TW201026701A - Pyrazolopyrimidine derivatives as histamine H4 receptor antagonists - Google Patents

Abstract

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

Description

[Technical Field] The present invention relates to a novel series of pyrazolopyrimidine derivatives, a process for the preparation thereof, a pharmaceutical composition comprising the same, and use thereof in therapy. [Prior Art] _ Histamine is one of the most potent mediators of an immediate allergic reaction. Although the effects of histamine on smooth muscle cell contraction, vascular permeability, and gastric acid secretion are well known, their effects on the immune system are beginning to be revealed. A few years ago, several independent research groups selected a novel histamine receptor called H4 (Oda T et al., J 5/0/CAew 2000, 275: 3 6 7 8 1 -6; Nguyen T et al, Mol Pharmacol 2001, 59: 427-33). Like other members of its family, it is a G-protein coupled receptor (GPCR) containing seven transmembrane segments. However, the H4 receptor has low homology with the other three φ histamine receptors (Oda T et al.); apparently only 35% homology with the H3 receptor. Although the expression of H3 receptors is limited to central nervous system cells, the expression of H4 receptors is mainly observed in cells of hematopoietic tissue, especially eosinophils, mast cells, basophils, dendritic cells and T-cells. The fact that the H4 receptor is highly distributed in cells of the immune system to (〇da T et al.) suggests that this receptor is involved in an immune-inflammatory response. Moreover, this hypothesis is more plausible because its gene expression can be modulated by inflammatory stimuli such as interferon, TNFa and IL-6. Of course, the H4 receptor is also expressed in other cell types, such as from rheumatoid arthritis ( -5 - 201026701)

Wojtecka-Lukasik E et al., Ann Rheum Dis 2006, 6 5 (

Suppl II): 129; Ikawa Y et al, Biol Pharm Bull 2005, 28: 2016-8) and osteoarthritis (Grzybowska-Kowalczyk A et al., European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, P- 11) Human synovial cells of the patient, and in the human gut (Sander LE et al, GW 2006, 55: 498-504). It has also been reported that the H4 receptor is more abundant in nasal polyps than in healthy people (J0kiiti A et al., Cell Biol Int 2007, 3 1 : 1367-70).

Recent studies of specific ligands for the H4 receptor have helped to define the boundaries of the pharmaceutical properties of this receptor. These studies demonstrate that several histamine-induced reactions in eosinophils, such as chemotaxis, conformational changes, and CD1 lb and CD54 upregulation, are specifically mediated by H4 receptors (Ling P et al. Man, B r J Pharmacol 2 0 04, 142 : 1 61 -71 ; Buckland KF et al., J. Aarmaco/ 2003, 140 : 1117-27). In dendritic cells, H4 receptors have been shown to affect the maturation, interleukin production and migration of these cells (Jelinek I et al, 1st Joint Meeting of European National Societies of Immunology, Paris, France, 2006, PA-1255). . Moreover, the role of the H4 receptor in mast cells has been investigated. Although H4 receptor activation does not trigger mast cell degranulation, histamine and other pro-inflammatory mediators are released; moreover, H4 receptors have been shown to mediate chemotaxis and loss of mast cells (Hofstra CL et al., PAfl) ^maco/ 五χρ ΓΑπ 2003, 305: 1212-21). As for T-lymphocytes, Η4 receptor activation has been shown to trigger sputum-cell migration, favorably attracting T-lymphocyte populations with inhibitory/regulated -6- 201026701 phenotypes and functions (Morgan RK et al., American Thoracic Society Conference) , San Diego, USA, 2006, P-536), and modulates activation of CD4+ T cells (Dunford PJ et al, J Immunol 2006, 176: 7062-70). As for the intestine, the distribution of the H4 receptor indicates that it may play a role in the control of peristalsis and gastric acid secretion (Morini G et al., European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, 0-1 0). 0 The various functions of the H4 receptor observed in eosinophils, mast cells and T-cells indicate that this receptor plays an important role in the immune-inflammatory response. In fact, h4 receptor antagonists have been used in peritonitis (Thurmond RL et al, JP h ar mac ο I Exp Ther 2004, 3 09 : 4 0 4 - 13), pleurisy (Takeshita K et al, / A armaco / In vivo activity was shown in a rat model of £ x corpus π 2003, 3 07 : 1 072-8 ) and scratches (Bell JK et al., Pharmacol 2004, 1 42 : 3 7 4 - 8 0 ). In addition, H4 receptor antagonists have been demonstrated in allergic asthma (Dunford PJ φ et al, 2006), inflammatory bowel disease (Varga C et al, five wr / Pharmacol 2 005, 522: 130-8), itching ( Dunford PJ et al, JA llergy Clin Immunol 2007, 119: 1 7 6-83 ), atopic dermatitis (C owden JM et al, J A11 ergy C1 i η I mmu η o 1 2 0 0 7 ; 119 ( 1) · ' S 2 3 9 (A bs 935), American Acad emy of Allergy, Asthma and Immunology 2 00 7 AAAAI Annual Meeting, San Diego, USA), eye inflammation (Zampeli E et al., European

Hi St amine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, 0-36), edema and hyperalgesia (Coruzzi 201026701 G # Λ , Eur J Pharmacol 2007, 5 63 : 2 40-4 ) and neuropathic 00 ( Cowart The in vivo activity is shown in the experimental model of MD φ A > J Med Chem. 2008 ; 51 (20): 6 5 47-57 ). It is therefore expected that H4 receptor antagonists can be used to treat or prevent allergic, immune and inflammatory diseases, and pain. Therefore, it is desirable to provide novel compounds having H4 receptor antagonistic activity, and these compounds are good drug candidates. In particular, preferred compounds should bind strongly to the histamine H4 receptor with little affinity for other receptors. In addition to being combined with the [4 receptor, the compound should exhibit good medicinal activity in a disease model in vivo. Moreover, the compound should reach the target tissue or organ when administered via the selected route of administration and have preferred pharmacokinetic properties. In addition, it should be non-toxic and demonstrate few side effects. SUMMARY OF THE INVENTION One aspect of the invention is a compound of formula I

NR!R2 where z

Ri and R2 together with the N atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of: (i) a heterocyclic group containing 2 N atoms and free of any other hetero atom-8 - 201026701 Wherein the heterocyclic group may be optionally substituted with - or a plurality of 4 alkyl groups: and (11) a heterocyclic group containing 1 N atom and free of any other hetero atom, wherein the heterocyclic group Substituted by a -NRaRb group and optionally substituted by one or more Ci 4 alkyl groups; wherein the heterocyclic groups (i) and (ii) may be 4 - to 7-membered monocyclic, 7 - To 8 -Bei bridged bicyclic or 8_ to ι2_ fused bicyclic; ❹ ^ Rl is 7^ Η or Cl-4 院基' and R_2 is azetidinyl, and the mouth is slightly D'BJg pyridine Or azacycloheptyl, which may be optionally substituted with one or more C,-4 alkyl groups;

Ra is a hydrazine or a Ci 4 alkyl group;

Rb represents hydrazine or Ci 4 alkyl; $ Ra and Rb together with the N atom to which they are bonded form azetidinyl, indolyl, piperidinyl or azepanyl, which may Optionally substituted with one or more C, -4 alkyl groups; Φ R3 represents hydrazine or NH2; RS may be either N1 or N2 in the pyrazole ring; when Rs is attached to N1, or R4 is R6 And R5 represents R7' or R4 represents R7 and R5 represents R8, or R4 and R5 may be bonded to form a -c3_5 alkylene group, which group may be optionally substituted by one or more Cl 8 alkyl groups; When Rs is attached to N2, R4 represents R6 and R5 represents R7; R6 represents H, ChH alkyl, C3.8 cycloalkyl-Co-"alkyl, <:3-8 heterocycle Alkyl, aryl-Cq.h alkyl, heteroaryl-C〇-n alkyl, aryl-9 - 201026701 yl-NH-Co-ii alkyl, heteroaryl-NH-Co.u Base, R9-CQ-u alkyl or Rw-WC. ·! 1 alkyl; Κ·7 series means H, Cl-6, K3-8 ring-base-C〇.6 yard, Ci-6 alkoxy-C-6 yard or (匚3_8 ring yard base) - C〇-6院基)-〇-Ci-6院; RS stands for C3-8 cycloalkyl-Co-u alkyl, Cs_8 heterocycloalkyl-Co."alkyl, aryl-Co -H alkyl, heteroaryl-Co.u alkyl, aryl-NH-C2-"alkyl, heteroaryl-NH-C2-11, r9-C2-ii, or Ri〇- W-C2-i丨 base » R9 means -CONR11R11, -NR 1 1 C Ο R! 1 ' -NRi i SO2R1 j· S 〇2 NR 1 1 R 1 1 ' -NR j 1 CONR 1 1 Ri 1 ' -CONHSO2R]) ' -CO2R11 ' -S02R,, n, NR! ! or 1H-tetrazol-5-yl; R10 means H, Ci-11, Rii-O-Ci-m, C3 -8 ring-based _C〇-H alkyl, C3-8 heterocyclic compound-Co-丨丨院, aryl-Co·丨丨院, heteroaryl-Co-"alkyl, aromatic Base-nh_c2-h alkyl, heteroaryl-nh-c2mi, or R9-C1-1

The Ru system represents H, Cl-6, and C3-8 ring yard base - C〇-6 yard base or square base-C. The base of the system; w represents 〇, s, 80 or s〇2; wherein in R6, Rs and Ri〇, 'any-hospital group can be optionally substituted by - or a plurality of quiescent atoms, and any cycloalkyl group And each of the heterocycloalkyl groups may be optionally substituted with one or more substituents independently selected from the group consisting of: Cl-0 alkyl, halogen, aryl and R9 = aryl means arbitrarily via one or more R 12 Substituted phenyl, -10- 201026701 Heteroaryl represents an aromatic 5 or 6-membered monocyclic or 8 to i 2 membered bicyclic ring containing up to four independently selected from the group consisting of nitrogen, oxygen and sulfur. a hetero atom, which group may be optionally substituted by one or more groups R 1 2 ; and each R] 2 independently represents a Cl 4 alkyl group, a dentate ' Ci 6 alkoxy group, a Ci 6 haloalkyl group, Cl.6 haloalkoxy, CN, hydroxy_c "alkyl, c〇2Ri]_c〇-6, C〇NHS〇2R"-C〇-6 院基, (1 -四哩_5_ base )_(^06院

Base, -CONRhRh, -S〇2NRiiRm, .sOrCu fluorenyl, _NRnSOyC^i alkyl, .NRllCONRllRii, _NRiiC〇Rii or _NR] 1R1 1. The invention also relates to salts and solvates of the compounds of formula I. Certain compounds of formula I may have a palmitic center which produces a variety of stereoisomers. The present invention is directed to each of these stereoisomers and to mixtures thereof. The compounds of formula I show high affinity for H4 histamine receptors. Thus, another aspect of the invention relates to a compound of formula I

Wherein: 1 and R2 together with the N atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of: (i) a heterocyclic group containing 2 N atoms and free of any other hetero atom-11" 201026701 a group wherein the heterocyclic group is optionally substituted by one or more C^4 alkyl groups; and (ii) a heterocyclic group containing 1 N atom and free of any other hetero atom The cyclic group is substituted by a -NRaRb group and optionally substituted by one or more (^.4 alkyl groups; wherein the heterocyclic groups (i) and (H) may be 4 to 7 _ member single ring, 7_ to 8-membered bridged bicyclic or 8_ to 12-membered fused bicyclic ring; or R! is represented by ^1 or (:^4 alkyl, and R2 represents azetidinyl Or a ratio of alkalyl, piperidinyl or azepanyl, which may be optionally substituted with one or more alkyl groups;

Ra is a hydrazine or (^_4 alkyl group;

Rb represents a hydrazine or a Cy alkyl group; or Ra and Rb together with the hydrazine atom to which they are bonded form an azetidinyl group, a succinyl group, a piperidinyl group or an azepanyl group, which may optionally be Substituted by one or more C1M alkyl groups; R3 represents hydrazine or NH2;

Rs may be located at N1 or N2 of the pubic ring; when Rs is attached to N1, or R4 means R6 and R5 means r7' or R4 means R7 and R5 means R8, or R4 and R5 may be bonded Combining to form a -C3_5 alkylene group, this group may be optionally substituted by one or more Ci 8 alkyl groups; when the R·5 line is attached to N2, r4 represents r6 and r5 represents r7; Represents 11, (: 1.11 alkyl, (: 3_8 cycloalkyl-(:()-11 alkyl, (: 3.8 heterocycloalkyl-Co." alkyl, aryl-Cgii alkyl, heteroaryl) _Cqii alkyl, -12-

201026701 aryl-NH-Co.] decyl, heteroaryl-NH-C fluorenyl or R i 〇-W - C 〇-! ! alkyl; R7 represents H, C!.6 alkyl, C3 -8 cycloalkyl-Cw alkyl or (C3-8 cycloalkyl-C〇-6 alkane - R8 represents C3.8 cycloalkyl-Co.n alkyl, C group, aryl-Cq-11 Anthracenyl, heteroaryl-C〇-ll alkyl, heteroaryl-NH-C2-Ualkyl, R9-C2. alkyl;

R9 represents -CONRhRh, -NR, ,COR S Ο 2 N R 1 1 R 1 1 ' -NR, 1CONR1 jR,, ' -C0NHS02Rh ' -\11111111 or 1//-tetrazol-5-yl;

Rio is H, C^n alkyl, Rh-OC! C〇-ii, C3-8 heterocyclic-Cq-11, 3 heteroaryl-Co.u alkyl, aryl φ alkyl Or R9-CUl !alkyl; R&quot; means H, Cl-6 alkyl, c3.8 cycloalkyl compound; w system means 〇, s, SO or so2; wherein Κ·6, R8 and RI〇 Any one of the substituents is substituted by an atom, and any of the cycloalkyl groups and the hetero or one or more substituents independently selected from the group consisting of aryl groups and R9; the aryl group means optionally one or more R , 2 institutes ] -11 yard base , R9-C0.11 hospital - C〇.6 yard base, Ci_6 courtyard oxygen B ) -O-Cm alkyl; 丨 3-8 heterocyclic base - Cq-m alkane Base, aryl-NH-Cm 11 or R10-W-C2.il ]1 , - NR 1 1 S Ο 2 R 1 1 , - C Ο 2 R 1 1 ' - S Ο 2 RI 1 - -11 Affiliation, C3-8 ring-based base-g, aryl-Co-n alkyl, yl, heteroaryl-NH-C2-H-C〇-6 or aryl-C〇-6 1 Optionally, one or more cycloalkyl groups may be optionally substituted: C丨-6, phenyl, halogen K; -13- 201026701 Heteroaryl means aromatic 5- or 6-membered monocyclic or 8_ to - member bicyclic ring containing up to four independently selected from nitrogen, oxygen and sulfur An atom, this group may be optionally substituted by one or more groups 1^2; and each Rl2 independently represents a Cu alkyl group, a halogen, a mountain-6 alkoxy 'Ci-6 haloalkyl group, Ci- 6 haloalkoxy, CN, hydroxy-C〇-6 alkyl, CO2RH-C0-6 alkyl, CONHSO2RH-C0-6 alkyl, (1 dan-tetrazol-5-yl)-C〇-6 alkane Base, -CONRuRh, -SOiNRuRH, -SOyCu alkyl, ·NRi!SOz-C].6 alkyl, -NRi 1 CONRi! Ri 1, -NRuCORh or -NR 1 1 R1 1 ; Another aspect of the invention relates to a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease mediated by histamine H4 receptor. More preferably, the disease mediated by histamine H4 receptor is an allergic, immunological or inflammatory disease or pain. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prophylaxis of an allergic, immunological or inflammatory disease or pain. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof, which is used in the manufacture of a medicament for the treatment of an allergic, immunological or inflammatory disease. More preferably, the allergic, immune or inflammatory disease is selected from the group consisting of respiratory diseases, eye diseases, skin diseases, inflammatory bowel-14-201026701 diseases, rheumatoid arthritis, multiple sclerosis, skin lupus, whole body Lupus erythematosus and transplant rejection. Even more preferably, the allergic, immune or inflammatory disease is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataract, dermatitis (eg atopic Dermatitis), psoriasis, urticaria, itching, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of pain. More preferably, the pain is selected from the group consisting of inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-operative pain, migraine, cancer pain, visceral pain, osteoarthritis pain, and neuropathic pain. Another aspect of the invention pertains to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease mediated by histamine H4 receptor. More preferably, the disease mediated by histamine h4 receptor is over Φ sensitizing 'immune or inflammatory disease or pain. </ RTI> Another aspect of the invention relates to a compound of formula I or a pharmaceutically acceptable compound thereof Salt, which is used to treat or prevent allergic, immune or inflammatory diseases or pain. Another aspect of the invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of an allergic, immunological or inflammatory disease. More preferably, the allergic, immune or inflammatory disease is selected from the group consisting of respiratory diseases, ocular diseases 'skin diseases, inflammatory bowel diseases, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and Transplant -15- 201026701 Rejection. Even better - the allergic, immune or inflammatory disease is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataract, dermatitis (eg ectopic Sexual dermatitis), psoriasis, urticaria, itching 'ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection. Another aspect of the invention pertains to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of pain. More preferably, the pain is selected from the group consisting of inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-operative pain, migraine, cancer pain, visceral pain, osteoarthritis pain, and neuropathic pain. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of a disease mediated by histamine H4 receptor. More preferably, the disease mediated by histamine H4 receptor is an allergic, immunological or inflammatory disease or pain. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of an allergic, immune or inflammatory disease or pain. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of an allergic, immunological or inflammatory disease. More preferably, the allergic, immune or inflammatory disease is selected from the group consisting of respiratory diseases, eye diseases, skin diseases, inflammatory bowel diseases, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and Transplant rejection. Even more preferably, the allergic, immune or inflammatory disease is selected from the group consisting of gas-16-201026701 fe, allergic rhinitis, chronic obstructive pulmonary disease (C 〇p D ), allergic rhinoconjunctivitis, dry eye, cataract Dermatitis (eg atopic dermatitis), psoriasis, urticaria, itching, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus Transplant rejection. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of pain. More preferably, the pain is selected from the group consisting of inflammatory pain, inflammatory hyperalgesia, hyperalgesia, postoperative pain, migraine, cancer pain, visceral pain, osteoarthritis pain, and neuropathic pain. Another aspect of the invention relates to a method of treating or preventing a disease mediated by a histamine 受体 4 receptor in an individual, preferably a human, in need thereof, comprising administering to the individual a compound of formula I or a medicinal thereof Acceptable salt. More preferably, the disease mediated by the tissue I female 4 receptor is an allergic, immunological or inflammatory disease or pain. Another aspect of the invention relates to a method of treating or preventing an allergic, immune or inflammatory disease or pain in an individual, preferably a human, in need thereof, comprising administering to the individual a compound of formula I or a medicament thereof Acceptable salt. Another aspect of the invention relates to a method of treating or preventing an allergic, immunological or inflammatory disease in an individual, preferably a human, in need thereof, comprising administering to the individual a compound of formula I or a pharmaceutically acceptable compound thereof Accept the salt. More preferably, the allergic, immune or inflammatory disease is selected from the group consisting of respiratory diseases, eye diseases, skin diseases, inflammatory bowel diseases, rheumatoid arthritis, -17-201026701 multiple sclerosis, skin lupus, whole body Lupus erythematosus and transplant rejection. Even more preferably, the allergic, immune or inflammatory disease is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataract, dermatitis (eg, atopic Dermatitis), psoriasis, urticaria, itching, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus and transplant rejection. Another aspect of the invention relates to a method of treating or preventing pain in an individual, preferably a human, in need thereof, which comprises administering to the individual a compound of formula I or a pharmaceutically acceptable salt thereof. More preferably, the pain is selected from the group consisting of inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-operative pain, migraine, cancer pain, visceral pain, osteoarthritis pain, and neuropathic pain. Another aspect of the invention relates to a A method of preparing a compound of formula I as hereinbefore defined, which comprises:

(a) reacting a compound of formula II with a compound of formula (or its amine group in protected form)

Π III /, where Ri, R2, R3, R4 and R5 have the aforementioned meanings, if necessary, followed by @# any protecting group which may be present; or -18- 201026701 (b) a compound of the formula iIb and a compound of the formula (or Amine-protected form) reaction

Lib I»# where R13 represents a leaving group and R, R2, R3, R4 and R5 have the aforementioned meanings, if necessary, then remove any protecting groups that may be present; or (c) in one or several steps Compound I is converted to another compound of formula I. In the previous definition, the term Cx_y alkyl means a straight or branched alkyl chain having from X to y carbon atoms. For example, a CL4 alkyl group means a straight or branched alkyl chain having from 1 to 4 C atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second-butyl Base and third-butyl. ® The term Cc alkyl means that the alkyl group is not present.

The Cb6 haloalkyl group means a group which is produced by substituting one or more hydrogen atoms of the C, -6 alkyl group with one or more halogen atoms which may be the same or different (i.e., fluorine, chlorine, bromine or iodine). Examples include, in particular, trifluoromethyl, fluoromethyl, fluorenyl-chloroethyl, 2-chloroethyl, 1-fluoroethyl, 2-fluoroethyl, 2-bromoethyl, 2-iodoethyl, 2, 2,2·trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 2,2,3,3-tetrafluoropropyl' 2,2,3,3,3-five Fluoropropyl, heptafluoropropyl, 4-fluorobutyl, nonafluorobutyl, 5,5,5-trifluoropentyl and 6,6,6-trifluorohexyl. -C3-5 stretching base (related to the group formed by Κ·5), when -19-201026701 RS is attached to N1, in the compound of formula I 'system means 3 to $ carbon atoms The linear chain of the base chain, that is, the group of the formula -(CH2) 3-5 -. As indicated by the definition of the compound of formula I, the -C3.5 alkylene group may be optionally substituted by one or more c i -8 alkyl groups, preferably by one or more methyl groups. Examples of r4 and r5 which together form a -C3·5 alkylene group include, inter alia:

A Cj.8 cycloalkyl group or a moiety of the C3_8 cycloalkyl-Cq y alkyl group is a saturated carbocyclic ring having 3 to 8 carbon atoms and may be a monocyclic or bridged bicyclic ring. Sex group. Examples include, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2 21]heptyl and bicyclo[2.2.2]octyl. The term C3-8 ring-based base - C.y. hospital base includes c3-8 ring-based base and C3-8 cycloalkyl-Ch alkyl group. The C3_8 ring-based base - Cby-based group means a group formed by substituting one or more hydrogen atoms of the Ci-y alkyl group with one or more C3-8 cycloalkyl groups which may be the same or different. Preferably, the Ci-y yard base is replaced by one or two C3·8 ring yard bases, preferably by a ^8 ring yard base. The C3-8 ring-based group may replace two deuterium atoms on the same C atom of the c atom or the same C atom on the same base (in this case, the cycloalkyl group shares a c atom with the alkyl group), such as the following as an example Group: -20- 201026701 2-cyclopropyl butyl group, one of which is located on the C atom, the butyl group (1-ethyl-cyclopropyl)methyl group substituted by a cyclopropyl group, on the same C atom The butyl C3-8 cycloalkylalkyl group in which two oximes are substituted by a cyclopropyl group includes, in particular, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, a cycloheptylmethyl group, Cyclooctylmethyl, bicyclo[2.2.1]heptylmethyl, dicyclopropylmethyl, (1-methyl-φcyclopropyl)methyl, (1-cyclopentylmethyl-cyclopropyl) )methyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 2,2-dicyclopropyl-ethyl, 2-ring Hexyl-2-cyclopropyl-ethyl' 2-(1-methyl-cyclopropyl)ethyl, 1-cyclopropyl-1-methylethyl, hydrazine-cyclopropylethyl, 1-ring Butylethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 3-cyclopropylpropyl, 3-cyclobutylpropyl, 3 -cyclopentylpropyl, 3-cyclohexylpropyl, 1-cyclopropyl-2-methylpropyl, 4-cyclopropylbutyl, 3-cyclopropylbutyl, 2-cyclopropylbutyl , 1-cyclopropylbutyl, 4-cyclobutylbutyl, 4-cyclopentylbutanyl, 5-(1-propyl-cyclobutyl)-pentyl, 7-(1-methyl- Cyclopropyl)-heptyl, 4-cyclohexylbutyl, 5-cyclopropylpentyl, 6-cyclopropylhexyl, 7-cyclopropylheptyl, 8-cyclopropyloctyl, 9-cyclopropyl Base group, 10-cyclopropyl fluorenyl group and 11-cyclopropyl undecyl group. In the definition of a compound of formula I, when the C3-8 cycloalkyl group is optionally substituted with one or more groups independently selected from the group consisting of Ci-6 alkyl, halo, aryl and R9, such substituents It may be the same or different and may be on any of the C3-8 cycloalkyl carbons, including the carbon that bonds the ring to the rest of the molecule. -21 - 201026701 C3-8 Heterocyclic, or a moiety of the C3-8 heterocyclic compound _Cq-ii, a saturated heterocyclic ring, which may be monocyclic or bridged A bicyclic group having 3 to 8 C atoms and up to three heteroatoms independently selected from n, fluorene and S, wherein the N or S atom can be oxidized. The ring may optionally contain up to two pendant oxy groups on the carbon or sulphur ring. The heterocyclic ring can be attached to the remainder of the molecule via any effective C or N ring atom (eg, morphine-2-yl, morphine-3-yl, morphine-4-yl, oxime-slightly- 1-based, pyrrolidin-2-yl and pyrrolidin-3-yl). Examples include, in particular, an oxiranyl group, azetidinyl, a propylene-based compound, a tetrahydrofuranyl group, a hydrazone [I-based group, a pyrazolyl group, an isothiazolidinyl group, a piperidinyl group, a Polinyl, piperazinyl '2-sidedoxy-tetrahydrofuranyl, 2-oxo-[1,3]dioxolane, 2-sided oxy-oxazolidinyl, 2-sided oxy -imidazolidinyl, 2-oxo-[1,3]histazine, 2-oxo-piperidyl, thiomorpholinyl, 1,1 bis-oxy-thiomorpholine Base, nitrogen sulfhydryl, [1,4]diazepine, [I,4]oxazepine, 2-sided oxy-indolyl, 1,1-di-oxy-[1,2 Thiazinyl, 2-oxo-[1,3]diazepine, 7-sided oxy-bicyclo[2_2.1]heptyl and 1,3-diaza-bicyclo[2.2. 2] Octyl. The term C3·8 heterocycloalkyl-C〇-M building group thus includes C3.8 heterocyclic anhydride and c3-8 heterocycloalkylalkyl. &lt;:3_8 Heterocycloalkyl-alkyl means a group formed by one or more hydrogen atoms which may be substituted by one or more C3·8 heterocycloalkyl groups which may be the same or different. Preferably, the Ci-h alkyl group is substituted by one or more C3_8 heterocycloalkyl groups. More preferably, it is substituted with a C 3.8 heterocycloalkyl group. Examples of c 3 -8 heterocycloalkyl-Cuh alkyl include, in particular, pyrrolidin-2-ylmethyl, sulphodine_3_ -22- 201026701 methyl, morpholin-3-ylmethyl, tetrahydrotetrahydrofuran 2-ylmethyl, (yl-[1,3]oxazinidine-6-yl)-m-methyl, 2-piperidin-3-yl-ethyl-l-yl-propyl-propyl, 1-methyl _2_Sun glare you 2 piperazine-丨-yl-ethyl, 2-methyl-3-3 (pyrrolidine-3-yl)-propyl'3-methyl-4-nir*嗪-丨·yl-butyl, 4_(tetrahydro- 3-, di-butyl, 2-oxo-oxygen, 2-piper from Η-丄-空-3·yl)-butyl, 5-f [713智 m (tetrahydrofuran-3-yl)-pentyl, 6·aza-heterocyclic 1 gan-I-gan "勹Γτι» furan. ν μ劲u天天_ 3 -yl)_pentane-1-yl-hexyl , 7-morpholine_4 W 4-yl-heptyl, 6-methyl-8-(pyrrolidin-1-yl)-octyl, 9-azetidine. #J院_2·基-壬基,10-piperazin-1-yl-indenyl, 10-pyrrolidin-1-yl-indole, ~一一垂' 1〇- (5·sideoxy - pyrrolidin-2-yl-indenyl 2-yl-+-alkyl. Group '10_(5. oxo-pyrrolidin-2-yield 11-(tetrahydro-furan 1 ® 3_yl)- Undecyl and n-pyrrolidine-alkyl.

In the definition of a compound of formula I, when substituted by one or more independently selected from the group C, any of the cycloalkyl groups, when indicated to the c3.8 heterocycloalkyl group, may be any of the substituents, halogen, aryl and R9 The geita® may be the same or different and may be located on the c3-8 hetero-active c or N atom 'including the C atom that bonds the ring to the rest of the molecule. ❹ The term aryl-C (^y alkyl includes aryl and aryl-C^-y alkyl. aryl-C^-y alkyl means aryl substituted with Cl_y alkyl - or a plurality of hydrogen a group formed by an atom. Preferably, the alkyl group is substituted by one or two aryl groups, and more preferably by an aryl group. Examples of the arylalkyl group include, in particular, a benzyl group, a 1-phenyl group. , 2-phenylethyl, 1-phenyl-b methyl-ethyl, 2,2-diphenyl-ethyl, 3-phenylpropyl, 2-phenyl-1-methyl-propyl , 4_phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 4-phenylhexyl, 2-methyl-3-phenylhexyl, 7-phenylheptyl, 5-phenyl Heptyl, 7,7-diphenyl-heptyl, 8-phenyloctyl, 7-phenyloctyl, 9-phenylindenyl-23- 201026701, 6-methyl-7-phenyl-indole , 9,9-diphenyl-fluorenyl, 10-phenylindenyl, 9-phenylindenyl, 11-phenyl--institutional, and 9-phenyl-institutional, wherein the phenyl It may be optionally substituted as shown in the definition of the above aryl group. The term heteroaryl, or a moiety of a group or a heteroaryl-Co.m alkyl group, means containing up to four independently selected from nitrogen. Aromatic 5- or hetero atom of oxygen and sulfur a 6-membered monocyclic or 8- to 12-membered bicyclic ring. A heteroaryl group can be attached to the remainder of the molecule via any effective C or N atom in the aromatic ring (eg, imidazol-1-yl, imidazole) 2-yl, imidazol-4-yl, imidazol-5-yl, pyridox-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl, or pyridin-6-yl) Examples of the aryl group include, in particular, 1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, furan, imidazole, Isoxazole, isothiazole, oxazole, pyrazole, pyrrole, thiazole, thiophene, 1,2,3-triazole, 1,2,4-triazine, indapazine, tower exposure, sputum ratio, pyridinium , benzopyrene, benzofuran, benzothiazepine, benzothiophene, imiline and diarrhea, imipenem, imipenem, imidazopyrimidine, carbazole, oxime, isoindole , iso-paraphylline, naphthyridine, ruthenium and bismuth, 卩 哗 哗 卩 卩 卩 卩, 卩 哩 喃 喃 喃 嘿 嘿 嘿 嘿 嘿 嘿 嘿 嘿 嘿 嘿 嘿 嘿 嘿 嘿 嘿 嘿 、 、 、 、 、 、 、 、 、 、 , when a specific instance refers to a double ring of general terms, includes all possible atomic configurations. For example, the term pyr Azolopyridine is understood to include such groups as: 1 pyrazolo[3,4-6]pyridine, pyrazolo[1,5-α]pyridine, 1//-pyrazolo[3,4-C Pyridine, 1 pyrazolo[4,3-c]pyridine and 1 i/-pyrazolo[4,3 -6]pyridine; the term imidazopyrazine is understood to include such groups as 1H-imidazole. [4,5 4]pyrazine, imidazo[1,2-α]pyrazine and imidazo[1,5-α]pyridin, and the term pyrazolopyrimidine is understood to include such groups as 24- 201026701 : 1 ugly - shame and [3,4 - d] pyrimidine, 1 //-pyrazolo[4,3 -]pyrimidine 'ti 哗 哗[1,5-α]pyrimidine and pyrazolo[i , 5_c] pyrimidine. Heteroaryl can be replaced by ~ or a plurality of R 2 groups which may be the same or different and may be located at any effective position. The H-aryl-Co-H alkyl group includes a heteroaryl group and a heteroaryl-Cun alkyl group. Heteroarylalkyl means a group resulting from the substitution of one or more hydrogen atoms of the g Cu oxime group with the same or different heteroaryl groups. Preferably, the broth base is substituted with one or two heteroaryl groups, and more preferably by a heteroaryl group. Examples of heteroaryl-(:, _!! alkyl include, in particular, furan-2-ylmethyl, pyridin-3-ylmethyl 'quinoline-3-ylmethyl, oxazole-2-ylmethyl' 1H_pyrrol-2-ylmethyl, 丨_pyridine-3-yl-ethyl, 2-pyridine-2-yl-propyl, 3-pyridine-3-yl-propyl, 丨-methyl-2-pyridine 3-yl-propyl, 4-pyridine-2-yl-butyl, 3-pyridine-2-yl-butyl, 5-furan-2-yl-pentyl, 6-furan-2-yl-hexyl, 3 - (1Η-pyrrol-2-yl)-hexyl, 7_(1Η-pyrrole_2-ylφ)-heptyl, 7-furan-2-yl-heptyl, 6-methyl-7-pyridine-2- -heptyl, 8-furan-2-yl-octyl, 8-(3Η-imidazolyl-4-yl)-octyl, 9-pyran-2-yl-fluorenyl, 10-furan-2-yl-fluorenyl , 10-isoxazol-3-yl-indenyl, η_furan-2-yl-undecyl and azetidine-2-yl-deca-alkyl, wherein the heteroaryl group is optionally as described above Substituted as indicated in the definition of base. The term aryl-NH-Co-h alkyl includes aryl-fluorene- and aryl-ΝΗC 1 - 1 1 aryl. aryl refers to aryl _ The ΝΗ-group replaces the group formed by one hydrogen atom of the c 1 courtyard group. -25- 201026701 The term heteroaryl-NH-Cm institute includes Heteroaryl-NH- and heteroaryl-NH-C^halkyl. Heteroarylalkyl means a group formed by substituting a hydrogen atom of a Cx-11 alkyl group with a heteroaryl-NH- group. The term R^-Cg·^ home base includes Rg- and a home base. R9-Cx-ii home base means replacing one or more hydrogen atoms of a Cx-ii alkyl group with an interrelated or different r9 group. The group formed. Preferably, the Cx-U-institution is substituted with an R9 group. The term Rio-W-Co.u alkyl includes R^-W- and a group.

The Rio-W-Cx-h hospital base means a group formed by substituting one or more hydrogen atoms of the cx_M yard group with an R1Q-W- group. Preferably, the cx-u alkyl group is substituted with an R1〇-W- group.

a Cl. 6 alkoxy group - or a moiety of a group or a d-6 alkoxy-C!-6 alkyl group - is a group of the formula c -6 alkyl-hydrazine-, wherein the alkyl moiety has The meaning of the former definition. Examples include, in particular, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, second-butoxy, tert-butoxy, pentyloxy and hexyloxy base.

Cl-6 oxy-Cu-based means a group formed by replacing one or more hydrogen atoms of a C -6 alkyl group with one or more identical or different C 6 alkoxy groups as defined above. . Preferably, the 'C -6 alkyl group is substituted with one c i · 6 alkoxy group. Examples of C!-6 alkoxy-C,·6 alkyl include, in particular, the groups methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, Isobutoxymethyl 'second · butoxymethyl, tert-butoxymethyl, dimethoxy-26- 201026701 methyl, 1-methoxyethyl, 2-methoxy B 1,2-diethoxyethyl, 1-butoxyethyl, 2_3-methoxypropyl, 2-butoxypropyl, 1-methoxy 3-third - Butoxypropyl, 4-methoxybutyl, 3-methoxyhexyl.

Ci-6 haloalkyl means a group which is substituted by one or more of the same (i.e., fluorine, chlorine, bromine or iodine) substituted with 0 of the alkoxy group. Examples include, in particular, trifluoromethoxy. Chloroethoxy, 2-chloroethoxy ' 1-fluoroethoxy, 2-ethoxy, 2-iodoethoxy, 2,2,2-trifluoroethoxy 3-fluoropropoxy, 3-Chloropropoxy, 2,2,3,3-2,2,3,3,3-pentafluoropropoxy, heptafluoropropoxy, 4-fluorooxy, 2-chloropentyloxy And 3-chlorohexyloxy. The term hydroxy-C〇-6 alkyl group includes a hydroxyl group and a hydroxyl group via a base-Cl.6 yard group means one or more via a group 5 φ — or a plurality of hydrogen atoms. Preferably, c, hydroxy is substituted. Examples include, in particular, the group hydroxymethyl 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropene, 1-hydroxypropyl, 2,3- Dihydroxypropyl, 4-hydroxy, 2-hydroxybutyl and 1-hydroxybutyl. The term CO2R11-C0.6 in-house includes -CO2R1 alkyl. CChRn-Cualkyl means one or more - a group formed by one or more hydrogen atoms of a C02 alkyl group, more than 2-ethoxyethyl, di-butoxyethyl, 2-ethoxypropyl, oxyhexyl, and 2-butyl or Different Atom or one or more hydrogen atoms, fluoromethoxy, 1-.fluoroethoxy, 2-bromo, pentafluoroethoxy, tetrafluoropropoxy, butoxy, nonafluorobutane-C 1.6 home ί=C 1 _ 6-based -6 alkyl group via one, 1-hydroxyethyl, yl, 2-hydroxypropylbutyl, 3-hydroxybutan 1 and COsRj, -Cj.e Rl group Substitution of Ci-6 Jia' Cb6 alkyl system -27- 201026701 is substituted by a -C Ο 2 R 1 1 group. The term C〇NHS〇2R&quot;-Cg-6 alkyl group includes -COnhsc^r&quot; and CONHSOAu -Cu alkyl. CONHSC^Rh-C丨·6 alkyl means a group formed by replacing one or more hydrogen atoms of the alkyl group with - or a plurality of _c〇NHSn丨 groups. Preferably, Cm alkane The base system is replaced by a -C0NHS02R&quot; group. The term (1 good-tetraki-5-yl)-c〇_6 base system includes (1 ugly _ four 哗 _5 · base) - and (1 ugly - Tetrazol-5-yl)-Cl-6 alkyl. (1-open-tetradec-5-yl)-Cu-based radical means - or more (January-tetrazol-5-yl)-based The group is substituted with a group formed by one or more hydrogen atoms of the ^6 alkyl group. Preferably, the 'C!-6 alkyl group is substituted with a (1 tetrazol-5-yl) group. .8 ring hospital -CQ.6 alkyl)-fluorene-Cl-6 alkyl means a group of (C3-8 cycloalkyl-cQ-6 alkyl)-hydrazine-group substituted by a C1-alkyl group or a plurality of hydrogen atoms Preferably, the q.6 alkyl group is substituted with one (c3 8 cycloalkyl-c〇-6 alkyl)-0- group.

Rn-0-Ci^ialkyl means a group formed by substituting one or more hydrogen atoms of the C丨-fluorenyl group with the same or different Rll_〇_ group. Preferably, the Cl_1 1 courtyard group is substituted with an R 1 1 - 〇 - group. As indicated by the compounds of formula I, any of R.sup.6, R8 and R, 0 may be optionally substituted with one or more halo groups. This means C-decyl and Cx.n alkyl which form part of the following groups: c3_8 cycloalkyl-Coa, C3.8 heterocyclic-C 〇· ii, aryl Base _ C 〇 _ i , affinity, heteroaryl-c 〇-1 1 fluorenyl, aryl-N Η - C x • fluorenyl, heteroaryl _ N η - cx _ 1 丨院-28 - 201026701, R9-CVH alkyl, Rm-W-Cx.h alkyl and Rn-0-Ci.H alkyl. Halogen group or its abbreviation halo means fluorine, chlorine, bromine or iodine. Preferred halogen atoms are fluorine and chlorine, and more preferably fluorine. The term "saturated" means a group that does not have any double or para-bonding. A "bridged bicyclic" group means having two shared atoms (bridge ends) connecting three chains (bridges) such that two bridges having a higher atomic number form a primary ring' and a bridge having a lower atomic number is " bridge". A β "fused bicyclic" group means a bicyclic system consisting of two atoms sharing two adjacent rings. ^ In the definition of NI^Rz, 1 and ana 2 together with the ν atom to which they are bonded A cyclic group of the above (i) or (ii) is formed. The heterocyclic group of class (i) is a saturated heterocyclic group containing 2 N atoms and free of any other hetero atom 'and which may be 4 to 7 membered monocyclic, 7 to 8 - Member bridged bicyclic or 8- to 12-membered fused bicyclic. Examples include, in particular, piperazinyl, homopiperazinyl, 2,5-diaza-bicyclo[2.2.&quot; heptyl, 2,5-diaza φ hetero-bicyclo[2.2.2] octyl, VIII Hydrogen-pyrrolo[1,2-pyrazazinyl, octa-la-l-[3,4-b]pyridinyl, octahydro-pyrrolo[3,2-c]pyridyl and octahydrolatine [3] , 4-c]pyrroline group. The groups may be optionally substituted by one or more C]alkyl groups which may be located at any effective c or N atom. The heterocyclic group of the class (ii) is a saturated heterocyclic group containing 1 N atom and containing no other hetero atom, wherein the heterocyclic group is substituted by a -NRaRb group, And it can be a heart to 7_member single ring, 7_ to 8-member bridging bicyclic or 8- to 12_member fused bicyclic, preferably 4_ to 7_-29 - 201026701 single ring. Examples of (ii) include, in particular, 3-amino-azetidinyl, 3-methylamino-azetidinyl, 3-dimethylamino-azetidinyl, 3-amine -pyridylpyridinyl, 3-methylamino-pyrrolidinyl, 3-dimethylamino- lysole, 4-amino-piperazyl, 4-methylamino-piperazyl, 4-Dimethylamino-p-stound and 6-methylamino-3-aza-bicyclo[3.1.〇] __ 3-yl. These groups may be further optionally substituted as indicated in the definition of the compound of formula I above. In the definition of a compound of formula I, it is mentioned that R5 may be located at Νι or N2 of the pyrazole ring. Thus 'the compounds of formula I include the following two types of compounds:

When two or more groups having the same number are indicated in the definition of a substituent, '(for example, -CONR, 丨!^, -S02NR, 1R1 i, or -NR, , 1^ !, etc.)' is not Indicates that they must be the same. Each of the lines is independently selected from the list of possible meanings indicated for the group, and thus it may be the same or different, and the statement ''arbitrarily substituted by one or more' means that the group may pass through one or A plurality of 'preferably 1, 2, 3 or 4, more preferably 1, 2 or 3, and more preferably substituted with 1 or 2 substituents, with the proviso that the group has a sufficient position to be substituted The substituents may be the same or different and may be in any of the effective positions. Throughout the specification, the term "treatment" means elimination, -30-201026701 reduces or ameliorates the cause or effect of the disease. For the purposes of the invention, a therapeutic system includes, but is not limited to, relieving, alleviating or eliminating one or more symptoms of the disease; narrowing the extent of the disease; stabilizing (ie, not worsening) the disease state; delaying or slowing the progression of the disease; improving or reducing the disease state; Amelioration of the disease (partially or comprehensively.) "Prophylaxis" as used in the present invention means preventing the occurrence of a disease in an individual susceptible to rickets or having a risk factor but not showing symptoms of the disease. Prevention also includes preventing the individual from having the disease. The invention is therefore related to a compound of formula I as defined above. In another embodiment, the invention relates to a compound of formula I, wherein: 1 and R2 together with the N atom to which they are bonded form a radical selected from the group consisting of Saturated heterocyclic group: (i) a heterocyclic group containing 2 N atoms and free of any other hetero atom, wherein the heterocyclic group may be optionally substituted by one or more Ci.4 alkyl groups And (Π) a heterocyclic group containing 1 N atom and no other hetero atom, wherein the heterocyclic group is substituted by one -NRaRb group and optionally passed through one or more Cb4 alkane a substituent; wherein the heterocyclic group (i) and (ii) may be a 4- to 7-membered monocyclic ring, a 7- to 8-membered bridged bicyclic ring or an 8- to 12-membered fused bicyclic ring. In a specific embodiment, the invention relates to a compound of formula I, wherein Ra and Rb independently represent hydrazine or &lt;^-4 alkyl. In another embodiment, the invention relates to a compound of formula I, - 31 - 201026701 wherein Ra and Rb are independently represented by hydrazine, methyl or ethyl. In another embodiment, the invention relates to a compound of formula I, Wherein Ra and Rb independently represent hydrazine or methyl. In another embodiment, the invention relates to a compound of formula I, wherein Ra and Rb represent hydrazine. In another embodiment, the invention relates to A compound of formula I, wherein Ra is Η and Rb represents Η or Cm alkyl. In another embodiment, the invention relates to a compound of formula I, wherein Ra represents 15 and Rb represents H, methyl or Further, in another embodiment, the invention relates to a compound of formula I, wherein Ra represents hydrazine and Rb represents η or methyl. In another embodiment, the invention relates to a compound of formula I Wherein Ra is represented by Η and Rb is represented by (^^alkyl. In another embodiment, the invention is a compound of formula I wherein Ra is Η and Rb represents methyl or ethyl. In another embodiment, the invention is a compound of formula I, wherein Ra represents hydrazine and Rb represents methyl. In another embodiment, the invention relates to a compound of formula I, wherein R1 and R2 together with the N atom to which they are bonded form a saturated heterocyclic group which contains 1 N atom and does not contain any other hetero atom Wherein the heterocyclic group is substituted by a -NRaRb group and optionally substituted by one or more C)-4 groups; wherein the heterocyclic group may be 4_ to 7_ Single ring, 7- to 8-member bridged bicyclic or 8_ to 12_member fused bicyclic. In another embodiment, the invention is a compound of formula I, -32- 201026701 wherein 1^ and R2 together with the N atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of:

N-Ra

Ν ——(8)

Rd, Ν,

Hey.

Ν—

Rc

Hey.

(6) (f) (g) (η) wherein Ra and Rb have the meanings described above for the quinone compound, r. It means 11 or C, _4 alkyl ' is preferably hydrazine or methyl, more preferably H, and Rd means Η # or &lt; 1-4 alkyl, preferably hydrazine or methyl. In another embodiment, the invention relates to a compound of formula I, wherein Ri and R2 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group (a) to (h) selected from the group consisting of Ra and Ra Rb, Re and Rd independently represent a ^1 or Cm alkyl group, preferably Ra, Rb, R. And Rd independently represents η or methyl' and more preferably Ra, Rb and Rd independently represent hydrazine or methyl and Rc represents hydrazine. In another embodiment, the invention relates to a compound of formula I, wherein Ri and R2 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group selected from (a) -33 to 201026701 and (b) a group, wherein Ra and Rb have the meaning previously for a compound of formula I; and R. It represents hydrazine or a Ci-4 alkyl group, and is preferably hydrazine. In another embodiment, the invention relates to a compound of formula I, wherein I and 112 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group selected from (a) and (b), and Ra , Rb and R. It is independently represented by η or C^.4 alkyl, and preferably Ra, Rb and Rc each independently represent hydrazine or methyl, and more preferably Ra and Rb independently represent hydrazine or methyl and Re represents Η ❿ 0 In another embodiment, the invention relates to a compound of formula I, wherein 1 and R2 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group selected from (a) and (b), Ra system Indicates Η, Rb indicates Η or Ci-4 yard base and the system is not defective. In another embodiment, the invention relates to a compound of formula I, wherein 1 and R2 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group selected from (a) and (b), and Ra is H. Rb represents hydrazine or methyl^ and Rc represents hydrazine. In another embodiment, the invention relates to a compound of formula I, wherein 1 and R together with the ruthenium atom to which they are bonded form a saturated heterocyclic group selected from (a) and (b), and Ra is represented by H, Rb represents a methyl group and Rc is not deuterated. In another embodiment, the invention relates to a compound of formula I, wherein 1 and R together with the ruthenium atom to which they are bonded form a saturated heterocyclic group selected from (a) and (b), Ra , Rb and Re indicate Η. In another embodiment, the invention relates to a compound of formula I, wherein Ri and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (a).

Ra\ /Rb

N

I ❹ (8) wherein Ra and Rb have the meanings previously expressed for the compound of formula I, and R. It is represented by H or Ci_4 alkyl, and preferably Rc represents H. In another embodiment, the invention relates to a compound of formula I, wherein R1 and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (a) and Ra, Rb and R. It is independent of Η or Cl-4, and preferably Ra, Rb and Rc independently represent hydrazine or methyl, and more preferably Ra and Rb independently represent hydrazine or methyl and Rc represents hydrazine. In another embodiment, the present invention relates to a compound of the formula wherein R1 and R2 together with the bonded ruthenium atom form a saturated heterocyclic group of formula (a) 'Ra system means Η, Rb It means Η or Cl_4 alkyl and Re means Η. In another specific embodiment, the present invention is a compound of the formula wherein R1 and R2 together with the ruthenium atom to which they are bonded form a saturated miscellaneous oxime of formula (a), _ anthraquinone group 'Ra Represents Η, Rb represents Η or methyl and Rc represents Η. In the specific embodiment, the present invention relates to a compound of formula I, -35- 201026701 wherein 1^ and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (a), Ra This indicates Η, and Rb represents a methyl group and R. The system shows Η. In another embodiment, the invention relates to a compound of formula I, wherein Ri and R2 together with the &gt;^ atom to which they are bonded form a saturated heterocyclic group of formula (a) and Ra, Rb And the Rc system indicates Η. In another embodiment, the present invention is a compound of the formula wherein Ri and Ra together with the atom to which they are bonded form a saturated heterocyclic group of formula (b).

(9) wherein Ra and Rb have the meanings previously expressed for the compound of formula 1, and Re represents H-Cy alkyl, and is preferably r. It is η. In another embodiment, the invention relates to a compound of formula I, wherein Ri and R2 together with the x atom to which they are bonded form a saturated heterocyclic group of formula (b), and Ra, Rb and R . It is preferred that H or &amp; *alkyl group' is preferably Ra, Rb and Re independently represent hydrazine or methyl group, and more preferably Ra and Rb represent fluorene or methyl group and Rc represents η. In another embodiment, the invention relates to a compound of formula I, wherein 1 and Ra together with the N atom to which they are bonded form a saturated heterocyclic group of formula (b) 'Ra is a fluorene, Rb It means Η or C]_4 alkyl-36 * 201026701 and RC means H. In the aspect of the invention, the present invention relates to a compound of the formula I, wherein R1 and R~2 together with the N atom to which they are bonded form a saturated heterocyclic ring of the formula (b), and the Ra system represents H, Rb represents a hydrazine or a methyl group and "is a hydrazine. In addition, specifically, the Ri and Han 2 saturated heterocyclic groups are Η. In the aspect of the invention, the present invention relates to a compound of the formula I, which is in accordance with The bonded germanium atoms together form the ceramic of formula (b), the Ra system represents Η, the Rb represents methyl and the Rc is in the form of a , , ,, the present invention relates to a compound of formula I, wherein Ri and r % 2 contiguous with the N atoms bonded thereto to form a saturated heterocyclic group of formula (b) _ π ^ @ _ ' and Ra, Rb and Rc represent Η. In an embodiment, the present invention relates to a compound of formula I, Another specific R1 system represents Η $

Or C!_4, and R2 represents azetidinyl, oxaridinyl, and piperidine V

Indenyl or aziridine, this group may be optionally substituted with one or more c 1 -4 fluorenyl groups. In a specific embodiment, the present invention relates to a compound of formula I, wherein R1 represents H and R2 represents 1-methyl-pyrrolidin-3-yl or pyrrolidin-3-ylindole. In the present invention, the invention relates to a compound of formula I, wherein the rule 3 is hydrazine. In another embodiment, the invention is a compound of formula I, wherein R3 is ΝΗ2. In another embodiment, the invention is directed to a compound of formula I, which is attached to N1 from -37 to 201026701. In another embodiment, the invention relates to a compound of formula I, wherein the Rs is attached to N2. In another embodiment, the invention relates to a compound of formula I, wherein R5 is attached to N1; and R4 represents R6 and R5 represents R7, or R4 represents R7 and R5 represents R8. In another specific embodiment, the invention relates to a compound of the formula wherein R5 is attached to N1; R4 represents r6 and r5 represents r7, or r4^ and R·5 are bondable to form -c3-5 An alkyl group, which may be optionally substituted with one or more cW8 alkyl groups. In another embodiment, the invention relates to a compound of formula I, wherein R5 is attached to N1; r4 represents R6; and r5 represents r7. In another embodiment, the invention relates to a compound of formula I, wherein Rs is attached to N1; R4 represents R7 and r5 represents r8, or r4 and R5 may be bonded to form a -C3_5 alkylene group, The group may be optionally substituted by one or more C^-8 alkyl groups. In another embodiment, the invention relates to a compound of formula i, wherein R5 is attached to N1; R is R7; and r5 is r8. In another embodiment, the invention relates to a compound of formula I, wherein R5 is attached to N1; and R4 and Rs are bonded to form a _C3 5 alkylene group which may optionally be subjected to one or more Substituted by C 1 -8 alkyl. In another embodiment, the invention relates to a compound of formula I, wherein R5 is attached to N1; and R4 and Rs are bonded to form a _c4 alkyl group, which may optionally be subjected to ~ or more c, 8 alkyl substituted. -38-201026701 In another embodiment, the invention relates to a compound of formula I, wherein R6 represents H, Chu alkyl, C38 cycloalkyl-Cqh alkyl, c3-8 heterocycloalkyl-C〇- Ii, aryl-Cl_n alkyl, heteroaryl_Cl_n alkyl, aryl-NH-Cq-h alkyl, heteroaryl_nh_Cg_h alkyl, RrCo-n or R^-W-Co .&quot;Alkyl, any of which may be optionally substituted by one or more halogen atoms (preferably fluorine), and any of the cycloalkyl and heterocyclic rings

The pendant group may be optionally substituted with one or more substituents independently selected from the group consisting of Ci-6 alkyl, halogen, aryl and r9. In another embodiment, the invention relates to a compound of formula I, wherein R6 represents hydrazine, Cl.u alkyl, C3 8 cycloalkyl-c〇&quot;alkyl, C3 8 heterocycloalkyl-c〇 _丨丨alkyl, aryl-c丨丨丨alkyl, heteroaryl-I丨丨 alkyl, aryl-NH-Cg.h alkyl, heteroaryl s_nh_Cq &quot;alkyl, R9_c〇丨] Base or R 1 〇 · W - C 〇 - 1 1 yard base. In another embodiment, the present invention relates to a hydrazine compound, wherein R 6 is represented by n is ^ -t=f* M-η alkyl, C3.8 cycloalkyl-Cqii alkyl, R9_ C〇 -malkyl or alkyl, wherein any -alkyl group may be optionally substituted by one or more halogen atoms (preferably fluorine)' and any of the cycloalkyl groups may be optionally independently selected from one or more The following substituents take c&quot; alkyl, halogen, aryl and r9. 1 In another embodiment, the invention relates to 3 H, wherein the ~ is a H'c.u or a C3.8 ring-based Co-H alkyl or Rw-W-Co-h alkyl. In another embodiment, the invention relates to a 3r compound, wherein R6 represents Cl-U alkyl, c3-8 cycloalkyl _Cc_&quot; into K9-C0-1 1 -39- 201026701 alkyl or RiO -W-Co-M alkyl, each of which may be optionally substituted by one or more halogen atoms (preferably fluorine), and any of the cycloalkyl groups may be optionally independently selected by one or more Substituted by the following substituents: CL6 alkyl, halogen, aryl and R9. In another embodiment, the invention relates to a compound of formula I, wherein Re represents Cu alkyl, C3-8 cycloalkyl-Co-η alkyl, R9-C0-U, or RiQ-W-Cq -1 1 垸 base. In another specific embodiment, the present invention relates to a compound of formula I, wherein the Re group represents H, a Ci-ii or a C3-8 ring-based-hospital group, any of which may optionally be One or more halogen atoms are substituted (preferably fluorine)' and any of the cycloalkyl groups may be optionally substituted by one or more substituents independently selected from the group consisting of C, -6 alkyl, halogen, aryl And r9. In another embodiment, the invention is a compound of formula I, wherein R6 represents H, alkyl or c3.8 cycloalkyl-Co-M alkyl. In another embodiment, the invention relates to a compound of formula I, wherein R6 represents C, ·&quot; alkyl or C3-8 cycloalkyl-Co-w alkyl, any of which may be optionally Substituted by one or more halogen atoms (preferably fluorine) ' and any of the cycloalkyl groups may be optionally substituted by one or more substituents independently selected from the group consisting of Cj-6, halogen, aryl And R9. In another embodiment, the invention relates to a compound of formula I, the center of which represents a heart alkyl group or a cycloalkyl-"-^ alkyl group. In another embodiment, the invention relates to A compound of formula I, wherein R6 represents Ch&quot;alkyl or Cs-8 cycloalkyl, preferably Ci 6 alkyl or C3-6 cycloalkyl, wherein any -alkyl group may optionally be passed through one or more halo- 40-201026701 Substituted (preferably fluorine)' and any of the cycloalkyl groups may be optionally substituted by one or more substituents independently selected from the group consisting of Ci-6 alkyl, halogen, aryl and oxime. In a specific embodiment, the invention relates to a compound of formula I, wherein h represents q-u alkyl or c:3.8 cycloalkyl, preferably Ci4 alkyl or c3-6 cycloalkyl. In an embodiment, the invention relates to a compound of formula I, wherein Re represents C, an &quot;alkyl or CM cycloalkyl, preferably Ci 6 alkyl or C3-6 cycloalkyl, wherein any Each of the groups may be optionally substituted with one or more halogen atoms (preferably fluorine) and each of the cycloalkyl groups may be optionally substituted with one or more substituents independently selected from the group consisting of Ci6 alkyl and halogen. In another embodiment, the invention relates to a compound of formula I, wherein R6 represents C^n alkyl, wherein any -alkyl group may be optionally passed through - or a plurality of halogen atoms Substituted (preferably fluorine). In another embodiment, the invention relates to a compound of formula I, Φ wherein R6 represents a ChH alkyl group. In another embodiment, the invention relates to a compound of formula I, Wherein R.6 represents a Ci-6 alkyl group. In another embodiment, the invention relates to a compound of formula I, wherein R6 represents C3-8 cycloalkyl-Cqiialkyl, each of which is an alkyl group. Optionally substituted by one or more halogen atoms (preferably fluorine), and any of the cycloalkyl groups may be optionally substituted by one or more substituents independently selected from the following: Cl-6, halogen , aryl and r9. In another embodiment, the invention relates to a compound of formula T, wherein R6 of -41 - 201026701 represents C: 3-8 cycloalkyl, which may optionally pass one or more Substituted independently by a substituent selected from the group consisting of C^6 alkyl, halogen, aryl, and R9, in another embodiment, The invention relates to a compound of formula I, wherein R6 represents C3.8 cycloalkyl, which group may be optionally substituted with one or more substituents independently selected from the group consisting of: &lt;^.6 alkyl and halogen. In a specific embodiment, the invention relates to a compound of formula I, wherein R6 represents C3-8 cycloalkyl, preferably C3-6 cycloalkyl. In another embodiment, the invention relates to a compound of formula I Wherein r6 is a cyclobutyl group. In another embodiment, the invention relates to a compound of formula I, wherein R6 represents Rm-W-Co-h alkyl, each of which may optionally be Substituted by one or more halogen atoms (preferably fluorine). In another embodiment, the invention is a compound of formula I, wherein R7 represents hydrazine, Cm alkyl or C3-8 cycloalkyl-C〇.6 alkyl. In another embodiment, the invention relates to a compound of formula I, wherein R7 represents hydrazine or a Cu alkyl group. In another embodiment, the invention relates to a compound of formula I, wherein R7 represents η, methyl or ethyl. In another embodiment, the invention relates to a compound of formula I, wherein R7 represents hydrazine or methyl. In another embodiment, the invention is a compound of formula I, wherein R7 represents hydrazine. In another embodiment, the invention relates to a compound of formula I, in which the R7 system of the formula -42 to 201026701 is 11 or c, -6 alkyl, preferably methyl. In another embodiment, the invention is directed to a compound of formula I wherein R7 is a C3-8 cycloalkyl-C&quot;alkyl group. Further, in the specific embodiment, the present invention relates to a compound of the formula I, wherein the R7 group represents a Cl-6 courtyard oxygen-C!-6 hospital base. In another embodiment, the invention relates to a compound of formula I, wherein R8 is a C3-8 cycloalkyl-Co-H alkyl group, an aryl-Co-u alkyl group or an alkyl group, any of which Each of the alkyl groups may be optionally substituted by one or more halogen atoms (preferably fluorine), and any of the cycloalkyl groups may be optionally substituted with one or more substituents independently selected from the group consisting of: c 6 alkane Base, halogen, aryl and R 9 . In another embodiment, the invention relates to a compound of formula I, wherein R8 represents C3-8 cycloalkyl-cQ. decyl, aryl-c〇-&quot;alkyl or R 9 _ C 2 - 1 1 yard base. In another embodiment, the invention relates to a compound of formula I, wherein Rs in φ represents C3·8 cycloalkyl-C. And, an alkyl group, each of which may be optionally substituted by one or more halogen atoms (preferably fluorine), and any of the cycloalkyl groups may be optionally independently selected from one or more selected from the group consisting of Substituted by the substituent: Cj.6 yard, halogen, aryl and Κ·9. In another embodiment, the invention relates to a compound of formula I, wherein R8 represents aryl-Co., ! alkyl, each of which may be optionally substituted by one or more halogen atoms ( Preferred fluorine). In another embodiment, the invention relates to a compound of formula I, wherein R8 represents an arylalkyl group, any of which may be optionally substituted by one or more halogen atoms at -43 to 201026701 (more Good fluorine). In another embodiment, the invention relates to a compound of formula I, wherein Rs represents an aryl-C2-4 alkyl group, each of which may be optionally substituted with one or more halogen atoms (more Good fluorine). In another embodiment, the invention relates to a compound of formula I, wherein R9-C2-1 ialkyl, wherein any of the alkyl groups are each optionally substituted by one or more halogen atoms (preferably fluorine). In another embodiment, the invention relates to a compound of formula I, wherein Rs represents Rm-WC^malkyl, wherein any of the alkyl groups may be optionally substituted by one or more halogen atoms (preferably fluorine). In another embodiment, the invention is a compound of formula I, wherein R9 is not -C02R&quot;, -CONRnR&quot; or _s〇2R&quot;. In another embodiment, the invention relates to a compound of formula I, wherein C is alkyl, C3-8 cycloalkyl-C〇11 alkyl, aryl-C〇-ii alkyl or alkyl, wherein Each of the monoalkyl groups may be optionally substituted by one or more halogen atoms (preferably fluorine) and each of the cycloalkyl groups may be optionally substituted with ~ or a plurality of substituents independently selected from the group consisting of: Cl_6 alkane Base, halogen (preferably fluorine), aryl and R9. In another embodiment, the invention is directed to a compound of formula I, wherein W is deuterium. In another embodiment, the invention relates to a compound of formula I, wherein R11 represents hydrazine or CU6 alkyl. In another embodiment, the invention relates to a compound of formula I, wherein R9-C2_n alkyl, wherein any alkyl group is optionally substituted by one or more halogen atoms, respectively. Good fluorine); and R9 represents -C02RH, -CONRhRh or -S〇2Rn. In another embodiment, the invention relates to a compound of formula I, wherein Rio represents Rg-C, alkyl, any of which may be optionally substituted by one or more halogen atoms (preferably fluorine) And R9 represents -C〇2Rh, -CONRhRh or -S〇2Rh. In another embodiment, the invention is directed to a compound of formula I, wherein R3 represents NH2; and R5 is attached to N1. In another embodiment, the invention relates to a compound of formula I, wherein R3 represents NH2; R5 is attached to N1; and R4 represents R6 and R5 represents R?' or R4 represents R? and r5 Represents r8. In another embodiment, the invention relates to a compound of formula I, wherein R3 represents NH2; R5 is attached to n1; R4 represents R6; R5 represents R·7; or R4 and R5 may be bonded to form _C3^alkyl, this group may be optionally substituted by one or more C, -8 alkyl groups. φ In another embodiment, the invention relates to a compound of formula I, wherein R3 represents NH2; R5 is attached to N1; R4 represents R6; and R5 represents R7. In another embodiment, the invention relates to a compound of formula I, wherein R3 represents nh2; r5 is attached to N1; R4 represents R7; R5 represents R8; or R4 and R5 are bonded to form _C3_5 An alkyl group, which may be optionally substituted with one or more C i -8 alkyl groups. In another embodiment, the invention relates to a compound of formula I, wherein R3 represents NH2; R5 is attached to N1; r4 represents R7; and r5-45-201026701 is ΤΚ. In another embodiment, the R3 system represents nh2; the -C3_5 alkylene group is formed and substituted. Another embodiment! R3 represents nh2; Table Tpc R7; or R4 and optionally mono- or polyalkyl, c3.8 cycloalkyl-alkyl; and R i 〇 is: aryl-CG- Any of the n-alkyl or i-alkyl groups may be optionally substituted with any of the cycloalkyl groups: C!. Another specific embodiment of the 6-alkyl group, wherein R3 represents NH2; represents R7; and R6 is a hospital base, R9- C. "!" Alkane S Cl-11, C3.8 ring Cl-ll, wherein one or more halogen atoms are passed through one or more independent halogens (preferably fluorine), : 1 a compound of formula I, the Rs of which is attached to N1; and the R4 and 5 are bonded to this group optionally in one or more than one Ci 8 alkyl form, the invention being related to a compound of formula I, Attached to N1; h system represents R6; R5 system L can be bonded to form -CM alkyl group, which is substituted by C丨·8 yard group; heart system represents η, Cl-U Co-M alkyl group 'Alkyl or Ri〇_w_c〇ii hair CVh alkyl, C3_8 cycloalkyl _Cg•&quot; alkyl, R9-C!•&quot; alkyl, wherein one or more of the ruler 6 and Riq The halogen atom is substituted (preferably fluorine) and is intended to be one or more substituents independently selected from the group consisting of halogen (preferably fluorine), aryl and r9. In the case of II, the present invention relates to a compound of formula 1, wherein the heart is attached to N1; R4 represents r6; R5 represents H, C丨-丨, alkyl, C38 cycloalkyl_c〇&quot; ^qW-Co-h alkyl; and Rl. The alkyl-Co-w alkyl group, the arylalkyl group or any of the alkyl groups of r9_R.6 and R_1q may be optionally substituted (preferably fluorine) and any of the cycloalkyl groups may be optionally selected from the following Substituted by a substituent: C, _6 alkyl, ruthenyl and R9.

❹ -46- 201026701 In another embodiment, the invention relates to a compound of formula I, wherein R3 represents NH2; R5 is attached to N1; R4 represents R6; R5 represents R7; or R4 and Rs are bondable Combining to form a _C3 5 alkylene group, which group may be optionally substituted by one or more Cl-8 alkyl groups; and r6 represents H, a hospital group or a &lt;:3.8 cycloalkyl-Cqii alkyl group, Any of the alkyl groups may be optionally substituted by one or more halogen atoms (preferably fluorine), and any of the cycloalkyl groups may be optionally substituted with ~ or a plurality of substituents independently selected from the group consisting of: g Ch Institute, halogen, aryl and R9. In another embodiment, the invention relates to a compound of formula I, wherein R3 represents NH2; h is attached to N1; R4 represents r6; r5 represents R7; and R6 represents H, C丨丨丨An alkyl group or a C3 8 cycloalkyl-c〇ii alkyl group, each of which may be optionally substituted by one or more halogen atoms (preferably fluorine) and any of the cycloalkyl groups may optionally be subjected to one Or substituted with a plurality of substituents independently selected from the group consisting of Ci-6 alkyl, halogen, aryl and R9. In another specific embodiment, the present invention relates to a compound of the formula: wherein R3 represents NH2; RS is attached to N1; r4 represents r6; r5 represents R?' or R4 and Rs are bondable Forming a _c3 5 alkyl group, this group may be optionally substituted with a plurality of substituted Cm alkyl groups; and R6 represents a Cl_n alkyl group or a C3-8 cycloalkyl group, preferably a Ci^ alkyl group or a C3 6 cycloalkane group. Any one of which may be optionally substituted by one or more halogen atoms (preferably fluorine), each of which may be optionally substituted by one or more substituents independently selected from the group consisting of: 6 alkyl, halogen, aryl and R9. In another embodiment, the invention relates to a compound of formula 1, wherein R3 represents NH2; R5 is attached to N1; R4 represents R6; R5-47-201026701 represents R7; and represents Cl-u An alkyl group or a c3.8 cycloalkyl group, preferably a c 1-6 phenyl group or a (: 3 δ cycloalkyl group, each of which may be optionally substituted by a plurality of ® atoms (preferably fluorine) And any of the cycloalkyl groups may be optionally substituted with one or more substituents independently selected from the group consisting of Cm alkyl, _, aryl, and R9. In another embodiment, the invention is related a compound wherein R3 represents NH2; Rs is attached to N1; R4 represents Rs; r5 represents R?; and Re represents Cl8 cycloalkyl, preferably C3_6 cycloalkyl, any of which may be Optionally substituted with one or more substituents independently selected from the group consisting of C, -6 alkyl, halo, aryl, and more preferably R6 represents cyclobutyl. In another embodiment, the invention A compound of formula I wherein R3 represents NH2; r5 is attached to N1; R4 represents r6; R5 represents R7; and R6 represents C3-8 cycloalkyl, preferably c3-6 cycloalkyl, The group may be optionally substituted by one or more substituents independently selected from the group consisting of: Cl-6 alkyl and halogen. In another embodiment, the invention relates to a compound of formula I, wherein R3 represents NH2; R5 is attached to N1; R4 represents R6; R5 represents R7; and Re represents C3-8 cycloalkyl, preferably c3-6 cycloalkyl. In another embodiment, the invention relates to a compound of formula I Wherein R3 represents NH2; Rs is attached to n1; R4 represents R6; R5 represents R7; and R6 represents cyclobutyl. In another embodiment, the invention relates to a compound of formula I, wherein R3 Represents NH2; Rs is attached to n1; R4 represents R6; R5 is 201026701 represents R7; or R4 and R5 are bonded to form -c3.5 alkyl, which may optionally pass one or more Ci_8 alkyl substituted; and R7 represents Η, &lt;^_6 alkyl or C3_8 cycloalkyl-C〇_6 alkyl. In another embodiment, the invention relates to a compound of formula I, wherein R3 The system represents NH2; the R5 line is attached to N1; the R4 line represents R6; the R5 line represents R7; and the R&gt;7 series does not represent H, C!-6, or C3-8 ring yard base - C〇-6 Base. Another concrete In one aspect, the invention relates to a compound of formula I, wherein R3 represents NH2; R5 is attached to N1; R4 represents R6; R5 represents R7: or R4 and R5 may be bonded to form -c3_5 alkyl, This group may be optionally substituted by one or more C -8 alkyl groups; and R 7 represents hydrazine or C, -6 alkyl, preferably hydrazine or methyl. In another embodiment, the invention relates to a compound of formula I, wherein R3 represents NH2; R5 is attached to Ν1; R4 represents R6; R5 represents R7; and R7 represents hydrazine or Cm alkyl, Jiayu or methyl. In another embodiment, the invention relates to a compound of formula I, wherein R3 represents NH2; R5 is attached to Ν1; R4 represents R6; R5 represents R7; or R4 and R5 are bonded to form -C3_5 An alkyl group, which group may be optionally substituted by one or more &lt;^_8 alkyl groups; and R7 represents a Ch alkyl group, preferably a methyl group. In another embodiment, the invention relates to a compound of formula I, wherein R3 represents NH2; R5 is attached to N1; R4 represents R6; R5 represents R7; and R7 represents Ch alkyl, preferably A base. In another embodiment, the invention relates to a compound of formula I, wherein Rs in -49-201026701 represents NH2; RS is attached to Νι; I is represented; Rs represents R8; or R4 and RS are bondable To form a -Cw alkyl group, this group may be optionally substituted by one or more alkyl groups; and represents a c3 8 cycloalkyl-Co.&quot;alkyl, aryl-Co-&quot; alkyl or尺9』2^院基, any of the alkyl groups may be optionally substituted by one or more halogen atoms (preferably gas)' and any of the cycloalkyl groups may be optionally independently selected from one or more Substituted by the following substituents: Ci_6, halogen, aryl and r9. In another embodiment, the invention relates to a compound of formula I, wherein R3 represents NH2; Rs is attached to N1; R4 represents R7; r5 represents R8; and R8 represents C3-S cycloalkylane Any one of the alkyl groups of the aryl group, the aryl group, or the Rp-ChM group may be optionally substituted by one or more _ atoms (preferably fluorine) and any of the cycloalkyl groups may be optionally used. Substituted by one or more substituents independently selected from the group consisting of Cl-6 alkyl, halogen, aryl and R9. In another embodiment, the invention relates to a compound, wherein Rs represents NHZ; Rs is attached to n1; r4 represents r7; r5 represents Rs; and Re represents aryl-Cq. H-based, preferably aryl-c!-! 丨-based and more preferably aryl-C2·4 alkyl, wherein any -alkyl group can be optionally substituted by one or more halogen atoms (preferably fluorine). In another embodiment, the invention relates to a compound of formula I, wherein Κ·3 represents NH 2 ; R 5 is attached to N 1 ; R 4 represents R 7 ; R 5 represents Rs ; or R 4 and R 5 may be bonded to form _C3 5 alkyl, this group may be optionally substituted by one or more C, -8 alkyl; and R 7 represents η or C! -6 alkyl, preferably hydrazine, methyl or ethyl. -50- 201026701 In another embodiment, the invention relates to a compound of formula I, wherein R.3 represents NH2; Rs is attached to N1; R4 represents r7; r5 represents R·8; and R? It means hydrazine or an alkyl group, preferably hydrazine, methyl or ethyl. In another embodiment, the invention relates to a compound of formula I, wherein R3 represents ΝΗ2; Rs is attached to Ν; R4 represents r7; r5 represents Rs; or R4 and R5 may be bonded to form _C3 5 alkyl, this group φ may be optionally substituted by one or more c 11 alkyl groups; and R 7 represents fluorene. In another embodiment, the invention relates to a compound of formula I, wherein R3 represents ΝΗ2; Rs is attached to Ν1; R4 represents r7; R5 represents Rs; and R7 represents Η. In another embodiment, the invention relates to a compound of formula I, wherein Κ·3 represents NH2; R5 is attached to Ν1; R6 represents Η,, 院, C3.8cycloalkyl-Cq·&quot ; alkyl, alkyl or riq-W_c〇ii yard base, ruler 7 series not 15, €: 1_6 yard base or 〇 3-8 ring yard base _ (:; () _6 yard base; φ rule 8 series CL8 cycloalkyl-c.-&quot;alkyl, aryl fluorene....homogeneous or R9_Cm-based; and r1g represents alkyl, c38 cycloalkyl-c〇&quot; fluorenyl, aryl-C〇 Or a 119-Ci.H alkyl group; wherein any of the alkyl groups in r6, r8 and R! 0 may be optionally substituted by one or more halogen atoms (preferably fluorine) and any of the naphthenes The base may be optionally substituted with one or more substituents independently selected from the group consisting of: Cl-6, a halogen (preferably gas), an aryl group and R9. In another embodiment, the invention relates to A compound of formula I, wherein R3 represents NH2; R5 is attached to N1; and I represents R6 and R, -51 - 201026701 represents R·7, or R·4 represents R7 and r5 represents r8; r6 Table, Cl. &quot; alkyl, C3.8 cycloalkyl _C 〇. &quot; alkyl, RrCo-H alkane Rjo-W-Cm yard; R7 It means H, Cu, or C3_8 ring β C〇-6, and 8·8 is not 〇3·8 ring hospital base - Cq.ii 垸 base, Fangmou-yuan or R9-C2-ii焼And R1〇 represents C丨-丨1, K3-8-C❹-1 !, aryl-C 〇-,, or R 9 _ C i ! Any of the alkyl groups of the ampule 8 and R1() may be optionally substituted by one or more halogens (preferably fluorine) and any of the cycloalkyl groups may be optionally subjected to one or more substituents selected from the group consisting of Substitution: C -6 alkyl, halogen (preferably, aryl and R9. In another embodiment, the invention relates to the compound of formula I wherein R3 represents NH2; Rs is attached to N1; R6 represents H, q or C3-8 cycloalkyl-Co-u alkyl; R7 represents hydrazine or C, .6 burned and R8 represents aryl-CQ-M alkyl; wherein in r6 and r8 Each may be optionally substituted with one or more halogen atoms (preferably fluorine). In another embodiment, the invention relates to a compound of formula I wherein R3 represents NH2; R5 is attached to N1; and R4 It means that R6 represents r7, or r4 represents 117 and r5 represents r8; r6 is a fluorenyl group, a fluorenyl-fluorenyl group or a c3-8 cycloalkyl-Co. R7 represents Η^ alkyl; and R8 represents aryl-Co-H alkyl; wherein each of the quaternary 6 and R8 monoalkyl groups may be optionally substituted by one or more halogen atoms (preferably another In a specific embodiment, the invention relates to the compound of formula I wherein R3 represents NH2; R5 is attached to N1; R4 is represented; Η or homestead _ C 0 - 1 1 cycloalkane is in the atomic monofluoride) , -1 1 院; alkyl, and r5 is ΗC 1 -6 in fluoro), R5 is 201026701 represents R?; or R4 and R5 can be bonded to form _C3-5 alkylene This group may be optionally substituted by one or more Cu alkyl groups; r6 represents anthracene, fluorenyl or C:3·8 ring-yard-Cq-h; and r7 represents H, Ci-6 Or a C 3 · 8 ring-based group -C 〇 · ! ! alkyl; wherein in the group R 6 any - the hospital group can be optionally substituted by one or more halogen atoms (preferably fluorine) and Each of the cycloalkyl groups may be optionally substituted with one or more substituents independently selected from the group consisting of Cl-6, halogen (preferably fluorine), aryl and r9. In another embodiment, the invention is a compound of the formula wherein R3 represents NH2; Rs is attached to N1; r4 represents r6; r5 represents R7; and R6 represents H'Ch&quot; alkyl or C3 -8 cycloalkyl-Cgm alkyl; and R7 represents H, C, .6 alkyl or c3-8 cycloalkyl-Cq6 alkyl; wherein any of the alkyl groups in R6 can be optionally subjected to one or Substituted by a plurality of halogen atoms (preferably fluorine) and each of the cyclodecyl groups may be optionally substituted by one or more substituents independently selected from the group consisting of a C1-6 alkyl group, a halogen (preferably gas), an aryl group. And R9. In another specific embodiment, the invention relates to a compound of the formula ,, wherein R3 represents NH2; R5 is attached to N1; r4 is protected - n-4 is not R6; r5 is

R7; or R4 and R5 may be bonded to form a _C5 1 methylalkyl group, which may be optionally substituted by one or more Cu alkyl groups; R # , 6 is a C 丨 丨丨 alkyl group Or C3·8 丨兀 丨兀 - - - - - - - - - - - - - - - - - - - - - - _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Each of the ~alkyl groups may be optionally substituted by one or more halogen atoms (preferably a gas) and any of the ring groups may be optionally substituted by one or more independently selected from the following:

Cl-6, a halogen (preferably fluorine), an aryl group and R9. -53- 201026701 In another embodiment, the invention relates to a compound of formula I, wherein R3 represents NH2; Rs is attached to N1; R4 represents R6; r5 represents R7; Re represents alkyl or c3_8 a cycloalkylalkyl group; and R? represents H, Cu alkyl or Cm cycloalkyl-C()6 alkyl; wherein any alkyl group in R6 may optionally be passed through one or more halogen atoms Substituted (preferably fluorine) and any of the cycloalkyl groups may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl, halo (preferably fluorine), aryl and ruthenium. In another embodiment, the invention relates to a compound of formula I, wherein R3 represents NH2; R5 is attached to N1; R4 represents r6; rule 5 represents R7; or R4 and R_5 are bondable to form -Cl5 alkyl group, this group may be optionally substituted by one or more alkyl groups; r0 means Cl_M yard group or C3.8 ring yard group - Co · &quot;alkyl; and R_7 means η or c16 The base is preferably a hydrazine or a methyl group, and more preferably a methyl group; wherein any thiol group in the group r6 may be optionally substituted by one or more halogen atoms (preferably gas) and any cycloalkyl group Each may be optionally substituted with one or more substituents independently selected from the group consisting of Cu6 alkyl, halogen (preferably fluorine), aryl and R9. In another embodiment, the invention relates to a compound of formula I,

The R3 system represents NH2; the R5 system is attached to N1; the R4 system represents R.D 丨, and the R5 system represents R·7; the R·6 series represents Ci_&quot;院基基 or C3·8环院基-(^ 0_丨丨原基· and R7 represents Η or C!·6 alkyl, preferably Η or methyl, and more preferably methyl; wherein any of the alkyl groups in R6 can optionally pass one or more Substituted by ^ + (preferably fluorine) and any of the cycloalkyl groups may be optionally substituted by 〜 tm _ 4 substituents independently selected from the group consisting of C^6 alkyl, halogen-54-201026701, In another embodiment, the invention relates to a compound of formula I, wherein R3 represents NH2; R5 is attached to N1; R4 represents R6; R5 represents R7; and r6 represents C3_8 cycloalkyl_ Cq ii alkyl; and r7 represents H or Ci-6 alkyl, preferably hydrazine or methyl, and more preferably methyl; wherein any alkyl group in R6 may optionally be passed through one or more halogen atoms Substituted (preferably fluorine) and any of the cycloalkyl groups may be optionally substituted by one or more φ substituents independently selected from C, -6 alkyl, halogen (preferably fluorine), aryl and r9 In another embodiment, the present invention relates to Formula I And wherein R 3 is attached to N 1 ; R 4 is R 6; R 5 is R 7 ; Re is Cm cycloalkyl, preferably Cl 8 cycloalkyl, and more preferably cyclobutyl; R? represents an anthracene or a Cu alkyl group, preferably η or a methyl group and more preferably a methyl group; any of the cycloalkyl groups may be optionally substituted by one or more substituents independently selected from the group consisting of Ci_6 alkyl , halogen (preferably gas), aryl and R9. φ In another embodiment, the invention relates to a compound of formula I, wherein R3 represents NH2; R5 is attached to N1; R4 represents Re; Represents R7; Re represents cyclobutyl; and I represents Η or c^6, preferably Η or methyl, and more preferably methyl. In another embodiment, the invention relates to a compound of formula Wherein R3 represents ΝΗ2; Rs is attached to Ν1; R4 represents han7; R5 represents R8; and R7 represents "[or Cu alkyl, preferably η, methyl or ethyl' and more preferably H And Rs represents an aryl-Cq-h alkyl group, preferably an aryl-Ci-u alkyl group and a more preferred aryl-c: 2 - 4 alkyl group wherein any - alkyl group is each -55- 201026701 Optionally passing one or more halogen atoms Substituted (preferably fluorine). In another embodiment, the invention relates to a compound of formula I, wherein: 1 and R2 together with the N atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of : (i) a heterocyclic group containing 2 N atoms and free of any other hetero atom, wherein the heterocyclic group may be optionally substituted by one or more Ci.4 alkyl groups, and ❹ (ii) a heterocyclic group containing 1 N atom and free of any other hetero atom, wherein the heterocyclic group is substituted by one -NRaRb group and optionally may be subjected to one or more C 4 alkyl groups And wherein the heterocyclic group (i) and (ii) may be a 4_ to 7-membered monocyclic ring, a 7- to 8-fold bridged bicyclic ring or an 8- to 12-membered fused bicyclic ring; NH2; and R5 is attached to N1. In another embodiment, the invention relates to a compound of the formula τ, wherein: 譬R! and R2 together with the N atom to which they are bonded form a saturated heterocyclic group which contains 1 N atom and does not Containing any other hetero atom, wherein the heterocyclic group is substituted by a -NRaRb group and optionally substituted by one or more Cl-4 alkyl groups; wherein the heterocyclic group can be 4 - to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; R3 represents nh2; R5 is attached to N1. -56- 201026701 In another embodiment, the invention relates to a compound of formula I, wherein:

Ri and R2 together with the N atom to which they are bonded form a saturated heterocyclic group selected from (a) and (b), wherein 1 and have the meanings given above for the compound of formula I and Re represents hydrazine or Ci- 4 yard base and preferably R. The system represents Η; the R3 system represents ΝΗ2; and the R5 system is attached to Ν1. In another embodiment, the invention is a compound of formula I, wherein:

Ri and R2 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group selected from (a) and (b), and Ra and Rc independently represent Η or Cm alkyl, preferably Ra, Rb and Rc independently represents hydrazine or methyl, and more preferably Ra and Rb independently represent hydrazine or methyl and Re represents hydrazine; R3 represents NH2; and R5 is attached to N1. In another embodiment, the invention relates to a compound of formula I, wherein: 1 and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (a) wherein Ra and Rb have the foregoing For the meaning of the compound of formula I and Rc represents H or Cl_4 alkyl and preferably Rc represents H; R3 represents NH2; and R5 is attached to N1. In another embodiment, the invention relates to a compound of formula I, -57- 201026701 wherein: the heart and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (a) wherein Ra , 趴 and Rc independently represent Η or Cm 院基's preferred Ra, Rb and R. The oxime or methyl group is independently represented, and more preferably, Ra and Rb independently represent oxime or methyl group and Re represents η; Κ·3 represents ΝΗ2; and R 5 is attached to Ν1. In another embodiment, the invention is directed to a compound of formula I, wherein:

Ri and R2 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group of formula (b) wherein Ra and Rb have the above meanings for the compound of formula I and Rc represents H or Ci 4 alkyl and preferably The Re system represents η; represents νη2; and R 5 is attached to Ν 1. In another embodiment, the invention is a compound of formula I, wherein:

Ri and R2 together with the bonded argon atoms form a saturated heterocyclic group of formula (b) 'wherein Ra, and Re independently represent 1^ or C^-4 院基' preferably Ra, Rb&amp; Re independently represents hydrazine or methyl group, and more preferably Ra and Rb independently represent hydrazine or methyl group and rc represents η; R3 represents ΝΗ2; and R 5 is attached to Ν1. In another embodiment, the invention relates to a compound of formula I, wherein: -58- 201026701 R 1 and R 2 together with the N atom to which they are bonded form a saturated heterocyclic group: (i) contains 2 N atoms and free of any other hetero group, wherein the heterocyclic group may be optionally subjected to one or more; and (ii) contains 1 N atom and does not contain any other hetero group, wherein the heterocyclic ring The group is substituted by one or more C, _4 alkyl groups via a -NRaRb group g; wherein the heterocyclic groups (i) and (ii) may be 4- to oxime bridged double rings or 8 - to 12-membered fused bicyclic ring; R3 represents νη2; R 5 is attached to Ν 1; R4 represents R6 and r5 represents r7, or r4 and -C3-5 alkyl, this group may be optionally Ground-based or multi-only substitution. Φ In another embodiment, the present invention is related to the formula wherein: and R2 together with the N atom to which it is bonded form a group which contains 1 N atom and does not contain any other heterocyclic group. a _NRaRb group is substituted and may be substituted by a plurality of alkyl groups; wherein the heterocyclic group singular ring ' to 8 _ bridging bicyclic or 8- to 12-membered fused Κ · 3 series means nh2 ; R 5 is attached to N 1 ; is substituted with a heterocyclic group of a heterocyclic group Cj-4 alkyl substituent selected from the group consisting of a heterocyclic group and may be arbitrarily monocyclic, 7- to R5 may be bonded to form 3 a compound of the compound I, which is a saturated heterocyclic atom, wherein the arbitrarily one or _ is 4- to 7-member bis bicyclic; -59- 201026701 R4 represents IU and Rs represents R7 Or, r4 and r5 may be bonded to form a -C3-5 alkylene group, which may be optionally substituted with one or more Cl-8 alkyl groups. In another embodiment, the invention relates to a compound of formula I, wherein: 1 and R2 together with the N atom to which they are bonded form a saturated heterocyclic group selected from (a) and (b), wherein 1^ and Rb have the aforementioned meanings for the compound of the formula 且 and R. Indicates Η or C!_4 alkyl and preferably Re represents Η;

Ri system indicates ΝΗ2;

Rs is attached to Ν1; R4 represents R6 and Rs represents R7, or r4 and r5 may be bonded to form a -C3.5 alkyl group, which may be optionally substituted by one or more Cl-8 alkyl groups . In another embodiment, the invention is a compound of formula I, wherein:

Ri and R2 together with the N atom to which they are bonded form a saturated heterocyclic group selected from (a) and (b), and Ra and Rc independently represent Η or Cm alkyl, preferably Ra, "and Rc independently represents η or methyl, and more preferably Ra and Rb independently represent fluorene or methyl and Re represents hydrazine; R3 represents nh2; R5 is attached to N1; R4 represents R6 and r5 represents r7, Or r4 and r5 may be bonded to form a _C^5 alkylene group, which may be optionally substituted by one or more Cl-8 alkyl groups -60-201026701. In another embodiment, the invention is related A compound of formula I, wherein: 1 and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (a) wherein Ra and Rb have the meanings given above for the compound and Rc represents η or C!-4 alkyl and preferably Re represents H; R3 represents NH2; 0 Rs is attached to N1; R4 represents r6 and r5 represents r7, or r4 and r5 may be bonded to form -C3-5 An alkyl group, which may be optionally substituted by one or more Cl-8 alkyl groups. In another embodiment, the invention relates to a compound of formula I, wherein: R! and R2 together with the bond thereof N atom together a saturated heterocyclic group of the formula (a), wherein Ra, Rb and R independently represent a hydrazine or a Cl 4 alkyl φ group. Preferably, Ra, Rb and Rc independently represent hydrazine or a methyl group, and more preferably Ra and Rb independently represents hydrazine or methyl and Rc represents η; R3 represents ΝΗ2; R5 is attached to Ν1; R4 represents and Rs represents R7, or R4 and R5 may be bonded to form _C3·5 alkylene Further, the group may be optionally substituted by one or more Cu alkyl groups. In another embodiment, the invention relates to a compound of formula I, wherein: -61 - 201026701

Ri and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (b) wherein Ra and Rb have the meanings as defined above for the compound and Rc represents H or (^.4 alkyl and Preferably, R represents H; R 3 represents Ν Η 2 ; R 5 is attached to Ν 1 ; h represents R 6 and R 5 represents R 7 , or R 4 and R 5 may be bonded to form -C3-5 alkylene The radical 'this group may be optionally substituted by one or more Cl-8 alkyl groups. In another embodiment, the invention relates to a compound of formula I, wherein: and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of the formula (b), wherein Ra, Rb and R&lt;: independently represent a fluorene or a Cl_4 group, preferably Ra, Rb and R. independently represent an anthracene or a methyl group, and more preferably Ra and Rb independently represents hydrazine or methyl and Rc represents hydrazine; R3 represents ΝΗ2; R5 is attached to Ν1; represents R6 and R5 represents R7, or R4 and R5 may be bonded to form a -alkyl group, The group may be optionally substituted by one or more &lt;^-8 alkyl groups. In another embodiment, the invention relates to a compound of formula I, wherein: and 112 together with the N atom to which it is bonded form a saturated heterocyclic group selected from the group consisting of: (i) a heterocyclic group containing 2 N atoms and containing no other hetero atom; wherein the heterocyclic group may optionally be subjected to one or more a tetraalkyl-substituted: and (ii) a heterocyclic group containing 1 N atom and free of any other hetero atom, wherein the heterocyclic group is substituted by a _NRaRb group and optionally One or more C. .4 alkyl substitutions; 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; &amp; R 3 represents N Η 2 ; R 5 is attached to Ν 1 ; R 4 represents R 6 ; and R 5 represents R 7 . In another embodiment, the invention is related a compound, of which:

R1 and R2 together with the N atom to which they are bonded form a saturated heterocyclic group which contains 1 N atom and does not contain any other hetero atom, wherein the Φ heterocyclic group is via a -NRaRb group Substituted and optionally substituted by one or more of the substituents; wherein the heterocyclic group may be a 4 to 7 membered monocyclic ' 7- to 8-membered bridged bicyclic or 8 to 12_ The fused bicyclic ring; R 3 represents Ν Η 2 ; R 5 is attached to ] st1 ; R 4 represents r 6 ; and R 5 represents r 7 . In the specific embodiment, the present invention relates to a compound of formula I, wherein: -63- 201026701 R! and R2 together with the N atom to which they are bonded form a (a) and

(b) a saturated heterocyclic group, of which! ^ and Rb have the aforementioned meanings for the compound of formula I and R. Η or Q-4 alkyl and preferably Re represents Η; Κ·3 represents ΝΗ2; R5 is attached to Ν1; R4 represents R6; and R5 represents R7. m In another embodiment, the invention is a compound of formula I, wherein:

Ri and R2 together with the N atom to which they are bonded form a saturated heterocyclic group selected from (a) and (b), and Ra, Rb and L independently represent η or Cm's base 'better Ra, And independently represents η or methyl, and more preferably Ra and Rb independently represent hydrazine or methyl and Re represents hydrazine; R3 represents NH2; R 5 is attached to N 1 ; ❹ R4 represents r6; and R5 Represents R7. In another embodiment, the invention is directed to a compound of the formula:

Ri and Rz together with the ^^ atom to which they are bonded form a saturated heterocyclic group of formula (a) wherein Ra and Rb have the meanings previously described for the compound of formula I and Rc represents h* Ci,4 alkyl and Preferably, η is represented; R3 represents NH2; -64 - 201026701 R5 is attached to N1; R4 is represented by R6; and R5 is represented by Tp: Κ·7. In another embodiment, the invention relates to a compound of formula I, wherein: -1 and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (a) wherein Ra, Rb and Re independently represents hydrazine or Cu alkane _ group' preferably Ra, Rb and Rc independently represent hydrazine or methyl group, and more preferably Ra and Rb independently represent hydrazine or methyl group and Rc represents hydrazine; R 3 represents Ν Η 2 ;

Rs is attached to Ν1; R4 is expressed as R6;

Rs represents R7. In another embodiment, the invention relates to a compound of formula I, wherein: φ R1 and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (b) wherein Ra and Rb have The foregoing is for the meaning of the compound of formula I and Rc represents Η or (^_4 alkyl and preferably R. represents H; R 3 represents Ν Η 2;

Rs is attached to Ν1; R4 is expressed as r6;

Rs represents r7. In another embodiment, the invention relates to a compound of formula I, wherein: -65-201026701 R! and ruler 2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (b), Among them Ra, Rb and R. Independently representing a 1 or C^.4 yard, and preferably Ra, Rb and Re independently represent a fluorene or a methyl group, and more preferably 1 and Rb independently represent a hydrazine or a methyl group and Rc represents a hydrazine, and More preferably, Ra means Η, Rb means methyl and Rc means Η; R3 means ΝΗ2;

Rs is attached to Ν1; R4 is R6; and _© R5 is R7. In another embodiment, the invention is a compound of formula I, wherein:

Ri and R2 together with the N atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of: (i) a heterocyclic group containing 2 N atoms and no other hetero atom, wherein the heterocyclic ring The aryl group may be optionally substituted by one or more s--4 alkyl groups: and ❿ (ii) a heterocyclic group containing 1 N atom and no other hetero atom, wherein the heterocyclic group is Substituted by a -NRaRb group and optionally substituted by one or more alkyl groups; wherein the heterocyclic groups (i) and (ii) may be 4- to 7-membered monocyclic, 7 - to 8-membered bridged bicyclic or to I2-membered fused bicyclic ring; R3 is represented by NH2; R5 is attached to N]; and R4 and R.5 are bonded to form - C3·5 The group may be optionally substituted with -66 - 201026701 or a plurality of C 1 alkyl groups. In another embodiment, the invention is directed to a compound of formula I, wherein:

R1 and R2 together with the N atom to which they are bonded form a saturated heterocyclic group containing 1 N atom and no other hetero atom, wherein the heterocyclic group is substituted by a _NRaRb group And optionally substituted by one or more alkyl groups; wherein the heterocyclic group may be 4_ to 7_member φ single ring, 7 to 8_membered bridged bicyclic or 8- to 12-member Fused bicyclic; R3 represents NH2; R5 is attached to N1; and R4 and R5 are bonded to form _C3 5 alkyl, which may optionally pass one or more C, -8 Substituted by an alkyl group. In another embodiment, the invention is a compound of formula I, wherein:

R1 and R·2 together with the N atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of (a) and succinic (b), wherein 1 and Rb have the meanings for the formula compound and R. Represents hydrazine or Cl-4 alkyl and preferably R. The system represents Η; the R3 system represents νη2;

The Rs is attached to Ν1; and R·4 and R5 are bonded to form a _C3·5 alkylene group which may be optionally substituted by one or more C!-8 alkyl groups. In another embodiment, the invention relates to a compound of formula I, wherein: -67- 201026701

Ri and R2 together with the N atom to which they are bonded form a saturated heterocyclic group selected from (a) and (b), and Ra, Rb and L independently represent η or Cm alkyl, preferably Ra, Rb &amp;; R. Independently represents η or methyl, and more preferably Ra and Rb independently represent fluorene or methyl and Re represents η; ^•3 represents ΝΗ2; R 5 is attached to Ν 1 ; and R4 and Rs are bonded To form a _C3_5 alkylene group, this group may be optionally substituted with one or more C, -8 alkyl groups. In another embodiment, the invention relates to a compound of formula I, wherein: 1 and R2 together with the atom to which they are bonded form a saturated heterocyclic group of formula (a) wherein Ra and Rb have The foregoing meanings for the compound of formula I' and Rc means Η or &lt;^_4 alkyl and preferably Re represents η; R3 means NH2; R5 is attached to N1; and R4 and Rs are bonded Forming a _C35 alkylene group, this group may be optionally substituted with one or more Cbs alkyl groups. In another embodiment, the invention is directed to a compound of formula I, wherein:

Ri and R2 together with the atom to which they are bonded form a saturated heterocyclic group of formula (a), wherein Ra, and R are independently represented by 匕 "alkyl" preferably Ra, Rb and R. independently The ground represents a hydrazine or a methyl group, and more preferably, Ra and Rb are uniquely methyl or methyl and Re is a hydrazine;

Rs represents ΝΗ2; 201026701 R 5 is attached to N 1 ; and R 4 and Rs are bonded to form _C3 5 alkyl, which may be optionally substituted by one or more Cl-S alkyl groups. In another embodiment, the invention relates to a compound of formula I, wherein: R] and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (b) wherein Ra and Rb have The foregoing is for the meaning of the compound Φ of the formula I' and the RC means Η or Ci 4 alkyl and preferably Re represents Η; the rule 3 represents ΝΗ2; the R 5 is attached to Ν 1 ; and the b and RS are bonded To form a _C3 5 alkyl group, this group may be optionally substituted with one or more Cl-8 alkyl groups. In another embodiment, the invention is a compound of formula I, wherein: R1 and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (b), wherein Ra, Rb and Re independently represents H or Cm fluorenyl group. Preferably Ra, Rb and Re independently represent fluorene or methyl group, and more preferably Ra and Rb independently represent hydrazine or methyl group and Re represents hydrazine; R3 represents ΝΗ2; Attached to Ν1; and R4 and R·5 are bonded to form a _C3 5 alkylene group, which group may be optionally substituted with one or more C, I alkyl groups. In another embodiment, the invention relates to a compound of formula I, wherein: -69- 201026701 1 and R2 together with the N atom to which they are bonded form a saturated heterocyclic group selected from: (i) a heterocyclic group containing 2 N atoms and free of any other hetero atom, wherein the heterocyclic group may be optionally substituted by one or more (^-4 alkyl groups:

(Π) a heterocyclic group containing 1 N atom and free of any other hetero atom, wherein the heterocyclic group is substituted with one -NRaRb group and optionally passed through one or more C^-4 An alkyl group; wherein the heterocyclic group (i) and (ii) may be a 4- to 7-membered monocyclic ring, a 7- to 8-membered bridged bicyclic ring or an 8- to 12-membered fused bicyclic ring; - 3 is a NH2; R5 is attached to N1; and R4 means R7 and R5 are R8, or R4 and R5 are bonded to form a -C3·5 stretching group. This group can be optionally subjected to one or Substituted by a plurality of Cl_8 alkyl groups.

In another embodiment, the invention is a compound of formula I, wherein:

Ri and R2 together with the N atom to which they are bonded form a saturated heterocyclic map which contains 1 N atom and does not contain any other hetero atom, wherein the @bad group is replaced by a _NRaRb group And optionally substituted by one or more C^-4 theater groups; wherein the heterocyclic group may be 4_ to 7_ member soils '7- to 8·member bridging bicyclic or 8_ to It is fused to bicyclic; Κ·3 is expressed as nh2;

Rs is attached to N1; and -70-201026701 R4 means R? and R5 means R8, or R4 and r5 may be bonded to form -C3-5 alkylene group, which may optionally pass one or more Substituted by a Cl_8 alkyl group. In another embodiment, the invention is a compound of formula I, wherein:

Rj and R2 together with the N atom to which they are bonded form a saturated heterocyclic group selected from (a) and (b), wherein 113 and Rb have the meanings given above for the compound of formula I 0 and Rc represents Η or C _4 alkyl and preferably Re represents Η; R3 represents ΝΗ2; R5 is attached to Ν1; and R4 represents R7 and Rs represents Rs, or R4 and R5 may be bonded to form -C3_5 alkyl This group may be optionally substituted by one or more Cl-8 alkyl groups. In another embodiment, the invention relates to a compound of formula I, φ wherein: 1 and R 2 together with the N atom to which they are bonded form a saturated heterocyclic group selected from (a) and (b), And Ra ' Rb and Re independently represent Η or Cu alkyl, preferably Ra, Rb and R. The oxime or methyl group is independently indicated, and more preferably, Ra and Rb independently represent hydrazine or methyl and R. Line represents Η; R3 represents ΝΗ2; R5 is attached to Ν1; and R4 means that r7 and R5 are Rs, or R4 and r5 are bonded to form -C3.5 alkyl, which may be optionally Substituted by one or more Cb8 alkyl groups -71 - 201026701. In another embodiment, the invention relates to a compound of formula I, wherein: R1 and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (a), wherein Ra and Rb have the foregoing The meaning of the compound of formula I' and Rc means Η or C, -4 alkyl and preferably Re means Η; rule 3 means ΝΗ2; R 5 is attached to Ν 1; and R · 4 means R7 and R5 represents R8, or R4 and R5 may be bonded to form a -C3-5 alkylene group which may be optionally substituted by one or more Ci-8 alkyl groups. In another embodiment, the invention relates to a compound of formula I, wherein: R1 and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (a), wherein Ra ' Rb. Re independently represents hydrazine or Cw alkyl group. Preferably, Ra, Rb and Rc independently represent hydrazine or methyl group, and more preferably Ra and Rb independently represent η or methyl and Re represents Η; R3 represents νη2; 5 is attached to Ν 1 ; and R 4 is represented by R 7 and R 5 is not Re, or Κ 4 and R 5 may be bonded to form -C 3 ·5 alkyl, which may optionally pass one or more Substituted by a Cu alkyl group. In another embodiment, the invention relates to a compound of formula I, wherein: -72-201026701 R! and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (b), wherein Ra and Rb have the above meanings for the compound of formula I' and Rc represents 11 or Cu alkyl and preferably Re represents H; represents NH2; is attached to N1; and R4 represents R7 and R5 represents R_8, Or R4 and r5 may be bonded to form a _C3-5 alkylene group which may be optionally substituted by one or more Ci-8 alkyl groups. In another embodiment, the invention is a compound of formula I, wherein:

Ri and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (b) wherein Ra, Rb and R. Independently indicating Η or C!-4 院基' preferably Ra, Rb and Re independently represent Η or methyl, and more preferably Ra and Rb independently represent Η or methyl and Rc represents Η; Κ·3 ΝΗ2; 0 Ι is attached to Ν1; and means that R7 and R5 are R8, or R4 and R5 are bonded to form _C3-5 alkyl, which may optionally pass one or more CbS Substituted by an alkyl group. In another embodiment, the invention relates to a compound of formula I, wherein: and R2 together with the N atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of: (i) containing two N atoms And a heterocyclic group which does not contain any other hetero atom - 73- 201026701, wherein the heterocyclic group may be optionally substituted by one or more C, _4 alkyl groups; and (ii) contains 1 N atom and a heterocyclic group containing no other hetero atom, wherein the heterocyclic group is substituted with one -NRaRb group and optionally substituted with one or more C!-4 alkyl groups; wherein the heterocyclic ring The groups (i) and (ii) may be 4_ to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; R3 represents NH2; φ R5 is attached And N1; and IU means R7 and R5 means R8. In another embodiment, the invention is a compound of formula I, wherein:

Ri and R2 together with the N atom to which they are bonded form a saturated heterocyclic group which contains 1 N atom and does not contain any other hetero atom, wherein the heterocyclic group is substituted by a -NRaRb group And optionally substituted by one or more &lt;3^4 alkyl groups; wherein the heterocyclic group may be 4-7 to 7-membered ❹monocyclic '7- to 8-membered bridged bicyclic or 8 - to 12-member fused bicyclic; Κ·3 is not nh2; R5 is attached to N1; R·4 is not Κ7 and r5 is Rg. In another embodiment, the invention is a compound of formula I, wherein:

Ri and Rz together with the N atom to which they are bonded form a saturated heterocyclic group selected from (a) and (b), wherein Ra&amp; Rb has the above meaning for the compound of the formula 74-74- 201026701, preferably 1 And Rb independently represent hydrazine or (^.4 alkyl; and Re represents hydrazine or Ci-4 alkyl, preferably hydrazine. More preferably, Ra, Rb and Rc independently represent hydrazine or methyl group' and are even better Ra and Rb independently represent hydrazine or methyl and Rc represents hydrazine; R3 represents ΝΗ2; R5 is attached to N1; and R4 represents R7 and R5 represents Rs. In another embodiment, 'present invention A compound of formula I, wherein: and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (a) wherein Ra and Rb have the meanings described above for the formula 'better Ra and Rb independently represents a ruthenium or a Cu-based group; and 1^ is not a ruthenium or a Ci_4 fluorenyl group, preferably H. More preferably Ra, Rb and 1 independently represent a ruthenium or a methyl group, and even more preferably Ra and Rb independently η or methyl and Rc represent Η; R3 represents ΝΗ2; R5 is attached to Ν1; and Κ·4 is not Κ7 and β·5 is not 尺8. In another embodiment 'The invention is related to the formula Ϊ a compound, wherein: R, and R2 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group of formula (b) wherein Ra and Rb have the meanings of the above-mentioned compounds, preferably Ra and Rb are independent The ground represents ^1 or Cm, and Rc represents Η or Cm alkyl, preferably Η. More preferably Ra, Rb and R. Independently -75- 201026701 means hydrazine or methyl, and even better! Rb independently represents η or methyl and Rc represents Η; R3 represents ΝΗ2; is attached to N1; and R4 represents R7 and R&gt;5 represents R8. In another embodiment, the invention is a compound of formula I, wherein:

Ri and R2 together with the N atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of: (i) a heterocyclic group containing 2 N atoms and containing no other hetero atom, wherein the heterocyclic ring The aryl group may be optionally substituted by one or more Cl-4 alkyl groups: and (ii) a heterocyclic group containing 1 N atom and free of any other hetero atom, wherein the heterocyclic group is One -NRaRb group is substituted and optionally substituted by one or more Cl 4 alkyl groups; wherein the heterocyclic groups (i) and (ii) may be 4 to 7-membered monocyclic, 7 to 8 _ member bridged bicyclic or 8_ to 12-membered fused bicyclic ring; R3 represents NH2; R5 is attached to N1; represents R6 and R5 represents r7, or R4 and R5 can be bonded to form -C3-5 The alkyl group 'this group may be optionally substituted with one or more CU8 alkyl groups; and the L system represents a Ci-H alkyl group, preferably a Cu alkyl group. In another embodiment, the invention relates to a compound of formula I, -76- 201026701 wherein: 1 and R2 together with the N atom to which they are bonded form a saturated heterocyclic group containing 1 N atom And does not contain any other hetero atom, wherein the heterocyclic group is substituted by ~_NRaRb group and can be optionally substituted by one or more Ci-4 groups; wherein the heterocyclic group can For the 7-membered monocyclic, 7- to 8-shell-bridged bicyclic or 8_ to 12-membered fused bicyclic; Κ·3 represents NH2; 0 R 5 is attached to N 1 ; R4 represents R6 and r5 represent r7, or r4 and R5 may be bonded to form a -C3-5 stretching group. This group may be optionally substituted by - or a plurality of Ci 8 alkyl groups;

Re represents an alkyl group, preferably a C 6 alkyl group. In another embodiment, the invention is a compound of formula I, wherein:

Ri and R2 together with the N atom to which they are bonded form a saturated heterocyclic group selected from (a) and φ (b), wherein 1 and Rb have the meanings given above for the compound of formula I and Re represents Η or C ^4 alkyl and preferably R.系·3 represents Η2; R 5 is attached to Ν 1 ; R 4 represents R 6 and R 5 represents R 7 , or R 4 and R 5 may be bonded to form -C 3.5 alkyl, this group The group may be optionally substituted by one or more C,-8 alkyl groups; and R6 represents a C丨丨 alkyl group, preferably a C丨_6 alkyl group. -77- 201026701 In another embodiment, the invention relates to a compound of formula I, wherein: R! &amp; R2 together with the N atom to which it is bonded form a saturated impurity selected from (a) and (b) a cyclic group, and Ra, Rb and Rc independently represent Η or Cm alkyl, preferably Ra, Rb and Rc independently represent fluorene or methyl, and more preferably 1 and Rb independently represent hydrazine or methyl and Re Department indicates Η;

Rs represents NH2;

Rs is attached to N1; R4 represents R6 and R5 represents R7, or R4 and R5 may be bonded to form -C3-5 alkyl, which may optionally be passed through one or more C, -8 Substituted by an alkyl group; and R6 represents a c丨-丨]alkyl group, preferably (: 6 alkyl group. In another embodiment, the invention relates to a compound of formula I, wherein:

Ri and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (a) having a center and Rb having the above meaning for the compound of formula I and Rc means fluorene or alkyl and preferably Re Line represents H; R 3 represents N Η 2 ; R 5 is attached to Ν 1 ; b represents R6 and R5 represents r7, or r4 and r5 may be bonded to form -C3-5 alkyl, this group The group may be optionally substituted by one or more Ci 8 alkyl groups; and R6 represents a c丨-fluorenyl group, preferably a C 6 alkyl group. In another embodiment, the invention is a compound of formula I, -78- 201026701 wherein:

Ri and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of the formula (a), wherein Ra, Rb and Re independently represent an anthracene or a Cu alkyl group, preferably Ra, Rb and Re are independently represented Η or methyl, and more preferably Ra and Rb independently represent η or methyl and Re represents Η; R3 represents ΝΗ2; R 5 is attached to Ν 1; @R4 represents R6 and R5 represents R7, or R4 and R5 may be bonded to form a _C3-5 alkylene group which may be optionally substituted by one or more Ci.8 alkyl groups; and L is an alkyl group, preferably a Cu alkyl group. In another embodiment, the invention relates to a compound of formula I, wherein: R1 and R2 together with the N atom to which they are bonded form a cyclic group of formula (b), wherein 1 and Rb have the aforementioned formula The meaning of the compound refers to 'and Rc means Η or Cm alkyl and preferably R. Line represents H; I represents nh2; R 5 is attached to N 1 ; h represents R6 and R5 represents R7, or R4 and R5 may be bonded to form -C3·5 alkyl, which may be optionally Substituted by one or more Cl-8 alkyl groups; and b represents a Cy i alkyl group, preferably a G-6 alkyl group. In another embodiment, the invention relates to a compound of formula I, wherein: -79- 201026701

Ri and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (b) wherein Ra, Rb and R. Independently &lt;^-4 alkyl, preferably Ra, Rb and Rc independently represent anthracene or methyl, and more preferably Ra and Rb independently represent anthracene or methyl and R. Line represents Η; R3 represents νη2; R5 is attached to Ν1;

R4 represents R6 and R5 represents R7, or R4 and R5 may be bonded to form a -C3-5 alkylene group, which group may be optionally substituted by one or more &lt;^-8 alkyl groups; Indicates an alkyl group, preferably a Cu alkyl group. In another embodiment, the invention is a compound of formula I, wherein:

Ri and 112 together with the N atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of: a heterocyclic group containing 2 N atoms and no other hetero atom

a group wherein the heterocyclic group is optionally substituted by one or more C1_4 alkyl groups: and (Η) a heterocyclic group containing 1 N atom and free of any other hetero atom, wherein the heterocyclic ring The group is substituted by a -NRaR_b group and may be optionally substituted by one or more Cl 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 _2_ member fused double ring; R3 system represents NH2; R 5 line is attached to N 1 ; -80- 201026701 R4 represents R6 and Rs represents r7, or R4 and Rs may be bonded to form a -C3-5 alkylene group, which may be optionally substituted by one or more octaalkyl groups; and R6 represents a Cm cycloalkylalkyl group, preferably a cycloalkane More preferably, C 3-6 cycloalkyl and more preferably cyclobutyl, each of which may be optionally substituted by one or more halogen atoms, and any of the cycloalkyl groups may be optionally subjected to Substituted by one or more substituents independently selected from the group consisting of Ci6 alkyl, halogen, aryl and R9. In another embodiment, the invention is a compound of the formula wherein 'R1 and R2 together with the N atom to which they are bonded form a saturated heterocyclic group' which contains 1 N atom and does not contain any Other heteroatoms wherein the heterocyclic group is substituted by one -NRaRb group and may be optionally substituted by one or more (^-4 alkyl groups; wherein the heterocyclic group may be 4 to 7 _ member monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic; R3 represents NH2; R5 is attached to N1; R4 represents R6 and r5 represents r7 , or r4 and r5 may be bonded to form a -C3-5 alkylene group, which may be optionally substituted by one or more Cl.8 alkyl groups; and R6 represents a c3_8 cycloalkyl-Cow alkyl group, Preferred (: 3-8 cycloalkyl, more preferably cs-6 cycloalkyl, and still more preferably cyclobutyl, each of which may be optionally substituted by one or more halogen atoms, and any ring The alkyl groups may each optionally be substituted with one or more substituents independently selected from the group consisting of c, -6 alkyl-81 - 201026701, halogen, aryl and R9. In another embodiment, the invention is About the combination of formula I , among them:

Ri and together with the N atoms it is bonded to form are selected from (a) and

(fc) a saturated heterocyclic group 'where 1 and ! ^ has the above meaning for the compound of formula I and Re represents Η or Cl 4 alkyl and preferably Rc represents Η; R3 represents ΝΗ 2 ;

Rs is attached to Ν1; R4 represents R6 and Rs represents R?, or &4 and R5 may be bonded to form -C3-5 extensions. This group may optionally be passed through one or more Ci8 alkane Substituted; and R.6 is a C3-8 ring-based group - c〇_u fluorenyl group, any of which may be optionally substituted by one or more halogen atoms, and any cycloalkyl group Each may be optionally substituted with one or more substituents independently selected from the group consisting of Ci6 alkyl, halogen, aryl and R9. In another embodiment, the invention is directed to a compound of the formula:

Ri and R2 together with the ruthenium atoms to which they are bonded form a saturated heterocyclic group ' and the R' selected from (a) and (b). Independently representing Η or Cm alkyl, preferably Ra, and Re independently represent η or methyl, and more preferably Ra and Rb independently represent Η or methyl and represent η; R 3 represents Ν Η 2 ; Attached to Ν1; -82- 201026701 R·4 represents R6 and R·5 represents R7, or 114 and r5 may be bonded to form a -C3-5 stretching group, which may optionally be-- Substituted by a plurality of Ci8 yards; and R6 represents a C3·8 cycloalkyl-Co-&quot;alkyl group, preferably a c3 8 cycloalkyl group, more preferably a C3-6 ring-yard group' and even more preferably a cyclobutene Any one of the substituents may be optionally substituted by one or more halogen atoms, and any of the ring-based groups may be optionally substituted by one or more substituents independently selected from the group consisting of: c16 alkyl, Otto, square and R_9. In another specific embodiment, the invention relates to a compound of formula Z, wherein _

Ri and R·2 together with the N atom to which they are bonded form a saturated heterocyclic group of the formula (a), wherein 1 and Rb have the aforementioned formula! The meaning of the compound, and Rc represents 11 or C, .4 alkyl and preferably Rc represents η; R3 represents NH2; R5 is attached to N1; #R4 represents R6 and R5 represents R7, or R4 and r5 may be bonded to form a -C3-5 alkyl group, which may be optionally substituted by one or more alkyl groups; and ru is a cs_8 cycloalkyl-Cq ii alkyl group, preferably c3 8 a cycloalkyl group, more preferably a C3.6 cycloalkyl group, and still more preferably a cyclobutyl group, each of which may be optionally substituted by one or more halogen atoms, and any of the cycloalkyl groups may be optionally used. Substituted by one or more substituents independently selected from the group consisting of C16 alkyl, halo, aryl and R9. In another embodiment, the invention is related to the formula -83 to 201026701 wherein:

Ri and Han 2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (a), wherein Ra, Rb and R. Independently represents hydrazine or Cu alkyl group. Preferably Ra, Rb and Re independently represent hydrazine or methyl group, and more preferably Ra and Rb independently represent hydrazine or methyl group and Rc represents hydrazine; R 3 represents Ν Η 2 R5 is attached to Ν1; R·4 represents 116 and r5 represents r7, or 114 and r5 may be bonded to form a -C3-5 alkyl group, which may optionally be passed through one or more Ci8 alkane Substituted; and

Re represents a c3-8 cycloalkyl-Comalkyl group, preferably a c3-8 cycloalkyl group, more preferably a C3-6 cycloalkyl group, and still more preferably a cyclobutyl group, each of which may optionally be subjected to a butyl group. One or more halogen atoms are substituted, and any of the cycloalkyl groups may be optionally substituted with one or more substituents independently selected from the group consisting of c16 alkyl 'halogen, aryl and R9. In another embodiment, the invention relates to a compound of formula I, wherein: R! and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (b) wherein Ra and Rb have The above meaning for the compound of formula I' and Rc means H or alkyl and preferably Re means H; R3 means nh2; R5 is attached to N1; heart means Re and R5 means R7, or R4 And R5 may be bonded to form a -Cm alkyl group, which group may be optionally substituted by one or more Ci 8 alkyl groups -84 - 201026701; and R6 represents a C3-8 ring-based alkyl-Com alkyl group 'Any of the - the base groups are each optionally substituted by one or more halogen atoms, and any of the cycloalkyl groups may be optionally substituted with one or more substituents independently selected from the group consisting of C16 alkyl, halogen. , aryl and r9. In another embodiment, the invention relates to a compound of formula I, wherein: 0 Ri and together with the N atom to which it is bonded form a saturated heterocyclic group of formula (b) wherein Ra, Rb and Re Independently represents Η or C,-4 alkyl ' preferably Ra, Rb and Re independently represent fluorene or methyl, and more preferably Ra and Rb independently represent hydrazine or methyl and Rc represents hydrazine; R3 represents νη2 R 5 is attached to Ν 1 ; R 4 represents r 6 and r 5 represents r 7 , or r 4 and r 5 may be bonded to form a -C3-5 alkyl group, which may optionally pass one or more Cl 8 -alkanes Substituted by Φ; and

Re series table τρ: C3-8 ring yard base - C〇-ii yard base, preferably C3-8 ring yard base, more preferably c3-6 cycloalkyl group, and even more preferably cyclobutyl group, any one of which Each of the groups may be optionally substituted by one or more halogen atoms, and any of the cycloalkyl groups may be optionally substituted with one or more substituents independently selected from the group consisting of C -6 alkyl, halogen, aromatic Base and R9. In another embodiment, the invention is directed to a compound of formula I wherein:

Ri and R2 together with the N atom to which they are bonded form a -85-201026701 saturated heterocyclic group selected from the group consisting of: (I) a heterocyclic group containing 2 N atoms and no other hetero atom. Wherein the heterocyclic group is optionally substituted by one or more Cl 4 - groups: and (II) a heterocyclic group containing 1 N atom and free of any other hetero atom, wherein the heterocyclic group Substituted by a _NRaRb group and optionally substituted by one or more Ci-4 alkyl groups; wherein the heterocyclic groups (i) and (π) may be 4_ to 7_membered monocyclic, 7_ to 8_membered bridged bicyclic or 8- to 12-membered fused bicyclic ring; R3 represents nh2; R 5 is attached to N 1 ; Κ·4 represents R7; R5 represents r8; Alkyl-Cq ualkyl, preferably aryl-Ci ii alkyl and more preferred aryl-C2-4. In another embodiment, the invention is a compound of formula I, wherein:

R1 and R2 together with the N atom to which they are bonded form a saturated heterocyclic group which contains 1 N atom and does not contain any other hetero atom, wherein the heterocyclic group is substituted by a _NRaRb group And optionally substituted by one or more C, 4 hospital bases; wherein the heterocyclic group can be 4_ to a single ring 7_ to 8_member bridging bicyclic or 8- to 12-member Fused bicyclic; R3 represents NH2;

R 5 is attached to N -86-

201026701 R4 represents the heart = R5 represents R8;

The Re system represents an aryl-c〇-丨丨院 base, preferably an aryl group-C-丨丨院3 佳方基-C2-4 yard base. In another embodiment, the invention relates to a formula of formula I wherein: 1 and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (a) b) wherein 1 and Rb Having the above meaning for the compound of 3, preferably, Rb independently represents 11 or Ch annoying and R. It means Η or C _4 alkyl, preferably H. More preferably, Ra and Rb independently represent a hydrazine or a methyl group, and more preferably, Ra and Rb independently represent a methyl group and an Rc system represents hydrazine; and R3 represents ΝΗ2;

Rs is attached to Ν1; and R4 represents R7; R5 represents R8; and R8 represents aryl-Co-decylalkyl, preferably aryl-Ci-fluorenyl aryl-C2.4 alkyl. In another embodiment, the invention relates to a compound of formula I wherein: 1 and 112 together with the N atom to which they are bonded form a formula (a) and a heterocyclic group, wherein Ra and Rb have the aforementioned formula Preferably, Ra and Rb independently represent hydrazine or Cm alkyl; and represent hydrazine or alkyl, preferably H. More preferably Ra, Rb, and Re alone; ί j and more -, and ( :I: base; and Rc Η or more, Rc of the saturate -87 - 201026701 Η or methyl 'and More preferably! ^ and Rb independently represent η or methyl and Rc represents Η;

Rs represents ΝΗ2; attached to Ν1; and R4 represents R7;

Rs represents R8;

The R8 group is a non-aryl-Co-n-based group, preferably an aryl-Ci-i-based group and more preferably an aryl-C2_4 alkyl group. In another embodiment, the invention is a compound of formula I, wherein:

Ri and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (b) wherein Ra and Rb have the meanings previously described for the compound of formula I, preferably Ra and Rb independently represent 11 or Cm alkane And Rc is not deuterated or Cm alkyl is preferably H. Better Ra, Rb and Re independently

The table is not methyl or methyl' and further preferably 3 and Rb independently represent η or methyl and Rc represents η; R3 represents ΝΗ2;

Rs is attached to Ν1; and R4 represents R7; R5 represents R8; and R8 represents aryl-Cmalkyl' preferred aryl-Ci &quot;alkyl and more preferably aryl-c2 4 alkyl. In another embodiment, the invention relates to a compound of formula I, wherein: -88 - 201026701 11 and 112 together with the N atom to which they are bonded form a saturated heterocyclic group selected from: (i) a heterocyclic group containing 2 N atoms and free of any other hetero atom, wherein the heterocyclic group may be optionally substituted by one or more C, 4 alkyl groups: and (Π) contains 1 N atom And a heterocyclic group which does not contain any other hetero atom, wherein the heterocyclic group is substituted by one -NRaRb group and may be optionally substituted by one or more (^-4 alkyl groups; wherein the heterocyclic ring The groups (i) and (ii) may be 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8 to 12-membered fused bicyclic rings; Κ·3 series means NH2; R 5 Attached to N 1 ; R 4 represents r 6 and r 5 represents r 7 ' or r 4 and R 5 may be bonded to form a -C 3 ·5 alkylene group, which may be optionally subjected to - or a plurality of Cl 8 alkyl groups Substituted; φ R6 represents hydrazine, alkyl or C3-8 cycloalkyl-C.·&quot;alkyl; and R7 represents Η, (^_6 alkyl or C3-8 cycloalkyl-CV6 alkyl. In a specific embodiment, the invention relates to a compound of formula I, Wherein: the core and R.sup.2 together with the N atom to which they are bonded form a saturated heterocyclic group which contains 1 N atom and does not contain any other hetero atom, wherein the heterocyclic group is via a -NR a R b group substituted and optionally substituted by one or more Ci·4 fluorenyl groups; wherein the heterocyclic group may be a 4_ to 7_membered monocyclic ring, a 7- to 8-member bridge Bicyclic or 8- to 12-membered fused bicyclic; -89-201026701 Κ·3 indicates nh2; R 5 is attached to N1: R·4 indicates r6; R·5 indicates r7; R6 indicates H, C丨·decyl or c3_8 cycloalkyl-Co-decyl; and R7 represents anthracene, mountain-6 alkyl or C3-8 cycloalkyl-C〇_6 alkyl. In a specific embodiment, the invention relates to a compound of formula I, wherein:

Ri and R2 together with the N atom to which they are bonded form a saturated heterocyclic group selected from (a) and (b), wherein Ra and "have the meaning of the foregoing compound for formula I and Re represents Η or (^ _4 alkyl and preferably Re represents Η; R 3 represents Ν Η 2 ;

Rs is attached to Ν1; R4 is R6; R5 is TfC R7; R6 is H, ChH alkyl or C3-8 cycloalkyl-Co-H alkyl; and Κ·7 is not H , Ci-6 yard base or C3-8 ring yard base - C〇-6 yard base. In another embodiment, the invention relates to a compound of formula I, wherein: 1 and R 2 together with the N atom to which they are bonded form a saturated heterocyclic group selected from (a) and (b), And Ra, Rb and R. Independently represents Η or Cm alkyl, preferably Ra, Rb and R. Independently represents hydrazine or methyl, and more preferably Ra and Rb independently represent hydrazine or methyl and Re represents hydrazine; -90-201026701 R3 represents NH2; R5 is attached to N1; R4 represents R6; R 5 represents R 7 ; represents H, (V&quot; alkyl or c3 8 cycloalkyl-Cq H alkyl; and R7 represents H, CU6 alkyl or c38 cycloalkyl-cQ6 alkyl. In an embodiment, the invention relates to a compound of formula I, wherein: ^ and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (a) wherein 1 and Rb have the aforementioned formula The meaning of the compound I' and Rc means 11 or Ci4 alkyl and preferably Re means H; R3 means NH2; R5 is attached to N1; R4 means R6; R5 means r7; ®R6 means H, C1-11 alkyl or c3_8 cycloalkyl-C.-&quot;alkyl; and R7 represents hydrazine, Cu alkyl or C3 8 cycloalkyl-Cq 6 alkyl. In another embodiment The present invention relates to a compound of formula I, wherein: I and h together with the N atom to which they are bonded form a saturated heterocyclic group of formula (a) wherein Ra, Rb and R independently represent a hydrazine or an alkyl group. 'Optimal Ra, Rb and Re independent surface Η or methyl, and more preferably Ra and Rb are unique or methyl and Rc represents Η; I represents ΝΗ2; -91 - 201026701 R5 is attached to N1; Κ·4 is not R6; R5 Represents R7; R6 represents H, alkyl or c38 cycloalkyl-C〇-ll alkyl; and R7 represents H, C!-6 alkyl or c38 cycloalkyl-Cq-6 alkyl. In the present invention, the invention relates to a compound of formula I, wherein:

Ri and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (b) wherein 1^ and Rb have the above meanings for the compound of formula I, and Rc represents 11 or C, -4 Alkyl and preferably R. Line represents H; R3 represents nh2; attached to N1; R4 represents R6;

Rs represents r7; !^6 represents 11, (: 1-11 alkyl or (: 3.8 cycloalkyl-(:.-11 alkyl); and R7 represents anthracene, Cu alkyl or C3_8 cycloalkyl- Cq-6 alkyl. φ In another embodiment, the invention relates to a compound of formula I, wherein:

Ri and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (b), wherein Ra, Rb and Re independently represent 11 or a Cu alkyl group, preferably Ra, Rb and Rc independently represent Η or methyl, and more preferably Ra and Rb independently represent hydrazine or methyl and Re represents hydrazine; R3 represents ΝΗ2; R5 is attached to Ν1; -92-201026701 R4 represents R6; R5 represents R7; R6 represents H, C, -&quot;alkyl or C3_8 cycloalkyl-Co.&quot;alkyl; and R7 represents H, Cu alkyl or C3.8 cycloalkyl-C〇-6 alkyl. In another embodiment, the invention is a compound of formula I, wherein:

Ri and R2 together with the N atom to which they are bonded form a φ saturated heterocyclic group selected from the group consisting of: (a heterocyclic group containing 2 N atoms and containing no other hetero atom) wherein the heterocyclic ring The aryl group may be optionally substituted with one or more Cl.4 alkyl groups: and (Η) a heterocyclic group containing 1 N atom and no other hetero atom, wherein the heterocyclic group is — The _NRaRb group is substituted and optionally substituted by - or a plurality of c, -4 alkyl groups; wherein the heterocyclic groups (i) and (ϋ) may be 4_ to 7_membered single ring Φ, 7 _ to 8 - member bridged bicyclic or 8- to 1 2-membered fused bicyclic ring; R 3 system represents Ν Η 2 ; R 5 system attached to Ν 1 ; R4 system represents R6;

Rs represents R7; or Κ·4 and R5 may be bonded to form a ^ / by 1. The core is _C3_5 alkyl, this group may be optionally substituted by one or more C] _8 alkyl; R6 Is a Cm, alkyl or C38 cycloalkyl-Cq alkyl group, any of which may be optionally substituted by ~ or a plurality of halogen atoms, and any of -93-201026701 cycloalkyl groups may be optionally Substituted by one or more substituents independently selected from the group consisting of Cu alkyl, halogen, aryl and r9; and R 7 represents deuterium or Cl 6 alkyl, preferably η or methyl, more preferably methyl and In a specific embodiment, the invention relates to a compound of formula I, wherein: R2, together with the ruthenium atom to which it is bonded, forms a saturated heterocyclic group containing one N atom and no other hetero atom, wherein The heterocyclic group is substituted by a -NRaRb group and may be optionally substituted by - or a plurality of alkyl groups; wherein the heterocyclic group may be a 4 to 7 membered monocyclic ring, 7 to 8-membered bicyclic or 8- to 12-membered fused bicyclic; R3 represents NH2; R5 is attached to N1; R4 represents R6; R5 represents R7; or R4 and Rs can be bonded Combine to form - C35 alkyl This group may be optionally substituted by one or more C 8 alkyl groups; R 6 represents Cy, a deutero group or a C 3 8 cycloalkylalkyl group, each of which may optionally be subjected to one or more halogens Substituted by an atom, and any of the cycloalkyl groups may be optionally substituted with one or more substituents independently selected from the group consisting of Cu alkyl, halogen 'aryl and r9; and R 7 represents deuterium or Ci-6 alkyl Preferably, H or methyl, more preferably a compound of methyl hydrazine I. In another embodiment, the invention is related to formula -94 to 201026701 wherein: 1 and R2 together with the N atom to which they are bonded form The saturated heterocyclic group of the formulae (a) and (b) wherein 1 and have the meanings for the compound of the formula I, preferably Ra and Rb independently represent a η or Cl4 group; and Rc represents Η or Cm Alkyl group, preferably η. More preferably, R_a, Rb and Rc independently represent hydrazine or methyl' and further preferably Ra&amp; Rb independently represents η or methyl and Rc represents Η; I Rs represents ΝΗ2; 9 R5 is attached to Ν1; 4 is a Tpc R 6 ; R 5 represents R 7 ; or R 4 and R 5 may be bonded to form a -c 3 5 alkyl group, which may be optionally substituted by one or more C 8 alkyl groups;

Re represents a C丨-decyl group or a c3-8 cycloalkyl-C〇-fluorenyl group, each of which may be optionally substituted by one or more halogen atoms, and any φ naphthenic The base may be optionally substituted by one or more substituents independently selected from the group consisting of Cm alkyl, halogen, aryl and r9; and R·7 represents hydrazine or Cu alkyl, preferably η or methyl, More preferably, in another embodiment, the invention relates to a compound of formula I, wherein: 尺 and Rz together with the ruthenium atom to which they are bonded form a saturated heterocyclic group of formula (a) Wherein, Ra and Rb have the meanings as defined above for the compound of formula I, preferably Ra and Rb independently represent η or (^_4 alkyl; and Rc is -95-201026701 or C4, preferably 1^ The R, R _ 吏 Ra Ra Ra and Re independently represent Η or methyl, and even more preferably 1 and R b independently represent H or methyl and R c are not Η; R 3 represents ΝΗ 2 ;

Rs is attached to N1; R4 is represented by r6; R5 is represented by R7; 2R·4 and R·5 are bondable η to form _ς; 35 extend the base, and the group can be arbitrarily passed one or more Substituted by C,·8 alkyl;

Re is a C?• decyl or CM cycloalkyl-c〇丨丨 alkyl group, any of which can be optionally substituted by one or more halogen atoms, and each of the ring bases can be Optionally substituted with one or more substituents independently selected from C: 6 alkyl, halogen, aryl and r9; and R 7 represents deuterium or Ci-6 alkyl, preferably deuterated or methyl, In a further embodiment of the preferred methyl hydrazine, the invention relates to a compound of formula I, wherein:

Ri and R2 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group of formula (b) wherein Ra and Rb have the above meanings for the compound of formula I, preferably Ra and Rb independently represent H or Cm alkane And Rc represents a hydrazine or a Cu alkyl group, preferably hydrazine. More preferably, Ra, Rb and R&lt;= independently represent hydrazine or methyl group, and even more preferably 113 and Rb independently represent hydrazine or methyl and Rc represents hydrazine; R 3 represents Ν Η 2; 201026701 R5 is attached In the case of N1; R 4 represents R 6 , R 5 represents R 7 ; or R 4 and Rs may be bonded to form a _C 3 5 alkyl group, which may be optionally substituted by one or more alkyl groups; And an alkyl group or a C3_8 cycloalkyl-(:〇_&quot; alkyl group, each of which may be optionally substituted by one or more tooth atoms, and any of the cycloalkyl groups may be optionally subjected to one or Substituted by a plurality of substituents independently selected from the group consisting of Cu alkyl, halogen, aryl and r9; and R7 represents hydrazine or (^-6 alkyl, preferably η or methyl, more preferably methyl 0. In an embodiment, the invention relates to a compound of formula I, wherein: phantom and R2 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of: (i) containing two germanium atoms and not a heterocyclic group containing any other hetero atom, wherein the heterocyclic group is optionally substituted by one or more Cl -4 alkyl groups; and (ii) contains 1 N atom and does not contain any other hetero atom a heterocyclic group wherein the heterocyclic group is substituted with one -NRaRb group and optionally substituted with one or more C^4 alkyl groups; wherein the heterocyclic groups (i) and (ii) It may be a 4_ to 7_membered monocyclic ring, a 7- to 8-membered bridged bicyclic ring or an 8- to 12-membered fused bicyclic ring; R3 is a NH2; -97- 201026701 R5 is attached to N1; R4 is Represents R6; R5 represents R7; R6 represents c^8 cycloalkyl-Comalkyl, preferably C34 cycloalkyl, more preferably c3.6 cycloalkyl and even more preferably cyclobutyl, any of which is alkane Each of the groups may be optionally substituted by one or more halogen atoms, and any of the cycloalkyl groups may be optionally substituted with one or more substituents independently selected from the group consisting of Ci.6 alkyl, halogen, aryl And R?; and R? represents hydrazine or C!-6 alkyl, preferably hydrazine or methyl, more preferably methyl hydrazine. In another embodiment, the invention relates to a compound of formula I, wherein:

Ri and Rz together with the bonded argon atoms form a saturated heterocyclic group containing 1 N atom and no other hetero atom, wherein the heterocyclic group is via a -NRaRb group Substituted and optionally substituted by or with a plurality of Ci-4 alkyl groups; wherein the heterocyclic group may be 4 to 7 members, monocyclic, 7 to 8 membered bicyclic or 8- to 12- Member fused bicyclic; R3 represents NH2; R5 is attached to N1; R4 represents r6; R5 represents R7; R6 represents (:3·8 cycloalkyl-Co-w) Preferred is a C38 cycloalkyl group, more preferably a cs-6 cycloalkyl group and still more preferably a cyclobutyl group, each of which may be optionally substituted by one or more halogen atoms. Each of -98-201026701 may be substituted by one or more substituents independently selected from the group consisting of: Cl_6 alkyl, halogen, aryl and R9; and R·? is not a sputum or Ci-6 In another embodiment of the invention, the present invention relates to a compound of formula I, wherein: the heart and R2 together with the bonded &gt;! atom-forming formula (a) And (φ b ) saturated heterocyclic group Wherein, Ra and Rb have the meanings for the above-mentioned compounds of the formula: '11' and Rb independently represent η or (^.4 alkyl; and L means Η or Cu alkyl' preferably η. More preferably Ra, Rb And rc independently represents hydrazine or methyl group' and further preferably Ra&amp; Rb independently represents η or methyl and Re represents Η; R 3 represents Ν Η 2 ; R 5 is attached to ν 1 ; Represents R6; ^R5 represents R7; R6 represents Cmcycloalkyl-Co.&quot;alkyl, preferably c38 cycloalkyl, more preferably C3.6 cycloalkyl and even more preferably cyclobutyl, of which Each of the alkyl groups may be optionally substituted by one or more halogen atoms, and any of the cycloalkyl groups may be optionally substituted with one or more substituents independently selected from the group consisting of: CI 6 alkyl, halogen, aromatic And R7; and R7 represents hydrazine or C -6 alkyl group, preferably H or methyl group, more preferably methyl hydrazine in another specific embodiment, the present invention is a compound of the formula, -99- 201026701 Wherein: R and R together with the N atom to which they are bonded form a saturated heterocyclic group of formula (a) wherein 113 and Rb have the meanings previously described for the compound of formula I. Preferably Ra and Rb independently represent η Or Ci- 4 alkyl; and Rc represents H or Cm alkyl, preferably H. More preferably, Ra, Rb and Re independently represent anthracene or methyl' and further preferably, and Rb independently represents η or methyl and Rc Line represents Η; R3 represents ΝΗ2; R5 is attached to N1; R4 represents R6: R5 represents R7; R6 represents C3-8 cycloalkyl-Co·&quot; alkyl, preferably c3 8 cycloalkyl More preferably, C3_6 cycloalkyl and more preferably cyclobutyl, each of which may be optionally substituted by one or more halogen atoms, and any of the cycloalkyl groups may optionally be passed through one or more Substituted independently of the following substituents: hi alkyl, halogen 'aryl and R9; and R7 represents deuterium or C,-6 alkyl, preferably deuterated or methyl, more preferably methyl. In the present invention, the present invention relates to a compound of the formula:

Ri and R2 together with the bonded ruthenium atom - form a saturated heterocyclic twin group of formula (b) wherein Ra and Rb have the meanings of the above-mentioned "combination", preferably Ra and Rb independently Represents 11 or CM alkyl; and L represents M Cl-4, and preferably H. More preferably Ra, oxime and &amp; independently -100 - 201026701 represents hydrazine or methyl, and more preferably 1 and Rb independently represent hydrazine or methyl and Rc represents hydrazine; R3 represents νη2; R5 is attached Ν1; R4 represents R6; R5 represents R7; R6 represents C3-8 ring-based-C. 11 yard base, preferably C3-8 ring yard base, more preferably C3_6 cycloalkyl group and even more preferably cyclobutyl group, any of which may be optionally substituted by one or more opaque atoms' Any of the cycloalkyl groups may be optionally substituted by one or more substituents independently selected from C, -6 alkyl, halogen, aryl and R9; and R7 represents η or C!-6 alkyl, Preferably, hydrazine or methyl, more preferably methyl hydrazine, in another embodiment, the invention relates to a compound of formula I, wherein:

Ri and R2 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of: (i) a heterocyclic group containing 2 N atoms and no other hetero atom, wherein the heterocyclic ring The heterocyclic group may be optionally substituted by one or more (^-4 alkyl groups: and (ii) a heterocyclic group containing 1 N atom and containing no other hetero atom, wherein the heterocyclic group is One -NRaRb group is substituted and optionally substituted by one or more C!-4 alkyl groups; wherein the heterocyclic groups (i) and (ii) may be 4- to 7-membered monocyclic-101- 201026701, 7- to 8-membered bicyclic or 8- to 12-membered fused bicyclic; R3 represents NH2; R5 is attached to N1; R4 represents R7; R5 represents R8; R7 represents Η or Cm Alkyl group, preferably hydrazine, methyl or ethyl, and more preferably Η; and R8 represents an aryl-Co.u alkyl group, preferably an aryl-C^n alkyl group and a more preferred aryl group-C2-4 In a specific embodiment, the invention relates to a compound of formula I, wherein:

Rl and R2 together with the N atom to which they are bonded form a saturated heterocyclic ring

An atom and free of any other heteroatoms wherein the NRaRb group is substituted and optionally represented by one or R3 represents NH2; the R5 is attached to. wherein the heterocyclic group can be a 4 to 7 member ring Wow or 8- to 丨 2_ member fused bicyclic; R4 represents r7; R5 represents R8; R 7 represents 或 or C] more preferably 且; and alkyl is preferably Η, methyl or ethyl, And

Rs represents aryl aryl group ~ C2.4 yard base. The present invention is preferably a compound of formula I wherein: 1 and R2 together with the N atom to which they are bonded are formed in another embodiment. a saturated heterocyclic group of the formulae (a) and (b), wherein Ra and Rb have the meanings as defined above for the compound of the formula I, preferably Ra and Rb independently represent 11 or a Ci.4 alkyl group; Or Ci-4 yard base 'better H. More preferably, Ra, Rb and Rc independently represent anthracene or a methyl group, and more preferably 1 and Rb independently represent η or I methyl and Rc represents hydrazine;

W R3 represents nh2; R5 is attached to N1; Κ·4 represents R7; R5 represents R8; R7 represents hydrazine or Cm alkyl, preferably hydrazine, methyl or ethyl, and more preferably Η; R8 is a non-square group - Cq-Identyl group, preferably an aryl group - Cl _11 yard base and more. Good base group - C2-4 fluorenyl group. In another embodiment, the invention relates to a compound of formula I, wherein: heart and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (a) wherein Ra and Rb have the foregoing The meaning of the compound of formula I 'better Ra and Rb independently denotes hydrazine or Cl 4 alkyl; and Rc denotes hydrazine or Cm alkyl, preferably η. More preferably, Ra, Rb and Re independently represent hydrazine or methyl group and are even better! ^ and Rb independently represent η or methyl and Rc are also Η; -103- 201026701 R3 represents nh2; R5 is attached to N1; R4 represents R7; R5 represents R8; R7 represents H or Cm Base, preferably H, methyl or ethyl, and more preferably oxime;

Rs represents an aryl-Cm alkyl group, preferably an arylalkyl group and more preferably an aryl-C2_4 fluorenyl group. In another embodiment, the invention relates to a compound of formula I, wherein: and R2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (b), wherein Ra and Rb have the aforementioned The meaning of the compound of formula I 'better Ra and Rb are independently represented! 1 or Cw alkyl; and Rc represents 11 or Ch alkyl, preferably oxime. More preferably, Ra, Rb and independently represent anthracene or methyl, and more preferably 1 and Rb independently represent η or methyl and RC represents Η; ΝΗ2; attached to Ν1; R4 represents R7;

Rs represents R8; R7 represents hydrazine or C&quot; alkyl, preferably hydrazine, methyl or ethyl, and more preferably Η; and R8 represents arylalkyl, preferably aryl-C^nalkyl and More preferred is an aryl-C2.4 alkyl group. -104-

201026701 Moreover, the present invention includes all possible combinations of the specific and preferred embodiments described above. In additional embodiments, the invention relates to a compound of formula I selected from the group consisting of Examples 1 to 58. In additional embodiments, the invention relates to a compound of formula I in an H4 receptor assay such as described in Examples 59 or 60, which provides greater than 5% inhibition of I activity, preferably better than! μΜ, and more than 0.1 μΜ. The compounds of the present invention contain one or more basic nitrogens and thus form salts with inorganic acids. Examples of such salts include, inter alia, inorganic acids, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid, and organic acids such as methanesulfonic acid, trifluoromethanesulfonic acid 'ethanesulfonate Salts of acid sulfonic acid, potential-yin benzene sulfonic acid, fumaric acid, oxalic acid, acetic acid, cis acid, ascorbic acid, citric acid, lactic acid, tartaric acid, malonic acid, acid, succinic acid and propionic acid. The compounds of the present invention may contain one or more φ protons and, therefore, may also form a salt with a base, which also forms part of the present invention. Examples of such salts include: salts with inorganic cations such as sodium, calcium, magnesium, lithium, aluminum, zinc, and the like; and pharmaceutically acceptable amines, alkylamines, hydroxyalkylamines, lysines , arginine, ... methyl glycosamine, procaine and the like. There are no restrictions on the salts that can be used, as long as they are acceptable for therapeutic purposes. The term pharmaceutically acceptable salt means in accordance with medical judgment in contact with tissues of humans and other animals without undue toxicity 'sexuality, allergic reactions and salts of such persons. A pharmaceutically acceptable salt: a sample of the implementation ', its 〇μΜ: a good machine or such as a salt salt; a phenene butanol acid potassium, such as grape medicine for stimulation technology -105-201026701 . Salts of the compounds of formula I may be prepared during the final isolation and purification of the compounds of the invention, or may be prepared by conventional methods of treating the compound of formula I with a sufficient amount of the desired acid. Salts of the compounds of formula I can be converted to other salts of the compounds of formula I by ion exchange using ion exchange resins. The compounds of formula I and their salts may differ somewhat in physical properties, but are equivalent for the purposes of the present invention. All salts of the compounds of formula I are included within the scope of the invention. 化合物 The compounds of the invention may form complexes with solvents which are reacted in or precipitated or crystallized from the solvent. These complexes are referred to as solvates. The term solvate as used in the present invention denotes a complex stoichiometric complex formed from a solute (a compound of formula I or a salt thereof) and a solvent. Examples of the solvent include pharmaceutically acceptable solvents such as water, ethanol, and the like. The complex with water is called a hydrate. Solvates of the compounds of the invention (or salts thereof), including hydrates, are included within the scope of the invention. The compounds of formula I may exist in different physical forms, i.e., amorphous and crystalline. Moreover, the compounds of the invention may have the ability to crystallize in more than one form, a feature known as polymorphism. Polymorphs can be distinguished by various physical properties well known in the art, such as X-ray diffraction patterns, melting points or solubility. All physical forms of the compounds of formula I, including all polymorph forms ("polymorphs"), are included within the scope of the invention. Certain compounds of the invention may exist in several optical isomers and/or in several non-image isomer forms. The non-image isomers can be separated by conventional techniques such as chromatography or partial crystallization. Optical isomers can be optically isolated. -106- 201026701 Technically isolated, producing optically pure isomers. Such isolation can be carried out on any of the palm-forming synthetic intermediates or the products of formula I. Optically pure isomers can also be prepared individually using mirror-specific synthesis. The present invention encompasses all individual isomers and mixtures thereof (e.g., mixtures of racemic or non-image isomers), whether by synthesis or by physical mixing. The compound of Formula 1 can be obtained by following the method described below. It will be apparent to those skilled in the art that the exact method used to prepare a particular compound may vary depending on its chemical structure of Φ. Moreover, in some of the following methods, it may be desirable or desirable to protect the reactive or unsettled groups with conventional protecting groups. The nature of such protecting groups and methods of their introduction or removal are well known to the art (see, for example, Greene Tw. and Wuts p GM, &lt;*Pr〇tective Groups in Organic Synthesis), John Wiley &amp; Sons, No. 3 Version, 1 999). Unless otherwise stated, in the following methods, the meaning of the different substituents is as defined above for the compound of the formula. The compound of formula I can be borrowed as shown in the following scheme By reacting a compound of the formula φ with a compound of formula III: -107- 201026701

Wherein Ri, R2, R3, R4 and Rs have the meanings previously described for the compound of formula I and R1S represents a leaving group such as a halogen atom or a triflate. The reaction between the compounds of the formulae II and III can be carried out using, for example, a coupling agent such as PyBOP (benzotriazole-bupropion-oxytripyrrolidinium hexafluorophosphate), @ in a suitable solvent such as 1,4-dioxane. , tetrahydrofuran, dichloromethane, dimethylformamide, acetonitrile or a mixture thereof, preferably in acetonitrile, in the presence of a base such as Ύ-diisopropylethylamine, dimethylaniline, diethyl The reaction is carried out with aniline, triethylamine or 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) 'preferably triethylamine). The reaction can be carried out by heating at room temperature or under heating. Or a compound of formula I can be prepared by reacting a compound of formula III with a reactive derivative (IIb) of a compound of formula II which is present in the compound of formula II by standard procedures from -108 to 201026701 The hydroxy group is converted to a cleavage group such as a halogen or a triflate, preferably chlorine. The -OH group derived from the compound of formula II can be reacted with a halogenating agent such as POCl3 by arbitrarily storing N,N-diethylaniline or hydrazine, hydrazine-dimethylaniline, or a suitable solvent such as 1,4 - reacting with P0C13/PC15 in the presence of dioxane or 1,2-dichloroethane, and converting to a leaving group such as a halogen, preferably chlorine. The reaction is carried out by heating preferably at a temperature between 10 ° C and 140 ° C. The hydroxy group of the compound of formula II can be converted to a triflate group by reaction with trifluoromethanesulfonic anhydride in the presence of pyridine. The resulting reactive derivative of the hydrazine compound (lib) is then reacted with a compound of formula III to yield a compound of formula I. The reaction is carried out in a suitable solvent (such as ethanol, methanol, butanol, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile or toluene, preferably ethanol) in a base (including organic amines, especially In the presence of, for example, triethylamine, diisopropylethylamine, dimethylaniline and diethylaniline, or an inorganic base such as K2co3, preferably comprised between 50 ° C and 1 40 ° C. Execution by heating at a temperature. Heating may be carried out by heating or by microwave irradiation at a wattage which allows the temperature mentioned above. Generally, the amine substituent of the compound of formula III is first protected against the formation of by-products prior to the reaction between the formula III and III or the compound of lib and III. Any suitable protecting group can be used, such as, for example, a butyloxycarbonyl (Boc) group. When the amine substituent of formula II and / or III and / or lib compound is protected, a subsequent deprotection step may be required, which is carried out under standard conditions. When the protecting group is Boc, the deprotection can be -109-201026701 by adding a strong acid (such as HCl) to a suitable solvent (such as 1,4-dioxane, diethyl ether or methanol) or trifluoroacetic acid to dichloro The solution in methane is carried out directly on the crude product obtained. The compound of formula III is commercially available or can be prepared by procedures described in the literature. The compound of formula II can be prepared by reacting a compound of formula IV with cyanamide or formamide depending on the nature of the substituent R3 (NH2 or Η), as shown in the following scheme:

Wherein R3, R4 and Rs have the meanings indicated by formula I, and R14 represents methyl or ethyl. The reaction with cyanamide is in the presence of an acid such as HCl, in a suitable solvent |f such as 1,4-dioxane or diethyl ether' by means of a suitable temperature (usually between room temperature and reflux temperature) It is preferably carried out by heating under reflux. The reaction can be carried out by subsequent addition of a base such as sodium hydroxide at a suitable temperature (better than reflux). The reaction with formamide is carried out by heating the compound I v in pure formamide at a suitable temperature (usually between 10 ° C and 200 ° C). The compound of formula IV can be prepared by reduction of a compound of formula V, as shown in the following scheme: -110 - 201026701

Wherein R4 and R5 have the meanings indicated by formula I and R14 represents methyl or ethyl. This reaction can be carried out under standard conditions used for catalytic hydrogenation, such as h2 or ammonium formate in the presence of a catalyst such as palladium on carbon.

Compounds of formula V can be prepared by nitrating a compound of formula VI, such as

The flow chart is shown below: r4

Wherein R·4 and Rs have the meanings of formula I and r14 represents methyl or ethyl. The reaction is carried out by reacting a compound of the formula VI with a mixture of nitric acid and sulfuric acid. This reaction is usually carried out at a suitable temperature (preferably at room temperature) between 〇 ° C and reflux temperature after the initial addition of acid in 〇 〇 c without any additional solvent. The presence of an ester group in the compound of formula VI can be hydrolyzed during the nitration step, so a subsequent esterification step may be necessary. The nitration can also be carried out directly from the compound of the formula VI having a carboxylic acid group (i.e., the compound of the formula vid) under the above conditions, and the nitration from the acid is preferably carried out at a temperature of 6 (TC). Performing a subsequent esterification step to produce a compound of formula V. Conversion of the carboxylic acid group to an ester can be carried out at room temperature by the corresponding alcohol under standard conditions such as, for example, HC1 in 1,4-dioxane or The compound of formula VI wherein R4 represents r6 or r7 and R5 represents R7 or R8 of formula I (ie, compounds of formulas via and VIb) are commercially available or may be borrowed. Prepared by reacting a compound of formula VII with a compound of formula VIII, as shown in the following scheme:

R4 R4

VII VIII Via VIb wherein R4 and R5 have the meanings given for formula I and R14 represents methyl or ethyl. This reaction is carried out in a suitable solvent such as ethanol or acetic acid and under heating (preferably to reflux). The compounds of formula VII and formula VIII are either commercially available or can be readily prepared from commercially available compounds by known methods. A compound of formula V wherein R5 is attached to N1 and R4 and R5 are bonded to form a -c3_5 alkylene group (i.e., a Vc compound) can be prepared by nitration of a compound of formula Vic, as shown in the following scheme: 112- 201026701

Vic

Among them, Ri4 has the meaning disclosed previously. The reaction can be carried out under the nitration conditions previously disclosed for the compound of formula VI. Preferably, the reaction is carried out by adding a nitric acid-sulfuric acid solution to the compound Vic which is cooled at 〇 °C. This situation

Under the deprotection of the ester group. A compound of the formula Vic can be prepared by reacting a compound of the formula IX with a compound of the formula X according to the scheme shown below:

Wherein R14 has the meaning previously disclosed. This reaction can be carried out in a suitable solvent such as φ xylene and heating (preferably at reflux temperature). The compound of the formula X is a commercially available product or can be easily obtained from a commercially available compound by a known method. The compound of formula IX can be obtained from a compound of formula XI as follows:

XI IX

The initial nitrosation is carried out by adding concentrated HCl to the compound XI-113-201026701 dissolved in water and treating it with sodium nitrite at a suitable temperature (preferably room temperature). Trifluoroacetic anhydride is then added to yield a cyclized compound of formula IX. The compound of formula XI is commercially available or can be prepared by procedures described in the literature. Another option is a compound of formula I (wherein r4 represents r6 or r7, and Rs represents R7 or Rs, a compound of formula I, ie, compounds of formulas la and lb) may be by formula R5-X (XII) An alkylating agent is prepared by alkylating a compound of formula I wherein R5 represents hydrazine, i.e., a compound of formula Ic, as shown in the following scheme:

Wherein Ri, R2, R3, R4 and R5 have the meanings described for the general formula I, and X represents a leaving group such as a halogen such as Cl, Br or I. This reaction can be carried out in the presence of a base such as Cs2C03, K2C03, NaHH or NaH (preferably NaH) in a suitable solvent such as, for example, acetone, toluene, I,2-dimethoxyethane (preferably dimethylformamide). It is carried out at a suitable temperature (including between room temperature and reflux temperature, preferably room temperature). Typically, the amine substituent (N R i R2 ) in the compound of formula I c is suitably protected prior to the alkylation reaction. Alternatively, the alkylation can be carried out in a slightly prior step of the process to produce a compound of formula I. For example, alkylation can be carried out from a compound of formula V wherein Rs is a hydrazine, i.e., a compound of formula Vd, with an alkylating agent R5-X ( ΧΠ ) to yield a compound of formula V, as shown in the following scheme: 114- 201026701

Vd X «I v ❹ wherein Rm represents a methyl group or an ethyl group, and x represents a leaving group such as a halogen such as Cl, Br or I. This reaction can be carried out under the alkylation conditions previously disclosed for the compound of formula Ic. Alternatively, starting from Formula VI (wherein R5 is oxime, a compound of the formula Vic), the alkylating agent R5-X (XII) can be used to produce a compound of formula VI, as shown in the following scheme:

Vic XII VI wherein Rm represents a methyl group or an ethyl group, and X represents a leaving group such as a chelating substance such as Cl, Br or I. This reaction can still be carried out under the alkylation conditions previously disclosed for the compound of formula Ic. Further, specific compounds of the present invention can be prepared under standard experimental conditions starting from other compounds of formula I, by appropriate conversion of the functional groups, in one or several steps, using reactions well known in organic chemistry. As mentioned above, the compounds of the invention exhibit potent histamine H4 receptor antagonistic activity. Thus, the compounds of the invention are expected to be useful in the treatment of diseases mediated by H4 receptors in mammals, including humans. The H4 receptor mediated by the compounds of the invention may be mediated by the H4 receptor. The -115-201026701 disease line includes, inter alia, allergic, immunological or inflammatory diseases or pain. Examples of allergic, immunological or inflammatory diseases which can be treated or prevented using the compounds of the invention include, without limitation: respiratory diseases such as asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD): ocular diseases, such as Allergic rhinoconjunctivitis, dry eye and cataract; skin disease, such as dermatitis (eg atopic dermatitis), psoriasis, urticaria and itching; inflammatory bowel disease, such as ulcerative colitis and Crohn's disease; Rheumatoid arthritis; multiple sclerosis; cutaneous lupus; systemic lupus erythematosus; and transplant rejection. Examples of pain conditions which can be treated or prevented using 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 embodiment, the compounds of the invention are used to treat or prevent allergic, immune or inflammatory diseases. In a more preferred embodiment, the compound of the present invention is for the treatment or prevention of an allergic, immunological or inflammatory disease, which is selected from the group consisting of respiratory diseases, eye diseases, skin diseases, inflammatory bowel diseases, rheumatoid arthritis. Arthritis, multiple sclerosis 'skin lupus, systemic lupus erythematosus and transplant rejection. In a further preferred embodiment, the allergic, immunological or inflammatory disease is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataract, dermatitis. (eg atopic dermatitis), psoriasis, urticaria, itching, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus 'systemic lupus erythematosus and -116 - 201026701 Transplant rejection. In another preferred embodiment, the compounds of the invention are used to treat or prevent pain, preferably inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-operative pain, migraine, cancer pain, visceral pain, bone Arthritis pain or neuropathic pain. Detection of the ability of a compound to interact with a histamine H4 receptor is well known in the art. For example, h4 receptor binding assay can be used, such as g as detailed in Example 59. Another test that can be used is the detection of binding of GTP [r -35s] to membranes exhibiting h4 receptors. Functional assays of h4 receptor-expressing cells can also be used, for example in systems that measure the activity of any kind of cell mediated by a second messenger associated with the η 4 receptor, such as intracellular cAMP levels or Ca2+ Activity. In this regard, selective immunofluorescence forward scatter detection (GAFS) can be used to determine elastin-like white blood cells (eg, human eosinophilic white blood cells) to determine the anti-H4 receptor activity, as in Example 60. Detailed description; this detection is well known to the skilled artisan (see, for example, the method disclosed by Buckland KF et al. 2003, listed in the prior art section above), which is incorporated herein by reference. In vivo assays which can be used to test the activity of the compounds of the invention are also well known in the art (see, for example, the literature cited in the in vivo animal models of the prior art section, especially for peritonitis, pleurisy, allergic asthma, inflammatory bowel disease). In vivo animal models of atopic dermatitis, itching, and pain 'all references are incorporated herein by reference. Selective profiles of the compounds of the invention can be tested using standard histamine receptor binding assays using various histamine receptors, as disclosed in Example 59-117-201026701. Alternatively, to test for selectivity to other receptors or ion channels, the corresponding radioligand replacement assay can be used according to standard procedures documented in the literature (see, for example, the Cerep-Le Bois l'EvSque 2008 catalogue and the Reference material). To test the selectivity of the enzyme, the enzyme activity from the product from which it is formed can be determined. When the active compound is selected, the 10 μΜ test must produce an activity that inhibits the activity of the Η4 receptor by more than 50% in the test provided in Example 59. More preferably, the compound exhibits greater than 50% inhibition at 1 μΜ in this assay, more preferably 0.1 μΜ. The preferred compound should also exhibit strong activity in the GAFS assay of Example 60; preferably, in this assay, the compound should exhibit greater than 50% inhibition at 10 μΜ, more preferably 1 μΜ and even more preferably 0.1 μΜ. Preferred compounds should exhibit a selective affinity for the Η4 receptor over their receptors', particularly η3, toxic assays, adrenaline, dopamine and serotonin receptors. The invention also relates to a pharmaceutical composition comprising a compound of the invention (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients. The excipient must be &quot;acceptable&quot; in terms of being compatible with the other ingredients of the composition and not damaging the subject. The compounds of the present invention can be administered in the form of any pharmaceutical formulation, the properties of which are well known, depending on the nature of the active compound and the route of administration. Any route of administration can be used, such as oral, parenteral, nasal, ocular, topical, and rectal administration. In a preferred embodiment, the compounds of the invention are administered orally. In another embodiment, the compound of the present invention is administered topically -118-201026701 The solid composition for oral administration includes troches, granules and capsules. In either case, the manufacturing process is based on a simple mixture of the active compound and the excipient, dry granulation or wet granulation. Such excipients may be, for example, diluents such as lactose, microcrystalline cellulose, mannitol or dibasic calcium phosphate; binders such as, for example, starch, gelatin or putopurine; disintegrants such as sodium carboxymethyl starch Or croscarmellose sodium; and a lubricant such as, for example, magnesium stearate, stearic acid or talc. Tablets may be additionally coated with suitable excipients by known techniques to delay their disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time, or simply improving their organoleptic properties or their stability. The active compound can also be incorporated by application to the inert particles using a natural or synthetic film coating. It may also be a soft gelatin capsule in which the active compound is mixed with a water or oily vehicle such as coconut oil, mineral oil or olive oil. Powders and granules for preparing an oral suspension by adding water can be obtained by mixing the active compound with a dispersing or wetting agent, a suspension and a preservative. Other excipients such as sweeteners, flavoring agents, and coloring agents may also be added in liquid form for oral administration including inert diluents generally used (such as pure water, ethanol, sorbitol, glycerin, polyethylene glycol). (macr〇g〇ls) and propylene glycol) emulsions, solutions, suspensions, syrups and elixirs. These compositions may also contain adjuvants such as wetting agents, suspending agents, sweetening agents, flavoring agents, preservatives, and buffering agents. The injectable preparation for parenteral administration of the present invention comprises a sterile solution -119 - 201026701, suspension or emulsion in an aqueous or nonaqueous solvent such as propylene glycol, polyethylene glycol or vegetable oil. These compositions may also contain adjuvants such as wetting agents, emulsifying agents, dispersing agents and preservatives. It can be sterilized by any known method or prepared as a sterile solid composition which is dissolved in water or any other sterile injectable medium immediately prior to use. It can also be started from sterile materials and maintained under these conditions throughout the process. The compounds of the invention may also be formulated for topical administration to treat conditions such as the eye, skin and gastrointestinal tract that occur in areas or organs accessible through the path. Formulations include creams, lotions, gels, powders, solutions and dressings in which the compound is dispersed or dissolved in a suitable vehicle. When administered intranasally or by inhalation, the compound can be formulated into an aerosol which can be readily released from the compound using a suitable propellant. Among other factors, the dosage and frequency of administration depend, inter alia, on the nature and severity of the condition to be treated, the age, general condition and weight of the patient, as well as the particular compound being administered and the route of administration. For example, a suitable dosage range is from about 0.01 mg/kg to about 100 mg/kg per amp, in a single or divided dose. [Embodiment] The present invention is illustrated by the following examples. EXAMPLES The following abbreviations are used in the examples: AcN: acetonitrile

Boc: third-butoxycarbonyl-120- 201026701

Cone : Concentration DMAP : 4-dimethylaminopyridine DMF: dimethylformamide

EtOAc: ethyl acetate acetonitrile EtOH: ethanol Η: hour MeOH: methanol Min: minute MS: mass spectrometry

PyBOP: hexafluorophosphate (benzotriazol-1-yloxy)tripyrrolidinium THF: tetrahydrofuran tR: residence time LC/MS: liquid chromatography-mass spectrometry LC-MS spectra were determined using one of the following methods: 1 ·· X-Terra MS C18 column, 5 μιη (100 mm X 2.1 mm) 'Temperature: 30 ° C ' Flow rate: 〇 · 35 mL / min, dissolving agent: A = AcN, B = NH4HC03 10 mM, gradient : 0 min A is 10%; 10 min Α is 90%; 15 min Α is 90%. Method 2: Acquity UPLC BEH C18 1,7 μιη (2.1 x 50 mm) column, temperature · 40 ° C, flow rate: 0.5 0 mL/min, dissolving agent: A = AcN, B = NH4HC03 1 〇 mM, gradient : 0 min A is 10%; 0.25 min A is 10%; 3.00 min A is 90%; 3.75 min A is 90%. -121 - 201026701 Reference Example 1 Methyl [(3/?)-pyrrolidin-3-yl]carbamic acid tert-butyl ester (a) [( 3R ) -1-benzylpyrrolidin-3-yl] A Tert-butyl carbamic acid tert-butyl dicarbonate (1 1.6 g, 53.07 mmol) dissolved in 15 mL of CH 2 C 12 was added to (3 Λ) · benzyl methyl pyrrolidine-3-amine (10 g, 52.55 mmol) in 115 115 mL CH2C12. 〇 Cooled in the solution. The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated, and the crude product was purified eluted eluted eluted eluted eluted eluted eluted with LC-MS (method 1): tR = 9.55 min; m/z = 291 (MH+). (b) the title compound

The compound obtained in the previous step (1 4.5 g, 50. M mmol), Pd/C (10% '50% in water) (3 g) and ammonium formate (12.7 g, 2 00.5 mmol) in MeOH (390 mL) The mixture in water (45 mL) was heated under reflux for 5 h. The reaction was filtered through celite <RTI ID=0.0></RTI> and the filter was washed with EtOAc and MeOH. The solvent was evaporated to dryness to give the title compound (yield: 100%). JH NMR ( 300 MHz, CDC13 ) δ : 1.38 ( s, 9 Η ) , 1.72 ( m, 1 Η ) , 1.96 (m, lH) , 2.53 (s, NH) , 2.80 (s, 3H), 2.87 ( m, 1 H ) , 2.93 (m, lH) &gt; 3.11 ( m, 2H ) , 4.58 ( m, 1 H ). -122-201026701 Reference Example 2 Azetidine azetidine-3-yl(methyl)carbamate (a) [1-(Diphenylmethyl)azetidin-3-yl] Tert-butyl methylate was prepared according to the procedure described in section a) of Example 1, except that 1-(methyl)methylazetidin-3-amine was substituted for (3i?)-1-benzyl-3-pyrrole Pyridin-3-amine gave the desired compound in 73% yield. LC-MS (method 1): mp = EtOAc (m (m (m (m))) Ventilation. Add j (10%, 50% in water) (929 mg), and the solution was stirred for 18 hours in a H2 atmosphere. The reaction was washed with celite and MeOH over celite. The solvent was evaporated to dryness to give a mixture of the title compound and the same equivalent of diphenylmethane, which was used in the next step. 'H NMR (300 MHz, CD3〇D) δ : 1.44 ( s, 9H ) , 2 3H ) &gt; 3.56 ( m, 2H ) &gt; 3.71 ( in, 2H ) &gt; 4.75 ( m, 1 Reference Example 3 a Ethyl 4-cyclobutyl-2,4-dioxybutanoate Addition of cyclobutylmethyl ketone (9.0 g, 91.7 mmol) to ethylaminodiphenyl g Shanjiao at 60 ΙΠ Pd/C Μ Gas filtration and 5.66 g of the original was made into a solution of .88 (s, Η) sodium alkoxide (-123-201026701 29.7 g, 21% in ethanol) in ethanol (7 mL), and the mixture was stirred at room temperature. After 10 min, diethyl oxalate (13.4 g, 91.7 mmol) was added slowly, and the mixture was heated at 6 5 ° C for 4 h. The reaction mixture was evaporated to dryness and diluted with 1 N EtOAc and EtOAc. The EtOAc was re-extracted. The combined organic phase was washed with EtOAc EtOAc EtOAc EtOAcjjjjjjj m/z = 199 ( MH + ). Reference Example 3b 6,6-Dimethyl-2,4-di- oxyheptanoic acid ethyl ester Reference Example 3b was prepared according to the procedure described in Reference Example 3 a, but 4,4-Dimethyl-2-pentanone was used as the starting material. - MS (Method 2) · 'tR = 1.81 min; m/z = 215 (MH+). Reference Example 4a 5 -cyclobutyl-1 Η-pyrazole-3-carboxylate ethyl hydrazine hydrate (2.02 g, 40.3 Methyl) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The filtrate was concentrated to dryness and acetic acid (30 mL) was added to the residue. After heating the mixture at 100 ° C for 8 h, the solvent was evaporated to dryness. The crude product was obtained using a hexane/EtOAc mixture with increasing polarity as a solvent. Purification by chromatography on silica gel afforded 5.72 g of the desired compound -124 - 201026701 (yield: 73%). LC-MS (method 2): tR = 1.82 min; m/z = 195 (MH+) Reference Example 4b 5 - Neopentyl-1 ugly-pyrazole-3-carboxylate Reference Example 4b was prepared according to the procedure similar to Reference Example 4a, but using Reference Column 3b as a starting material. LC-MS (Method 2): tR = 2.〇7 min; m/z = 21 1 (MH+). Reference Example 5 a 5-Cyclobutyl-4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester 65% nitric acid (6 1111 〇 at 〇 ° (: slowly added to concentrated sulfuric acid (23 1111 〇. This nitric acid The sulfuric acid solution was then slowly added to Reference Example 4a (4_0 g, 20.6 mmol) which was previously cooled in an ice bath. The mixture was then allowed to reach room temperature and stirred for 3 hours, then poured onto ice and extracted twice with chloroform. The organic phase was dried with EtOAc (EtOAc) (EtOAcjjjjjjjjj 5 b 5 -Pentyl-4-nitro-17/-pyrazole_3_carboxylic acid ethyl ester Reference Example 5 b was prepared according to the procedure described in Reference Example 5 a, but using reference column 4b as starting material LC-MS (method 2): tR = 2.13 min; 111/2 = 256 (MH+). -125 - 201026701 Reference Example 5 c 5 -cyclobutyl-1-methyl-4-nitro-1// - Pyrazole-3-carboxylic acid ethyl ester Reference Example 5 c was prepared according to the procedure similar to Reference Example 5 a, but using Reference Example 22 as starting material. *H NMR (300 MHz, CDC13) δ: 1.35 (t , 3Η) &gt; 1.9-2.2 ( m, 2H) , 2.3-2.5 (m, 4H) &gt; 3.8 ( m, 1 H &gt; 3.85 ( s, 3H ), 4.4 ( q, 2H ) 〇 Reference Example 6 a 5 -Isopropyl-4·nitro-1H-pyrazole_3_carboxylic acid 65% nitric acid at 60 ° C (6.3 (mL) was slowly added to a solution of 5-isopropyl-1//-pyrazole-3-carboxylic acid (5.0 g, 32.5 mmol) in concentrated sulfuric acid (25 mL), and the mixture was stirred at 60 ° C After 4 hours, it was cooled to room temperature and poured onto ice. The precipitated solid was collected by filtration, washed with water and dried in vacuo to give 5.7 g of the title compound (yield: 95%) 〇LC-MS (method) 2): tR = 0.55 min; m/z = 200 (MH+). Reference Examples 6b to 6c The following compounds were prepared according to the procedure described in Reference Example 6 a 'but using a suitable starting material in place of 5-isopropyl Base-1-pyrazole-3-carboxylic acid: -126- 201026701 Reference example name starting material method (LC-MS) tR(min) m/z (ΜΗ) 6b 4-nitro-5-propyl-1H -pyrazole-3-carboxylic acid 5-propyl-li/-pyridin-3-carboxylic acid ethyl ester 2 0.54 198 6c 5-tris-butyl-4-nitro-17/-pyrazole-3-carboxylic acid ( 1) 5-Tris-butyl-1//-pyridin-3-carboxylic acid ethyl ester 2 0.99 212 (1) The product is isolated as a mixture of ethyl ester and carboxylic acid. It was not precipitated from water and extracted with chloroform. Φ Reference Example 7a 5-Isopropyl-4-nitro-1//-pyrazole-3-carboxylic acid methyl ester Reference Example 6a ( 5.72 g, 31.2 mmol), MeOH (55 mL) and 4 M HCl 1 A mixture of 4-dioxane solution (55 mL) was stirred at 70 &lt;0&gt;C for 7 hr then concentrated to dryness affording 5.9 g of the title compound (yield: 89%). LC-MS (method 2): tR = 1.53 min; m/z = 212 ( ΜΗ '). ® Reference Examples 7b to 7d The following compounds were prepared according to the procedure described in Reference Example 7 a 'but using the appropriate starting materials: -127- 201026701 Reference Example Name Starting Materials Method (LC-MS) tR(min) m/ z (ΜΗ) 7b 4-Nitro-5-propyl-1//-pyridin-3-carboxylic acid methyl ester Reference Example 6b 2 1.61 212 7c 5-Terti-butyl-4-nitro-1// -pyrazole-3-carboxylic acid ethyl ester Reference Example 6c(l) 2 2.01 242 (Μί^) 7d 4-Nitro-1//-pyrazole-3-carboxylic acid ethyl ester 4-nitro-li/-pyrazole 3-carboxylic acid (1) 2 1.02 184 (1) EtOH was used instead of MeOH as a solvent. Reference Example 8a 5-Isopropyl-1-methyl-4-nitro-1//-pyrazole-3-carboxylic acid methyl ester Methyl iodide (2.49 g, 17.5 mmol) was added dropwise at 〇 °C Refer to Example 7a (3.4 g, 15.9 mmol) in a mixture of EtOAc (5. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated, and the residue was diluted with water and diethyl ether. The phases were separated and the aqueous phase was re-extracted with additional ether. The combined organic phase was dried with Na2S〇4 and collapsed to dryness. The crude product obtained was a mixture of two possible isomers and purified by chromatography on a grit, using a mixture of hexane/Et〇Ac with increasing polarity as the dissolving agent. Initially dissolved 1 6 g (yield: 44%) of the isomer '5-isopropyl-2-methyl-7-nitropyrazole-3-carboxylic acid methyl ester, which was later required to be 0.91 g Compound (yield: 25%), LC-MS (Method 2): m.m. Reference Example 8b -128-201026701 1-Methyl-4-nitro-5-propyl_17/•pyrazole-3_carboxylic acid methyl ester Reference Example 8b was prepared according to the procedure similar to Reference Example 8a, but used Reference column 7b is used as the starting material. LC-MS (method 2): tR = 1.91 min; m/z = 228 (MH+) Reference Example 9a 4-Amino-5-isopropyl-indole-methylpyrazole_3_carboxylic acid methyl ester art reference example A solution of 8a (0.9 g, 3.97 mmol) in MeOH (34 mL) was evaporated. 10% Pd/C (90 mg) was added, and the solution was again ventilated with argon and stirred for 5 hours under H2 atmosphere. The reaction was passed through a Celite® and the filter was washed with MeOH. The solvent was evaporated to dryness to give the desired compound (yield: 98%). LC-MS (method 2): tR = 1.16 min; m/z = 198 (MH+). Reference Examples 9b to 9f φ The following compounds were prepared in a similar manner to that described in Reference Example 9 a, except that the appropriate starting material was used instead of Reference Example 8a: -129- 201026701 Reference Example Name Starting Material Method LC-MS) tR(min m/z (M+H+) 9b 4-Aminomethylmethyl-5-propyl-L·?/-pyridin-3-carboxylic acid methyl ester Reference Example 8b 2 1.18 198 9c 4-Amino-5- Isopropyl-1//-pyridin-3-carboxylic acid methyl ester Reference Example 7a 2 1.03 184 9d 4-Amino-5-cyclobutyl-1//-pyridin-3-carboxylic acid ethyl ester Reference Example 5a ( l) 2 1.40 210 9e 4-Amino-li/-Shame-3-carboxylate Reference Example 7d(2) 2 0.61 156 9f 4-Amino-5-cyclobutyl-1-methyl-17/ - Pyrazole-3-carboxylic acid ethyl ester Reference Example 5c (2) (3) (1) EtOH was used instead of MeOH as a solvent. Three hydrogenation cycles are required to complete the reaction. (2) EtOH is used instead of MeOH as solvent. (3) 'H NMR (300 MHz, CDC13) δ: 1.4 (t, 3H) &gt; 1.9-2.2 (m, 2H) &gt; 2.3-2.5 (m, 4H), 3.3 (brs, 2H, NH2) '3.55 (m, lH), 3.75 (s, 3H), 4.4 (q, 2H). Reference Example 1 0 a 4-Amino-5-tertiary-butyl-1//-pyrazole-3-carboxylic acid ethyl ester

A solution of ammonium formate (2.6 g, 41.4 mmol) in water (3 mL). Finally, 10% Pd/C (50% in water) (250 mg) was added and the mixture was then heated to reflux for 3 hours. The reaction was filtered through Celite® and the filter was washed with EtOH. The solvent was evaporated to dryness. The phases were separated and the aqueous phase was re-extracted with additional EtOAc. The combined organic phase was dried over Na2SO4 and concentrated to dryness to afford 3.93 g of desired compound (yield: 9%). -130- 201026701 LC-MS (Method 2): tR = 1.48 min; m/z = 212 (MH+). Reference Example 10b 4-Amino-5-neopentyl-1open-pyrazole-3-carboxylic acid ethyl ester Reference Example 1 Ob was prepared according to the procedure described in Reference Example 1 〇a, but using Reference Column 5b as a starting point Starting material. LC-MS (method 2): tR = 1.67 min; m/z = 226 (MH+). Reference Example 1 1 a 5-Amino-3-isopropyl-2-methyl-2//-pyrazolo[4,3-ίpyrimidin-7-ol The compound obtained in Reference Example 9a (766) Add cyanoguanamine (653 mg, 15.5 mmol) to a solution of 1,4-dioxane (17.5 mL), then slowly add 4 Μ HC1 in 1,4-dioxane (8 mL). The resulting suspension was stirred at room temperature for 2 hours and then refluxed overnight. The solvent was evaporated, 2N aqueous NaOH (30 mL) was then evaporated and evaporated The reaction mixture was allowed to cool to room temperature and the pH was adjusted to 6 to 7 with 2N aqueous HCl. The resulting precipitate was filtered, washed with EtOAc EtOAcjjjjjjj LC-MS (method 2): tR = 0.94 min; m/z = 208 (MH+). Reference Example 1 1 b to 1 1 i The following compounds were prepared in a similar manner to the procedure described in Reference Example 1 1 a, using the appropriate starting materials: -131 - 201026701 Example name starting material method (LC-MS) tR ( Min) m/z (MH+) lib 5-amino-3-isopropyl-2//-pyrazolo[4,3-rf]pyrim-7-ol Reference Example 9c 2 0.70 194 11c 5-Amine Base-2 • Methyl-3 -propyl-2i/_ pyridinium 1 [4,3-ί oxime steep -7-ol Reference Example 9b 2 0.92 208 lid 5-Amino-3-cyclobutyl-2 Open-pyrazolo[4,3-rf]pyrimust-7-ol Reference Example 9d 2 0.87 206 lie 5-Amino-3-decyl-butyl-2//-pyridinium [4,3 -^ pyrimidine-7-ol Reference Example 10a 2 1.07 208 Ilf 5-Amino-3-neopentyl-2//-pyrazolo[4,3-cardyrimidine-7-ol Reference Example 10b 2 1.13 222 Hg 5-Amino-2,3-dimethyl-2i/-pyridox[4,3-ί oxime-s--7-ol 4-amino-1,5-dimethyl-1H-pyridyl Methyl azole-3-carboxylate 2 0.39 180 llh 5-Amino-2//-pyrazolo[4,3d]pyrimidin-7-ol Reference Example 9e 2 0.29 152 lli 5-Amino-3-cyclobutyl -2-methyl-2//-pyrazolo[4,3-c-pyrimidin-7-ol Reference Example 9f 2 1.11 220 Reference Example 1 2 a 1-( 5-Amino-3-isopropyl- 2//-pyrazole [4,3-ί/]pyrimidin-7-yl)azetidin-3-yl(methyl)aminocarbamic acid tert-butyl ester The compound obtained in the title lib (0.75 g, 3.88 mmol) in acetonitrile ( Triethylamine (22.1 mL), PyBOP ( 2.45 g, 4.70 mmol) and Reference Example 2 (2.1 g of a 1:1 mixture with 2.1 g of diphenyl-132 - 201026701 methane) were added to the suspension in 38 mL). 1.08 g of amine, 5.79 mmol). The resulting mixture was heated at 80 ° C overnight. The reaction mixture was concentrated to dryness, and the residue was purified by chromatography on silica gel eluting with hexane/EtO Ac mixture as a solvent to yield 1.4 g of the desired compound (yield · quantitative) ° LC-MS (method 2) : tR = l .61 min; m/z = 362 ( MH+). Reference Example 1 2 b to 1 2 i The following compound was obtained by a procedure similar to that of Reference Example 1 2a, but using the appropriate starting material: -133 - 201026701 Example name starting material method (LC-MS) tR (min m/z (MH+) 12b (8)-1-(5-Amino-3-isopropyl-2H-pyrido[4,3-rf]pyrimidin-7-yl)pyrrolidin-3-yl (Methyl) carbamic acid tert-butyl ester Reference example lib and Reference Example 1 2 1.77 376 12c 1-(5-Amino-3-cyclobutyl-2H-pyrido[4,3^]pyrimidine- 7-based heterocyclic butyl 3-methyl (methyl) carbamic acid tert-butyl ester reference example lid and reference example 2 2 1.67 374 12d (8)-1 -(5-amino-3-cyclobutyl -2//-pyrido[4,3-ί/]pyrimidin-7-yl)pyrrolidin-3-yl(methyl)aminocarbamic acid tert-butyl ester Reference Example lid and Reference Example 1 2 1.80 388 12e 1-(5-Amino-3-tri-butyl-2//-pyrazolo[4,3-c/]pyrimidin-7-yl)azetidin-3-yl (methyl Amino carboxylic acid tert-butyl ester reference example lie and reference example 2 2 1.78 376 12f (7?) small (5-amino-3-second-butyl -2- 2//-pyrazolo[4,3 -rf]pyrimidin-7-yl)pyrrolidin-3-yl(methyl)aminocarbamic acid tert-butyl ester Reference example lie and reference 1 2 1.93 390 12g Η5-Amino-3-neopentyl-2//-pyrazolo[4,3-uracil-7-yl)azetidin-3-yl(methyl)amine Formic acid tert-butyl ester Reference Example Ilf and Reference Example 2 2 1.81 390 12h (8)-1-(5-Amino-3-neopentyl-2//-pyrazolo[4,3d]pyrimidin-7-yl Pyrrolidin-3-yl(methyl)aminocarbamic acid tert-butyl ester Reference Example Ilf and Reference Example 1 2 1.95 404 12i 1 -(5-Amino-2,3-dimethyl-2//- Pyrazolo[4,3, phenanthroline-7-yl-heterocyclobutane--3 (methanosine-tert-butyl ester reference example llg and reference example 2 2 1.56 348 -134- 201026701 Reference Example 1 3 3,3-diphenylpropyl methanesulfonate A sulfonium chloride (2.16 g, 18.8 mmol) was slowly added to 3,3-diphenylpropan-1-ol (4.0 g, 18·8 mmol) And a solution of triethylamine (5.7 g, 5 6.5 mmol) in dichloromethane (18 mL), chilled with ice, then the mixture was warmed to room temperature and stirred overnight. dilution. The phases were separated and the aqueous phase was extracted twice more with dichloromethane. The combined organic phases were dried over Na2SO4 and concentrated to dryness afforded crude material 1H NMR (3 00 MHz, CDC13) δ: 2.53 (m, 2H), 2.91 (s, 3H), 4.13-4.21 (m, 3H), 7.2-7.35 (m, 10H). Reference Example 1 4 4,5,6,7-Tetrahydro[1,2,3]oxadiazolo[3,4ω]pyridine-8-carb-3-olate Concentrated HC1 (6.6 mL, 79.7 mmol) Add to a slurry of 2-piperidinecarboxylic acid (10. 1 g, 76.9 mmol) in water (55 mL). A solution of sodium nitrite (5.88 g, 85.1 mmol) in water (25 mL) was slowly added and the mixture was stirred at room temperature for 3 hr. Dilute with dichloromethane and separate the phases. The aqueous phase was saturated with sodium chloride and extracted twice more with dichloromethane. The combined organic phase was dried over Na 2 SO 4 and concentrated to dryness. The residue was dissolved in diethyl ether (200 mL) by means of ultrasonics and cooled at -5t. Trifluoroacetic anhydride (17.9 g, 85.1 mmol) was added slowly, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated to dryness and the residue was purified by chromatography on silica gel eluting with </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The product was dissolved in water (75 mL) and dichloromethane (75 mL). The combined organic phase was dried in NazSCU and concentrated to dryness to yield 8.81 g of desired compound (yield: 82%). 1H NMR (3 00 MHz, CDC13) δ: 1.95 (m, 2H), 2.14 (m, 2H), 2.54 (bs, lH, OH?), 2.67 (t, 2H, J = 6.3 Hz), 4.28 (t , 2H, J = 6 Hz). Reference Example 1 5 4,5,6,7-tetrahydropyrazolo[,5-α]pyridine-2-ecarboxylate ethyl propionate ethyl ester (2.4 mL, 23.7 mmol) was slowly added to Reference Example 14. (2.99 g, 21.3 mmol) in a solution of xylene (mixture of isomers, 40 mL). The mixture was heated to reflux for 6 hours and the solvent was distilled off. The residue was purified by chromatography on silica gel using hexane/EtO Ac g compound as the eluting solvent, yielding 2.3 g of the desired compound (yield: 5 6%) ° LC-MS (Method 2): tR = 1.63 min; m/z = 195 (MH+). Reference Example 1 6 3-Nitro-4,5,6,7-tetrahydropyrazolo[1,5-α]pyridine-2-carboxylic acid ethyl ester Toluene nitric acid (20 mL) was obtained. (: Slowly added to concentrated sulfuric acid (20 mL). This 5 iao acid-sulfuric acid solution was then slowly added to Reference Example 15 (4.5 g, 23.4 mmol) which was previously cooled in an ice bath. The mixture was then allowed to reach chamber-136. - 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 / EtOAc mixture as a dissolving agent gave 3 · 9 7 g of the desired compound (yield: 70%). LC-MS (Method 2): tR = 1.8 9 min; m/z = 240 (MH+). 1 7 3 -amino- 4,5,6,7-tetrahydroindole-p-[1,5-α]pyrridine-2-carboxylic acid ethyl ester ammonium formate (2.1 g, 33.2 mmol) in water ( The solution in 2.4 mL) was added to a solution of Reference Example 16 (3.97 g, 16.6 mmol) in EtOH (45 mL). Finally, 1% Pd/C (50% in water) (200 mg) was added. It was then heated to reflux for 4 hours. The reaction was passed through a pad of celite, and the filter was washed with EtOH. The solvent was evaporated to dryness and the residue was eluted with hexane/EtOAc mixture as a solvent. Purification by chromatography on EtOAc (EtOAc: EtOAc (EtOAc) 8 2-Amino-7,8,9,10-tetrahydropyrido[1',2':1,5]pyrazolo[4,3-3]pyrimidin-4-ol Prepared in Reference Example 17 Add cyanoguanamine (2 〇 3 g, 48.4 mmol) to a solution of the obtained compound (2.53 mg, m mm 〇l) in 1,4-dioxane (55 mL) and then slowly add 4 Μ H C1 ι, 4 - 2 chewed solution (24 mL). The resulting suspension was stirred at room temperature for 3 hours, then refluxed at -137-201026701 overnight. Evaporate solvent and add 2 N aqueous NaOH (70 mL). The resulting mixture was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature. pH was adjusted to 6 to 7 with aqueous 3N HCl solution. The formed precipitate was collected by filtration, washed with water and then with diethyl ether, and finally under vacuum Drying gave 2.04 g of the title compound (yield: 80%). LC-MS (method 2): tR = 0.59 min; m/z = 206 (MH+). Reference Example 1 9 1-(5-(double- Tris-butoxycarbonylamino)-2,3-dimethyl-2//-pyrazole [4, 3 4]pyrimidin-7-yl)azetidin-3-yl(methyl)carbamic acid tert-butyl ester di-t-butyl ester (2.0 g, 9.2 mmol) 'TEA (0.96 mL) , 6·9 mmol) and DMAP (42 mg, 0.34 mmol) were added to a solution of the title compound 12i (1. g, 2.88 mmol) in THF (11 mL). The resulting solution was stirred overnight at room temperature under argon. The solvent was evaporated and the crude product was purified by chromatography on silica gel using hexane/EtOAc mixture of 0.5% TEA as a solvent to afford the desired compound (yield: 31%). LC-MS (method 2): tR = 2.55 min; m/z = 548 (MH+). Reference Example 2 0 (5-(bis-indolyl-butoxycarbonylamino)-3-(bromomethyl)-2-methyl-2//-pyrazolo[4,3-ί/] Pyrimidin-7-yl)azetidin-3-yl(methyl)aminocarbamic acid tert-butyl ester-138- 201026701 Bromo sulfoximine (32.5 mg, 0.18 mmol) and benzoyl peroxide (2.3 mg, 0.009 mmol) was added to a mixture of methylene chloride (2.5 mL) and chloroform (0.5 mL). The mixture was heated at 90 ° C for 3 h under argon and then cooled to room temperature. The reaction mixture was then diluted with chloroform and washed twice with a saturated NaHC03 solution. The organic phase was dried over Na 2 SO 4 and concentrated to dry. The residue was purified by chromatography on silica gel eluting with EtOAc/EtOAc. *H NMR ( 3 00 MHz, CDC13) δ : 1.42 ( s, 9 Η) &gt; 1.45( s, 9 Η) , 1.48 ( s, 9 Η) &gt; 2.98 ( s, 3 Η ) , 4.16 ( s, 3 Η) , 4.3-4.7 ( m,4 Η ) - 5.2 ( br s, 1 H ) - 4.84 ( s, 2 H ) Reference Example 2 1 (i?) -1-methylpyrrolidine-3-amine II Hydrochloride (a) ( Λ ) -1-methylpyrrolidin-3-ylaminocarbamic acid tert-butyl ester 37% aqueous solution of formaldehyde (1.19 mL, 14.6 mmol) and (subsequent and gradually) sodium borohydride (0.61 g, 16·1 mmol) was added to a solution of &lt;RTI ID=0.0&gt;&gt; The resulting mixture was stirred at room temperature under argon overnight. The solvent was evaporated and the crude was dissolved in CH.sub.3 and washed with brine then washed with sat. The organic phase was dried over Na.sub.2SO.sub.sub.ssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss ( m, 1H ) &gt; 2.25 ( m, 2H ) &gt; 2.33 ( s, 3H ) , 2.52 (m, 2H) ' 2.77 (m, lH) &gt; 4.16 ( m, 1H ) , 4.86 (m, NH) (b) A mixture of the title compound (0.85 g, 4.25 mmol), EtOAc (EtOAc) (EtOAc) 1 hour. It is then evaporated to dryness. The crude product was dissolved in MeOH EtOAc (EtOAc) *H NMR ( 3 00 MHz, CD3〇D) δ : 2.15 ( m, 1 Η ) , 2.55 ( m,lH) , 2.91 (s, 3Η) ' 3. 1 5 ( m, 1H ) , 3.3-3.85 ( m, 3H ) - 4.10 ( m, 1H ). Reference Example 2 2 5 -Cyclobutyl-1-methyl-1//- thiazol-3-carboxylate ethyl ester methyl hydrazine (70 mg, 1.5 mmol) was added to Reference Example 3a (0.3 g, 1.5 mmol) A solution in acetic acid (2 mL). The resulting solution was heated in a sealed tube at 10 ° C for 3 h. The solvent was evaporated, toluene was added, and the mixture was again concentrated to dryness. The crude product obtained was purified by chromatography on EtOAc EtOAc (EtOAc:EtOAc: LC-MS (method 2): tR = 1.92 min; m/z = 209 (MH+). -140-201026701 Reference Example 23a 1-( 5-Amino-2//-pyrazolo[4U]pyrimidin-7-yl)azetidin-3-yl(methyl)aminocarboxylic acid Third - Butyl ester followed the procedure described in Reference Example 1 2 a, but using Reference Example 1 1 h and Reference Example 2 as starting materials, and the crude compound was purified by reverse phase chromatography using a mixture of increasing polarity of water/acetonitrile as the dissolution. To give the title compound. 0LC-MS (Method 2): tR=l.37 min; m/z = 320 (MH+). Reference Example 23b 1-(5-Amino-2/ί-pyrazolo[4,3-ί/]pyrimidin-7-yl)pyrrolidine-(3Λ)-3-yl(methyl)aminocarbamic acid Tri-butyl ester Reference Example 23b was prepared according to the procedure similar to Reference Example 23a, but using Reference Column 1 1 h and Reference Example 1 as starting materials. LC-MS (method 2): tR = 1 - 52 min; m/z = 3 34 (MH+). Reference Example 24 4-ethylguanidinium phenylethyl sulfonate was similar to the procedure described in Reference Example 13 except that #-(4-(2-hydroxyethyl)phenyl)acetamide was used as a starting material. , the title compound was obtained. LC-MS (Method 2): χκ~\ .21 min; m/z = 258 (MH+). Example 1 3-isopropyl-2·methyl-7-((3Λ)-3-(methylamino)pyrrolidin-1-yl-141 - 201026701 )-2H-pyrazolo[4,3 -rf]pyrimidine-5-amine

Triethylamine (4.4 mL), PyBOP (0·49 g, 0.94 mmol) and Reference Example 1 (0.24 g) were added to a suspension of the compound obtained in Example 11a (0.15 g, 0.72 mmol) in acetonitrile (8 mL). , 1 · 16 mmol ). The resulting mixture was heated at 80 ° C overnight. The reaction mixture was concentrated to dryness. EtOAc EtOAc m. The aqueous phase was re-extracted with EtOAc and the combined organics dried with Na.s. To this intermediate was added HCl (4 Μ solution in 1,4-dioxane, 5 mL) and 1,4-dioxane (20 mL), and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated to dryness. The residue was dissolved in water and washed twice with EtOAc &lt The 1 N NaOH solution was added to the acidic aqueous phase until basic pH and extracted three times with chloroform. The combined organic phases were dried over anhydrous Na 2 SO 4 and concentrated to dryness. The obtained crude product was purified by chromatography eluting with EtOAc/EtOAc/EtOAc. LC-MS (method 2): tR = 1-19 min; m/z = 290 (MH+). Examples 2 to 7 The following compounds were prepared in a similar manner to that described in Example 1 'but using the appropriate starting materials: -142- 201026701 Example Name Starting Materials Method (LC-MS) tR(min) m/z ( MH+) 2 3-isopropyl-2-methyl-7-(3-(methylamino Cyclobutane-1-yl)-2H-赃 beer also [4,3-ί/]pyrimidine-5 -Amine Reference Example 11a and Reference Example 2 2 1.13 276 3 7-(3-Aminoazetidin-buyl)-3-isopropyl-2-methyl-2/ί-pyrazole[4 , 3W]pyrimidine D--5-amine Reference Example 11a and azetidine azetidine-3-ylaminocarbamate 2 0.97 262 4 7-((3i?)-3-Aminopyrrole D- 1-yl)-3-isopropyl-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-5-amine Reference Example 11a and [(3Λ)-pyrrolidin-3-yl] Aminobutyric acid tert-butyl ester 2 1.05 276 5 2-methyl-7-(3-(methylamino)azetidin-1-yl)-3-propyl-2//-pyridinium And [4,3-rf]pyrimust_5_amine reference example lie and reference example 2 2 1.13 276 6 2-methyl-7-((3/?)-3-(methylamino)D ICP Steep-1 -yl)-3-propyl-2//_ pyridyl lung "4,3W]pyrimidine-5-amine reference example lie and reference example 1 2 1.22 290 7 2,3-dimethyl-7- (3-(methylamino) nitrogen Cyclobutan-1-yl)-2-pyrazolo[4,3-ί/]pyrimidine-5-amine Reference Example 11g and Reference Example 2 2 0.75 248 Example 8 3-Isopropyl-7 -(3-(Methylamino)azetidin-1-yl)-2//-pyrazolo[4,3]pyrimidin-5-amine and HCl (in 1,4-dioxane) 4 Μ solution, 1 mL), 1,4-dioxane (1 〇m L ) was added to Reference Example 1 2 a, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to dryness. Wash twice with EtOAc and discard the EtOAc. Add 1 N NaOH solution to the acidic aqueous phase until -143-201026701 basic pH, and evaporated to dryness. The solid was concentrated to dryness. The crude product was purified using EtOAc/EtOAc/EtOAc. LC-MS (Method 2) · tR = 0.88 min'· m/z = 262 (MH+). Examples 9 to 15 The following compounds were prepared according to the procedure described in Example 8, but using the appropriate starting substance:

-144- 201026701 Example name Starting material method (LC-MS) tR(min) m/z (MH+) 9 3-isopropyl-7-((3i?)-3-(methylamino)pyrrole Pyridin-1-yl)-2H-pyrazolo[4,3-ί/]pyrimidine-5-amine Reference Example 12b 2 0.94 276 10 3-Cyclobutyl-7-(3-(methylamino)nitrogen Heterocyclobutane-1-yl)-bizozolo[4,3d]pyrimidin-5-amine Reference Example 12c 2 0.95 274 11 3-Cyclobutyl-7-((3Λ)-3-(methyl Amino)pyrrolidinyl)-2//-pyrazolo[4,3-^]pyrimidine-5-amine Reference Example 12d 2 0.98 288 12 3-Terve-butyl-7-(3-(A Aminoamino)azetidin-1-yl)-2^-pyrazolo[4,3-rf]pyrimidin-5-amine Reference Example 12e 2 1.08 276 13 3-second"-7-( (3Λ)-3-(Methylamino)pyrrolidin-1-yl)-2open·pyrazolo[4,3-cardyrimidine-5-amine Reference Example 12f 2 1.08 290 14 7-(3-( Methylamino)azetidin-1-yl)-3-neopentyl-2//-pyrazolo[4,3-ίpyrimidine-5-amine Reference Example 12g 2 1.17 290 15 7- ((3/?)-3-(methylamino) Π疋 Π疋_1_yl)-3-neopentyl 哩[4,3d]pyrimidine-5-amine Reference Example 12h 2 1.22 304 Implementation Example 1 6 2 -ethyl-3-isopropyl-7-((3Λ)-3-(methylamino)pyridinium Acridine-i-yl)-2H-pyrazolo[4,3-c/]pyrimidine-5-amine 0.8 a) (and)-1-(5-amino-2-ethyl-3-isopropyl - 2//-(]Bizozolo[4,3-d]啼 steep-7-yl)p-pyrrol-3-yl(methyl)aminocarbamic acid third_butane vinegar sodium hydride (34.9 mg For 55% dispersion in mineral oil, -145- 201026701 mmol), slowly add to Reference Example 12b (300 mg, 0.8 mmol) in DMF (15 mL) in a solution previously cooled at 0 ° C. After stirring for 20 min', ethyl iodide (99.7 mg, 0.64 mmol) was added dropwise, then allowed to warm to room temperature and stirred for 1 hour. The reaction was terminated and the solvent was distilled off by adding a few drops of water. Purification by chromatography on silica gel using the increasing polarity of EtOAc/MeOH mixture as the eluent to give 193 mg of the desired compound (yield: 60%) LC-MS (Method 2): tR = 2.29 min; m/z = 404 ( MH+). b) The title compound (a·19 g, 〇·48 mmol), 1,4-dioxane (20 mL) and 4 M HCl in 1,4-dioxane (2 mL) The mixture was stirred at room temperature for 2 hours and then concentrated to dryness. The residue was dissolved in water, washed with EtOAc EtOAc. The 1 N NaOH solution was added to the acidic aqueous phase until basic pH and extracted three times with chloroform. The combined organic phase was dried over anhydrous Na 2 SO 4 to concentrate to dryness. The obtained crude product was purified by chromatography eluting with EtOAc (EtOAc) LC-MS (Method 2) ·· t R = 1. 3 7 min ; m/z = 3 04 ( MH+ ). EXAMPLES 7 to 3 5 The following compounds were prepared in a similar manner to that described in Example 16., using the appropriate starting material: -146 - 201026701 Example name starting material method (LC-MS) tR (min) mlz (MH+) 17 2-ethyl-3-isopropyl-7-(3-(methylamino)heterocyclobutane-1-yl)-2-pi-pyrene and "4,3-3]pyrimidine Steep-5-amine Reference Example 12a and Ethyl iodide 2.29 290 18 3-Cyclobutyl-2-methyl-7-(3-(methylamino)azetidin-1-yl)-2 //-pyrazolo[4,3-ί/]pyrimidine-5-amine Reference Example 12c and methyl iodide 2 1.21 288 19 3-Cyclobutyl-2-ethyl-7-(3-(methylamine) (Heterocyclobutane-1-yl)-2//-pyridox[4,3-cardyrimidine-5-amine Reference Example 12c and Ethyl iodide 2.39 302 20 3-Cyclobutyl-2-methyl Benzyl-7-((3i?)-3-(methylamino)pyrrolidine small group)-2//-pyrypin #"4,3-rf]pyrimidine-5-amine Reference Example 12d and methyl Iodine 2 1.24 302 21 3-Cyclobutyl-2-ethyl-7-((3i?)-3-(methylamino)pyrrolidin-1-yl)-2i/-pyridinium and "4,3 -ί/]pyrimidine-5-amine reference example 12d and ethyl iodide 2 1.41 316 22 3-tris-butyl-2-methyl-7-(3-(methylamino)azetidine Alkan-1-yl)-2//-pyridinium [4,3-3 Pyrimidine-5-amine Reference Example 12e and methyl iodide 2 1.31 290 23 3-Terti-butyl-2-ethyl-7-(3-(methylaminoindolebutan-1-yl)- 2//-pyrazolo[4,3-ίpyrimidine-5-amine Reference Example 12e and Ethyl iodide 2.47 304 24 3-T-butyl-2-methyl-7-((3i?) -3-(Methylamino)pyrrole-1-yl)-2//-pyridox[4,3-peptazur-5-amine Reference Example 12f and methyl iodide (1) 2 1.37 304 24b 3 -Third-butyl-1-methyl-7-((3 magic-3-(methylamino)-p-tau-1-yl)-1//-pyrazolo[4,3-^? Pyrimidine-5-amine reference example 12f and methyl Yao (1) 2 1.44 304 -147- 201026701 25 3-tert-butyl-2-ethyl-Τα〗 External 3-(methylamino)pyrrolidine-1 -yl)-2//-pyrazolo(4,3-c/J pyrimidine-5-amine Reference Example 12f and ethyl iodide (1) 2 1.49 318 25b 3-Terti-butyl-1-ethyl- 7-((3i?)-3-(Methylamino)pyrrole D-1,4-yl)-1//-pyrazolo[4,3-c pyrimidin-5-amine Reference Example 12f and Ethyl Iodine (1) 2 1.59 318 26 2-methyl-7-(3-(methylamino)azetidin-1 -yl)-3-neopentyl 2//-pyrazolo[4, 3-ί pyrimidin-5-amine Reference Example 12g and methyl iodide 2. 1.37 304 27 2-ethyl-7-(3-(methylamino)nitrogen环丁院-1 -yl)-3-neopentyl 2//-pyrazolo[4,3-cardyrimidine-5-amine Reference Example 12g and Ethyl iodide 2 1.55 318 28 2-methyl-7 -((3i?)-3-(methylamino)-portion ratio slightly de-form-1-yl)-3_neopentyl-2//-pyrazolo[4,3d]pyrimidin-5- Amine Reference Example 12h and methyl iodide 2 1.41 318 29 3-isopropyl-7-(3-(methylamino)azetidin-1-yl)-2-propyl-2 ugly-pyrazole And [4,3d]pyrimidine-5-amine Reference Example 12a and propyl iodide 2.48 304 30 2,3-diisopropyl-7-(3-(methylamino)azetidin-1- -2H-pyridox[4,3-^pyrimust-5-amine reference example 12a and isopropyl iodide (2) 2 1.54 304 30b 1,3-diisopropyl-7-(3- (Methylamino)azetidinyl)pyridinium[4,3d]pyrimidine-5-amine Reference Example 12a and isopropyl iodide (2) 2 1.60 304 31 3-isopropyl-7 -((3i?)-3-(methylamino) striata-1 -yl)-2-propyl-2-pyrazole[4,34]pyrim-5-amine Reference Example 12b and C Base iodine 2 1.55 318 -148- 201026701 32 3-isopropyl-7-((3i?)-3-(methylamino) mouth ratio slightly steep-1 -yl)-2-phenylethyl· 2/ /-pyrazolo[4,3-ί/]pyrimidine-5-amine Reference Example 12b and phenylethyl bromide 2.79 33 2-(3,3-__•Phenylpropyl)-3-isopropyl-7-((3/?)-3-(methylamino)pyrrolidin-1-yl)-2// -pyrazolo[4,3-J]pyrimidine-5-amine Reference Example 12b and Reference Example 13 2 2.27 470 34 5-(5-Amino-3-isopropyl-7-((3Λ)-3- (Methylamino)pyrrolidin-1-yl)-27/-pyrazolo[4,3-Phenylpyrimidine-2-yl)pentanoic acid ethyl ester Reference Example 12b and 5-bromopentanoic acid ethyl ester 2 1.64 404 35 3-isopropyl-2-(2-methoxyethyl)-7-((3Λ)-3-(methylamino)0-pyridin-1-yl)-2//- Pyrazolo[4,3-d]pyrimidin-5-amine Reference Example 12b and 1-bromo-2-methoxyethane 2 1.20 334 (1 ) 'Form two possible N in the alkylation reaction - Alkyl-pyrazole isomers. It was isolated by preparative HPLC after de Boc protection. (2) In the alkylation reaction, two possible N-alkyl-pyrazole meta isomers are formed. It is separated by column chromatography. The two Boc-protected N-alkyl-pyrazole sites are separately deprotected from the isomer system.

Example 3 6 5-(5-Amino-3-isopropyl-7-((3Λ)-3-(methylamino)pyrrolidin-1-yl)-27/-pyrazolo[4, 3-rf]pyrimidin-2-yl)pentanoic acid, lithium salt, lithium hydroxide monohydrate (1.58 mg, 0.04 mmol) was added to Example 34 (6.9 mg, 0_0 mmol) in THF (0.17 mL) and water ( In a solution of 0·1 7 mL), it was stirred overnight at room temperature. The volatiles are evaporated to dryness to give the title compound as a lithium salt as a quantitative yield. LC-MS (method 2): tR = 0.85 min; m/z = 376 (MH+). -149-201026701 Example 3 7 4-[(3/〇-3-(Methylamino)D-pyrrolidine-1-yl]-7,8,9,10-tetrahydropyrido[1, , 2, : 1,5]pyrazolo[4,3_ii]pyrimidine-2-amine

Triethylamine (43 mL), pyBOP (5.95 g, 11.4 mmol) and Reference Example 1 (2.82 g) were added to a suspension of the compound obtained in Example 18 (丨·81 g, 8.79 mmol) in acetonitrile (64.5 mL). , 14.1 mmol). The resulting mixture was heated overnight at 80 °. Additional Reference Example 1 (1·41 g, 7.04 mmol) and PyBOP (3 g, 5.76 mmo1)' mixture were added and heated at 80 °C for an additional 24 hours. The reaction mixture was concentrated to dry <RTI ID=0.0></RTI> <RTI ID=0.0> The aqueous phase was re-extracted with EtOAc. The residue was purified by chromatography on silica gel using an increasing polarity hexane / EtOAc mixture as a solvent to afford intermediate intermediates. To the intermediate was added HCl (4 Μ solution in 1,4-dioxane, 30 mL) and EtOH (15 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated to dryness. The residue was dissolved in water, washed with EtOAc EtOAc. The 1 N NaOH solution was added to the acidic aqueous phase until basic pH and extracted three times with chloroform. The combined organic phases were dried over anhydrous Na 2 SO 4 and concentrated to dryness. The crude product thus obtained was purified by chromatography on silica gel using a mixture of chloroform/MeOH/concentrated NH3 with increasing polarity as a dissolving agent, followed by further purification by neutral oxidative gel chromatography using EtOAc/MeOH with increasing polarity. / Concentrated NH3 as a dissolving agent provided 607 mg of the title compound (yield: 24%). LC-MS (method 2): tR = 0.97 min; m/z = 288 (MH+). -150-201026701 Examples 38 to 40 The following compounds were prepared in a similar manner to that described in Example 37, using the appropriate starting materials: Example name starting material method (LC-MS) tR (min) m/z ( MH+) 38 4-[3-(Methylamino)azetidin-1-yl]-7,8,9,10-tetrahydropyrido[1',2':1,5]pyridinium And [4,3-rf]pyrimidin-2-amine Reference Example 18 and Reference Example 2 2 0.95 274 39 4-[(3Λ)-3-Aminopyridinium is slightly steeper-1-yl]-7,8,9 , 10-tetrahydropyrazine and [1,2': 1,5]pyrazolo(4,3-...pyrimidine-2-amine Reference Example 18 and [(3Λ)-pyrrolidin-3-yl]amine Formic acid third-butyl ester 2 0.93 274 40 4-(piperazin-1 -yl)-7,8,9,10-tetrahydropyrido[1',2':1,5]pyrazolo[4 3-cpyrimidin-2-amine Reference Example 18 and piperazine-1-carboxylic acid tert-butyl ester 2 0.93 274 Example 4 1 7-(3-(methylamino)azetidin-1- The title compound was synthesized according to the procedure described in Example 1, but using Reference Examples 11h and 2 as starting materials. LC-MS (method 2) : tR = 〇. 3 9 min ; m/z = 22 0 ( MH+). Example 42 3-(Methoxymethyl)-2-methyl-7-(3-(methylamino)azetidin-151 - 201026701 alk-1-yl)-2//-pyrazole And [4,3-ί/]pyrimidine-5-amine is heated to a mixture of Reference Example 20 (27 mg, 0.04 mmol) and sodium methoxide (0.5 mL of 25% w/w MeOH) in MeOH (1 mL) The mixture was refluxed overnight. The reaction mixture was dried with water, pH was adjusted to 8 with EtOAc, and then extracted with chloroform three times. The combined organic phase was dried over anhydrous Na2SO4 and concentrated to dryness. -MS purification (method: XBridge Prep Cl 8 ( 5μηι ) OBD 19x100 mm column, flow rate: 20 mL/min, eluent: A = AcN, B = NH4HC〇3 7 5 mM, gradient: 0 min a is 10% ; 1.00 min a is 10%; 8.00 min A is 80%) and the product-containing fraction is concentrated to dryness to provide 1.37 mg of the title compound (yield: 12%) LC-MS (Method 2): tR = 0.84 min; m/z = 27 8 (MH+). Example 43 7-(3-(Methylamino)azetidin-1-yl)-2-phenylethyl-2//-pyrazole [4,3-rf]pyrimidin-5-amine

Sodium hydride (41 mg in 55% dispersion in mineral oil, 0.94 mmol) was carefully added to a solution of Reference Example 23a (200 mg, 0.63 mmol) in DMF (3 mL). The mixture was stirred at room temperature for 15 min and then phenethyl bromide (1 16 mg, 0.63 mmol). It was then allowed to warm to room temperature and stirred overnight. The reaction was stopped by adding a few drops of water and then concentrated to dryness. The residue was diluted with water and chloroform. The phases were separated and the organic phase was washed with 1 N EtOAc. The crude product obtained was purified by chromatography on silica gel eluting with EtOAc/MeOH </ </ </ </ </ </ To the solution was added 3), the reaction mixture was stirred at room temperature for 3 hr and then the mixture was dissolved in MeOH (4.5 mL). The hydrazine was then filtered and the MeOH was discarded. The solution containing the immobilized product NH3 in MeOH was stirred for 15 min and evaporated to dryness to give 3 8.9 mg of the title compound (yield LC-MS (method 2): tr = 1.4 2 min; m/z = 3 24 (Example 4 4 to 5 5 The following compounds were prepared according to procedures similar to those described in Example 43: ❿ Precursor. _ acetic acid (2 mL to dryness. Residue (50Wx2, 100, MeOH) The washing is followed by filtration with 2 N. Filtration: 20%) 0 MH+ ). Obtained, but using -153 201026701 Example name Starting material method (LC-MS) tR(min) m/z (MH+ 44 2-(cyclopropylmethyl)-7-(3-(methylamino)azetidinyl)-2-pyrido[4,3-rf]pyrimidine D-5 -Amine Reference Example 23a and (Bromomethine 2 1.10 274 45 2-benzyl-7-(3-(methylamino)azetidinyl)-2H-pyrazolo[4,3 -c-pyridyl-5-amine Reference Example 23a and benzyl bromide 2. 1.34 310 46 7-(3-(Methylamino)azetidin-1-yl)-2-(3-phenylpropane Base)-2//-pyrazolo[4,3-cardyrimidine-5-amine Reference Example 23a and 1-bromo-3-phenylpropane 2 1.57 338 47 7-(3-(methylamino)nitrogen Heterocyclobutane-1-yl)-2-pentyl-2i/- Pyrazolo[4,3-rf]-but-5-amine Reference Example 23a and 1-chloropentane 2 1.44 290 48 #-(4-(2-(5-Amino-7-(3-(A) Aminoamino)azetidin-1-yl)-2//-pyrazolo[4,3-pyrimidin-2-yl)ethyl)phenyl)acetamide Reference Example 23a and Reference Example 24 2 1.10 381 49 2-(2-Ethoxyethyl)-7-(3-(methylamino)azetidin-1-yl)-2H-pyrazolo[4,3-ί/ Pyrimidine-5-amine reference example 23a and 1-bromo-2-ethoxyethane 2 0.99 292 50 2-isopentyl-7-(3-(methylamino)azetidin-1 -yl)-2//-pyrazolo[4,3-c/]pyrimidin-5-amine Reference Example 23a and 1-bromo-3-methylbutane 2 1.43 290 51 2-(2-ring Hexylethyl)-7-(3-(methylamino)azetidinyl)· 2//-pyrazolo[4,3-c pyrimidine-5-amine Reference Example 23a and 1- Bromo-2-cyclohexylethane 2 1.77 330 52 7-((3/?)-3-(methylamino)pyrrolidin-1 -yl&gt;2-phenylethyl-2//-pyrazole [4,3-ί/]pyrimidine-5-amine Reference Example 23b and phenylethyl bromide 2 1.46 338 -154- 201026701 53 7-((3 Magic-3-(methylamino)pyrrole-1 -yl )-2-(3-propenylpropyl)· 2//-pyrazolo[4,3-cardyrimidine-5-amine Reference Example 23b and 1-bromo-3-benzene Propane 2 1.66 352 54 7-((3;?)-3-(methylamino)pyrrolidin-1 -yl)-2-pentyl-2//-pyrazolo[4,3-d]pyrimidine H-Conden-5-amine Reference Example 23b and 1-Chlorine Institute 2 1.54 304 55 2-Phase-7-((3/?)-3-(Methylamino)pyrrolidin-1-yl)-2H -pyrazolo[4,3-ί〇dark-5-amine Reference Example 23b and Benzyl bromide 2 1.38 324 Example 5 6 to 5 8 The following compounds were prepared according to the procedure described in Example 1, but suitably used Starting material: Example name Starting material method (LC-MS) tR(min) m/z 56 7-((3Λ)-3-Aminopyrrolidin-1-yl)-3-cyclobutyl- 2-Methyl-2//-pyrazolo[4,3-rf]cand-5-amine Reference Example Chuan and [(3R)-pyrrolidin-3-yl]carbamic acid tert-butyl ester 2 1.15 288 57 7--3-Aaminopyrrolidinyl)-2-methyl-3-propyl-2//-pyrazolo[4,3W] Chelate D--5-amine Reference Example 11c [(3R)-Pyrrolidin-3-yl]carbamic acid tert-butyl ester 2 1.09 276 58 3-isopropyl-#7-(l-methylpyrrolidine-(3/0-3-yl) -2//-pyrazolo[4,3-c pyrimidine-5,7-diamine reference example lib and reference example 21(1) 2 1------ 0.92 276 (1) omission of HC1 The final place of the 1,4-dioxane solution . Example 5 9 Competitive binding assay of [3H]-histamine to human histamine H4 receptor - 155 - 201026701 To perform binding assay, cell membrane prepared using a stable CHO recombinant cell line derived from the expression human histamine H4 receptor Extract (Euroscreen/Perkin-Elmer) The compound to be tested is 1 〇nM [ 3H ]-histamine and 15 cell membrane extract at a selected concentration in a total volume of 250 μί 50 mM Tris-HCl, pH 7.4, 1.25 mM EDTA was incubated in duplicate at 60 °C for 60 minutes. Non-specific binding was defined in the presence of 100 μΜ unlabeled histamine. The reaction was terminated by filtration using a vacuum collector (Multiscreen Millipore) in a 96-well plate (Multiscreen HTS Millipore) which had been previously immersed in a 0.5% polyethylenimine solution for 2 hours at 〇 °C. The plate was then washed with 50 mM Tris (pH 7.4), 1 · 25 mM EDTA at 〇 ° C, and the filter was dried at 50 to 60 ° C for 1 hour, after which a scintillation counting liquid was added to use a yS plate scintillation counter. The combined radioactivity was determined. The compounds of Examples 1 to 58 were assayed in this assay and showed greater than 50% inhibition of binding to human histamine receptor H4 at 1 〇 μΜ. The compounds of Examples 1 to 58 (except 3, 25b, 3 Ob and 36) further showed greater than 50% inhibition of binding to human histamine receptor H4 at 1 μΜ. Example 6 0 histamine-induced shape change detection of human eosinophils (selective control spontaneous fluorescence forward scattering detection, GAFS) In this test, human hemoglobin-induced white blood cells induced by histamine were measured by flow cytometry. Shape changes, detected by an increase in cell size (-156-201026701 forward scattering, FSC). Polymorphonuclear leukocytes (PMNL, part of neutrophils and eosinophils) are prepared from whole blood of healthy human volunteers. Briefly, 'Red blood cells are prepared by sedimentation in 1.2% dextrin (SIGMA), and the leukocyte-rich fraction (PMNL) is isolated from the top layer by centrifugation at 450 g for 20 minutes in the presence of Ficoll-Paque® (Biochrom). ). PMNL was resuspended in PBS buffer at a concentration of l.lxlO6 cells/ml/tube, pretreated with different concentrations of test compound (dissolved in PBS) for 30 minutes at 37 °C, followed by 3 000 nM histamine ( Fluka) stimuli for 5 minutes. Finally, triacetal (final concentration of 1% in PBS) was added to stop the reaction and maintain the cell shape. Cell shape changes were analyzed by flow cytometry (FACS Calibur, BD Biosystems). The eosinophilic blood cell line in PMNL is selected based on its higher spontaneous fluorescence relative to neutrophils (fluorescent channel FL2). Cell shape changes are detected by a forward scatter signal (FSC). The results are expressed as a percentage change in the test compound induced by histamine at each concentration. In this test, Examples 1, 2, 4 to 8, 10, 12 to 14, 16 to 24, 24b '25, 26 to 30, 31, 32, 34, 37 to 47, 49, 50, 52, 53 and A compound of 56 to 58 which produces greater than 50% inhibition of histamine-induced changes in human eosinophilic white blood cell shape at 1 μΜ. •157-

Claims (1)

201026701 VII. Patent application scope: Among them: Rl and R2 together with the key it! ^Atoms together form a saturated heterocyclic group selected from: (I) a heterocyclic group containing 2 N atoms and free of any other hetero atom, wherein the heterocyclic group can be optionally subjected to one or a plurality of Cl4 alkyl groups; and (II) a heterocyclic group containing 1 N atom and free of any other hetero atom, wherein the heterocyclic group is substituted by a -NRaRb group and optionally Substituted by one or more Ci 4 alkyl groups; /, the heterocyclic groups (i) and (H) may be 4_ to 7_membered monocyclic, 7_ to 8_membered bridged bicyclic or 8- To I2-membered fused bicyclic ring; or Ri represents hydrazine or alkyl, and r2 represents azetidinyl, masculine, piperidinyl or azepanyl, which may optionally be passed through a Or a plurality of C 1-4 alkyl substitutions; Ra represents hydrazine or Cb 4 alkyl; Rb represents hydrazine or Cl 4 alkyl; or Ra and Rb together with the N atom to which they are bonded form azetidinyl -158- .201026701, pyrrolidinyl, piperidinyl or azepanyl, which may be optionally substituted by one or more alkyl; means hydrazine or NH2; R5 may be located in the pyrazole ring of n1 or N2 ; when h is attached to N1 Or R4 represents R6 and R5 represents R7' or R4 represents R7 and R5 represents R8, or R4 and R5 may be bonded to form -c3_5 alkylene, which may optionally be via - or multiple Cl_8 Alkyl &amp;substituted; when Rs is attached to N2, R4 represents R6 and R5 represents R7; R6 represents hydrazine, Chn alkyl, C3.8 cycloalkyl-Co-H alkyl 'C3_8 Ring-based base - C〇.ii alkyl, aryl-Cni alkyl, heteroaryl-Cm alkyl, aryl-NH-CQ.n alkyl, heteroaryl-NH-Co-h alkyl, L -Cm alkyl or Rm-W-Co.h alkyl; represents η, C 6 alkyl, C 3 8 cycloalkyl _Cq_6 alkyl, Cl 6 alkoxy-Ch alkyl or (C38 cycloalkyl _C &lt;;).6 alkyl)-〇-Cl_6 alkyl; φ R8 represents C3-8 cycloalkyl-Co-H alkyl, C3-8 heterocycloalkyl-Co-H alkyl, aryl-Cq- h alkyl, heteroaryl-Cq.h alkyl, aryl-NH-C2_n, heteroaryl-NH-C2-nalkyl, R9-C2-nalkyl or R^-W-Clh alkane R9 is a representation of -CONR, 1 Ri 1, -NRhCORh, -NRi , SO2R11, -SOzNRj jR, j , -NR, 1CONR1 1R1 1 ' -C0NHS02Rii ' -CO2R1 1 , -S〇2R&quot;, _NR&quot;R&quot; Or 1//-tetrazol-5-yl; Rl 〇 表 T T; H, Ci.11 Base, Rii-0-Ci.ii Institute base. C3-8 ring yard base _ C〇-H alkyl group, C3-8 heterocycloalkyl-CG-U alkyl group, aryl-Co-H alkyl group, - 159- 201026701 Heteroaryl-CVl1 alkyl, aryl-NH-Cm alkyl, heteroaryl-NH-C2-n alkyl or IU-Ci·decyl; H, C!.6, C3.8 ring-yard base - C〇-6 or aryl-C〇-6 alkyl; W series means 0, s, 5〇 or s〇2; wherein in r8 and rig, any alkyl Each of which may be optionally substituted by - or more than H, and any of the cycloalkyl and heterocycloalkyl groups may be optionally substituted with a substituent independently selected from the group consisting of: Cl-6 alkyl, halogen, aryl and The base system represents a phenyl group optionally substituted by one or more R丨2; the heterocyclic group represents an aromatic 5- or 6-membered monocyclic ring or an 8- to 12-membered bicyclic ring, and #含· has the most Four heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, which group may be optionally substituted by one or more groups ri 2; and the name Ru is independently represented by Cl-6 alkyl, halogen, Cl6 alkane Oxyl, Cl_6 fluorene, (^.6 haloalkoxy, cn, hydroxy-C〇-6 alkyl, COzRh-Coj decyl, CONHSChRH-Co.e alkyl, (1//-tetrazole- 5-yl)-C〇_6 alkyl, -C〇NR1iR&quot;, -sc^NRnRn, -SOrCu alkyl, -NRhSC^-Cu alkyl, -NRnCONRnRn, -NRnCOR, or -NRi 1 R, 1 Or its salt. 2. A compound according to claim 1 wherein R3 is NH2. The compound of any one of claims 1 or 2, wherein the compound is attached to N1. -160- 201026701 4 is a compound of the third aspect of the patent application, wherein r R6 and RS means that R7' or R4 and R5 may be bonded to form _c '. The ground is replaced by a plurality of Cl_8 alkyl groups. 5. The compound of claim 3, wherein R2 is derived from R4, and R5 is R7. ‘, 衣希系示示伸基示示示6· The compound of claim 3, wherein R R7 and Rs means Rs' or ruler 4 and Rs can be bonded to form 'This group can be optionally substituted with - or a plurality of Ci I alkyl groups. A compound according to claim 3, wherein R R 7 and R 5 represent R 8 . 8. The third aspect of the patent application is bonded to form -c 3 _ 5 alkyl, C, · 8 alkyl. A compound of the formula wherein R4 and the group are optionally subjected to one or more compounds, 〇-6. Wherein R7 is as shown in any one of claims 1 to 7 wherein R7 represents H, Cl-6 alkyl or C3-8 cycloalkyl-C 1 0 · The compound of claim 9 is not Η or C丨·6 alkyl. 1 1 · A compound of the first aspect of the patent application, which is represented by hydrazine, methyl or ethyl. I. 7 series Table 1 2 'As the compound of claim 11 of the patent scope, ρ ρ shows methyl. "Dry R7 is shown in Table 13. Demonstration. For example, the compound of claim n, wherein L is a compound of the invention, as described in any one of the claims 1 to 9 or 9 to 13 -161 - 201026701 , alkyl group, c3.8 group · C 1 . ! !院: base, Rii-Co-! can be optionally alkyl group can be any C, 15. as shown, C!" or R10-WC A plurality of halogen atoms are independently selected from the group consisting of R9 〇16. ! Any of them may be optionally subjected to an alkyl group or a halogen. 1. 7. As shown in the above, a ChH alkane: each optionally arbitrarily via a group, a halogen, or a: 1 8 · wherein R6 represents H, a C1 alkyl group, or a c38 naphthenic ring. _c〇ii Heterocycloalkyl-Cq.h alkyl, aryl-Ci m alkyl, heteroaryl, aryl-NH_C〇-n alkyl, heteroaryl-NH-Co-n alkane Or RlQ-wc〇-ualkyl, wherein any alkyl group is substituted by one or more halogen atoms, and any cycloalkyl and heterocyclic ring is substituted by one or more substituents independently selected from the group consisting of Replaced: halogen, aryl and r9. The compound of claim 14 wherein r6 is an alkyl group, a C3-8 cycloalkyl group, a C9-8 alkyl group, an alkyl group, and a R9_Cqii alkyl group, an alkyl group; any of the alkyl groups may be optionally subjected to one or Substituted, and any of the cycloalkyl groups may be optionally substituted with one or more substituents: Ci 6 alkyl, halogen, aryl, and the compound of claim 15 wherein R6 is a Or a C3_8 cycloalkyl-Cqm alkyl group; wherein any of the yard bases are substituted by one or more halogen atoms, and each of the ring-ring groups is substituted with one or more substituents independently selected from the group consisting of: Cl-6, Aryl and R9. Patent No. 16 of the patent application, in which r6 is a base or a C3-8 ring-based Co-&quot; hospital base; any of the bases are replaced by ~ or a plurality of halogen atoms, and any ring base Each of the substituents may be substituted with one or more substituents selected from the group consisting of Ci6 aryl and R9. The compound of claim 17 of the patent scope, wherein R6 is a table -162-.201026701 7Γ: Ci-11 yard base or C3-8 ring yard base. 1 9 · For example, the compound of claim 18, wherein R6 is not C 1 · 1 1 yard. 20. The compound of claim 19, wherein r6 is a C i. 6 hospital base. 2 1 · For example, the compound of claim 16 of the patent scope, wherein R 6 is not a C3-8 ring-based base - Co.il yard base; any of the yard bases may each optionally pass 0- or more halogens The atoms are substituted, and any of the cycloalkyl groups may be optionally substituted with one or more substituents independently selected from the group consisting of C, 6 alkyl, halogen, aryl and R9. 22. A compound according to claim 21, wherein r6 is a C3_8 cycloalkyl group. 2 3. A compound according to claim 22, wherein R 6 represents a cyclobutyl group. 24. A compound according to any one of claims 1, 2, 3, 6, 7, or 9 to 13 of φ, wherein Rs represents aryl-Cm, alkyl. 25. A compound according to claim 24, wherein R8 represents an aryl-C2_4 alkyl group. 26. The compound of any one of claims 1 to 25 wherein Ri and R2 together with the N atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of: (i) containing 2 N a heterocyclic group containing an atom and not containing any other hetero atom, wherein the heterocyclic group may be optionally substituted by one or more C, -4 alkyl groups; and -163-201026701 (Π) contains 1 N a heterocyclic group containing an atom and not containing any other hetero atom, wherein the heterocyclic group is substituted by one -NRaRb group and optionally substituted by one or more (^-4 alkyl groups; wherein the hetero The cyclic groups (i) and (ii) may be 4_ to [membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic. 27] as claimed in item 26 a compound wherein Ri and R2 together with the N atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of: Wherein Rc and Rd independently represent 11 or Cm alkyl. 28. A compound as claimed in claim 27, wherein R&lt;= indicates Η. 29. The compound of claim 27 or 28, wherein R! and R2 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group selected from (a) and (b). -164-201026701 3 0. A compound according to claim 29, wherein R1 and r2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (a). 31. The compound of claim 29, wherein 1 and r2 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (b). The compound of any one of claims 1 to 31, wherein Ra and Rb independently represent 11 or d_4. 3 3 · A compound of claim 3, wherein Ra and Rb independently represent an anthracene or a methyl group. 34. A compound according to claim 3, wherein the Ra line represents Η and the Rb represents a methyl group. 35. A compound as claimed in claim 3, wherein Ra and Rb represent hydrazine. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 3. A compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 35, which is for use in therapy. A compound according to any one of claims 3 to 5, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease mediated by histamine H4 receptor. 39. A compound according to claim 38, or a pharmaceutically acceptable salt thereof, wherein the disease mediated by the histamine Η* receptor is an allergic, immunological or inflammatory disease or pain. The use of a compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, for the manufacture or prevention of histamine H4 A drug that is mediated by a body. 41. The use of claim 40, wherein the disease mediated by the histamine H4 receptor is an allergic, immunological or inflammatory disease or pain. 42. A process for the preparation of a compound of formula I according to claim 1 which comprises: (a) reacting a compound of formula II with a compound of formula III (or an amine group thereof protected form) II III #中, R2, R3, r4 and r5 have the meaning of $2 as in claim 1 of the patent application 'If necessary, then remove any protecting groups that may be present; or (b) make the compound of formula lib and the compound of formula ( Or its amine protected form) reaction -166- 201026701 Lib HNRiRz III wherein the ruler 13 represents the detachment group and the 1^, 1^, 113, 114 and 115 have the meanings described in claim 1 and, if necessary, remove any protecting groups which may be present in the ®; Or (c) converting a compound of formula I into another compound of formula I in one or several steps. -167- 201026701 IV. Designated representative map: (1) The representative representative of the case is: None (2) The symbol of the representative figure is simple: No 201026701 V. If there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention: Formula I -4 -