride mixture). The reaction is carried out by heating (preferably at a temperature between 100 ° C and 140 ° C.) Similarly, by reacting with trifluoromethanesulfonic anhydride in the presence of pyridine The hydroxyl group of the compound is converted to a triflate group, or the hydroxyl group of the compound of the formula is converted into a reaction with p-toluenesulfonyl chloride in the presence of a solvent such as dichloromethane and a base such as triethylamine. a tosylate group. The resulting reactive derivative of the compound of formula 11 (ie, a compound of formula IIB) is then reacted with a compound of formula III to form a compound of formula I. The reaction is carried out in a suitable solvent (such as ethanol, methanol, butyl). Alcohol, hydrazine, hydrazine dimethyl carbamide, dimethyl selenium, tetrahydrofuran, toluene or acetonitrile Preferably in the presence of a base (which includes an organic amine such as triethylamine, hydrazine, hydrazine-diisopropylethylamine, dimethylaniline and especially diethylaniline) and under heating ( Preferably, the heating is carried out at a temperature between 50 and 1 ° C. The heating may be by microwave or by microwave irradiation at a wattage capable of achieving the above temperature. The amine substituent of the compound of the formula is protected to prevent the formation of by-products prior to the reaction of the compound of formula 11 with a compound of formula 111 or a compound of formula -118-200940529 IIB with a compound of formula: in the same manner, if desired, may also be protected. The amine of the compound of the formula II and the compound of the formula IIB may be any suitable protecting group such as, for example, a butoxycarbonyl group (Boc). When the amine substituent of the compound of the formula II and / or the compound of the formula III and / or the formula IIB When the system is protected, subsequent deprotection steps may be necessary under standard conditions. Therefore, when protecting the system Boc, a strong acid such as HCl can be added to the appropriate solvent (such as 1,4-two). a solution in methane, diethyl ether or methanol) or three The obtained crude product is directly subjected to a deprotection reaction in a dichloromethane solution of acetic acid. The hydrazine compound is commercially available or can be obtained by a method 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:

II wherein h is as described in formula I and R9 represents Ci_4 alkyl. The reaction is carried out in a suitable solvent, preferably ethanol, and in the presence of a base such as potassium carbonate, sodium butoxide or sodium ethoxide and preferably sodium methoxide. The reaction can be carried out by heating at a suitable temperature (usually a temperature between room temperature and reflux temperature, preferably a reflux temperature). The compound of the formula IV is commercially available or can be readily prepared by a conventional method from a compound commercially available from -119 to 200940529. For example, as shown in the reaction scheme below, the compound of formula IV can be derived from the carboxylic acid V after conversion of the carboxylic acid to its corresponding mercapto chloride by using conventional methods (such as by the presence of butyllithium) Reacting with a monopropionic acid Ci-4 alkyl ester such as ethyl malonate (see Journal of Organic Chemistry 2000, 65, 24, 8402) or by the presence of lithium diisopropylamide Preparation of C^-4 alkyl acetate (such as ethyl acetate) (see Tetrahedron Letters 1991, 3 2, 52, 773 1 )): 〇0 0

Wherein is as described in formula I and R9 represents a Cu alkyl group. As described in the literature Monatsh Chem 1 989, 120, 89 1 and shown in the reaction diagram below, by the alcohol VI and the 4-chloro-3-oxobutyric acid Ci-4 alkyl ester (such as 4-chloro- The compound of the formula IV can be easily obtained by reacting 3-ethyloxybutyrate (wherein R! represents (i), wherein R4 and R5 represent oxime and η represents 1):

Wherein R6 is as described in formula I and R9 represents a Cu alkyl group. Furthermore, the present invention can also be obtained by a conventional reaction of organic chemistry and starting from other compounds of the formula I under standard experimental conditions by a suitable functional group conversion reaction, -120-200940529, in one or more steps. Certain compounds. Examples of the conversion reaction include reduction of an alkyl ester to obtain a primary alcohol, hydrolysis of the ester to obtain a carboxylic acid, reaction of the ester with an amine to give a corresponding decylamine, addition of an ester to a Grignard reagent to obtain a tertiary alcohol, and benzyloxy The methyl group is debenzylated to form a hydroxymethyl group which can be alkylated. In some of these conversion reactions, protecting the reactive group or restless group by using a conventional protecting group may or may be recommended. ❹ As described above, the compounds of the present invention exhibit potent histamine H4 receptor antagonist activity. Thus, the compounds of the present invention are expected to be useful in the treatment of diseases which are mediated by H4 receptors in mammals, including humans. Diseases which can be treated by the compounds of the formula I according to the invention include, in particular, allergic, immune or inflammatory diseases or pain. Examples of allergic, immune or inflammatory diseases which may be treated by the compounds of the invention include, but are not limited to, respiratory diseases such as asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD); eye diseases such as allergic rhinoconjunctivitis G, dry eye Symptoms and cataracts; skin diseases such as dermatitis (eg atopic dermatitis), psoriasis, measles and dysentery; intestinal inflammatory diseases such as ulcerative colitis and Crohn's disease; rheumatoid arthritis; Multiple sclerosis; cutaneous lupus; systemic lupus erythematosus; and transplant rejection. Examples of pain symptoms which can be treated by the compounds of the present invention include, in particular, inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-operative pain, migraine, cancer pain, visceral pain, osteoarthritis pain, and neuropathic pain. In a preferred system, the compounds of the invention are used to treat allergies, 200940529 immune or inflammatory diseases. In a preferred system, the compounds of the invention are used to treat a respiratory disease, an eye disease, a skin disease, an intestinal inflammatory disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus or transplant rejection. Allergic, immune or inflammatory disease. In yet another preferred system, 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, different) Position dermatitis), psoriasis, urticaria, jatropha, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus or transplant rejection In a more preferred system, the compounds of the invention are useful for the treatment of pain, preferably inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-operative pain, migraine, cancer pain, visceral pain, pain of bone inflammation and Neuropathic pain. Analysis of the ability of compounds to interact with histamine H4 receptors is well known in the art. For example, H4 receptor binding assays can be used, as described in Example 65. Another useful assay is the GTP [Y-35S] binding assay that binds to the cell membrane of the H4 receptor. It is also possible to use a functional assay for the expression of cells of the H4 receptor to determine, for example, a system for measuring any kind of cellular activity, such as intracellular cAMP amount or Ca2, mediated by a second messenger associated with the H4 receptor. + transfer. A very useful functional assay for the determination of anti-H4 receptor activity is a gated autofluorescence of eosinophils (eg, human eosinophils) as detailed in Example 66. Forward Scattering Analysis (Gated AutofIuorescence 200940529

Forward Scatter assay (GAFS)); this analysis is known to the art (see, for example, the literature disclosed by Buckland KF et al, 2003 (cited in the prior art section hereby incorporated herein by reference). In vivo assays useful for testing the activity of the compounds of the invention are also known in the art (see, for example, the above-mentioned prior art section for the various references listed in the in vivo animal model, particularly with peritonitis, pleurisy, Allergic asthma, intestinal inflammatory disease, atopic dermatitis, hypertrophy @ and the in vivo model of pain are all incorporated herein by reference. The selective profile of the compounds of the invention can be tested using a standard histamine receptor binding assay similar to that described in Example 65 using a variety of different histamine receptors. In addition, to test the selectivity of other receptors or ion channels, follow the literature (see, for example, the Cerep-Le Bois l'EvSque 2008 catalogue and references therein), and the corresponding radioligand displacement analysis can be used. . To test the selectivity of the enzyme, the enzyme catalytic activity can be determined from the product produced by the enamel. After administration of different species (e.g., mice, rats, or monkeys) via either route, the CNS distribution can be examined by measuring brain to plasma concentrations. To select the active compound, the test performed at 10 μΜ in the test provided in Example 65 must produce an activity that inhibits the H4 receptor by more than 50%. In this analysis, the compound should preferably have an activity of more than 50% inhibition at 1 μΜ (still more preferably 0.1 μΜ). Preferred compounds should also have potent activity in the GAFS analysis of Example 66; in this assay, the compound should preferably be at 1 〇μΜ (more preferably 1 μΜ -123- 200940529 and still better 〇·1 μΜ) has an activity of more than 50% inhibition. Preferred compounds have a more selective affinity for the Η4 receptor than for other receptors (especially Η3 receptor, muscarinic receptor, adrenergic receptor, dopamine receptor and serotonin receptor). The invention also relates to a pharmaceutical composition comprising a compound of formula I (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients. Such excipients must be "acceptable" in being miscible with the other ingredients of the composition and are not deleterious to the recipient. The compounds of the present invention can be administered in the form of any of the pharmaceutical modulators, the nature of which will depend on the nature of the active compound and the route of administration. Any administration route can be used, such as oral, parenteral, nasal, ocular, topical, and rectal administration. Solid compositions for oral administration include tablets, granules and capsules. In any event, the method of manufacture is based on simple mixing, dry granulation or wet granulation of the active compound with excipients. The excipient can be, for example, a diluent (such as lactose, microcrystalline cellulose, mannitol or dibasic calcium phosphate), a binding agent (such as, for example, starch, gelatin or polyvinylpyrrolidone), a disintegrating agent (such as a carboxy group). Sodium methyl starch or croscarmellose sodium) and a lubricant such as, for example, magnesium stearate, stearic acid or talc. By using conventional techniques, the tablet may be additionally coated with a suitable excipient to achieve the purpose of disintegration and absorption delay of the tablet in the gastrointestinal tract, thereby providing a sustained action for a longer period of time, or simply improving The special sensibility or stability of the tablet. The active compound can also be applied to the plaque by using a natural or synthetic film coating. Soft gelatin capsules are also possible in which the active compound -124-200940529 is mixed with a water or oily medium such as coconut oil, mineral oil or olive oil. Powders and granules of the oral suspension can be prepared by adding water by mixing the active compound with a dispersing or wetting agent, a suspending agent and a preservative. Other excipients (e.g., sweeteners, flavoring agents, and coloring agents) may also be added. Liquid forms for oral administration include emulsions, solutions, suspensions, syrups and elixirs containing conventional inert diluents such as purified water, ethanol, sorbitol, glycerol, polyethylene glycol, and propylene glycol. These compositions may also contain co-adjuvants (such as wetting agents, suspending agents, sweetening, perfuming agents, preservatives, and buffering agents). Injectable formulations for parenteral administration according to the present invention comprise a sterile solution, suspension or emulsion in a water-soluble or water-insoluble solvent such as propylene glycol, polyethylene glycol or vegetable oil. These compositions may also contain co-adjuvants (such as wetting agents, emulsifying agents, dispersing agents, and preservatives). The compositions may be sterilized by any conventional method or prepared as a sterile solid composition which will dissolve in water or any other sterile injectable medium immediately prior to use. It can also be initiated from sterile materials and maintained under sterile conditions throughout the manufacturing process. The compounds of the invention may also be formulated for topical administration to treat conditions which occur in areas or organs accessible through such routes, such as the eye, skin and intestines. Modulators include lotions, lotions, gels, powders, solutions, and patches, wherein the compound is dispersed or dissolved in a suitable vehicle. For nasal or inhalation administration, the compound can be formulated into an aerosol and the compound can be conveniently liberated from the aerosol using a suitable propellant. -125- 200940529 The dosage form and dosage rate will depend, inter alia, on the nature and severity of the condition to be treated, the age, general condition and weight of the patient, and the particular compound and route of administration to be administered. As an example, a suitable dosage range is from about 0.01 mg/kg to about 100 mg/kg per day, and such doses can be administered in a single dose or in divided doses. The invention will now be illustrated by the following examples. [Embodiment] The following abbreviations are used in the examples:

AcN: acetonitrile EtOAc: ethyl acetate c ο n C : concentrated DMF: hydrazine, hydrazine-dimethylformamide DMS0: dimethyl hydrazine EtOH: ethanol g: gas MeOH: methanol Min: minute

PyBOP: (benzotriazol-1-yloxy)tripyrrolidinyl hexafluorophosphate TEA: triethylamine THF: tetrahydrofuran tR: storage time LC-MS: liquid chromatography-mass spectrometry using one of the following methods To determine the LC_MS spectrum: -126- 200940529 Method 1: X-Terra MS C18 column 5 μιη (100 x 2.1 mm)' temperature 30 ° C, rate 0.35 ml / min, the solution is A = AcN, Β = NH4HCO3 10 mM, gradient 0 min A 10%, 10 min A 9〇% and 15 min A 9 0 %.

Method 2: Acquity UPLC BEH C18 Column 1. 7 μιη (2. 1x50 mm), temperature 40 ° C, rate 0. 50 ml / min, the solution is A = AcN, Β = NH4HC03 10 mM, gradient is 0 minutes A 10%, 0. 25 minutes A 10%, 3. 00 minutes A 90% and 3. 75 minutes A 90%. Reference Example 1 Tetrabutyl methyl [(3R)-pyrrolidin-3-yl]aminecarboxylate (a) [(3 R)-l-benzylpyrrolidin-3-yl]methylaminecarboxylic acid tert-butyl ester Di-tert-butyl dicarbonate (11. 6 g, 5 3. 07 mmol; solution dissolved in CH2C12 (15 ml) was added to the cooled (PR under TC)·1·benzyl-N-methylpyrrolidine-3-amine (10 g, 52. 5 5 mM) in CH2C12 〇 (1 15 ml) solution. The resulting solution was stirred at room temperature for 18 hours. The solvent was evaporated and the crude product was chromatographed eluted with hexane/EtOAc mixture of EtOAc (EtOAc). 5 g, yield 9 5 %). LC-MS (method 1): tR = 9. 55 minutes; m/z = 291 (MH + ). (b) Subject compound The above compound is heated under reflux (14. 5 g, 50. 14 millimolar), Pd/C (10%, 50% in water) (3 g) and ammonium formate (12. 7 g, 200. A mixture of 5 mmol -127 - 200940529 ears) in MeOH (390 ml) and water (45 ml) for 5 hours. The reaction mixture was filtered through Celite® and the filter was rinsed with EtO Ac and MeOH. Evaporate the solvent to dryness to form the oily target compound (10. 6 g, yield 100%). !H RMN (300 MHz, CDC13) δ : 1. 38 (s, 9Η), 1. 72 (m, 1H), 1. 96 (m, 1H), 2. 53 (s, NH), 2. 80 (s, 3H), 2. 87 (m, 1H), 2. 93 (m, 1H), 3. 11 (m, 2H), 4. 58 (m, 1H). Reference Example 2 Tetrahydroindol-3-yl(methyl)aminecarboxylic acid tert-butyl ester (a) [1-(Diphenylmethyl)tetrahydroindol-3-yl]methylaminecarboxylic acid tert-butyl ester Following the method described in part (a) of Reference Example 1, but using 1-(diphenylmethyl)_N-methyltetrahydroindol-3-amine instead of (3R)· 1-block -N-methyl lalocyl-3-amine gave the desired compound (73% yield) 〇LC-MS (method 1): tR = 10. 14 minutes; m/z = 353 (MH + ). (b) the target compound, the compound obtained above (6. 18 g, 17. A solution of 53 mM in Me 〇H (60 mL) and EtOAc (15 mL) Pd/c (10%, 50% water) (9 2 9 m g) was added and the solution was again purged with argon and stirred under hydrogen for 18 hours. The reaction was filtered through Celite® and the filter was washed with EtOAc and MeOH. Evaporate the solvent to a dry state to form a mixture of the target compound and 1 equivalent of diphenylmethyl -128- 200940529 (5. 66 g), which is used directly in the following steps. *H RMN (300 MHz, CD3〇D) δ : 1-44 (s, 9Η), 2. 88 (s, 3H), 3. 56 (m, 2H), 3. 71 (m, 2H), 4. 75 (m, 1H). Reference Example 3 Ethyl 4-cyclohexyloxy-3-oxobutanoate cyclohexanol (2. 43 g, 24_3 millimoles) added to NaH (2. 12 g, 0 55 % in mineral oil, 48. A suspension of 6 mmol of anhydrous diethyl ether (16 ml) was added and the resulting mixture was stirred at room temperature for 75 minutes. Then slowly add ethyl 4-chloro-3-oxobutanoate (1. 64 ml, 12. 1 mmol) and stirred overnight at room temperature. After adding a few drops of water, the solvent was evaporated to dryness and the residue was diluted with water. The pH was adjusted to 4 with IN HC1 and extracted three times with diethyl ether. The combined organic phase was dried over Na 2 SO 4 and concentrated to dryness &&lt;RTIID=0.0&gt;&gt;&gt;&gt;&gt;&gt; ❹ *H RMN (3 00 MHz, CDC13) δ : 1. 28 (t, 3H), 1. 52 (m, 2H), 1. 74 (m, 4H), 1. 88 (m, 4H), 3. 31 (m, 1H), 3. 55 (s, 2H), 4. 1 1 (s, 2H), 4. 22 (q, 2H). Reference Examples 4 to 14 Following the procedure similar to that described in Reference Example 3, except that a suitable starting material was used in place of cyclohexanol, the following compounds were obtained: -129- 200940529 Reference Example Name Starting Material Method ( LC-MS) tR (min) m/z (MH+) 4 4-(cyclopropylmethoxy)-3-ethyloxybutanoic acid ethyl ester cyclopropylmethanol 2 1. 76 201 5 4-Cyclobutoxy-3-oxoethoxybutyric acid ethyl cyclobutanol 2 1. 85 201 6 Ethyl 4-cyclopentyloxy-3-oxobutanoate cyclopentanol 2 2. 11 215 7 4-Isopropoxy-3-oxoethoxybutyric acid ethyl ester Isopropanol 2 1. 69 189 8 4-Isobutoxy-3-oxoethoxybutyric acid ethyl isobutanol 2 2. 12 201 (ΜΗ) 9 4-(2,2-Dimethylpropoxy)-3-oxobutanoic acid ethyl ester 2,2-dimethylpropanol 2 2. 40 215 (ΜΗ) 10 4-tertoxy-3-oxooxybutyric acid ethyl butyrate 2 1. 90 201 (ΜΗ-) 11 4-(cyclopentylmethoxy)-3-oxooxybutyric acid ethyl ester cyclopentylmethanol 2 2. 38 227 (ΜΗ-) 12 4-((1 S,2R,4R)-bicyclo[2. 2. 1]Heptan-2-yloxy)-3-ethyloxybutanoate (1S,2R,4R)-bicyclo[2·2·1]heptan-2-ol 2 2. 42 239 (ΜΗ') 13 4-Benzyloxy-3-oxoethoxybutyrate ethyl benzyl alcohol 2 2. 10 235 (ΜΗ) 14 4-(Dicyclopropylmethoxy)-3-oxobutanoic acid ethyl ester Dicyclopropylmethanol 2 2. 27 239 (ΜΗ·) -130- 200940529 Reference Example 1 5 4-(4-Fluorophenoxy)_3_ethyloxybutyrate ethyl ester 4-fluorophenol (1. 36 g, 12. 1 mmol of DMSO (2 ml) solution was slowly added to the KOH powder (1. 36 g, 24. The resulting mixture was stirred for 15 minutes at room temperature in a 3 mM suspension of DMSO (25 ml). Then slowly add ethyl 4-chloro-3-oxobutanoate (1. 64 ml, 12. 1 mmol) and stirred overnight at room temperature. The reaction mixture was diluted with water and EtOAc (EtOAc) EtOAc. The combined organic phases were rinsed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by silica gel chromatography (using a hexane/EtOAc mixture with increasing polarity) to give the title compound (0. 60 g, yield 21%). LC-MS (Method 2): tR = 2. 13 minutes; m/z 239 (MH-). Reference Examples 16 to 17 Following the procedure similar to that described in Reference Example 15, except that a suitable starting material was used in place of 4-fluorophenol, the following compounds were obtained: Reference Example Name Starting Method ( LC-MS) tR (min) m/z (ΜΗ) 16 4-(2,4-difluorophenoxy)-3-ethyloxybutanoic acid ethyl ester 2,4-difluorophenol 2 2. 18 257 17 ethyl 4-(3,4-difluorophenoxy)-3-oxooxybutyrate 3,4-difluorophenol 2 2. 22 257 -131 - 200940529 Reference Example 1 8 2-Amino-6-(cyclohexyloxymethyl)pyrimidine-4-ol Hydroquinone hydrochloride (2. 23 g, 23. 4 millimolar) and sodium methoxide (1. To a solution of the compound obtained in Reference Example 3 (2 78 g, 12. 2 mmol) in anhydrous ethanol (195 ml), and the mixture was stirred overnight under reflux. The solvent was evaporated to dryness and the residue was purified eluting eluting eluting eluting eluting with LC-MS (Method 2): tR = 1. 38 minutes; m/z 224 (MH + ). Reference Examples 19 to 36 Following the procedure similar to that described in Reference Example 18, but using the corresponding starting materials, the following compounds were obtained: Reference Example Name Starting Method (LC-MS) tR (minutes) m/z 19 2-Amino-6-(cyclopropylmethoxymethyl)pyrimidine·4-ol Reference Example 4 2 0. 95 196 20 2-Amino-6-cyclobutoxymethylpyrimidin-4-ol Reference Example 5 2 0. 95 196 21 2-Amino-6-cyclopentyloxymethylpyrimidin-4-ol Reference Example 6 2 1. 22 210 22 2-Amino-6-isopropoxymethylpyrimidin-4-ol Reference Example 7 2 0. 85 184 23 2-Amino-6-isobutoxymethylpyridin-4-ol Reference Example 8 2 1. 22 198 -132 - 200940529 24 2-Amino-6-(2,2-dimethylpropoxymethyl)pyrimidine-4-ol Reference Example 9 2 1. 45 212 25 2-Amino-6-t-butoxymethyl alkidine-4-ol Reference Example 10 2 1. 05 198 26 2-Amino-6-(cyclopentylmethoxymethyl)pyran-4-ol Reference Example 11 2 1. 46 224 27 2-Amino-6-((lSJR,4R)-bicyclo[2. 2. 1] Hept-2-yloxymethylpyrimidine·4-ol Reference Example 12 2 1. 49 236 28 2-Amino-6-benzyloxymethylpyrimidin-4-ol Reference Example 13 2 1. 29 232 29 2-Amino-6·(4-aphenoxymethyl)pyrimidine-4-ol Reference Example 15 2 1. 37 236 30 2-Amino-6-(2,4-difluorophenoxymethyl)pyrimidine-4-ol Reference Example 16 2 1. 42 254 31 2-Amino-6-(3,4-difluorophenoxymethyl)pyrimidine-4-ol Reference Example 17 2 1. 48 254 32 2-Amino-6-phenoxymethylpyrimidin-4-ol 4-Phenoxy-3-oxoethoxybutyric acid ethyl ester 2 1. 30 218 33 2-Amino-6-methoxymethylpyrimidin-4-ol 4-methoxy-3-oxooxybutanoic acid methyl ester 2 0. 32 156 34 2-Amino-6-(2-methoxyethyl)pyrimidine, 4-alcohol 5-methoxy-3-indolyl valerate methyl ester 2 0. 40 170 35 2-Amino-6-(tetrahydropyran-4-yl)pyrimidine-4-ol 3-oxo-3-tetrahydropyran-4-yl)propionic acid ethyl ester 2 0. 47 196 36 2-Amino-6-[(dicyclopropylmethoxy}methyl]pyrimidin-4-ol Reference Example 14 2 1. 35 236 -133- 200940529 Reference Example 3 7 3-Alkyloxy-3-((2R)-tetrahydrofuran-2-yl)propanoic acid ethyl ester (a) (R)-tetrahydro-2-indole chloride Grasshopper chlorine (3. 9 ml, 44. 7 millimolar) slowly added to (R) _ tetrahydro-2-nonanoic acid (4. 72 g, 40. 6 millimoles of anhydrous dichloromethane (16. In the suspension, 5, then cooled at 〇 ° C and finally 1 drop of DMF was added. The mixture was allowed to stir overnight at room temperature. Evaporate the solvent to dryness, add anhydrous dichloromethane and evaporate again to dryness to give the desired compound (5. 43 g, yield 99%) was used directly in the synthesis step described below. (b) The target compound will be butyl lithium (87. 5 ml, 1. 6M ancestral solution, 141. 4 millimolar) slowly added to ethyl monopropionate (9. 34 g, 70. 7 mmol of anhydrous THF (185 ml) was then cooled to -7 8 ° C under argon by using a hydrazine (1) bath. Remove the bath and raise the internal temperature to _51. The reaction mixture was then cooled again to -65 Torr and the compound obtained in the previous section was added (5·43 g, 40. 4 mmol of THF (10 ml) solution, followed by ί! 梓 for 1 hour at -65t:. The temperature was raised slightly and the crude reaction product was diluted with water. The THF was evaporated to dryness and the residue was diluted with &lt The combined organic phase was dried over sodium sulfate and concentrated to dryness to give a quantitative yield of the compound as a crude product which was used directly in the synthesis step described below. LC_MS (method 2): tR = 1. 39 minutes; m/z = 185 (MH. ). -134- 200940529 Reference Example 3 8 3 -Phenoxy-ethyl 3-((2S)-tetrahydrofuran-2-yl)propanoate followed the method described in Reference Example 37, but using (S) different The construct provides the desired compound in quantitative yield. LC-MS (Method 2): tR = 1. 39 minutes; m/z = 185 (MH. ). Reference Examples 39 to 40 〇 Following the method described in Reference Example 18, but using the corresponding starting materials, the following compounds were obtained: Reference Example Name Starting Method (LC-MS) tR (minutes) m/z (ΜΗ&quot;) 39 2-Amino-6-((2R)-tetrahydrofuran-2-yl)pyrimidin-4-ol Reference Example 37 2 0. 51 182 40 2-Amino-6-((2S&gt;tetrahydrofuran-2-yl)pyrimidin-4-ol Reference Example 38 2 - 0. 51 182 〇 Reference Examples 41 to 46 Following the procedure similar to that described in Reference Example 37, but using the appropriate starting material in place of (R)-tetrahydro-2-indoleic acid, the following compounds were obtained: -135 - 200940529 Reference example name Starting material method (LC-MS) tR (minutes) m/z (ΜΗ) 41 4-(4-Chlorophenoxy)-4-methyl-3-oxo-pentanoic acid B Ester 2-(4-chlorophenoxy)-2-methylpropionic acid 2 2. 71 283/281 42 (R)-4-Methoxy-3-oxoethoxypentanoate (R)-2-methoxypropionic acid (1) 43 (R)-4-methoxy-3- side Ethyl oxy-4-phenylbutanoate (R)-2-methoxy-2-phenylacetic acid (ϋ) 44 (S)-4-methoxy-3-all! J oxy-4-phenylbutyrate ethyl ester (S) 2-methoxy-2-phenylacetic acid (iii) 45 4,4-dimethyl-5-methoxy-3-oxirane Ethyl valerate Reference Example 56 (iv) 46 3-(1-(Methoxymethyl)cyclopentyl)-3-oxopropionic acid ethyl ester Reference Example 58 2 2. 17 229 (MH+) (i) JH NMR (3 00 MHz, CDC13) δ : 1. 28 (m, 6H), 3. 36 (s, 5H), 3. 82 (q, 1H), 4. 12 (q, 2H). (ii) NMR (3 00 MHz, CDCh) δ : 1. 23 (t, 3H), 3. 41 (s, 5H), 4. 15 (q, 2H), 4. 80 (s, 1H), 7. 39 (m, 5H) o (iii) ^ NMR (3 00 MHz, CDC13) δ : 1. 23 (t, 3H), 3. 41 (s, 5H), 4. 15 (q, 2H), 4. 80 (s, 1H), 7. 39 (m, 5H) o (iv) *H NMR (300 MHz, CDC13) δ: 1. 24 (s, 6H), 1. 32 (t, 3H), 3. 3-3. 4 (composite signal, 2H + 2H + 3H), 4. 24 (q, 2H). -136- 200940529 Reference Examples 47 to 53 Following the procedure similar to that described in Reference Example 18, but using the corresponding starting materials, the following compounds were obtained: Reference Example Name Starting Method (LC-MS) tR (min) m/z (MH+) 47 2-Amino-6-(2-(4-chlorophenoxy)propan-2-yl)pyridin-4-ol Reference Example 41 2 1. 76 280/282 48 2-Amino-6-((R)-l-methoxyethylpyrimidine-4-ol Reference Example 42 2 0. 43 170 49 2-Amino-6-((R)-phenyl(methoxy)methyl)pyrimust-4-ol Reference Example 43 2 1. 22 232 50 2-Amino-6-((S)-phenyl(methoxy)methyl)pyrimidine-4-ol Reference Example 44 2 1. 22 232 51 2-Amino-6-(1,1-dimethyl-2-methoxyethyl)pyrimidine-4-ol Reference Example 45 2 0. 98 198 52 2-Amino-6-(2-isopropoxyethyl)pyrimidin-4-ol Reference Example 54 2 0. 87 198 53 2-Amino-6-(1-(methoxymethyl)cyclopentyl)pyrimidine-4-ol Reference Example 46 2 1. 17 224 Reference Example 5 4 5-Isopropoxy-3-oxoethoxypentanoate ethyl acetate (2. 7 g, 20. 9 millimoles of THF (6. 7 ml) The solution was slowly added to sodium hydride (0. 97 g, 55% mineral oil dispersion, 22. 2 millimolar; rinsed with hexane under argon to remove the oil in ice-cold suspension in anhydrous THF (25 ml). Yu Yu. (: Order the -137- 200940529 mixture to stir for 45 minutes and then cool to -2 5 ° C. Slowly add butyl lithium (14. 4 ml, 1. 6M hexane solution, 23. 0 mmol) and the mixture was stirred at -25 °C for 45 minutes. Then add chloromethyl isopropyl ether (2. 5 g, 23·0 mmol) of THF (6. 7 ml) solution and the mixture was stirred for an additional 60 minutes at -25 °C. The reaction was quenched by the addition of ice-cooled <RTI ID=0.0># </RTI> <RTIgt; The combined organic phase was dried over sodium sulphate and concentrated to dryness to give the title compound as a crude product, which was used directly in the next step. LC-MS (Method 2): tR = 1. 79 minutes; m/z = 201 (MH·). Reference Example 5 5 Methyl 3-methoxy-2,2-dimethylpropanoate Methyl 2,2-dimethyl-3-hydroxypropanoate (5. 0 g,37. 8 millimolar) slowly added to sodium hydride (1. 8 g, 55% mineral oil dispersion, 41. 6 mmoles in ice-cold suspension in anhydrous THF (40 ml). The slurry was stirred at room temperature for 1 hour. Then add methyl iodide dropwise (8. 0 g, 56. 7 mmol) and the mixture was stirred overnight at room temperature. Water was slowly added and the mixture was further diluted with diethyl ether and saturated ammonium chloride solution. The phase layer was separated and the aqueous phase was again extracted with diethyl ether. The combined organic phase is dried over sodium sulfate and concentrated to dryness to give the title compound as a crude product as a crude product which is used directly in the next step. *H RMN (300 MHz, CDC13) δ : 1. 18 (s, 6Η), 3. 31 (s 3H), 3·34 (s, 2H), 3. 67 (s, 3H). -138- 200940529 Reference Example 56 3-Methoxy-2,2-dimethylpropanoic acid The compound obtained in Reference Example 55 (37. A mixture of 8 mmoles in methanol (29 ml), THF (29 ml) and IN NaOH (39 ml) was warmed overnight at 60 °C. The volatiles were removed by distillation and the residue was diluted with water. The basic phase was washed 3 times with hexane and then the hexanes were discarded. P Η was adjusted to be acidic with Q 3 N Hc 1 and the aqueous phase was extracted 3 times with chloroform. The combined organic phase is dried over sodium sulfate and concentrated to dryness to give the title compound (2. 88 g, yield 58%). RMN (3 00 MHz, CDC13) δ : 1. 18 (s, 6H), 3. 31 (s 3H), 3. 37 (s, 2Η), 1 1. 9 (width s, 1H). Reference Example 5 7 Methyl 1-(methoxymethyl)cyclopentanecarboxylate φ Butyllithium (25 ml, 1. 6 hexane solution, 40. 1 millimolar) slowly added to diisopropylamine (4. 1 g, 40. 1 mmol of anhydrous THF (48 ml) was then cooled to -78 °C under argon using an acetone-C 2 bath and the solution was stirred at -78 ° C for 30 min. . Methyl cyclopentanecarboxylate was slowly added at -78 °C (5. 0 g, 39. 0 mmol of THF (25 ml) was dissolved and the mixture was warmed to -4 ° C and stirred at -40 ° C for 30 min. Then slowly add chloromethyl methyl ether (3. 26 g, 39. 0 millimolar) of THF (12. 5 ml) solution and the mixture was allowed to warm to room temperature and stirred overnight. The THF was evaporated and the residue was diluted with water and ethyl acetate. The phases were separated and the -139-200940529 aqueous phase was again extracted with ethyl acetate. The combined organic phase is dried over sodium sulfate and concentrated to dryness to give the title compound as a crude product in quantitative yield (6. 8 g), which is used directly in the steps below. *H RMN (300 MHz, CDC13) δ: 1. 5 5 - 1. 75 (m, 6H), 2-2. 15 (m, 2H), 3. 33 (s, 3H), 3. 45 (s, 2H), 3. 72 (s, 3H). REFERENCE EXAMPLE 5 8 1-(Methoxymethyl)cyclopentanecarboxylic acid The title compound was obtained by the procedure similar to that described in Reference Example 56, but using the compound of Reference Example 57 as a starting material. *H RMN (300 MHz, CDC13) δ : 1. 6-1. 8 (m, 6Η), 2-2. 2 (m, 2H), 3. 4 (s, 3H), 3. 46 (s, 2H). Reference Example 5 9-Methyl(3-methyltetrahydroindol-3-yl)aminecarboxylic acid tert-butyl ester (a) [1-(Diphenylmethyl)-3-methyltetrahydroindole-3 -yl]-tert-butyl methylaminecarboxylate followed by a method similar to that described in part (a) of Reference Example 1, but using 1-(diphenylmethyl)-N,3-dimethyltetrahydroanthracene The 3-amine is substituted for (3R)-1-benzyl-N-methylpyrrolidin-3-amine to give the desired compound in quantitative yield. *H NMR (300 MHz, CDC13) δ : 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). -140- 200940529 (b) Standard compound The compound obtained in part (a) (6. 06 g, 16. A solution of MeOH (60 ml) and EtOAc (15 ml) was washed with argon. Then Pd/C (10%, 8 14 mg) was added and the solution was again purged with argon and stirred overnight under hydrogen. The reaction was filtered through Celite® and the filter was washed with EtOAc and MeOH. Concentrate the solvent to a dry state to form a mixture of the target compound and 1 equivalent of diphenylmethane (4. 55 g), which is used directly. 'H NMR (300 MHz, CDC13) δ : 1. 45 (s, 12H), 2. 67 (s, 3H), 3. 28 (m, 1H), 3. 61 (m, 1H), 3·87 (m, 1H), 4. 00 (m, 1H). REFERENCE EXAMPLE 60 1-(2-Amino-6-(methylmethyl) phenoxy-4-yl)tetrahydro[jy唉3-yl(methyl)aminecarboxylic acid tert-butyl ester 〇a) 1- (2-Amino-6-(benzyloxymethyl)pyrimidin-4-yl)tetrahydroindol-3-yl(methyl)aminecarboxylic acid tert-butyl ester was stirred overnight at 80 ° C. Reference Example 2 8 obtained compound (1 〇g, 43. 2 mmol; the amine obtained in Reference Example 2 (25. 7 g, a 1:1 mixture with diphenylmethane, equivalent to an amine (12. 9 g), 69. 1 millimole) and PyBOP (29. 2 g, 56. A mixture of 2 mM) of TEA (250 ml) and acetonitrile (42 0 ml). The reaction mixture was evaporated to dryness and the residue was diluted with water and ethyl acetate. The phase layer was separated and the aqueous phase was extracted again with ethyl acetate. The combined organic phase was dried over sodium sulfate and reduced to dryness by concentration -141 - 200940529. The crude product obtained was purified by silica gel chromatography (using a hexane/EtOAc/MeOH mixture with a mixture of polarities) to afford intermediate intermediates. The intermediate precursor was further purified by forming the intermediate precursor in EtOAc (40 ml) to give the title compound (14. 1 g, yield 81%). LC-MS (Method 2): tR = 2. 19 minutes; m/z 400 (MH + ). b) Standard compound The compound obtained in part (a) is heated under reflux (5. 2 g, 13. 2 millimoles), Pd/C (10%, 50% in water, 0. 5 g) and ammonium formate (1. 67 g, 26. a mixture of 4 millimolar) of EtOH (57 ml) and water (6. 9 ml) solution for 3 hours. The reaction mixture was filtered though EtOAc (EtOAc)EtOAc. The solvent is evaporated to dryness and the resulting crude product is subjected to a second hydrogenation reaction to form a target compound (3. 97 g, yield 9 7%) ° LC-MS (method 2): tR = 1. 38 minutes; m/z 310 (MH + ). Example 1 4-Cyclohexyloxymethyl-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-2-amine was stirred overnight at 80 ° C according to Example 18. Compound (4. 5 g, 20. 1 mmol; the amine obtained in Reference Example 2 (12. 0 g, a 1:1 mixture with diphenylmethane, equivalent to an amine (6_1 g), 32. 2 millimoles) and PyBOP (13. 6 g, 26. A mixture of 2 mM) of TEA (99 ml) and acetonitrile (170 ml). The reaction mixture was evaporated to dryness and the residue was purified from EtOAc EtOAc (EtOAc: EtOAc: EtOAc To the intermediate precursor, HCl (4M 1,4·dioxane solution, 125 ml) was added and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated to dryness. The residue was dissolved in water and washed twice with EtOAc and then EtOAc. The IN NaOH solution was added to the acidic aqueous phase until the pH was basic and the resulting solution was extracted three times with EtOAc. The combined organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The obtained crude product was purified by gelatin chromatography (using a mixture of a chloroform/MeOH/concentrated aqueous solution of increasing polarity as a solvent) to give the title compound (2. 6 g, yield 44%). LC-MS (Method 2): tR = 1. 60 minutes; m/z 292 (MH + ). Examples 2 to 5 2 Following the procedure similar to that described in Example 1, but using the corresponding starting materials in each of the Examples Φ, the following compounds were obtained: Example Name Starting Method (LC-MS) tR parts) m/z (mt) 2 4-cyclohexyloxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine Reference example J 18 and Reference Example 1 2 1. 53 306 3 4-(cyclopropylmethoxymethyl)&gt;6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidine-2-amine Example 19 and Reference Example 2 2 1. 23 264 4 4-(cyclopropylmethoxymethyl)-6-((3R)-3-(methylamino)pyrrolidinyl)pyrimidin-2-amine #考实施例19 and Reference Examples 1 ------- 2 1. 18 278 -143- 200940529 5 4-(Cyclobutoxymethyl)-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-2-amine Reference Example 20 and Reference Examples Example 2 2 1. 28 264 6 4-Cyclobutoxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine Reference Example 20 and Reference Example 1 2 1 . 24 278 7 4-Cyclopentyloxymethyl-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-2-amine Reference Example 21 and Reference Example 2 2 1. 44 278 8 4-Cyclopentyloxymethyl-6-((3R)-3-(methylamino)pyrrole-th-yl)pyrimidin-2-amine Reference Example 21 and Reference Example 1 2 1 . 42 292 9 4-Isopropoxymethyl-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-2-amine Reference Example 22 and Reference Example 2 2 1. 18 252 10 4-Isopropoxymethyl-6-((3R)-3-(methylamino)pyrrole-d-yl)pyrimidin-2-amine Reference Example 22 and Reference Example 1 2 1 . 17 266 11 4-Isobutoxymethyl-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-2-amine Reference Example 23 and Reference Example 2 2 1. 45 266 12 4-Isobutoxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine Reference Example 23 and Reference Example 1 2 1 . 43 280 13 4-(2,2-Dimethylpropoxymethyl)-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-2-amine Reference Example 24 and Reference f Example 2 2 1. 65 280 14 4-(2,2-Dimethylpropoxymethyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine Reference Example 24 and 参# Example 1 2 1. 64 294 15 4-tertoxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine Reference Example 25 and Reference Example I 2 1 . 29 280 200940529 16 4-(Cyclopentylmethoxymethyl)-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-2-amine Reference Example 26 and Reference Examples 2 2 1. 66 292 17 4-(Cyclopentylmethoxymethyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine Reference Example 26 and Reference Examples Example 1 2 1. 62 306 18 4-(((1 S,2R,4R)-bicyclo[2. 2. 1]hept-2-yloxy)methyl)-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidine-2-amine Reference Example 27 and Reference Example 2 2 1. 68 304 19 4-(((1 S,2R,4R)-bicyclo[2. 2. 1]hept-2-yloxy)methyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine Reference Example 27 and Reference Example 1 2 1. 64 318 20 4-Benzyloxymethyl-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidine-2-amine Reference Example 28 and Reference Example 2 2 1. 50 300 21 4-Benzyloxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine Reference Example 28 and Reference Example 1 2 1. 48 314 22 6-Methoxymethyl-4-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine Reference Example 33 and Reference Example 1 2 0. 81 238 23 6-Methoxymethyl-4-(3-(methylamino)tetrahydroindol-1-yl)pyrimidine-2-amine Reference Example 33 and Reference Example 2 2 0. 81 224 24 4-(3-(Methylamino)tetrahydroindole 唉-1-yl)-6-phenoxymethylpyrimidin-2-amine Reference Example 32 and Reference Example 2 2 1. 49 286 25 6-(2-methoxyethyl) 4-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-2-amine Reference Example 34 and Reference Example 2 2 0 . 90 238 26 4-(4-Veoxymethyl)-6-(3·(methylamino)tetrahydroindole-l-yl)pyrimidin-2-amine Reference Example 29 and Reference Example 2 twenty one. 55 304 -145- 200940529 27 Reference to 4-(2,4-difluorophenoxymethyl)-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidine-2-amine Example 30 and Reference Example 2 2 1. 61 322 28 4-(3,4-Difluorophenoxymethyl)-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidine-2-amine Reference Example 31 and reference Example 2 2 1. 65 322 29 4-(2,4-Difluorophenoxymethyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine Reference example 30 and reference embodiment 1 2 1. 61 336 30 4-(3,4-Difluorophenoxymethyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine Reference Example 31 And reference embodiment 1 2 1. 65 336 31 4-(3-Aminotetrahydroinden-1-yl)-6-isopropoxymethylpyrimidin-2-amine Reference Example 22 and tetrahydroindol-3-ylaminecarboxylic acid tert Ester 2 1. 03 238 32 4-((3R)-3-Aminopyrrolidin-1-yl)-6-isopropoxymethylpyrimidin-2-amine Reference Example 22 and [(3R)-pyrrolidin-3- Tert-butyl carbamate 2 1. 07 252 33 4-(3-(Methylamino)tetrahydroindol-1-yl)-6-(tetrahydropyran-4-yl)pyrimidin-2-amine Reference Example 35 and Reference Example 2 2 0. 96 264 34 4-(3-(Methylamino)tetrahydroindol-1-yl)-6-((S)-tetrahydrofuran-2-yl)pyrimidin-2-amine Reference Example 40 and Reference Examples 2 2 0. 99 250 35 4-((3R)-3-(Methylamino)pyrrolidin-1-yl)-6-((S&gt;tetrahydrofuran-2-yl)pyrimidine-2, amine Reference Example 40 and reference implementation Example 1 2 0. 95 264 36 4-(3-(Methylamino)tetrahydroindol-1-yl)-6-((R)-tetrahydrofuran, 2-yl)pyrimidin-2-amine Reference Example 39 and Reference Examples 2 2 0. 99 250 37 4-((3R)-3-(Methylamino)pyrrolidin-1-yl)-6-((R)-tetrahydrofuran-2-yl)pyrimidin-2-amine Reference Example 39 and reference Example 1 2 0. 97 264 -146- 200940529 38 4-(2-(4-Chlorophenoxy)propan-2-yl)-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidine-2 -Amine Reference Example 47 and Reference Example 2 2 1. 95 348/3 50 39 4-(2-(4-Chlorophenoxy)propan-2-yl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidine 2-Amine Reference Example 47 and Reference Example 1 2 1. 92 362/3 64 40 6-((R)-l-methoxyethyl)-4-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-2-amine Reference example 48 and reference embodiment 2 2 0. 95 238 41 4-(3-(Methylamino)tetrahydroindol-1-yl)-6-((R)-phenyl(methoxy)methyl)pyrimidine-2-amine Reference Example 49 And reference embodiment 2 2 1. 43 300 42 4-((3R)-3-(Methylamino)pyrrolidin-1-yl)-6-((R&gt;Phenyl(methoxy)methyl)-spotted-2-amine Reference Example 49 and Reference Example 1 2 1. 41 314 43 4-(3-(Methylamino)tetrahydroindol-1-yl)-6-((S)-phenyl(methoxy-methyl)pyrimidinylamine Reference Example 50 and Reference Examples Example 2 2 1. 43 300 44 4-Cyclohexyloxymethyl-6-[3-methyl-3-(methylamino)tetrahydroindol-1-yl]pyrimidin-2-amine Reference Example 18 and Reference Examples 59 2 1. 68 306 45 4-Isobutoxymethyl-6-[3-methyl-3-(methylamino)tetrahydroindol-1-yl]pyrimidin-2-amine Reference Example 23 and Reference Examples 59 2 1. 55 280 46 4-Isopropoxymethyl-6-[3-methyl-3-(methylamino)tetrahydroindol-1-yl]pyrimidin-2-amine Reference Example 22 and Reference Examples 59 2 1. 28 266 47 4-(1,1-Dimethyl-2-methoxyethyl)-6-(3-(methylamino)tetrahydroindol-1-yl)-dean-2-amine reference Example 51 and Reference Example 2 2 1. 28 266 48 4-(2-Isopropoxyethyl)-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidine-2-amine Reference Example 52 and Reference Example 2 twenty one. 17 266 -147- 200940529 49 4-(1-(Methoxymethyl)cyclopentyl)-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2- Amine Reference Example 53 and Reference Example 1 2 1. 41 306 50 4-[3-Methyl-3-(methylamino)tetrahydroindole-indole-yl]-6-[(2S)-tetrahydrofuran-2-yl]pyrimidine-2-amine Reference Example 40 and Reference Example 59 2 1. 06 264 51 4-[(Dicyclopropylmethoxy)methyl]-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-2-amine Reference Examples 36 and 3 -(Methylamino)tetrahydroindole dihydrochloride (*) 2 1. 53 304 52 4-(1-(Methoxymethyl)cyclopentyl)-6-(3-(methylamino)tetrahydroindol-1-pyrimidine-2-amine Reference Example 53 and reference Example 2 2 1. 44 292 (*) Acid treatment after the reaction was not carried out. Example 5 3 3-(((2-Amino-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-4-yl)methoxy)methyl)benzoate A The ester will be referred to the compound of Example 60 (300 mg, 0. 97 millimoles) slowly added to sodium hydride (46. 5 mg, 55% mineral oil dispersion, 1. 07 mmol) in ice-cold suspension in dry DMF (7 ml). The slurry was stirred at room temperature for 30 minutes. Slowly add methyl 3-bromomethylbenzoate (289 mg, 1. A solution of 26 mmol of DMF (1 ml) was added and the mixture was stirred overnight at room temperature. A few drops of saturated aqueous ammonium chloride solution were slowly added and the solvent was evaporated to dryness. The residue was partitioned between EtOAc and saturated aqueous ammonium chloride. The phase layer was separated and the aqueous phase was again extracted with EtOAc. The combined organic phase was dried over sodium sulfate and concentrated to dryness to give a Boc. To the intermediate was added HCl (4M 1,4-dioxane solution, 15 ml) and MeOH (20 ml), and the mixture was stirred at -148 - 200940529 at room temperature for one hour. The solvent was evaporated to dryness. The residue was dissolved in water and washed twice with EtOAc and then EtOAc. The IN NaOH solution was carefully added to the acidic aqueous phase until the pH was close to 8 and extracted three times with chloroform. The combined organic phases were washed with brine, dried over anhydrous Na.sub.2SO4 and concentrated to dryness to give the title compound (227 mg, yield 65%). LC-MS (Method 2): tR = 1. 47 min; m/z 3 5 8 (MH + ). Example 5 4 to 5 7 Following the procedure similar to that described in Example 5.3, but using the corresponding starting material in each of the examples instead of methyl 3-bromomethylbenzoate, the following compounds were obtained. : Example name starting material method (LC-MS) tR part clock) m/z (MH+) 54 4-(((2-amino-6-(3-(methylamino))tetrahydroindole- Methyl 4-bromopyrimidin-4-yl)methoxy)methyl)benzoate methyl 4-bromomethylbenzoate 2 1. 47 358 55 2-(((2-Amino-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-4-yl)methoxy)methyl)benzoate 2-(Chloromethyl)benzoic acid tert-butyl ester (*) 2 1. 48 358 56 4-(3-(Methylamino)tetrahydroindol-1-yl)-6-((4-(methylsulfonyl)benzyloxy)methyl)pyrimidin-2-amine 1 -(bromomethyl)-4-(methylsulfonyl)benzene 2 1. 15 378 57 4-(3-(Methylamino)tetrahydroindol-1-yl)-6-((3-(methylsulfonyl)benzyloxy)methyl)pyrimidine-2-amine oxime Bromomethyl)-3-(methylsulfonyl)benzene 2 17 378 (%) To carry out the Boc deprotection reaction and the acetification reaction, the Boc precursor was treated with HCl-MeOH at room temperature for 1 week. -149- 200940529 Example 5 8 2-[3-(((2-(amino)-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-4-yl)methoxy) Methyl)phenyl]propan-2-ol methyl magnesium bromide under nitrogen (0. 12 ml, 3 Μ ether solution, 〇. 35 mmol, slowly added to the compound of Example 53 (25 mg, 0.) cooled at 〇 °C. In a solution of 07 mmol (THF) (1 ml). The ice bath was removed and the resulting solution was warmed and stirred overnight at room temperature. Then cool again to 〇 °C and add additional methylmagnesium bromide (0. 1 2 ml, 3M ether solution, 0. 35 millimoles). The mixture was allowed to warm again to room temperature and stirred overnight at this temperature. The reaction mixture was diluted with saturated aqueous ammonium chloride and EtOAc. The phase layer was separated and the aqueous phase was extracted twice with EtOAc. The combined organic phase is rinsed with water, dried on anhydrous Na2SO4 and concentrated to dryness to give the title compound (1. 6 mg, yield 46%). LC-MS (Method 2): tR = 1. 32 minutes; m/z 358 (MH + ). Example 5 9 3-(((2-(amino)-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-4-yl)methoxy)methyl)phenyl ] Methanol lithium hydride under argon (0. 56 ml, IN THF solution, 0. 56 mmol) slowly added until cooled to zero. (: the compound of Example 53 below (50 mg, 0. 14 mM) in THF (〇_25 ml) solution. The ice bath was removed and the resulting solution was allowed to warm and stirred overnight at room temperature. Then cool again to 〇 ° C and add water (0. 34 ml) and IN NaOH (0. 5 ml). The precipitated aluminate was removed by filtration and the filtrate was concentrated to dryness. The residue -150- 200940529 was diluted with water and chloroform, the phase layer was separated and the aqueous phase was extracted twice with chloroform. The combined organic phase is dried over anhydrous sodium sulfate and concentrated to dryness to give the title compound (32. 2 mg, yield 70%). LC-MS (Method 2): tR = 1. 14 minutes; m/z 330 (MH + ). Example 6 0 to 6 1 Following the procedure similar to that described in Example 59, but using the corresponding starting material in each Example 0, the following compounds were obtained: Example Name Starting Method (LC-MS) tR (minutes) m/z (MH+) 60 [4-(((2-amino-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-4-yl)) Oxytoxy)phenyl]methanol Example 54 2 1. 09 330 61 [2-((2-Amino-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimust-4-yl)methoxyl)phenyl]methanol Example 55 2 1. 20 330 Lu Example 62 3-[((2-Amino-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-4-yl)methoxy)methyl]benzene Formic acid will be lithium hydroxide monohydrate (0. 92 mg, 0. 02 mmol) was added to the compound of Example 53 (3. 57 mg, 0. 01 millimolar) in THF (0. 2 ml) and water (0. 2 ml) of the mixture was mixed and the reaction mixture was stirred overnight at 5 (rc) and then concentrated to dryness to give a compound in quantitative yield as a lithium salt. LC-MS (Method 2): tR = 0. 75 minutes; m/z 344 (MH + ). -151 - 200940529 Example 63 3-[((2-Amino-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-4-yl)methoxy)methyl]benzene The compound of Example 53 was stirred at 70 ° C (25 mg, 0. 07 millimoles) in ammonia (1. The solution formed in 5 ml, 7N MeOH solution was allowed to stand for 5 days. It is then concentrated to a dry state to yield the target compound in quantitative yield. LC-MS (Method 2): tR = 1. 01 minutes; m/z 343 (MH + ). Example 64 3-[((2-Amino-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-4-yl)methoxy)methyl]-N-butyl The benzoylamine was stirred at 70 ° C for the compound of Example 53 (25 mg, 0. 07 mmol of butylamine (1 ml) solution for 3 days. It is then concentrated to dryness to yield the target compound in quantitative yield. LC-MS (Method 2): tR = 1. 48 minutes; m/z 399 (MH + ). Example 65 Competitive binding assay assay of [3H]-histamine to human histamine H4 receptor was assayed using cell membrane extracts from a stable recombinant CHO cell line expressing human histamine H4 receptor (Eur0SCreen) / Perkin-Elmer). The test compound is applied to the desired concentration at 50 ° C and 50 mM Tris-HCl at a total volume of n 250 μM, pH 7. 4, 1. In 25 mM EDTA, 10 -152 - 200940529 ηΜ [3H]-histamine and cell membrane extract (15 pg) were incubated for 60 minutes in a double replicate manner. Non-specific binding is defined in the presence of unlabeled histamine (1 〇〇 μΜ). Previously at 0 °C 0. The reaction was interrupted by filtration using a vacuum manifold (Multiscreen Mil lipore) with a 5% polyethylenimine treatment for 2 hours in a Multiscreen HTS Millipore. The plate was then subjected to 50 mM Tris (pH 7.) at 〇 °C. 4), 1. Rinse with 25 mM EDTA and allow the filter to dry at 50 to 60 ° C for 1 hour, add scintillation fluid after Φ and use P scintillation counter to determine the bound radioactivity. This analysis determines Examples 1 to 56, 58, 59 And a compound of 62 and the compounds exhibit an inhibitory effect on binding to the human histamine h4 receptor by more than 50% at a concentration of 1 μM. Example 6 Analysis of shape change induced by histamine in human eosinophilic white blood cells (Gate d aut o fl uore s cence for war dsc att er assay (GAFS)) In this analysis, the histamine-induced shape change of human eosinophils was determined by flow cytometry, which was detected by detecting an increase in cell size (forward scattering, FSC). Preparation of polymorphonuclear leukocytes (PMNL, a fraction containing neutrophils and eosinophils) in whole blood. In short, at 1. Separation of red blood cells by sedimentation in 2% dextran (SIGMA) and separation of leukocyte-rich fractions from the top layer by centrifugation at 450 g for 20-153-200940529 minutes in the presence of Ficoll-Paque® (Bioehrom) PMNL). Let PMNL be at l. Resuspended in PBS buffer at a concentration of lxio6 cells/ml/tube and pretreated at 37 °C for different concentrations of test compound dissolved in PBS for 30 minutes, followed by stimulation with 300 nM histamine (Fluka). minute. Finally, polyoxymethylene (final concentration 1% PBS solution) was added to stop the reaction and maintain the cell shape. Changes in cell shape were analyzed by flow cytometry (FACS Calibur, BD Biosystems). The eosinophilic white blood cells (fluorescent channel FL2) in the PMNL are gated based on the autologous fluorescence of the eosinophils in the PMNL compared to the neutrophils. The shape of the cells is monitored by a forward scatter signal (FSC). The results are expressed as % inhibition of the shape change induced by histamine for each concentration of the test compound. This assay measures the compounds of Examples 1 to 16, 18 to 54, 56, 58 and 59 and the compounds exhibit more than 50 changes in the shape of human eosinophils induced by histamine at a concentration of 1 μM. The inhibition of %.

-154-

Claims (1)

200940529 Application for Patent Park 1 - Formula I Compound Ο wherein R1 represents a group selected from (1) or (ii): X R4 R5 (i) X 4 Rs (ϋ); R 2 and R 3 together with the nitrogen atom to which they are bonded may form a single ring of 4 to 7 members, 7 to 8 member bridged bismuth or 8 to 12 member fused bicyclic saturated #cyclic group 'wherein the heterocyclic group may contain up to 2 nitrogen atoms and may not contain any other hetero atom' and optionally Or a plurality of substituents independently selected from Ci. 4 alkane-NRaRb, wherein the heterocyclic group contains 2 nitrogen atoms and the NRaRb group is substituted or contains 1 nitrogen atom and is substituted by 1 NRabb group; 4 mM C nitrogen or Μ Η C C or table f; 戈 戈 戈 Η Η { { { { { { { { { { { { { { { { { { { { { { { { { { { { { { { { { { { { { { { { { { { { Selective R3 can be used in the base -155- 200940529 Rb represents η or CU4 alkyl; or Ra and Rb and together with their bonded nitrogen atoms form tetrahydroindenyl, pyrrolidinyl, piperidinyl Or a nitrogen amide group, which may be optionally substituted by one or more 0-4 alkyl groups; R4 and R5 are each independently selected from η or Cl-4 alkyl, and additionally r4 or R5 may represent an aryl group or C3_8 cycloalkyl-CQ_ 6 alkyl, and additionally both R4 and r5 groups on the same carbon atom may be bonded to the carbon atom to form a c3-8 cycloalkyl group; 116 represents a selected from the group consisting of Cu alkyl, c3.8 cycloalkyl- a CG_6 alkyl group or an An-c ο-4 alkyl group, wherein any alkyl group is optionally substituted with one or more halo groups and the c3-8 cycloalkyl group is optionally independently one or more independently Substituted with a substituent selected from a C1-alkyl, halo or aryl group; R7 represents a saturated monocyclic 4 to 7 membered heterocyclic ring containing one oxygen atom and no other additional heteroatoms, wherein the ring may be via any available carbon atom Bonded to the remainder of the molecule, and wherein R7 is optionally substituted with or independently selected from the group consisting of Ci-4 alkyl or halo; η represents 1, 2 or 3; Ρ represents 〇, 1 or 2; An represents a phenyl group optionally substituted with one or more groups independently selected from C^-4 alkyl, halo, C,-4 alkoxy, Cu haloalkyl, C, _4 haloalkoxy, cyano, hydroxy-C〇_6 alkyl, 118(:02-&lt;:()_6 alkyl, R8S02NHCO-C〇_6 alkyl, (1H-tetrazol-5-yl) )-C〇_6 alkyl, -CONR8R8, -S〇2NR8R8, -S02R8 , -NR8S02R8,, - NR8CONR8R8 &gt; -NR8COR8 ^ -NR8R8 ; -156- 200940529 Rs represents H, ¢^-6 alkyl, C3-8 cycloalkyl-C〇.6 alkyl or aryl-C〇. 4 yard base; Κ·8' stands for Cl-6 yard base 'C3-8 ring yard base _C〇-6 yard base or aryl-C〇-4 alkyl group; and two other R8 or one R8 and one R8 ' may be bonded to each other to form - C2-5 stretching base; and aryl represents a phenyl group optionally substituted with one or more groups'. The one or more U series are independently selected from the group consisting of h-4 alkyl , halogen, (^_4 alkoxy, C^4 haloalkyl, Cij haloalkoxy, cyano or amine; or a salt thereof. 2. A compound according to claim 1 wherein R2 and R3 together with the nitrogen atom to which they are bonded may form a 4 to 7 membered monocyclic ring, a 7 to 8 member bridged double ring or an 8 to 12 member fused ring. a bicyclic saturated heterocyclic group wherein the heterocyclic group may contain up to 2 nitrogen atoms and does not contain any other hetero atom and may be optionally substituted by one or more substituted thiol groups independently selected from the group consisting of Cl_4 alkyl or NRaBb, The heterocyclic group contains two nitrogen atoms and is not substituted by the NRaRb group or contains one nitrogen atom and is substituted with one NRaRb group. 3. A compound according to claim 2, wherein R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of: -157- 200940529 Wherein Rc represents a hydrazine or a Cm alkyl group. 4. A compound according to claim 3, wherein R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) or (b) 5. As claimed in claim 3 A compound wherein R2 and R3 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (a). 6. A compound according to claim 3, wherein R3 and the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (b). 7. The compound of any one of claims 3 to 6 wherein Rc represents hydrazine. The compound of any one of claims 1 to 7 wherein Ra and Rb each represent a hydrazine or a C i -4 alkyl group. 9. A compound according to claim 8 wherein Ra and Rb each -158 to 200940529 represent a hydrazine or a methyl group. 1 〇 · For example, the compound of claim 9 and Rb represents a methyl group. 1 1 · As in the scope of patent application Nos. 1 to 10, wherein R4 and R5 are each independently selected from hydrazine or sulfonyl-4. 12. The compound of claim 11 represents hydrazine. φ 1 3 · As in the scope of claims 1 to 12, where Ri stands for (i). 1 4 . As claimed in the claims 1 to 13 wherein η represents 1 or 2. 1 5. The compound of claim 14 of the patent scope 〇16. In the scope of claims 1 to 15, wherein R6 represents a group selected from the group consisting of -8 alkyl, c3-8 cycloalkyl- ❿ C〇-2 The basis. 17. The compound of claim 16 is selected from the group consisting of C4_5 alkyl, C3_6 cycloalkyl-C〇-i alkyl or a group. 18. As claimed in claims 1 to 15, wherein R6 represents a group selected from the group consisting of -8-8 alkyl or (3-8 cycloalkyl), any of which may optionally be via one or more _yl® alkyl groups. Optionally substituted with one or more substituents independently selected from the group consisting of -4 alkyl, halo or aryl. wherein Ra represents a compound of the formula ,, 'a compound of which Κ·4 and R~5 , a compound, wherein η represents a compound of one, Co-alkyl or Αη-, wherein R6 represents a compound of one of Ari-C〇-2, and • C〇.6 alkyl And a compound according to claim 8 wherein R6 represents a selected from the group consisting of Ci.8 alkyl or C3.6 naphthenic. A compound of the formula C, wherein R6 represents a group selected from the group consisting of Cu alkyl or C3.6 cycloalkyl-C! alkyl. 2 1 · as claimed The compound of claim 20, wherein r6 represents an isobutyl or cyclopropylmethyl group. 22. The compound of any one of claims 1 to 15, wherein the rule 6 represents a group selected from the group consisting of 〇3-8 naphthenes. -(:().6 alkyl or octagonal-&lt;:().4 alkyl; ^, wherein any alkyl group is optionally substituted with one or more halo groups and the © 3-8 naphthenic The group may be optionally substituted by one or more substituents independently selected from the group consisting of CiM alkyl, halo or aryl. 23. The compound of claim 22, wherein Re represents The compound of the C3-8 ring-based base - Cq.i or the Ari-C〇 2 hospital base. 24. The compound of any one of claims 1 to 15, wherein R6 represents a selected from C3_8 a cycloalkyl-Cm alkyl group or a group of Ari-C()_2, wherein any alkyl group is optionally substituted with one or more halo groups and the C3 cycloalkyl group is optionally substituted by one or more Substituted, the one or more substituted indenyl groups are independently selected from the group consisting of hydrazine:, -4 alkyl, halo or aryl. 2 5. The compound of claim 24, wherein the compound is selected from the group consisting of C3-8 naphthenes A compound of any one of claims 1 to 15 wherein the compound is optionally substituted with one or more halo groups. 2 7 ·If the patent application scope is the 26th Wherein R 6 represents C!-5 alkyl. -160- 200940529 28. The compound of claim 27, wherein R6 represents isobutyl. 2 9. As claimed in claims 1 to 15. A compound of the formula wherein R6 represents C3.8 cycloalkyl-CQ-6 alkyl, wherein the alkyl group is optionally substituted with one or more halo groups and the C3_8 cycloalkyl group optionally has one or more substituents Alternatively, the one or more substituents are independently selected from the group consisting of Ci-4 alkyl, halo or aryl. A compound according to claim 29, wherein R6 represents a c3-8 cycloalkyl-Co.i alkyl group. 3 1. A compound according to claim 30, wherein R6 represents a C3-6 cycloalkyl-Ci alkyl group. 32. The compound of claim 31, wherein R6 represents cyclopropylmethyl. The compound of any one of claims 1 to 15 wherein R6 represents Ari-Cc&gt;-4 alkyl, wherein the alkyl group is optionally substituted with one or more halo groups. 34. The compound of claim 33, wherein R6 represents An-CQ_2 alkyl, wherein the alkyl group is optionally substituted with one or more halo groups. 35. The compound of claim 34, wherein R6 represents An-Alkenyl. 36. A compound according to any one of claims i to 17, 22 to 25 and 33 to 35, wherein ΑΓ1 represents a phenyl group substituted with a group selected from the group consisting of hydroxy-CG.6 alkyl, R8C02 -C〇.6 alkyl, -161 - 200940529 R8SO2NHCO-C0.6 alkyl, (1 H-tetradec-5-yl)-C〇_6, /CONRgRg ' -SOjNRgRg ' -S02Rg, &gt; -NR8S02R85 'NR8CONR8R8, -NR8COR8 or -NR8R8, and the groups are optionally further substituted with a group selected from (^-4 alkyl, halo or Ch alkoxy. 37. a compound of 36, wherein An represents a phenyl group substituted by a group at the meta position, the group being selected from the group consisting of hydroxy-C 〇 -6 alkyl, R8C02-C〇-6 alkyl, r8s〇2NHC〇-C〇. 6 alkyl, (1H-tetrazol-5-yl)-C〇_6 alkyl, -(:(^118118, -8〇2\118118, -802118, -NR8S02R8, -NR8CONR8R8'-NR8COR8 or -NRsRs, and the substituents are optionally substituted by a radical selected from the group consisting of Ci4 alkyl, _ or Cl. 4 oxime. 38. The compound of claim 36, wherein Ar , representing a phenyl group substituted with a base, Or a hydroxy-C().6 alkyl group, -CONR8R8, -S〇2R8, or -NR8COR8, and the group is optionally further substituted with a group selected from the group consisting of a C.4 alkyl group, a halogen or (^.4 alkoxy. 3 9. The compound of claim 38, wherein ΑΓι represents a phenyl group substituted by a group at a meta position selected from a hydroxy-CG.6 alkyl group, -CONR8R8 And -S〇2R8' or -Nr8COR8, and the groups are optionally further substituted with a group selected from the group consisting of a C.4 alkyl group, a halogen or a Cm alkoxy group. A compound of any one of 12, wherein R! represents (ii). -162- 200940529 4 1. A compound of claim 40, wherein p is 0. 42. A compound of claim 40 Wherein ρ is a compound of any one of claims 1 to 17, 22 to 25, and 33 to 35, wherein ΑΓι represents a phenyl group optionally substituted with one or more groups, One or more of the groups are independently selected from the group consisting of a C4 alkyl group, a halogen, a Ci_4 alkoxy group, a Ci_4 halogen compound group, a Ci_4 halogen alkoxy group, a chloro group or an amine group 〇@4. The compound of the first item, which is selected from the group consisting of: 4-cyclohexyloxymethyl-6-(3-(methylamino)tetrahydroindol-1-yl) pyridin-2-amine; -cyclohexyloxymethyl-6-((3 R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-2-amine; 4-(cyclopropylmethoxymethyl) -6-(3-(methylamino)tetrahydroindole-pyridyl-2-pyrimidine-2-amine; 4-(cyclopropylmethoxymethyl)-6-((3 R)-3-( Methylamino)pyrrolidinium-φ-pyridylpyrimidine-2-amine; 4-cyclobutoxymethyl-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidine- 2-amine; 4-cyclobutoxymethyl-6-((3 R)-3-(methylamino)pyrrolidin-1-yl)pyrimidine-2-amine; 4-cyclopentyloxymethyl -6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidine-2-amine; 4-cyclopentyloxymethyl-6-((3R)-3-(methylamino)卩ϋ 卩疋 卩疋-1-yl) pyrimidin-2-amine; -163- 200940529 4-isopropoxymethyl-6-(3-(methylamino)tetrahydroindol-1-yl) Pyrimidin-2-amine; 4-isopropoxymethyl-6-((3 R)-3-(methylamino)pyrrolidin-1-yl) spurred-2-amine, 4-isobutoxy Methyl-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidine 2-amine; 4-isobutoxymethyl-6-((3R)-3-(methylamino)pyrrolidin-1-yl)dark-2-amine; 4-(2,2- Dimethylpropoxymethyl)-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidine-2-amine; 4-(2,2-dimethylpropoxymethyl) 6-((3 R)-3-(methylamino)pyrrolidin-1-yl)pyrimidine-2-amine; 4-tertoxymethyl-6-((3 R)-3 -(methylamino)thiazolidin-1-yl)pyrimidin-2-amine; 4-(cyclopentylmethoxymethyl)-6-(3-(methylamino)tetrahydroindole- 1-yl)pyrimidin-2-amine; ❹ 4-(cyclopentylmethoxymethyl)-6-((3 R)-3-(methylamino)pyrrolidin-1-ylpyrimidine-2 -amine; 4-(((18,211,4 ft)-bicyclo[2.2.1]hept-2-yloxy)methyl)-6-(3-(methylamino)tetrahydroindol-1-yl Pyrimidine-2-amine; 4-(((lS,2R,4R)-bicyclo[2.2.1]hept-2-yloxy)methyl)-6-((3R)-3-(methylamino) Pyrrolidine-1-yl)pyrimidine-2-amine; 4-benzyloxymethyl-6-(3-(methylamino)tetrahydroindol-1-ylpyrimidine-2-amine; -164 - 200940529 4-Benzyloxymethyl-6-((3 R)-3-(methylamino)pyrrolidin-1-yl)pyrimidine-2-amine; 6-methoxymethyl- 4-((3 R)-3-(methylamino)pyrrolidin-1-yl)pyrimidine-2-amine; 6-methoxymethyl-4-(3-(methylamino)tetrahydrol吖唉-1-yl)pyrimidine-2-amine; 4-(3-(methylamino)tetrahydroindol-1-yl)-6-phenoxymethylpyrimidine-oxime 2-amine; 6- (2-methoxyethyl)-4-(3-(methylamino)tetrahydroindol-1-yl)pyrimidine-2-amine; 4-(4-fluorophenoxymethyl)-6 -(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-2-amine; 4-(2,4-difluorophenoxymethyl)-6-(3-(methylamine) Tetrahydroindol-1-ylpyrimidin-2-amine; 4-(3,4-difluorophenoxymethyl)-6-(3-(methylamino)tetrahydroindole-indole Chesin-2-amine; 4-(2,4-difluorophenoxymethyl)-6-((3 R)-3-(methylamino)pyrrolidin-1 -yl)pyrimidine- 2-amine; 4-(3,4-difluorophenoxymethyl)-6-((3 R)-3-(methylamino)pyrrolidin-1 -yl)pyrimidin-2-amine; 4 -(3-Aminotetrahydroindol-1-yl)-6-isopropoxymethylpyrimidin-2-amine» 4-((3R)-3-Aminopyrrolidin-1-yl)-6 -isopropoxymethylpyrimidin-2-amine; -165- 200940529 4-(3-(methylamino)tetrahydroindol-1-yl)-6-(tetrahydropyran-4- 4-pyrimidin-2-amine; 4-(3-(methylamino)tetrahydroindol-1-yl)-6-((S)-tetrahydrofuran-2-yl)pyrimidine-2-amine; 4- ((311)-3-(Methylamino)pyrrolidin-1-yl)-6-((8)-tetrahydrofuran-2-yl)pyrimidine-2-amine; 4-(3-(methylamino) Tetrahydroindol-1-yl)-6-((R)-tetrahydrofuran-2-yl)pyrimidine-2-amine; 4-((3R)-3-(methylamino)pyrrolidine-1- 6-((R)-tetrahydrofuran-2-yl)pyrimidine-2-amine; 4-(2-(4-chlorophenoxy)propan-2-yl)-6-(3-(methyl Amino)tetrahydroindol-1-ylpyrimidin-2-amine; 4-(2-(4-chlorophenoxy)propan-2-yl)-6-((3R)-3-(methyl Amino)pyrrolidin-1-yl)pyrimidine-2-amine; 6-((R)-l-methoxyethyl)-4-(3-(methylamino)tetrahydroindole-1- 4-pyrimidin-2-amine; 4-(3-(methylamino)tetrahydroindol-1-yl)-6-((R)-phenyl(methoxy)methyl)pyrimidin-2- Amine; 4-((3R)-3-(methylamino)thiazolidin-1-yl)-6-((R)-phenyl(methoxy)methyl)pyrimidin-2-amine; 4 -(3-(Methylamino)tetrahydroindol-1-yl)-6-((S)-phenyl(methoxy)methyl)pyrimidine-2-amine; 4-cyclohexyloxymethyl Base-6-[3-methyl- 3-( Methylamino)tetrahydroindol-1-yl]pyrimidin-2-amine; 200940529 4-isobutoxymethyl-6-[3-methyl-3-(methylamino)tetrahydroindole -1-yl]pyrimidin-2-amine; 4-isopropoxymethyl_6_[3_methyl_3_(methylamino)tetrahydroindole-yl]pyrimidin-2-amine; 4- (1,1-dimethyl-2-methoxyethyl)-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidine-2-amine; 4-(2-iso Propyloxyethyl)_6_(3_(methylamino)tetrahydroindole-1_yl) @pyrimidin-2-amine; 4-(1-(methoxymethyl)cyclopentyl)-6- ((3 R)-3-(methylamino)pyrrolidin-1 -yl)pyrimidine-2-amine; 4-[3-methyl-3-(methylamino)tetrahydroindole-1- 4-[(2S)-tetrahydrofuran-2-yl]-oxo-2-amine; 4-[(dicyclopropylmethoxy)methyl]_6_(3-(methylamino)tetrahydroindole唉-1-yl)pyrimidin-2-amine; 4-(1-(methoxymethyl)cyclopentyl)_6_(3-(methylamino)tetrahydroindole_ 〇 基) pyrimidine-2- Amine; 3-((2-amino-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-4-yl)methoxy)methyl)benzoate; 4-(((2-Amino-6-(3-(methylamino)tetrahydroindenyl-1)pyrimidine-4) Methyl-methoxy)methyl)benzoate; 2-(((2-amino-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-4-yl) Methyl methoxy)methyl)benzoate; 4-(3-(methylamino)tetrahydroindole-(methylsulfonyl) benzyloxy)methyl)pyrimidin-2-amine; -167- 200940529 4-(3-(Methylamino)tetrahydroindol-1-yl)-6-((3-(methylsulfonyl)benzyloxy)methyl)pyrimidin-2-amine ; 2-[3-(((2-Amino-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-4-yl)methoxy)methyl)phenyl] Propan-2-ol; [3-(((2-amino-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-4-yl)methoxy)methyl) Phenyl]methanol; [4-(((2-amino)-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-4-yl)methoxy)methyl)benzene [2-(((2-(methylamino)tetrahydroindol-1-yl)pyrimidin-4-yl)methoxy)methyl)phenyl Methanol: 3-[((2-(methylamino)tetrahydroV唉-1-yl)pyran-4-yl)methoxy)methyl]benzoic acid; 3-[((2-(methylamino)tetrahydroindole-i-yl) pyrimidine Pyridin-4-yl)methoxy)methyl]benzoin; and 3-[((2-(amino)-6-(3-(methylamino)tetrahydroindole-yl)) _4_yl)methoxy)methyl]-N-butylbenzamide, or a salt thereof. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 46. A compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 44, which is for use in therapy. 47. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease intermediated by histamine H4 receptor -168-200940529. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, for use in the treatment of allergy, immunity or inflammatory disease or pain. 49. Use of a compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease mediated by histamine H4 receptor. 〇 5 0. The use of the subject of the patent application, wherein the disease mediated by the histamine H4 receptor is an allergic, immune or inflammatory disease or pain. A process for the preparation of a compound of formula I according to claim 1 of the patent, which comprises: (a) reacting a compound of formula II with a compound of formula III (or an amine protected form thereof) Wherein Ri, R2 and R3 are as defined in claim 1 of the patent application, and if necessary, any protective groups which may be present are removed; or (b) the compound of formula 与 and the compound of formula III (or its amine group are protected) Type) Reaction -169- 200940529 N Hnr2r3 MB HI where L represents the leaving group and R!, R2 and R3 are as defined in item 1 of the scope of the patent application, and if necessary, remove any protecting groups that may be present; or (c) after one or several steps The compound of formula I is converted to another compound of formula I. -170- 200940529 : Refers to the pattern representation of the present generation } } 定一二 Refers to c C ' 七 None • · Ming said Single No simple • No. No. Rings Table Element G VIII. If there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention: Formula I R2R3 Q I