TW201041867A - Piperidin-pyrimidine derivatives as histamine H4 receptor antagonists - Google Patents

Abstract

Piperidin-pyrimidine 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

201041867 VI. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a series of novel piperidine-pyrimidine derivatives, methods of preparing the same, pharmaceutical compositions comprising the same, and therapeutic compounds thereof. use. [Prior Art] 〇 One of the most effective transmitters for histamine-based rapid allergic reactions. Although the effects of histone on smooth muscle cell contraction, vascular permeability, and gastric acid secretion are known, the effects of histamine on the immune system are now gradually revealed. A few years ago, a novel *histamine receptor named H4 was cloned by several independent research teams (see Oda T et al, J Biol Chem 2000, 2 7 5: 3 678 1 -6; Nguyen T et al, Mol Pharmacol 200 1, 5 9: 42 7-3 3 ). Like the other members of the H4 receptor family, the H4 receptor is a G protein-coupled receptor (GPCR) containing seven transmembrane segments. However, the H4 receptor has low homogeneity with the other three histamine receptors (see Oda T et al); it is noted that the H4 receptor shares only 35% homogeneity with the H3 receptor. The H3 receptor is only expressed in the cells of the central nervous system (CNS), but it has been observed that the system is expressed in cells of the hematopoietic system, especially eosinophils, mast cells, alkalophilic leukocytes, dendrites. Cells and T cells (see literature Oda T et al). The fact that the H4 receptor is highly distributed in cells of the immune system suggests that the H4 receptor' is involved in an immune inflammatory response. Furthermore, this hypothesis is manifested by the gene expression of the H4 receptor -5 - 201041867, which is enhanced by the regulation of inflammatory stimuli such as interferon, TNFa and IL-6. Nonetheless, the H4 receptor is also expressed in other types of cells (such as human synovial cells from patients with rheumatoid arthritis (see Wojtecka-Lukasik E et al, Ann Rheum Dis 2006, 6 5 ( Suppl II): 129; Ikawa Y et al, Biol Pharm Bull 2005, 28: 201 6-8) and human synovial cells from patients with osteoarthritis (see literature Grzybowska-Kowalczyk A et al, European Histamine) Research Society XXXVI Annual Meeting, Florence, Italy, 2007, P-11)) and synovial cells in the human gut (see Sander LE et al, Gut 2 006, 5 5· 49 8-5 04). It has also been reported that the performance of the H4 receptor in nasal polyps is increased compared to that in healthy human nasal mucosa (see J0kiiti A et al, Cell Biol Int 2007, 3 1: 1 3 67-70). Recent studies using specific ligands for this H4 receptor have helped to define the pharmacological properties of this H4 receptor. These studies have demonstrated that several responses induced by histamine to eosinophils (such as chemotaxis, conformational changes, and up-regulation of CD1 lb and CD54) are specifically mediated by the H4 receptor ( See literature, Ling P et al, Br J Pharmacol 2004, 142:16, 7 1; Buckland KF et al, Br J Pharmacol 2003, 140:1 1 1 7-2 7). The H4 receptor has been shown to affect dendritic cell maturation, cytokine production and migration (see document Jelinek I et al, 1st Joint Meeting of European National Societies of Immunology, Paris, France, 2006, PA-1 2 5 5 ). Furthermore, the role of the H4 receptor in mast cells has been studied. Although activation of the H4 receptor did not induce granulation of -6 - 201041867 mast cells, it released histamine and other pro-inflammatory transmitters; in addition, the H4 receptor has been shown to mediate the chemotaxis of mast cells. Sex and 15 transfer (see literature by Hofstra CL et al, J Pharmacol Exp Ther 2003, 305: 1 2 1 2-2 1 ). For T lymphocytes, activation of this H4 receptor has been shown to induce T cell migration and preferentially attract lymphocyte populations with suppressor/regulatory phenotypes and functions (see Morgan RK et al 1, American Thoracic Society Conference, San Diego, 〇 USA, 2006, P-536) and modulates the activation of CD4+ T cells (see Dunford PJ et al, J Immunol 2006, 167: 7062-70). For the intestine, the distribution of the H4 receptor suggests that the H4 receptor may play a role in the control of peristalsis and gastric acid secretion (see literature by Morini G et al, European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, OR). -10). The various functions of the H4 receptor observed on eosinophils, mast cells and T cells suggest that the h4 receptor may play an important role in the immune inflammatory response. In fact, H4 receptor antagonists have been used in murine peritonitis (see Thurmond RL et al, J Pharmacol Exp Ther 2004, 309: 404-13), murine pleurisy (see the paper Takeshita K et al, J Pharmacol Exp Ther 2003, 307: 1072-8) and murine dissemination (see literature Bell JK et al, Br J Pharmacol 2 0 0 4, 1 42: 374-80) showed in vivo activity in the model. In addition, by allergic asthma (see Dunford PJ et al, 2006), intestinal inflammatory disease (see article Varga C et al, Eur J Pharmacol 2005, 522:1 3 0-8), support (see Dunford) PJ et al, J Allergy Clin Immunol 2007, 1 1 9: 1 76- 201041867 83), atopic dermatitis (see document Cowden JM et al, J Allergy Clin Immunol 2007; 119 (1): S 2 3 9 ( Abs 93 5), American

Academy of Allergy, Asthma and Immunology 2007 AAAAI Annual Meeting, San Diego, USA), eye inflammation (see Zampeli E et al, European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, OR-36), edema and pain Allergies (see Coruzzi G et al, Eur J Pharmacol 2007, 563: 240-4) and neuropathic pain (see the literature)

The experimental model of Cowart M D et a 1., J Med Chem. 2008; 5 1 (2 0): 6547 -5 7) has demonstrated the in vivo activity of H4 receptor antagonists. Therefore, H4 receptor antagonists are expected to be useful in the treatment or prevention of allergic, immune and inflammatory diseases and pain. Thus, what we desire is a novel compound which provides activity of an h4 receptor antagonist and which is a good drug. In general, preferred compounds should bind strongly to the histamine H4 receptor and at the same time exhibit low affinity to other receptors. In addition to binding to the h4 receptor, the compound should further exhibit good pharmacological activity in a viable disease pattern. Furthermore, when administered by a selected route of administration, the compound should be able to reach the target tissue or organ and have beneficial pharmacokinetic properties. Furthermore, the compound should be non-toxic and has been shown to have only a few side effects. SUMMARY OF THE INVENTION One aspect of the invention pertains to compounds of formula I -8- 201041867 nh2

among them

Ri and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of: (i) a heterocyclic group containing two nitrogen atoms and containing no other hetero atom, wherein the heterocyclic group The ring group is optionally substituted with 1 or more C!.4 alkyl groups; and (ii) a heterocyclic group containing 1 nitrogen atom and no other hetero atom, wherein the heterocyclic group is one- NRaRb is substituted and optionally substituted with 1 or more C^4 alkyl; wherein the heterocyclic group (i) and (ii) are 4 to 7 membered monocyclic, 7 to 8 membered bridged bicyclic or 8 to 12-membered fused bicyclic ring; or Ri represents hydrazine or Ci.4 alkyl, and R2 represents tetrahydroindenyl, pyrrolidinyl, piperidinyl or hydrazinyl, optionally via 1 or more Ci- 4-alkyl substituted;

Ra represents hydrazine or Cy alkyl;

Rb represents a hydrazine or an alkyl group; or Ra and Rb together with the nitrogen atom to which they are bonded form a tetrahydroindenyl group, a stilly, a piperidinyl group or a hydrazinyl group, which are optionally via i -9 - 201041867 or multiple C^4 alkyl substitutions; R3 represents -COR4 ' -CONR4R4', -C〇2R4, S02NR4R4', R4 represents Cl-8, R5_Cl-8, or R6-C0.8 Optionally, in the Cm alkyl group, the Rs-Ci-8 alkyl group and the R6-CQ-8 alkyl group, one or more halogen groups are substituted and the alkyl chain group is optionally substituted; R4 represents Η or Ci-8 院基; and optionally R4 and R·4, bond formation - C3-5 stretching alkyl alkyl group - optionally substituted by 1 or more C 1 -8 alkyl; r5 Representative -CONR4'R7, -NR4 COR7 ' -NR NR4 S O2R7 ' -S〇2NR4'R7 ' -NR4 CONR4 R7 x _ ' -CO2R7 ' -OCOR7 ' -SO2R7 ' -NR4 R7 ' -〇H ^ 5-Base R6 represents a C3·8 ring-based, heterocyclic, aryl or intermediate r6 group optionally selected from 1 or more independently selected from (^-8 alkylalkyl, halogen 'Cm alkoxy, halogen C,- 8-alkoxy, -CN, C2.4 alkynyl, R5-CQ.s alkyl or Rs-C〇.s alkane

R7 represents Η, (:丨-8 alkyl, C3-8 cycloalkyl-C〇_8 j C〇.8院基', which is in the Ci_8 yard base, C3-8 ring yard base-Ci base-CQ_8 alkane Any alkyl group may optionally be subjected to one or more generations, and any one of the C3_8 cycloalkyl group and the aryl group may be independently selected from the group consisting of Ci-8 alkyl, haloCl.8 alkyl, halogen, C-S02R4 or -alkyl, wherein one of the alkyl groups is S-, -C 3 - 5 4 ' C Ο 2 R 7 ' * CONHSO2R7 奕1 Η -tetrazole-heteroaryl, the group a halogen-based C c 8 alkylthio group substituted with a aryl or aryl-0.8 aryl group and an aromatic halogen group taken from 1 or more 1 - 8 courtyard gas base, -10- 201041867 halogenated alkoxy a group of C, -8 alkylthio, -CN, C2-4 alkynyl or hydroxy oxime I 1 · ί alkyl; and optionally R4 in the R5 group, and R? linkage to form -C3. 5 alkylene group ''-C3_5 alkylene group-) is optionally substituted by 1 or more Cl.8 alkyl groups; and R8 represents a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein RS Optionally, one or more independently selected from the group consisting of (^-8 alkyl, haloalkyl, halogen, s-8 alkoxy, haloCl.8 alkoxy, Cl.8 alkylthio Substituents of -CN, C2_4 alkynyl or hydroxyCl-8 alkyl. The invention also relates to salts and solvates of the compounds of formula I. Certain compounds of formula I may contain chiral centers which may result in a variety of Stereoisomers. The present invention relates to each such stereoisomer and mixtures thereof. The compounds of formula I exhibit high affinity for histamine H4 receptors. Thus, another aspect of the invention pertains to therapeutic use. Compound I

among them

Ri and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group-11 - 201041867 which is selected from the group consisting of: (i) a heterocyclic group containing two nitrogen atoms and no other hetero atom Wherein the heterocyclic group is optionally substituted by 1 or more Cb4 alkyl groups; and (ii) a heterocyclic group containing 1 nitrogen atom and no other hetero atom, wherein the heterocyclic group is 1 -NRaRb-substituted and optionally substituted by 1 or more mountain-4 alkyl; wherein the heterocyclic group (1) and (ii) are 4 to 7 membered monocyclic, 7 to 8 membered bridged bicyclic or 8 to 12 a fused bicyclic ring; or R! represents a hydrazine or a Cl 4 alkyl group, and R 2 represents a tetrahydroindenyl group, a pyrrolidinyl group, a piperidinyl group or a hydrazinyl group, wherein the R 2 group optionally passes through one or more C groups, -4 alkyl substitution;

Ra represents hydrazine or cU4 alkyl;

Rb represents hydrazine or c! _4 alkyl; or Ra and Rb together with the nitrogen atom to which they are bonded form a tetrahydroindenyl group, a fluorene-stirring group, a pyridine group or a hydrazinyl group, which may be Optionally substituted with 丨 ii or a plurality of C,·4 alkyl groups; -C〇NR4R4, -C02R4, -SO2R4 or - R3 represents -C〇R4, S02NR4R4,; 棊, R5-CW alkyl or r6-c 〇-8 alkyl, wherein

R4, representing H or the home base R4 represents Ch8垸棊, in the C, -8 alkyl 'R_sr -12- 201041867 and optionally R4 and R4, the bond rk rk K" 踺 肜 肜 _C3- 5 alkylalkyl group, the -C3-5 alkylene group - optionally substituted by 1 or more C, 4 alkyl groups;

R5 represents -CONR4'R7, N NR4, COR7, -NR4, C02R7, - nr4 so2r7 ' -S〇2NR4-R7 , -NR4,CONR4 R7 , .CONHSO2R7 , -co2r7, -OCOR?, -s〇2r7, _NR4 , R7, _〇H or 1H·tetrazole _ 5-based;

R6 represents C3.8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the Re is optionally selected from one or more independently selected from C18 alkyl, halo Cis alkyl, halogen, C!- 8 alkoxy, dentic Ci 8 alkoxy, Cij alkylthio, -CN, C2-4 alkynyl, R5-CQ.8 alkyl or r8_C()-8 alkyl substituted R7 represents Η, C丨_ 8-alkyl, C3_8 cycloalkyl-c〇-8 alkyl or aryl·C〇-8 alkyl, wherein the Ci-8 alkyl, C3-8 cycloalkyl-cQ-8 alkyl and aryl-Cq In the -8 alkyl group, any alkyl group is optionally substituted by one or more halogen groups, and any one of the c3_8 cycloalkyl group and the aryl group is optionally selected from C or more independently selected from Cm. a base substitution of an alkyl group, a halogenated Cu alkyl group, a halogen, a Cm alkoxy group, a halogen 1·8 alkoxy group, a Cu alkylthio group, a —CN, a C2-4 alkynyl group or a hydroxy cU8 alkyl group; and optionally R R 4 ' and R 7 in the 5-group are bonded to form a -C 3 · 5 alkylene group - 'the -C 3 · 5 alkylene group--optionally substituted with 1 or more C 1 ·8 substituents; And R8 represents c3_8 cycloalkyl, heterocyclic, aryl or heteroaryl' wherein R8 is optionally selected from one or more independently selected from the group consisting of Cl-8, halogen c, _8 alkyl, halogen, Cu Group, a halogen Cl_8 alkoxy, alkylthio Cl_8 -13- 201041867, -CN, Cm Cl_8 a hydroxyl group or an alkynyl group substituted with the group. 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 relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a tissue mediated by histamine 受体 4 receptor. More preferably, the tissue mediated by the histamine 受体4 receptor is an allergic, immune or inflammatory disease or pain. Another aspect of the invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of an allergic, immune or inflammatory disease or pain. Another aspect of the invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of an allergic, immune or inflammatory disease. More preferably, the allergic, immune or inflammatory disease is selected from the group consisting of respiratory diseases, eye diseases, skin diseases, intestinal inflammation diseases, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus or transplant rejection. Still better, the allergic, immune or inflammatory disease is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease (c 〇 PD ), allergic rhinoconjunctivitis, dry eye, cataract, dermatitis (eg atopic Dermatitis), psoriasis, urticaria, jatropha, ulcerative colitis, C r 〇h η disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus or transplant rejection Another aspect of the invention relates to the use of a compound of formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of pain. More preferably, -14- 201041867 ^ pain system ^ spontaneous inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-operative pain, migraine, cancer pain, visceral pain, osteoarthritis pain or 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 histamine H4 receptor vector. More preferably, the disease caused by the histamine H4 receptor vector is an allergic, immune or inflammatory disease or pain. Another aspect of the invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of allergic, immune or inflammatory diseases or pain. Another aspect of the invention pertains to a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of an allergic, immune or inflammatory disease. More preferably, the allergic, immune or inflammatory disease is selected from the group consisting of respiratory diseases, eye diseases, skin diseases, intestinal inflammation diseases, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus or transplant rejection. Still better, the allergic, immune or inflammatory disease is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataract, dermatitis (eg atopic skin) Inflammation, psoriasis, urticaria, stagnation, ulcerative colitis, C r 〇h η disease 'rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus or transplant rejection. Another aspect of the invention pertains to a compound of formula i, or a pharmaceutically acceptable salt thereof, for use in the treatment 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 or neuropathic pain -15 - 201041867 Another aspect relates to 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 tissue mediated by the histamine Η* receptor is an allergic, immune or inflammatory disease or pain. Another aspect of the invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prophylaxis of an allergic, immune or inflammatory disease or pain. Another aspect of the invention pertains to a compound of formula I or a pharmaceutically acceptable thereof Salt is used for the treatment or prevention of allergies, immunity or inflammatory diseases. More preferably, the allergic, immune or inflammatory disease is selected from the group consisting of respiratory diseases, eye diseases, skin diseases, intestinal inflammation diseases, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus or transplant rejection. Still better, the allergic, immune or inflammatory disease is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataract, dermatitis (eg atopic dermatitis) ), psoriasis 'rice, phlegm, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus or transplant rejection. Another aspect of the invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the 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, or neuropathic pain. Another aspect of the invention relates to a method for treating or preventing a disease caused by histamine H4 receptor vector in an individual in need of treatment, preferably in a human body, -16-201041867, which comprises administering to the individual a compound of formula I or A pharmaceutically acceptable salt. More preferably, the histamine h4 receptor-mediated disease is an allergic, immune or inflammatory disease or pain. Another aspect of the invention relates to a method for treating or preventing an allergic, immune or inflammatory disease or pain in an individual in need of treatment, preferably in a human, comprising administering to the individual a compound of formula I or a pharmaceutically acceptable compound thereof Another aspect of the invention relates to a method for treating or preventing an allergic, immune or inflammatory disease in an individual in need of treatment, preferably in a human, comprising administering to the individual a compound of formula I or a pharmaceutically acceptable compound thereof Salt. More preferably, the allergic, immune or inflammatory disease is selected from the group consisting of respiratory diseases, eye diseases, skin diseases, intestinal inflammation diseases, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus or transplant rejection. Still 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 skin) Inflammation, psoriasis, urticaria, jatropha, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus or transplant rejection. Another aspect of the invention relates to a method of treating or preventing pain in an individual in need of treatment, preferably in a human, comprising administering to the subject 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, or neuropathic pain. -17- 201041867 Another aspect of the invention pertains to a process for the preparation of a compound of formula I above which comprises: (1) starting from a compound of formula II (or a protected form of the amine group) NH,

N nr,r2 HN' wherein 1^ and r2 are as defined in the compound of formula I, (a) when R3 represents -COR4 in the compound of formula I, the hydrazine compound and the acid or fluorenyl group of formula R4-COY Chlorine (wherein gamma OH or ci) is reacted; or (b) when R3 represents -CONR4R4 in the compound of formula I, the isomer of the formula 与 and the isocyanate of the formula R4-NC or the amine formazan of the formula r4r4, -NCOW (wherein W is a leaving group) reaction; or (C) when R3 represents -CONR4R4 in the compound of formula I, the compound of formula 11 is reacted with triphosgene or phosgene and subsequently with an amine of formula NHR4R4; When R3 represents -C02R4 in the compound of formula I, the hydrazine compound is reacted with a chloroformate of the formula R4-OCOCl; or (e) when R3 represents -C02R4 in the compound of formula I, the compound of formula η has been previously Reaction with an alcohol of the formula R4-OH reacted with a coupling agent; or (f) when R3 represents -C02R4 in the compound of formula I, the compound of formula 11 is compounded from -18-201041867 and reacted with triphosgene or phosgene and subsequently with formula R4- The alcohol reaction of OH; or (g) when R3 represents -S02R4 in the compound of formula I, the compound of formula II is reacted with sulfonium chloride of formula R4-so2ci; or (h) when the compound of formula I, R3 represents -SO2NR4R4 When the compound of formula II is reacted with the amine sulfonium chloride of the formula R4R4, -NS02C1; or (i) when R3 represents -S02NR4R4 in the compound of formula I, the compound of formula II is reacted with sulfonium chloride and subsequently with the formula NHR4R4 , the amine reaction; 〇 in any of the above (a) to (1), if necessary, subsequently remove any protecting groups that may be present; or (2) the compound of formula VI and the compound of formula I (or the amine group of which is protected) Type) reaction

Wherein Ri, R2 and R3 are as described above, and if necessary, subsequently remove any protecting groups which may be present; or (3) converting the compound of formula I into another compound of formula I via one or several steps. In the foregoing definitions, a Cx.y yard group as part of a group or group refers to a saturated straight or branched alkyl chain containing from X to y carbon atoms. From -19 to 201041867, Cb8 alkyl means a straight or branched alkyl chain having from 1 to 8 carbon atoms. Cr4 alkyl means a straight or branched alkyl chain having 1 to 4 carbon atoms and includes methyl 'ethyl, propyl, isopropyl, butyl, isobutyl, primary butyl and tertiary butyl base. The base of the C hospital does not exist in the base of the hospital. The halogen Cii alkyl group means a group of one or more hydrogen atoms of C, -8 alkyl group which may be substituted by one or more halogen atoms which may be the same or different (i.e., fluorine, chlorine 'bromine or hydrazine). Examples include, in particular, trifluoromethyl, fluoromethyl, hydrazine 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-pentafluoropropyl , heptafluoropropyl, 4-fluorobutyl, nonafluorobutyl, 5,5,5-trifluoropentyl, 6,6,6-trifluorohexyl ' 6,6,7,7,7-pentafluoro Heptyl and 8,8,8-trifluorooctyl.

The Ci-8 alkoxy group represents a group of the formula Ci-8, a group of 0-, wherein the thiol group is as defined above. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, tertiary butoxy, pentyloxy, hexyloxy, heptyloxy Base and octyloxy group. The haloalkoxy group means a group in which one or more hydrogen atoms of the Cl_8 alkoxy group are substituted by one or more halogen atoms which may be the same or different (i.e., fluorine, gas, bromine or valence). Examples include, in particular, trifluoromethoxy, fluoromethoxy, 1-chloroethoxy, 2-chloroethoxy, hydrazine-fluoroethoxy, 2-fluoroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 3-fluoropropoxy, 3-chloropropoxy, 2,2,3,3-tetrafluoropropene Oxy, 2.2.3.3.3- pentafluoropropoxy, heptafluoropropoxy, 4-fluorobutoxy, nonafluorobutoxy, 2-chloropentyloxy, 3-chlorohexyloxy, 2 - Chlorooctyloxy and 2-chloroheptyloxy-20- 201041867 base.

The Ci.8 alkylthio group represents a group of the formula Ct. 8 alkyl-S- wherein the alkyl moiety is as defined above. Examples include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, secondary butylthio, tertiary butylthio, pentylthio, hexylthio, heptane sulfur Base and octylthio group. The c2-4 alkynyl group means a straight or branched alkyl group having 2 to 4 carbon atoms and further containing one or two triple bonds. Examples include, in particular, ethynyl, Ιο propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and 1,3-butadiynyl. The hydroxy Cualkyl group means a group in which one or more hydrogen atoms of the mountain -8 alkyl group are substituted by one or more hydroxy groups. Preferably, the C!-8 alkyl group is substituted with one hydroxy group. Examples include, in particular, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 2,3 Dihydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 2-hydroxybutyl, 1-hydroxybutyl, 2-hydroxypentyl and 3-hydroxyheptyl.卤素 Halogen or its abbreviation halogen means fluorine, chlorine, bromine or iodine. Preferred halogen groups are fluorine and chlorine, and more preferably fluorine. As defined in the definition of R4 for Cu alkyl, Rs-Cu alkyl and R6-CQ.8 alkyl, any alkyl group may be optionally substituted by one or more halo groups which may be the same or different. The alkyl group is the &lt;^_8 alkyl group, the <^-8 alkyl group which is a part of the Rs-Cu alkyl group, and the CG_8 alkyl group which is a part of the R6-CQ.8 alkyl group, as described above. In the definition of R4, a methyl group of the alkyl chain of C.8 alkyl, R5-c, -8 alkyl and R6-CQ_8 alkyl (ie, a stretch of the Cu alkyl-21 - 201041867) a methyl group, a methyl group of the C, _8 alkyl group which is a part of the Rs-Cu alkyl group, and a methyl group of the C〇_8 yard group which is a part of the R6-Cq.8 Alternatively, it can be replaced by a 〇-based group. Examples of a methyl group in the alkyl group include, in particular, methoxymethyl, ethoxymethyl, ethoxyethyl, 2 ethoxypropyl, methoxycarbonyl, 1- Methoxypentyl, 3-propoxypropyl, 4-methoxybutyl, 4-ethoxybutyl, 5-methoxypentyl, 5-ethoxypentyl and 4-propoxy Butyl butyl.

The Rs-Cu alkyl group means a group in which one hydrogen atom of a C 8 alkyl group is substituted with an R 5 group. The R6-C〇_8 yard base includes the R6 base and the yard base. The ruler 6-匚1.8 yard base refers to a group formed by substituting a hydrogen atom of a Cu alkyl group with an R6 group. As defined above, R6 is C3.8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and thus ^-(:^alkyl includes C3.8 cycloalkyl-&lt;:()_8 Alkyl, heterocycloalkyl-CQ-8 alkyl, aryl-CG-8 alkyl and heteroaryl-C()-8 alkyl. As defined in the definition of a compound of formula I, R6 is optionally substituted by one or a plurality of substituents independently selected from the group consisting of c18 alkyl, halo c18 alkyl, halogen, C丨-8 alkoxy, halo C decyloxy, C 丨-8 alkylthio, -CN, C2_4 ' Alkynyl' R5-C()-8 alkyl or R8-CG-8 alkyl. The substituents may be the same or different. Preferably, R6 is optionally substituted with one or more groups, such groups Independently selected from Cu alkyl, halogen C&quot; alkyl, halogen, Cus alkoxy, 1-8 anthracene, 〇1_8 thiol, -CN, C2-4 fast radical, R5-C〇.8 Or b-Cualkyl, provided that only one substituent is selected from R5_C()_8g or R8-CG.8 alkyl. More preferably, R6 is optionally substituted by one radical -22- 201041867, which Independently selected from c, -8 alkyl, haloalkyl, halogen, Cm alkoxy, halogen C&quot; alkoxy, Cm alkylthio, -CN, C2-4 alkynyl, R5-C〇-8 Or R8 _Cq-8. In the C3-8 ring and aryl, the substituents may be on any available carbon atom, and in the heterocycloalkyl and heteroaryl, the substitution The group may be on any carbon or nitrogen atom that may be used. As a group or as part of a C3.8 cycloalkyl-CQ_8 alkyl group, the C3_8 cycloalkyl group may be a monocyclic group or a bridged bicyclic group. a saturated carbocyclic ring containing from 3 to 8 carbon atoms, wherein one or two carbon atoms are optionally oxidized to form a CO group. Examples include, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, cyclooctyl, cyclopentyl, bicyclo[2.2.1]heptyl and bicyclo[2.2.2]octyl. C3-8 cycloalkyl-&lt;:〇-8 alkyl includes (:3.8 Cycloalkyl and C3.8 cycloalkyl-

Ch8 alkyl. The C3-8 cycloalkyl-C丨_8 alkyl group represents a group formed by one or more hydrogen sulfonium hydrazino groups substituted by one or more C3_8 cycloalkyl groups which may be the same or different. Preferably, the Cu alkyl group is substituted by one or two c3.8 cycloalkyl groups and more preferably by a C3-8 cycloalkyl group. The (:3-8 cycloalkyl group can be substituted for the alkane a hydrogen atom on one carbon atom or two hydrogen atoms on the same carbon atom of the alkyl group (for which the c3-8 cycloalkyl group shares one carbon atom with the alkyl group), such as the following Base: -23- 201041867

2-cyclopropylbutyl butyl (wherein a ruthenium atom on C is replaced by a cyclopropyl group)

(1-Ethyl-cyclopropyl)methylbutyl (wherein two fluorene atoms on the same C are replaced by a cyclopropyl group) Examples of the C3.8 cycloalkyl-C alkyl group include, in particular, a cyclopropyl group. Cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyloctylmethyl, bicyclo[2.2.1]heptylmethyl'dicyclopropylmethyl-cyclopropyl)methyl, (1-ethyl-cyclopropyl)methyl, (1-cyclopenta 3-cyclopropyl)methyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-ring, 2-ring Hexylethyl, 2,2-dicyclopropyl-ethyl, 2-cyclohexyl-ethyl, 2-(1-methyl-cyclopropyl)ethyl, cyclopropyl-1-methyl, 1- Cyclopropylethyl, 1-cyclobutylethyl, 1-cyclopentylethyl, ethethyl, 3-cyclopropylpropyl, 3-cyclobutylpropyl, 3-cyclopentyl 3-ring Hexylpropyl, 1-cyclopropyl-2-methylpropyl ' 4-cyclopropylbutylcyclopropyl butyl, 2-cyclopropylbutyl, 1-cyclopropylbutyl, 4-cyclo, 4-cyclopentylbutyl, 4-cyclohexylbutyl, 5-cyclopropylpentylpropylhexyl, 7-cyclopropylheptyl and 8-cyclopropyloctyl. A heterocyclic ring as a moiety or as a part of a heterocycloalkyl-CG-8 alkyl group means a saturated or partially unsaturated heterocyclic ring which may contain from 2 to atom and up to 3 independently selected from ruthenium, osmium or The hetero atom of S is a single bicyclic ring and optionally fused to a benzene ring. One to three or S atomic groups of the heterocyclic ring are optionally oxidized to form CO, NO, and S02 groups, respectively. The heterocycloalkyl group can be used via any C or &gt; methyl, yl, ring, (1-methylmethyl-pentylethyl-2 -cyclopropylethyl 1-cyclohexyl, yl) , 3-butylbutyl, 6-cycloalkyl, 8 carbon rings or bridges | C, N SO or a halogen atom (-24- 201041867 which includes the C atom of the phenyl ring if fused with a phenyl group) The remainder of the molecule is attached. Examples of the heterocycloalkyl group include, in particular, an oxiranyl group, a tetrahydroindenyl group, an oxypropylene group, a tetrahydrofuranyl group, a pyrrolidinyl group, a pyrazolidine group, an isotetrahydrothiazole. , piperidinyl, morpholinyl, piperylene, 2-oxo-tetrahydrofuranyl, 2-oxo-[1,3]diindolyl, 2-oxooxyoxazinyl, 2-sided oxy-tetrahydroimidazolyl, 2-tert-oxy-[l,3] fluorenyl, 2-sided oxy-piperidinyl, thiozoline, 1,1-dioxy Base-thiozoline group, nitrogen 0 fluorenyl group, [I,4]diazepine, [I,4]oxazinyl, 2-sided oxy-azinyl, 1,1-dioxy -[1,2]thiazinyl, 2-oxo-[1,3]diazepine, 7-o-oxy-bicyclo[2.2.1]heptyl, 1,3-dioxene- Bicyclo[2.2.2]octyl, 2,3- Hydrogen-benzofuranyl, 2,3-dihydro-benzo[I,4]dioxin and 2-sided oxy-1,3-dihydro-β primers. The group includes a heterocyclic compound and a heterocyclic alkyl-C-alkyl group. A heterocycloalkyl-Ch8 alkyl group means that one or more hydrogen atoms of the Cls alkyl group may be the same or different heterocyclic rings. The alkyl group is substituted by the alkyl group. Preferably, the ci-8 alkyl group is substituted by 1 or 2 heterocycloalkyl groups and more preferably by one heterocycloalkyl group. Heterocycloalkyl-C! alkyl group Examples include, in particular, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, morpholin-3-ylmethyl, tetrahydrofuran-2-ylmethyl, (2-sideoxy-oxime, 3 ]0!11 and _6_yl)_methyl, 2_峨u-3-ylethyl, fluoren-1-ylpropyl, 1-methyl-2-indole-1-ylethyl , 2-methyl-3-(indolyl)-propyl, 3-methyl-4-indol-1-ylbutyl, 4-(tetrahydrofuran-3-yl)- Butyl, 5-(tetrahydrofuran-3-yl)-pentyl, 6-tetrahydroindol-1-ylhexyl, 7-glyphosyl-4-ylheptyl and 6-methyl-8-(pyrid-25-) 201041867 Ralidine-1-yl)-octyl. Aryl group as a base or as part of an aryl-CQ_8 alkyl group Refers to phenyl or naphthyl. Preferably, aryl represents phenyl. aryl-CQ-8 alkyl includes aryl and aryl-Cm alkyl. aryl-C!-8 alkyl represents C^8 alkyl a group of one or more hydrogen atoms formed by substitution of one or more aryl groups which may be the same or different. The c,-8 alkyl group is preferably one or two aryl groups and more preferably one aryl group. Replace. Examples of the aryl-Chs alkyl group include, in particular, a benzyl group, a 1-phenylethyl group, a 2-phenylethyl group, a 1-phenyl-1-methylethyl group, a 2,2-diphenylethyl group, 3-phenylpropyl, 2-phenyl-1-methylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 4-phenylhexyl, 2-methyl- 3-phenylhexyl, 7-phenylheptyl, 5-phenylheptyl, 7,7-diphenylheptyl, 8-phenyloctyl and 7-phenyloctyl. A heteroaryl group as a radical or as part of a heteroaryl-CG. η alkyl group means an aromatic 5 or 6 membered monocyclic ring or 8 to 12 containing up to 4 heteroatoms independently selected from ruthenium, osmium or S. Double ring. The heteroaryl group can be attached to the remainder of the molecule via any C or hydrazine atom available (eg, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazole-5-yl, pyridine- 2-Based, pyridin-3-yl, pyridin-4-yl, pyridin-5-yl or pyridin-6-yl). Examples of heteroaryl groups include, in particular, 1,2,4-oxadiazolyl, I,2,4-thiadiazolyl, I,3,4-oxadiazolyl, 1,3,4-thiadiazole Base, furanyl, imidazolyl, isotazolyl, isothiazolyl, Dfazolyl, pyrazolyl, pyrrolyl 'thiazolyl, thienyl, 1,2,3-triazolyl, 1,2,4- Triazolyl, pyridinyl, hydrazine, pyridyl, pyrimidinyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, imidazopyrene, imidazolium, Imidazopyridinyl, imi-26- 201041867 oxalopyrimidinyl, oxazolyl, fluorenyl, isodecyl, isoquinolyl, a naridinyl, pyrazolopyrrino, pyrazolopyridyl And pyrazolopyrimidinyl, fluorenyl, quinazolinyl, quinolyl and quinofolinyl. In the definition of heteroaryl, when a particular example refers to a bicyclic ring, the bicyclic rings include all possible configurations of the atoms. For example, pyrazolopyridyl includes, for example, 1 H-pyrazolo[3,4-b]pyridinyl, pyrazolo[l,5-a]pyridinyl, 1H-pyrazolo[3,4-c] Pyridyl, 1H-pyrazolo[4,3-c]pyridinyl and 1H-pyrazolo[4,3-b]pyridinyl; imidazopyrylene includes such as 1H-imidazo[4,5- b] pyridinyl, imidazo[l,2-a]pyroxy and imidazo[1,5-a]pyrrino; and pyrazolopyrimidyl includes, for example, 1 Η-pyrazolo[3, 4 - d ]pyrimidinyl, 1 Η-pyrazolo[4,3-d]pyrimidinyl, pyrazolo[1,5-a]pyrimidinyl and pyrazolo[l,5-c]pyrimidinyl. Heteroaryl-C〇-8 alkyl includes heteroaryl and heteroaryl-Cm alkyl. The heteroaryl-Cbs alkyl group means a group in which one or more hydrogen atoms of the Chs alkyl group are formed by substitution of one or more heteroaryl groups which may be the same or different. Preferably, the C, -8 alkyl group is substituted with one or two heteroaryl groups and more preferably with one heteroaryl fluorenyl group. Examples of heteroarylalkyl groups include, in particular, furan-2-ylmethyl, pyridine-3-ylmethyl, sialolin-3-ylmethyl, d-boxazol-2-ylmethyl ' 1H-pyrrole-2 -ylmethyl, 1-pyridin-3-ylethyl, 2-pyridin-2-ylpropyl, 3-pyridin-3-ylpropyl, 1-methyl-2-pyridin-3-ylpropyl, 4-pyridine-2-ylbutyl '3-pyridin-2-ylbutyl, 5-furan-2-ylpentyl, 6-furan-2-ylhexyl, 3-(1Η-pyrrol-2-yl) -hexyl, 7-(1Η-pyrrol-2-yl)-heptyl, 7-furan-2-ylheptyl, 6-methyl-7-pyridin-2-ylheptyl, 8-furan-2-yl Octyl and 8-(3H-imidazol-4-yl)-octyl. As described in the definition of R7, any alkyl group of (: 丨8 alkyl, C3_8 cycloalkyl-C〇-8 -27- 201041867) and aryl-C〇_8 alkyl optionally Substituted by one or more halo groups which may be the same or different. Any alkyl group means the C,-8 alkyl group and the C3_8 cycloalkyl-C()-8 alkyl group and the aryl_C()-8 alkyl group. a portion of the radical C0-8. In the definition of R7, when any of the C3_8 cycloalkyl and aryl groups is specified, optionally one or more independently selected from the group consisting of Cl 4 alkyl, hydrazine: ^ When substituted with an alkyl group of 8, alkyl, halogen, Cu alkoxy, halo Cm alkoxy, C&quot; alkylthio, -CN, C^4 alkynyl or hydroxyCl-8, the substituents may be the same or different And may be located on any of the C 3 s cycloalkyl and aryl groups available for use with carbon atoms including carbon atoms which are attached to the ring and the remainder of the molecule in the case of a C3-8 cycloalkyl group. In the definition of R8, when any of the c3_8 cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups is specified, optionally one or more independently selected from Ci-8 alkyl, halo C&quot; Alkyl, halogen, (^-8 alkoxy, halogen Ch alkoxy, C When substituted with a group of 8-alkylthio, -CN, C2_4 alkynyl or hydroxyCualkyl, the substituents may be the same or different and may be located in any of the c3-8 cycloalkyl and aryl groups. And may be located on any carbon or nitrogen atom of the heterocycloalkyl and heteroaryl groups. In the case of the c3-8 cycloalkyl group and the heterocyclic group, the substituent may also be attached to the ring and the molecule. The remainder of the carbon atom. R4 and R4, or R4, and R7 form a -c3_5 alkylene group - refers to a linear alkyl chain having from 3 to 5 carbon atoms, ie, formula -(CH2)3 a group of -5 - as described in the definition of a compound of formula I, the -C 3 · 5 alkyl group - optionally substituted by one or more Chs alkyl groups (preferably one or more methyl groups) Formed together - -28- 201041867 C3-5 alkyl-r- and examples of r4 and R4, or 114, and r7 include, inter alia:

"Saturated" means a group that does not contain any double or triple bonds. "Bridged bicyclic" group refers to a bicyclic system containing two common atoms (bridgeheads) connecting three non-cyclic chains (bridges) such that two bridges with a greater number of atoms form a primary ring and have fewer atoms. Bridge "bridge". In the definition of NRiRz, a "fused bicyclic" group refers to a bicyclic system of 8 to 12 atoms consisting of two adjacent rings sharing two common atoms, in the definition of NI^Rz, 'Rl and The nitrogen atom of the iso-bond may together form a heterocyclic group of the group (1) or (ii). The heterocyclic group of the (1) group is a saturated heterocyclic group which has 2 nitrogen atoms and does not contain any other hetero atom and which may be a 4 to 7 membered monocyclic ring, a 7 to 8 membered bridged double ring or an 8 to 12 membered fused ring. Double ring. Examples include, in particular, piperidinyl, heptanoyl, 2,5-diindole-bicyclo[2.2.1]heptyl, 2,5-diindole-bicyclo[2 2 2]octyl, octahydropyrrole [丨, 2· a] pyridinyl, octahydropyrrolo[3,4_b]pyridyl, octahydropyrrolo[3,2_c] -29- 201041867 pyridyl and octahydropyrrolo[3,4_c]pyrroline base. The groups are optionally substituted with one or more c i -4 alkyl groups which may be on any C or N atom available for use. a (n) heterocyclic group-based saturated heterocyclic group containing 1 nitrogen atom and containing no other hetero atom, wherein the heterocyclic group is substituted by a -NRaRb group and may be a 4 to 7 membered monocyclic ring, 7 Up to 8 members with a double ring or 8 to 12 member fused double rings, preferably 4 to 7 members with a single ring. Examples of the class (ii) include, in particular, 3-amino-tetrahydroindenyl, 3-methylamino-tetrahydroindenyl, 3-dimethylamino-tetrahydroindenyl, 3- Amino-pyrrolidinyl, 3-methylamino-pyrrolidinyl, 3-dimethylamino-pyrrolidinyl, 4-amino-piperidinyl, 4-methylamino-piperidinyl, 4-Dimethylamino-piperidinyl and 6-methylamino-3-indole-bicyclo[3.1.0]hex-3-yl. Such groups are further optionally substituted as defined above for the compounds of formula I. "Optionally substituted by one or more" means that one group may be passed through one or more (preferably 1, 2, 3 or 4, more preferably 1, 2 or 3 and more preferably 1 or 2) Substituent substitution, except that the group contains a usable position that is easily substituted. These substituents may be the same or different and may be located at any alternative position. Throughout the specification, "treating, means removing, slowing or ameliorating the cause or effect of a disease. For the purposes of the present invention, treatment includes, but is not limited to, mitigating, ameliorating or removing one or more symptoms of the disease, alleviating the disease. Degree, stabilizing the disease state (ie not worsening), delaying or slowing the progression of the disease, improving or palliative disease state and alleviating the pain (whether part or all). "Prevention," as used herein, means preventing the disease from occurring in the predisposition The disease -30- 201041867 or an individual with a risk factor but not showing signs of the disease. Prevention also includes preventing the recurrence of the disease in individuals who have previously suffered from the disease. Accordingly, the invention relates to compounds of formula I as defined above. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of: (i) containing two nitrogens a heterocyclic fluorenyl group which does not contain any other hetero atom, wherein the heterocyclic group is optionally substituted by one or more Cu alkyl groups; and (ii) contains one nitrogen atom and does not contain any other hetero atom. a heterocyclic group wherein the heterocyclic group is substituted with a -NRaRb group and optionally substituted with 1 or more &lt;^_4 alkyl; wherein the heterocyclic group (i) and (Π) are 4 to 7 members Single ring, 7 to 8 member bridged double ring or 8 to 2 member fused double ring. In another preferred embodiment, the invention is directed to a compound of the formula wherein I Ο and Rb each represent Η or C, _4 alkyl. In another preferred embodiment, the invention relates to compounds of formula I, wherein each of I and Rb represents η, methyl or ethyl. In another preferred embodiment, the invention is directed to a compound of formula I, wherein Ra and Rb each represent η or methyl. In another preferred embodiment, the invention relates to compounds of formula I, wherein I and Rb represent hydrazine. In another preferred embodiment, the invention relates to compounds of formula I, wherein I represents deuterium and Rb represents deuterium or Cl_4 alkyl. -31 - 201041867 In another preferred embodiment, the invention relates to compounds of formula I, wherein Ra represents hydrazine and Rb represents hydrazine, methyl or ethyl. In another preferred embodiment, the invention relates to compounds of formula I, wherein Ra represents deuterium and Rb represents deuterium or methyl. In another preferred embodiment, the invention is directed to a compound of formula I, wherein Ra represents hydrazine and Rb represents a Cu alkyl group. In another preferred embodiment, the invention relates to compounds of formula I, wherein Ra represents hydrazine and Rb represents methyl or ethyl. In another preferred embodiment, the invention relates to compounds of formula I, wherein Ra represents deuterium and Rb represents methyl. In another preferred embodiment, the invention is directed to a compound of formula I, wherein R1 and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of:

-32- 201041867 wherein Ra and Rb are as defined in the above formula I compounds, Rc represents hydrazine or a C1-4 alkyl group, preferably hydrazine or methyl group and more preferably H, and Rd represents hydrazine or ch-alkane Base, preferably hydrazine or methyl. In another preferred embodiment, the invention relates to a compound of formula I, wherein R, and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) to (h) and Ra, Rb , Rc and Rd each represent Η or C!.4 alkyl, preferably Ra, Rb, Rc and Rd each represent Η or methyl, and more preferably Ra, Rb and Rd each represent Η or A And Rc stands for Η. In another preferred embodiment, the invention relates to a compound of formula I, wherein R1 and R.2 together with the nitrogen atom to which they are bonded form a choice of (a), (b), (e) or (f) A saturated heterocyclic group wherein Ra and Rb are as defined in the above formula I, represents η or Ci-4 alkyl, preferably hydrazine or methyl and more preferably fluorene, and Rd represents hydrazine or C! -4 alkyl, preferably hydrazine or methyl. In another preferred embodiment, the invention relates to a compound of formula 1, wherein Ri 〇 and R 2 together with the nitrogen atom to which they are bonded form a saturated impurity selected from the group consisting of U), (b) ' (e) or (f) a ring group, and each of Ra, Rb, and Rd represents Η or Ci-4, preferably Ra, Rb, Rc, and Rd each represent Η or methyl, and more preferably Ra, Rb, and Rd, respectively. Represents Η or methyl and Re stands for Η. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) or (b) wherein Ra and Rb are The meaning as interspersed in the above formula 1 compound, and Re represents H or Cl-4, and preferably H. In another preferred embodiment, the invention relates to a compound of formula 1, wherein R, -33- 201041867 and R2, together with the nitrogen atom to which they are bonded, form a saturated heterocyclic group selected from (a) or (b). And Ra, Rb and R. Each represents hydrazine or a CL4 alkyl group, and preferably Ra, Rb and Re each represent a hydrazine or a methyl group, and more preferably, Ra and Rb each represent a hydrazine or a methyl group and Rc represents hydrazine. In another preferred embodiment, the invention relates to a compound of formula I, wherein R, and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) or (b), and Ra represents hydrazine, Rb represents hydrazine or Cu alkyl and Re represents hydrazine. In another preferred embodiment, the invention relates to a compound of formula I, wherein R, and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) or (b), and Ra represents hydrazine, Rb represents hydrazine or methyl and Rc represents hydrazine. In another preferred embodiment, the invention relates to a compound of formula I, wherein R, and R2, together with the nitrogen atom to which they are bonded, form a saturated heterocyclic group selected from (a) or (b), and Ra represents Η. Rb represents a methyl group and Rc represents a hydrazine. In another preferred embodiment, the invention relates to a compound of formula I wherein R1 and R2 and the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) or (b), and Ra, Rb And Rc stands for Η. In another preferred embodiment, the invention relates to a compound of formula I wherein Ri and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (a)

Ra Rb

N 201041867 wherein Ra and Rb are as defined in the above formula I compounds and R c represents hydrazine or C 4 -4-alkyl and preferably hydrazine. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (a) and Ra, Rb and Rc each represent Η Or Cm alkyl, and preferably Ra, Rb and Re each represent a hydrazine or a methyl group, and more preferably, Ra and Rb each represent a hydrazine or a methyl group and Rc represents hydrazine. In another preferred embodiment, the invention relates to a compound of formula I, wherein R1 and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (a), and Ra represents Η 'Rb represents hydrazine or cumane And Rc stands for Η. In another preferred embodiment, the invention relates to compounds of formula I, wherein R1 and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (a) 'Ra' represents Η 'Rb represents Η or methyl And Rc stands for Η. In another preferred embodiment, the invention relates to a compound of formula I, wherein R! 〇 and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (a), Ra represents hydrazine and Rb represents methyl And Rc stands for Η. In another preferred embodiment, the invention is directed to a compound of formula I, wherein R! and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (a), and Ra, Rb and Rc represent oxime. In another preferred embodiment, the invention relates to compounds of formula I, wherein R! and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (b) -35 - 201041867

Ra

Rb

c

(b) wherein Ra and Rb are as defined in the above formula I compounds and Rc represents hydrazine or Ch alkyl and preferably η. In another preferred embodiment, the invention relates to a compound of formula I, wherein R, and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (b), and Ra, Rb and Rc each represent Anthracene or Ci-4 alkyl, and preferably Ra, Rb and Re each represent an anthracene or a methyl group, and more preferably Ra and Rb each represent an anthracene or a methyl group and Rc represents an anthracene. In another preferred embodiment, the invention relates to a compound of formula I, wherein R, and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (b), Ra represents Η, and Rb represents Η or ( ^-4 alkyl and Rc represents η. In another preferred system, 'the invention relates to a compound of formula I, wherein Ri and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (b), Ra represents hydrazine, Rb represents hydrazine or methyl and Rc represents hydrazine. In another preferred system, the invention relates to a compound of formula I, wherein R1 and R2 together with the nitrogen atom to which they are bonded form formula (b) A saturated heterocyclic group, 113 represents H' Rb represents a methyl group and represents H. In another preferred system, the invention relates to a compound of formula I, wherein R i and R 2 together with the nitrogen atom to which they are bonded form ( b) a saturated heterocyclic group -36- 201041867, and Ra, Rb and Rc represent hydrazine.

In another preferred embodiment, the invention relates to a compound of formula ι, wherein I represents hydrazine or Ci 4 alkyl and R 2 represents tetrahydroindenyl, pyrrolidinyl, piperidinyl or aziridine, wherein R 2 is Optionally substituted with one or more Ci.4 alkyl groups, and preferably R! represents hydrazine and R2 represents 1-methyl-pyrrolidin-3-yl oxime in another preferred system, the present invention is directed to Formula I A compound wherein R3 〇 represents -COR4, -CONR4R4, -co2r4 or -so2r4. In another preferred embodiment, the invention relates to compounds of formula I, wherein r3 represents -cor4. In another preferred embodiment, the invention relates to compounds of formula I, wherein r3 represents -conr4r4. In another preferred embodiment, the invention relates to compounds of formula I, wherein r3 represents -co2r4. In another preferred embodiment, the invention is directed to a compound of formula I, wherein r3 Ο represents -S02R4. In another preferred embodiment, the invention relates to compounds of formula I, wherein r3 represents -S〇2NR4R4. In another preferred embodiment, the invention relates to a compound of formula I, wherein r4 represents Ci-8 alkyl, Rs-Cm alkyl or R6-Cq-8 alkyl, wherein the Cm alkyl, Rs-c丨-8 alkane In the group and the R6-C〇.8 alkyl group, any alkyl group may be optionally substituted with one or more halogen groups. In another preferred embodiment, the invention relates to a compound of formula I, wherein R4 represents C丨-8, a R 5 -C丨-8 or a R 6 -C 〇-8, wherein - 201041867

Any of the bases of the Ci-8, R5-Cl-8, and R6-Cq-8 bases may be optionally substituted with one or more halogen groups and one of the alkyl chains is methyl By -〇- replacement. In another preferred embodiment, the invention relates to a compound of formula I, wherein R4 represents Ci-8 alkyl or R6-C〇-8 alkyl', preferably Cu alkyl or R6-CU, wherein the Ci In the -8-yard, R6_C〇-8, and R6-Ci-8, any alkyl group may be optionally substituted with one or more halogen groups and one of the alkyl chains may be selected from methyl groups. Ground replaced by -0. In another preferred embodiment, the invention relates to a compound of formula I, wherein r4 represents Ci-8 alkyl or R^Co-8 alkyl', preferably Cm alkyl or Re-Cu alkyl, wherein the Ci- In the alkyl group, the R6-cq.8 alkyl group and the r6_Ci_8 alkyl group, any alkyl group may be optionally substituted with one or more halogen groups. In another preferred embodiment, the invention relates to a compound of formula I, wherein R4 represents Ci.8 alkyl or R6-C〇-8 alkyl 'preferably C|-8 alkyl or alkyl' wherein In the 8-alkyl group, the R6-Cq-8 alkyl group and the Rs-Cu alkyl group, any alkyl group is optionally substituted with one or more halogen groups and one methyl group of the alkyl chain is substituted. In another preferred embodiment, the invention relates to a compound of formula I, wherein r4 represents CU8 alkyl optionally substituted with one or more halo groups, wherein one methyl group of the alkyl chain optionally passes through - 〇 - alternative. In another preferred embodiment, the invention relates to a compound of the formula wherein R4 represents a CU8 alkyl group optionally substituted with one or more halo groups. In another preferred embodiment, the invention relates to a compound of formula I, wherein R4 represents a cu 8 alkyl group optionally substituted with one or more halo groups, wherein the methyl group of the -38-201041867 Replaced by -0. In another preferred embodiment, the invention relates to a compound of formula I, wherein r4 represents Rs-C 8 alkyl, wherein the alkyl is optionally substituted with one or more halo groups and wherein one of the alkyl chains The methyl group can be optionally replaced by ◦-. In another preferred embodiment, the invention is directed to a compound of formula I, wherein r4 represents R5-Ci-8 alkyl, wherein the alkyl group is optionally substituted with one or more haloin groups. In another preferred embodiment, the invention relates to a compound of formula I, wherein r4 represents Rs-C 8 alkyl, wherein the alkyl is optionally substituted with one or more halo groups and wherein one of the alkyl chains Methyl group is replaced by -〇-. In another preferred embodiment, the invention relates to a compound of formula I, wherein r4 represents Re-Co.8 alkyl, preferably R6-Cu8 alkyl, wherein any alkyl is optionally one or more halogen Substituent and wherein one of the alkyl chains is optionally substituted with -Ο-. In another preferred embodiment, the invention relates to compounds of formula I, wherein R4 represents Re-Co.8 alkyl, preferably R^-Cualkyl, any of which is optionally one or more Halogen substituted. In another preferred embodiment, the invention relates to a compound of formula I, wherein r4 represents Re-Co.8 alkyl, preferably RrCu8 alkyl, wherein any of the indentations are optionally substituted by one or more halo groups. And wherein one of the alkyl chains is methyl-substituted by -〇-. In another preferred embodiment, the invention relates to compounds of formula I, wherein R4 represents hydrazine or Ci.8 alkyl. -39- 201041867 In another preferred embodiment, the invention relates to compounds of formula I, wherein R 4 ' represents hydrazine. In another preferred embodiment, the invention relates to compounds of formula I, wherein r5 represents -oh, -nr4'r7, -conr4'r7, -co2r7 or -so2r7. In another preferred embodiment, the invention relates to compounds of formula I, wherein R5 represents -nr4, r7. In another preferred embodiment, the invention relates to a compound of formula I, wherein r6 represents c3.8 cycloalkyl (preferably monocyclic), aryl (preferably phenyl) or heteroaryl, wherein r6 is Optionally, one or more independently selected from the group consisting of Ci-8 alkyl, haloalkyl, halogen, Cm alkoxy, halo alkoxy, C,-8 alkylthio, -CN, C2-4 alkynyl Substituting R5-CQ.8 alkyl or R8-C〇-8 alkyl. In another preferred embodiment, the invention relates to a compound of formula I, wherein r6 represents an aryl group (preferably a phenyl group) or a heteroaryl group, optionally selected from one or more independently selected from a C alkyl group. , halogen c, .8 alkyl, halogen, Cu alkoxy, halogen Ci-8 alkoxy, Ci-8 thio, -CN, C2-4 fluorenyl, R5-C0-8 alkyl or R8- Substituent of the C〇_8 alkyl group. In another preferred embodiment, the invention relates to compounds of formula I, wherein R6 represents an aryl group (preferably phenyl) or a heteroaryl group, optionally selected from - or a plurality independently selected from Cm alkane Substituent substitution of a group, a halogen c, an -8 alkyl group, a halogen, an oxy group, a halogen Cm alkoxy group, a Cm alkylthio group, a -CN or a C2-4 alkynyl group. In another preferred embodiment, the invention relates to a compound of formula I wherein R6 represents a C3-8 cycloalkyl group (preferably a monocyclic ring), which is optionally independently selected from C!8 by one or #-40-201041867. Alkyl, halo (^-8 alkyl, halogen, Cl 8 alkoxy, halo Cw8 alkoxy, c, .8 alkylthio, -CN' c2.4 alkynyl, R5-CQ.8 alkyl or Substituent R8-Cq-8 alkyl group. In another preferred system, the invention relates to a compound of formula I, wherein R6 represents C3-8 cycloalkyl (preferably monocyclic), optionally via one Or a plurality of substituents independently selected from C!-8 alkyl, halo-Cu alkyl, halogen, Cl-8 alkoxy, halo-Cu-oxyl, Cl-S alkylthio, _CNS c2-4 alkynyl In another preferred embodiment, the invention relates to a compound of formula I, wherein r6 represents a heterocycloalkyl group, optionally selected from one or more independently selected from C1-8 alkyl, halo-octaalkyl, halogen, Substituent substitution of C!-8 alkoxy, halogen Ci-8 alkoxy, thiol, _CN, C2.4 alkynyl, r5-Cq-8 alkyl or R8_Cg-8 alkyl. In another preferred system The invention relates to a compound of formula I, wherein r6 represents a heteroaryl group, optionally through - or more Individually selected from ci-8 alkyl, halo c&quot; alkyl, halogen, Ch8 alkoxy, halo C^-8 alkoxy, Cm thiol, -CN, C2_4 alkynyl, R5-CQ-8 alkyl Or a R8-C〇-8 alkyl group substituted. In another preferred system, the invention relates to a compound of formula I, wherein r6 represents a heteroaryl group, which is optionally selected from one or more independently selected from C1-8 alkane. Substituent substitution of Ci_8 thiol, dentate, Ci-8 alkoxy, dentate Ci-8 alkoxy, Ci-8 thiol, -CN or C2-4 alkynyl. The invention relates to a compound of formula I, wherein R6 represents an aryl group (preferably a phenyl group) which is optionally selected from one or more independently selected from the group consisting of Cu8, Cu-Cu, halogen, Ci-8 Oxyl, halogen Ci-8 -41 - 201041867 Substituted by alkoxy, Ci.8 thiol, -CN, C2-4, R5-C〇-8 or R8-CQ_8 alkyl. In another preferred embodiment, the invention relates to compounds of formula I, wherein R6 represents an aryl group, preferably a phenyl group, optionally selected from one or more independently selected from the group consisting of Cl-8, halogen Ci-8 Affiliation, halogen, Ci-8 alkoxy, halogen Ci-8 alkoxy, C, -8 alkylthio, -CN or C2.4 Substituent substitution. In another preferred embodiment, the invention relates to compounds of formula I, wherein R4 represents hydrazine or Cm alkyl; R7 represents H, C decyl, C3-8 cycloalkyl-C0-2 alkane Or an aryl-C〇-2 alkyl group, wherein any alkyl group is optionally substituted with one or more halo groups and either one of the C3_8 cycloalkyl groups and aryl groups is optionally one or more Individually selected from the group consisting of Cu alkyl, halo-alkyl alkyl, halogen, C -8 alkoxy, halogen C b 8 oxo, C!-8 thiol, -CN, C2-4 fluorenyl or thiol Substituted by the base of Ci. 8; and optionally R4 in Rs, and R7 are bonded to form -C3-5 alkylene group - 'the -C 3 ·5 alkylene group - optionally through one Or a plurality of C,8 alkyl substitutions, in another preferred system, the invention relates to a compound of formula I wherein &amp; represents an anthracene or an alkyl group, wherein the alkyl group is optionally one or more halo groups Substituting; and optionally R4 in R5, and R7 are bonded to form -C3-5 stretching __' The -Cw alkyl group is optionally substituted by one or more C!-8 alkyl groups . In another preferred embodiment, the invention relates to compounds of formula I, wherein R represents aryl-C&quot;alkyl, wherein the alkyl group is optionally substituted with one or more yl groups and the aryl group is selectable One or more of the grounds are independently selected from the group consisting of C, _8 @-42- 201041867, halogen Cl-8, _, Ci-8, oxy, halogen, Cl.8, gas-based Cm alkylthio, -CN , a C2-4 alkynyl group or a hydroxy C -8 alkyl group is substituted in another preferred system, the invention relates to a compound of the formula, wherein 3 represents -cor4, -conr4r4, -co2r4 or -S02R4; And R4 represents Ci-8 alkyl or R6-CG-8 alkyl 'preferably R6-CU alkyl, wherein in the alkyl group, r6-c〇-8 alkyl group and e alkyl group, any alkyl group Optionally, one or more halo groups are taken to form #a 8 deuterated and one methyl group of the indole alkyl chain is optionally substituted by -〇. In another preferred embodiment, the invention relates to a compound of formula I, wherein Φ, 卞1 R 3 represents -cor4, -conr4r4, -co2r4 or -S02R4; and R4 represents Cu alkyl or R6-C〇_8 alkane a base, preferably an R6-Ci-8, wherein in the Cn, R6-C〇-8, and R6_c 0 ^ I-8 alkyl, any alkyl group is optionally Multiple halogen groups are substituted. In another preferred embodiment, the invention relates to compounds of formula I, wherein R3 represents -cor4, -conr4r4, -co2r4 or -so2r4; and 〇R4 represents Cu alkyl or R6-cQ-8 alkyl, preferably cumane Or an IU-Cu alkyl group, wherein in the Cu alkyl group, the R6-CQ-8 alkyl group and the Re-C^ alkyl group, any alkyl group is optionally substituted with one or more halogen groups and the alkane A methyl group of the base chain is replaced by a - hydrazine. In another preferred embodiment, the invention relates to a compound of formula I, wherein r3 represents -cor4, -conr4r4, -co2r4 or -so2r4; and R4 represents Ci-8 alkane optionally substituted with one or more halo groups The base 'where one methyl group of the alkyl chain is optionally substituted by -0. In another preferred embodiment, the invention relates to compounds of formula I, wherein r3 -43- 201041867 represents -COR4, -C〇NR4R4, -C02R4 or -S02R4; and R4 represents optionally one or more halo groups Substituted c^8 alkyl hydrazine in another preferred system. The invention relates to a compound of formula I, wherein R3 represents -COR4, -C〇NR4R4, -co2r4 or -so2r4; and R4 represents optionally one or A plurality of halogen-substituted Cn-based groups in which one of the alkyl chains is replaced by a-0-. In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents -COR4, -CONR4R4, -C02R4 or -S02R4; and R4 represents an alkyl group, wherein the alkyl group is optionally one or more Halogen-substituted and wherein one of the alkyl chains is optionally substituted by -0. In another preferred embodiment, the invention relates to a compound of formula I, wherein r3 represents -COR4, -CONR4R4', -CO2R4 or -S〇2r4; and R4 represents R5-c, ·8 alkyl' wherein the alkyl group Optionally substituted with one or more halo groups. In another preferred embodiment, the invention relates to a compound of formula I, wherein r3 represents -COR4, -CONR4R4', -CO2R4 or -S〇2r4; and Κ4 represents R6-C〇-8 院基' preferably In the art, any alkyl group may be optionally substituted with one or more halo groups and wherein one of the alkyl chains is optionally substituted. In another preferred embodiment, 'the invention relates to a compound of formula I, wherein r3 represents -COR4, -CONR4R4', -CO2R4 or -S〇2r4; and Rule 4 represents R6-Cq-8's base. Wherein the -44-201041867 alkyl group is optionally substituted with one or more halo groups. In another preferred embodiment, the invention relates to compounds of formula I, wherein R3 represents -COR4, -CONR4R4, -C02R4 or -S〇2R4; and R4 represents R6-C〇.s alkyl, preferably R6- A C..8 alkyl group, wherein any alkyl group is optionally substituted with one or more halo groups and wherein the methyl group of the alkyl chain is replaced by -0. In another preferred embodiment, the invention relates to compounds of formula I, wherein r3 〇 represents -co2R4; and R4 represents Cu alkyl or R6-CQ-8 alkyl, preferably Cu alkyl or R6-CU alkyl, wherein In the Cu8 alkyl group, the R6-C〇.8 alkyl group and the R6-C&quot; alkyl group, any alkyl group may be optionally substituted by one or more halogen groups and one of the alkyl chain groups may be methyl group-methyl. Selectively replaced by -0. In another preferred embodiment, the invention relates to compounds of formula I, wherein R3 represents -co2r4; and R.sup.4 represents Ci.8 fluorenyl or Rs-C. -8-yard, preferably Cn, 〇R6-CM alkyl, wherein in the Cu alkyl, r6-c〇-8 alkyl and Γ 0 alkyl, any alkyl group optionally Substituted by one or more halogen groups. In another preferred embodiment, the invention is directed to a compound of formula I, wherein R represents -C02R4; and Κ·4 represents C.8 hospital or R6-C〇-8, preferably qs# 1 - 8 iTC base or

R6-CM alkyl' wherein in the Cu alkyl group, R6-Cq-8 alkyl group and R R6 'Cl-8 alkyl group, any alkyl group is optionally taken by one or more halogen groups and the One methyl group of the alkyl chain is replaced by -0. In another preferred embodiment, the invention is directed to a compound of formula I, N*R, -45-201041867 represents -co2r4: and R4 represents a c1 substituent optionally substituted with one or more halo groups, wherein the alkane A methyl group of the base chain is optionally replaced by -〇. In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents -co2r4; and R4 represents C, -8 alkyl optionally substituted with one or more halo groups in another preferred system. The invention relates to compounds of formula I, wherein R3 represents -co2r4; and R4 represents a Cbsalkyl group optionally substituted with one or more halo groups, wherein one methyl group of the alkyl chain is replaced by -〇-. In another preferred embodiment, the invention relates to compounds of formula I, wherein R3 represents -C02R4; and R4 represents Rs-C!-8 alkyl' wherein the alkyl group is optionally substituted with one or more halo groups and Wherein a methyl group of the alkyl chain is optionally replaced by -0_. In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents -CO2R4; and R.sup.4 represents R5-C, -salkyl, wherein the alkyl group is optionally substituted with one or more halo groups. Replace. In another preferred embodiment, the invention relates to a compound of formula I, wherein r3 represents -C02R4; and R4 represents R6-C?-8 alkyl, preferably R6_Ci-8 alkyl, The monoalkyl group is optionally substituted with one or more halo groups and wherein the methyl group of the alkyl chain is optionally substituted with -?-. In another preferred embodiment, the invention relates to a compound of formula I, wherein r3 represents -co2r4; and R4 represents R6-C〇_8, and preferably R^-Cm, wherein any Optionally substituted with one or more halo groups. In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents -co2r4; and C) R4 represents R6-C〇-8, and preferably R6-Ci-8, wherein any alkane The substrate is optionally substituted with one or more halo groups and one methyl group of the alkyl chain is replaced by a - hydrazine. In another preferred embodiment, the invention relates to a compound of formula I, wherein r4 represents Rs-Ci.s alkyl, wherein the alkyl group is optionally substituted with one or more halo groups and one of the alkyl chains The base is optionally replaced by -〇·; and R5 represents -nr4,r7. In another preferred embodiment, the invention is directed to a compound of formula I, wherein r4 Ο represents Rs-Cu alkyl, wherein the alkyl group is optionally substituted with one or more _ groups; and R5 represents -NR4, R7. In another preferred embodiment, the invention relates to a compound of formula I, wherein R4 represents R6-Cq_8, and preferably Rg-Cu, wherein the aryl-system is optionally substituted with one or more halo groups. And a methyl group of the alkyl chain is optionally substituted by ○-; and R6 represents a C3-8 cycloalkyl (preferably monocyclic) 'aryl (preferably phenyl) or heteroaryl Wherein R6 is optionally one or more independently selected from the group consisting of Cl-8-47-201041867 alkyl 'halo-Cu alkyl, halogen, c^8 alkoxy, halo d-8 alkoxy, Ci-8 Substituent substitution of alkylthio, -CN, C2-4 alkynyl, r5_Cq 8 alkyl or R8_Cq 8 alkyl. In another preferred embodiment, the invention relates to a compound of formula I, wherein R_4 represents R6-CQ-8 alkyl', preferably Re-Cualkyl, wherein any alkyl group is optionally substituted by one or more halogens Substituent and wherein one methyl group of the alkyl chain is optionally substituted by -〇-; and R6 represents c3.8 cycloalkyl (preferably monocyclic), optionally via - or more Independently selected from Ci-8 alkyl, halo C, -8 alkyl, halogen, Ci-8 alkoxy, haloCu alkoxy, Ci-8 alkylthio, -CN, C2-4 alkynyl, R5- Substituent of C0-8 alkyl or R8-C〇-8 alkyl. In another preferred embodiment, the invention relates to compounds of formula I, wherein r4 represents R6-Cq-8 alkyl-, preferably R6-Cmalkyl, wherein any alkyl is optionally substituted with one or more halo And wherein a methyl group of the alkyl chain is optionally substituted by -0-; and r6 represents a heteroaryl group, optionally selected from one or more independently selected from a Cu alkyl group, a halogen Ci-8 alkane. Base, bacteriocin, Cu alkoxy, dentate Ci.8 alkoxy, c..8 alkylthio, -CN, C2-4 alkynyl, R5-CQ-8 alkyl or Rs-Co-8 alkyl Replaced by the base. In another preferred embodiment, the invention relates to compounds of formula I, wherein R3 represents -COR4, -CONR4R4, -C02R4, -SO2R4 or -S02NR4R4, preferably -COR4, -CONR4R4, -C02R4 or -S 〇2R4, and more preferably -CO 2 R 4 ; R4 represents C 8 alkyl or R 6 -CQ 8 alkyl, preferably c 8 .8 alkyl or -48- 201041867 R 6-CL 8 alkyl, wherein Any of the alkyl groups of C!-8 alkyl, R6-C〇-8 alkyl and .R6-Ci-8 alkyl optionally substituted by one or more halo groups and one of the alkyl chains The methyl group is optionally substituted with -〇-; and R 6 represents an aryl group (preferably a phenyl group) or a heteroaryl group, optionally selected from one or more independently selected from the group consisting of a Cu alkyl group and a halogen C m alkane. Base, dentate, Ci-8 alkoxy, tooth C 1 _8 alkoxy, C 丨 8 I thio group, -CN, C2-4 fast group, R5_C〇-8 alkyl or R8-CG- Substituted by an alkyl group. In another preferred embodiment, the invention relates to a compound of formula I, wherein r3 represents -COR4, -CONR4R4', -C02R4, -S02R4 or -S02NR4R4, 'preferably -cor4, -conr4r4, -co2r4 or S02R4 And more preferably -co2r4; R4 represents R6-CQ-8 alkyl, preferably Re-C^alkyl, wherein any alkyl group is optionally substituted by one or more halo groups and wherein the alkyl group The methyl group of the chain may alternatively be replaced by -0-; and R6 represents an aryl group (preferably a phenyl group) or a heteroaryl group, optionally via hydrazine - or a plurality of independently selected from Ci- 8 yard base, halogen Cu base, halogen, Ci-8 alkoxy, halogen Cbs alkoxy, alkylthio, -CN, C2-4 alkynyl, R5-C〇-8 alkyl or R8-CG- Substituted by an alkyl group. In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents -COR4, -CONR4R4''-co2r4, -so2r4 or -so2nr4r4, 'preferably -COR4, -CONR4R4,'-co2r4 or S02R4, And more preferably -c〇2R4; R4 represents R6_Cq-8, and preferably any of the alkyl groups are optionally substituted by one or more halo groups and wherein the alkyl chain is -49- 201041867 A methyl group is optionally substituted by -〇-; and R 6 represents an aryl group (preferably phenyl) which is optionally selected from one or more independently selected from the group consisting of Cl 8 , C ^ 8 yard base, halogen, Cu hospital oxygen, halogen Ci-8 alkoxy, C Bu 8 hospital sulfur, -CN, C2-4 alkynyl, R5-Cq_8 yard or R8_Cq_8 Substituted. In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents -COR4, -CONR4R4, -C02R4, -SO2R4 or -so2nr4r4, 'preferably -COR4, -CONR4R4', -C02R4 or SO2R4, And more preferably - C02R4; R4 represents R6-Cq-8 alkyl 'preferably RpCu alkyl, wherein any alkyl group is optionally substituted by one or more halo groups and wherein the alkyl chain is one The methyl group is optionally substituted by -〇-; and r6 represents an aryl group (preferably a phenyl group) which is optionally selected from one or more independently selected from the group consisting of Cu alkyl, halo-alkylalkyl, halogen, Substituent substitution of a Cl-8 alkoxy group, a halogen Cu alkoxy group, a Cu alkylthio group, a -CN or a C2-4 alkynyl group. In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents -co2R4; R4 represents an alkyl group, wherein the alkyl group is optionally substituted with one or more halo groups and wherein one of the alkyl chains The methyl group is optionally replaced by -〇-; and R5 represents -NR4, R7. In another preferred embodiment, the invention relates to compounds of formula I, wherein R 3 represents -co2r4; R4 represents R5-CL8 alkyl, wherein the alkyl group is optionally substituted by one or more than -50 to 201041867 halogen groups. And

Rs represents -nr4, r7; and R7 represents aryl-C〇.8 alkyl, preferably aryl-Ci-8 alkyl, wherein any alkyl group is optionally substituted with one or more halo groups, And any of the aryl groups may optionally be selected from one or more independently selected from the group consisting of Cl.8, the halogen Ci-8, the alizarin, the Ci.8 oxy, the Ci-8 methoxy, the Ci-8 Substituent of a thio group, a -CN, a c2-4 alkynyl group or a hydroxy C.8 alkyl group. In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents -co2r4; R4 represents Cu alkyl or r6-cg-8 alkyl, preferably Cu alkyl or R6_Ci_8, wherein Any of the alkyl groups of the Ci-8, R6-C〇-8, and R6-Ci-8 alkyl groups may be optionally substituted with one or more halo groups and one methyl group of the alkyl chain Optionally, substituted by -〇·; and R6 represents c3_8 cycloalkyl (preferably monocyclic), aryl (preferably phenyl) or heteroaryl, wherein R6 is optionally one or more Independently selected from the group consisting of Cn 〇 基 ''halogen C&quot; alkyl, halogen, Cu alkoxy, halo Cm alkoxy, Cu alkylthio, _CN, c2-4 alkynyl, R5-C〇-8 alkyl or R8 -C〇-8 alkyl group substitution. In another preferred embodiment, the invention relates to compounds of formula I, wherein r3 represents -co2r4; R4 represents Cu alkyl or R6-CQ-8 alkyl, preferably C^-8 alkyl or Re-C^ a base in which any one of the alkyl groups is optionally substituted with one or more halogen groups and the methyl group of the base chain of the hospital is available in the Ci 8 group, the r6_c〇-8, and the fluorenyl group. Alternatively, it is substituted: and -51 - 201041867 r6 represents an aryl group (preferably a phenyl group) or a heteroaryl group, wherein r6 is independently selected from one or more selected from the group consisting of Cu alkyl, halo-Cu alkyl ' Ci-8 The substituents of the oxy group, the halogen Ci-8, the C!-8 thiol, the _CN, the aryl, the R5-CG.8 or the R8-C〇-8. In another preferred embodiment, the invention relates to a compound of formula I, which represents -co2R4; R4 represents a R6-C0-8, preferably R6-Ci-8, 3-alkyl, optionally one or a plurality of halogen groups are substituted and the alkyl group is optionally substituted with -〇-; and r6 represents a c3-8 cycloalkyl group (preferably a monocyclic ring), which is optionally S or a plurality of independently selected from Cu An alkyl group, a halogenated Cu alkyl group, a halogen group, a (cyclo), a halogen Cm alkoxy group, a (^.8 alkylthio group, a -CN, a C2-4 alkynyl 8 alkyl group or a R8-Cq.8 alkyl group. In another preferred embodiment, the invention relates to a compound of formula I representing -C02R4; R4 represents R6-C〇-8, preferably R6-C1-8, a '3 alkyl, optionally Or a plurality of halo substituents and wherein the trans-methyl group is optionally substituted by -〇-; and R6 represents an aryl group (preferably a phenyl group) or a heteroaryl group, wherein R6 is optionally one or more Independently selected from the group consisting of Cu, a halogen Ci-8, a 'C】-8 alkoxy' halo (: 丨-8 alkoxy, Cm alkylthio, -CN, phenyl, R5-CQ_8 alkyl or -(:^alkyl group substitution. In another preferred system, the invention relates to a compound of formula I -C02R 4; is optional halogen, C2-4 acetylene, R3; one of them! [1] _ 8 courtyard oxygen 'R5-C〇- where r3: any of the zhyl chain is optional halogen, C2-4 alkyne wherein r3 - 52- 201041867 R4 represents R6-CQ-8 alkyl 'preferably RpCu alkyl, wherein any alkyl group is optionally substituted by one or more halo groups and wherein the alkyl chain One of the methyl groups is optionally substituted by -〇-; and r6 represents an aryl group (preferably a phenyl group) which is optionally independently selected from one or more selected from the group consisting of Ci-8 alkyl, halo-Ci-8 Substituent substitution of a halogen group, a halogen, a ds alkoxy group, a halogen Ci-8 alkoxy group, a Ci-8 alkylthio group, a -CN, a c2_4 alkynyl group, an R5-C〇_8 alkyl group or an R8-CQ-8 alkyl group In another preferred embodiment, the invention relates to a compound of formula I, wherein r3 represents -co2r4; R4 represents R6-C〇-8 alkyl, preferably R6-CU alkyl, any of which may be Optionally substituted with one or more halo groups and wherein one of the alkyl chains is optionally substituted; and R6 represents an aryl group, preferably a phenyl group, optionally one or more Independently selected from C&quot; alkyl, halo-Cl-8 alkyl, halogen Substituent of a Ci, alkoxy, haloalkoxy, c8 alkylthio, -CN or C2.4 alkynyl group. In another preferred system, the invention relates to a compound of formula I, Wherein R3 represents -co2r4; R4 represents R6-c〇-8 alkyl', preferably Rs-Cualkyl, wherein any of the indentations are optionally substituted with one or more halo groups and wherein the A methyl group is optionally substituted by -◦-; and R6 represents a heteroaryl group optionally selected from one or more independently selected from the group consisting of Ci-8 alkyl, halo-alkylalkyl, halogen, Cl-8. Substituent substitution of alkoxy, halo-alkoxy, Ci_8 thiol, -CN, C2-4 alkynyl, R5-CQ-8 or R8-C〇-8 alkyl. -53- 201041867 In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents _C〇R4, -conr4r4, -co2r4 or -S02R4, and more preferably -C02R4;

Ri and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of: (i) a heterocyclic group containing two nitrogen atoms and containing no other hetero atom, wherein the heterocyclic group The ring group is optionally substituted by one or more C, -4 alkyl groups; and (ii) a heterocyclic group containing one nitrogen atom and no other hetero atom, wherein the heterocyclic group is one- NRaRb is substituted and optionally substituted with 1 or more Ci.4 alkyl; wherein the heterocyclic group (i) and (ii) are 4 to 7 membered monocyclic, 7 to 8 membered bridged bicyclic or 8 to 12 members fused double rings. In another preferred embodiment, the invention relates to compounds of formula I, wherein R3 represents -cor4, -conr4r4, -co2r4 or -so2r4, and more preferably -C02R4;

Ri represents deuterium or Ci_4 alkyl and R2 represents tetrahydroindenyl, pyrrolidinyl, piperidinyl or aziridine, wherein R2 is optionally substituted by one or more Cb 4 alkyl groups, and preferably R i represents hydrazine and R 2 represents a 1-methyl-pyrrole D-1,3-yl group. In another preferred embodiment, the invention relates to compounds of formula I, wherein R3 represents -COR4, -C0NR4R4, -co2r4 or -so2r4, and preferably -C ο 2 R 4 ; and R1 and R2 and The bonded nitrogen atoms together form a saturated heterocyclic group selected from (a) to (h) -54 to 201041867, wherein Ra and Rb are as described in the above formula I, and each of R e and R d Representing Η or c 1 -4, preferably Ra, Rb, and Rd each represent Η or C丨_4 alkyl, more preferably Ra, Rb, Re, and Rd each represent Η or methyl' and Very preferably, Ra, Rb and Rd each represent a hydrazine or a methyl group and Rc represents hydrazine. In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents -cor4, -CONR4R4', -C02R4 or -so2r4, and more preferably - co2r4;

Ri and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a), (b), (e) or (f), wherein 1 and Rb are as described in the above formula The meaning 'and R. And Rd each represents hydrazine or Ci. 4 alkyl, preferably Ra, Rb, R. And Rd each represents an anthracene or a Cm alkyl group, and more preferably Ra, Rb, Rc and Rd each represent an anthracene or a methyl group, and very preferably Ra, Rb and Rd each represent an anthracene or a methyl group and R. Representative Η. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ο R3 represents -COR4, -CONR4R4, -co2r4 or -so2r4, and preferably -C02R4; and 1^ and R2 are bonded to them. The nitrogen atoms together form a saturated heterocyclic group selected from (a) or (b), wherein Ra and Rb are as defined in the above formula I, and R. Representing hydrazine or Cu alkyl, preferably Ra, Rb and RC each represent hydrazine or Cu alkyl, more preferably Ra, Rb and Rc each represent hydrazine or methyl, more preferably Ra and Rb, respectively. Represents hydrazine or methyl and Rc represents hydrazine, and preferably Ra represents hydrazine and Rb represents hydrazine or methyl and R. Representative Η, and particularly preferably Ra stands for Η, Rb stands for methyl and Re stands for Η. -55- 201041867 In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents -cor4, -CONR4R4, -C02R4 or -S02R4, and preferably -co2R4; and 1 and R2 and The bonded nitrogen atoms together form a saturated heterocyclic group of formula (a) wherein Ra and Rb are as defined in the above formula I compounds and Rc represents hydrazine or C Ϊ -4 alkyl, preferably Ra, Rb and R. Each represents Η or Cm alkyl' more preferably Ra, Rb and R. Each represents Η or methyl 'better, Ra and Rb each represent Η or methyl and Re stands for Η 'Very well Ra stands for H, Rb stands for Η or methyl and Re stands for Η, and particularly preferably Ra stands for Η ' Rb represents a methyl group and Rc represents η. In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents -cor4, -CONR4R4, -co2r4 or -S02R4, and preferably -co2r4; and the heart and R2 and the nitrogen bonded thereto The atoms together form a saturated heterocyclic ring of formula (b) wherein Ra and Rb are as defined in the compounds of formula I above, and R. Representing hydrazine or C, _4 alkyl, preferably Ra, Rb and Re each represent hydrazine or Cl-4 fluorenyl, more preferably Ra, :^ and each represent Η or methyl, more preferably Ra And Rb each represent a hydrazine or a methyl group and Rc represents η, and preferably Ra represents Η, Rb represents Η or methyl and Re represents Η, and particularly preferably Ra represents Η, Rb represents methyl and Rc represents Η. In another preferred embodiment, the invention relates to compounds of formula I, wherein R3 represents -COR4, -CONR4R4', -C02R4, -SO2R4 or -S〇2NR4R4', preferably -COR4, -CONR4R4, _co2r4 or - S〇2R4, and more preferably - co2r4; -56- 201041867 R4 represents Ci-8 alkyl, R5-Ci-8 alkyl or R6_C〇-8 alkyl, wherein the c, _8 alkyl, R5-C In the -8 alkyl group and the R6-C〇-8 alkyl group, any alkyl group may be optionally substituted with one or more halogen groups and one of the alkyl chain extension groups may optionally be via -0- Replace

Rs represents -NR4, R7; R6 represents C3_8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably C3-8 cycloalkyl, aryl or heteroaryl, wherein r6 is optionally Ο — or a plurality of independently selected from the group consisting of octadecyl, halogen C! -8 alkyl, halogen, d-8 alkoxy, halogen C 丨 8 alkoxy, Ci-8 alkylthio, -CN, C 2 4 Alkynyl, R5-C〇-8, or R8-Cq-8,

Ri and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of: (i) a heterocyclic group containing two nitrogen atoms and containing no other hetero atom, wherein the heterocyclic group The ring group is optionally substituted with 1 or more Ci-4 alkyl groups; and O (ii) a heterocyclic group containing 1 nitrogen atom and containing no other hetero atom, wherein the heterocyclic group is via _ The NRaRb group is substituted and optionally substituted with one or more C]-4 groups; wherein the heterocyclic group (i) and (ii) are 4 to 7 membered monocyclic, 7 to 8 membered bridged double rings or 8 To 12-member fused double rings. In another preferred embodiment, the invention relates to a compound of formula I, wherein r3 represents -c〇R4, -c〇nr4r4, -co2r4, -so2r4 or _S02NR4R4'' preferably - C〇R4, -C02R4 Or -S〇2R4, and more preferably -C02R4; -57- 201041867 R4 represents a Cu alkyl group, an R5-Cl.8 alkyl group or an r6_Cq_8 alkyl group, wherein the C,-8 alkyl group, Rs-C alkane In the alkyl group and the R6_Cq_8 alkyl group, any alkyl group may be optionally substituted by one or more halogen groups and one methyl group of the alkyl chain may be optionally substituted; R5 represents -NR4'R7; r6 represents Ca_8 a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, preferably a C3-8 cycloalkyl, aryl or heteroaryl group, wherein R6 is optionally selected from one or more selected from C!.8 Base, tooth Ci_8, base, alizarin, Cb8 alkoxy, halogen C!-8 alkoxy 'c&quot; alkylthio, -CN, C2-4 alkynyl, R5-C〇-8 alkyl or Substituted with a ^alkyl group; and 1^ and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) to (h) wherein Ra and Rb are as in the above compound of formula I The meaning of the description 'and R&lt;= and Rd each represent a Η or Ci.4 yard base, preferably Ra, Rb Rc and Rd each represent Η or c. 4. alkyl, more preferably Ra, Rb, R. And Rd each represents hydrazine or methyl group&apos; and preferably Ra, Rb and Rd each represent hydrazine or methyl and Rc represents hydrazine. In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents -COR4, -CONR4R4, .c〇2R4, -s〇2R4 or -S02NR4R4, 'preferably - COR4, -C〇NR4R4, , -C02R4 or -so2r4, and more preferably -c Ο 2 R 4 ; R4 represents a deuterium group, Rs-Cu alkyl group or r6_C()-8 alkyl group, wherein the C alkyl group, Κ!-8 alkyl group And R6_C()8 alkyl, optionally substituted by one or more halo groups and one methyl group of the alkyl chain is optionally substituted by -ο_; -58- 201041867 R5 Representative -NR4, R7;

Re represents a C3-S cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, preferably a C3-8 cycloalkyl, aryl or heteroaryl group, wherein the R6 group is optionally independently selected from one or more Cu alkyl, halo Cu alkyl 'halogen, Cl-8 alkoxy, halogen Ci.8 alkoxy, Cm alkylthio, -CN, C2.4 alkynyl, R5_C〇-8 alkyl or R8- a CQ-8 alkyl group substituted; and 1^ and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) or (b) fluorene, wherein Ra and Rb are as defined in the above formula I The meanings described in the compounds, and Re stands for Η or Ci-4, and preferably Ra, Rb and Rc each represent Η or (^-4 alkyl, more preferably Ra, Rb and R. It does not represent a hydrazine or a methyl group. More preferably, Ra and Rb each represent a fluorene or a methyl group and Rc represents a hydrazine, and preferably Ra represents fluorene, Rb represents hydrazine or methyl and Rc represents hydrazine, and particularly preferably Ra represents hydrazine. Rb represents a methyl group and Rc represents η. In another preferred system, the invention relates to a compound of formula I, wherein Κ·3 represents -cor4, -conr4r4, -C02R4, -so2r4 or -O S02NR4R4', preferably -COR4, -CONR4R4, -C02R4 or -SO2R4, and more preferably -co2r4; R4 represents a Cu alkyl group , Rs-Cu alkyl or R6_c〇-8 alkyl, wherein in the Ci-8 yard base, Rs-Cu yard base and R6-C〇_8 yard base, any one of the hospital bases may optionally pass one or a plurality of halogen groups are substituted and one methyl group of the alkyl chain is optionally replaced by -0-; R5 represents -nr4, r7; Κ·6 represents C3-8 cyclodecyl, heterocyclic, aryl Or a heteroaryl group - preferably a c3-8 cycloalkyl, aryl or heteroaryl group, wherein R6 is optionally selected from -59 to 201041867 one or more independently selected from C! -8 alkyl, halo C, -8 Alkyl, halogen, C.sup.8-8 alkoxy, halo Cm alkoxy, C&quot;alkylthio'-CN, C2-4 alkynyl, R5-C〇-8 alkyl or, -(:^alkyl Substituent; and 1^ and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (a) wherein Ra and Rb are as defined in the above formula I, and R represents Η Or a Cu alkyl group, preferably Ra, Rb and Re each represent a hydrazine or a Cu alkyl group, more preferably Ra, Rb and Re each represent a hydrazine or a methyl group, and more preferably Ra and Rb each represent Η Or methyl and Rc represents Η 'Very well Ra stands for Η 'Rb stands for Η or methyl and Rc stands for Η, and particularly preferably Ra stands for Η ' Rb represents a methyl group and Rc represents η. In another preferred system, the invention relates to a compound of formula I, wherein R3 represents -COR4, _c〇NR4R4, _C〇2R4, -S〇2R4 or _so2nr4r4'' is preferred. -COR4, _c〇NR4R4, _c〇2r4 or _8〇2114, and more preferably - co2r4; R4 represents Cu alkyl, R5_Ci_8 alkyl or R6_c&quot; alkyl, wherein the Cl_8, J*b· Η-,

In the Cl. 8 and R6-CQ_8 alkyl groups, any of the alkyl groups may be optionally substituted with one or more halogen groups such as &lt;1&gt; Selectively pass -0 - instead of ^; R5 represents -nr4, r7; R 6 represents C 3 8 ring pick up, hydrazine & Π t ^ s 雑 烷基 alkyl, aryl or heteroaryl, preferably C3_8 ring a aryl, aryl or a heterocyclic 4-heteroaryl group, wherein R6 is optionally selected from or independently selected from the group consisting of c18 alkyl, _alkyl, halogen, C&quot;alkoxy, halogen Ci.8 alkoxy, Cp

^ 1_8 Institute of sulfur, -CN, C2.4 alkynyl, R

Substituting a Co-8 or a R8-CQ-8 alkyl group and -60, 201041867 1^ and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (b) wherein Ra and Rb It is as described above for the compound of formula I, and Rc represents hydrazine or Cm alkyl, preferably Ra, Rb and Re each represent hydrazine or Cm alkyl group, more preferably Ra, Rb and R. Each represents η or methyl, and more preferably Ra and Rb each represent hydrazine or methyl and R. Representative Η, very preferably Ra stands for Η, Rb stands for Η or methyl and Rc stands for Η, and particularly preferably Ra stands for ’ ' Rb stands for methyl and R c stands for Η. In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents -COR4, -CONR4R4, -co2R4, -S02R4 or -S02NR4R4, preferably -COR4, -CONR4R4, -C02R4 or - S〇2R4, and more preferably -co2r4; R4 represents C^8 alkyl or Rb-Cod alkyl, preferably Cu alkyl or R 6 - C 1-8, wherein the C!-8 Any one of the alkyl groups, R 6 - C ο - 8 and R 6 _ C ! . 8 alkyl, optionally substituted by one or more halo groups and one methyl group of the alkyl chain Alternatively by -0-substituted; O R6 represents C3.8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably C3.8 cycloalkyl, aryl or heteroaryl and more preferably An aryl or heteroaryl group, wherein R6 is optionally one or more independently selected from the group consisting of Cl-8 alkyl, halo Cl. 8 alkyl, halogen, C 8 alkoxy, halo alkoxy, Ci- Alkylthio, -CN, C2-4 alkynyl, R5-C〇-8 or a R8-Cq-8 substituent; and R1 and R2 together with their bonded nitrogen atoms form a saturation a heterocyclic group selected from the group consisting of: (i) a heterocyclic ring containing two nitrogen atoms and containing no other hetero atom -61 a group of 201041867, wherein the heterocyclic group is optionally substituted with 1 or more CL4 alkyl groups; and (ii) a heterocyclic group containing 1 nitrogen atom and no other hetero atom, wherein the heterocyclic group is 1 -NRaRb group substituted and optionally substituted by 1 or more Cu alkyl groups; wherein the heterocyclic group (i) and (ii) are 4 to 7 membered monocyclic, 7 to 8 membered bridged double rings or 8 To 12-member fused double rings. In another preferred embodiment, the invention relates to compounds of formula I, wherein Rs represents -COR4, -CONR4R4, -CO2R4, -S02R4 or -S02NR4R4, preferably -cor4, -CONR4R4, -C02R4 or -S02R4 And more preferably - co2r4; R4 represents Ci.8 alkyl or R6-CG_8 alkyl, preferably (^-8 alkyl or R6-Ci-8), wherein the Ci-8, R6 -C〇-8, and R6-CU alkyl, any alkyl group optionally substituted with one or more halo groups and one methyl group of the alkyl chain optionally substituted by -0 Representative C3.8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably c3-8 cycloalkyl, aryl or heteroaryl and more preferably aryl or heteroaryl, wherein R6 Optionally, one or more independently selected from the group consisting of (^.8 alkyl, halo-Cl-8 alkyl, halogen, C丨-8 alkoxy, halogen C!-8 alkoxy, c-decylthio, a substituent of -CN, C2-4 alkynyl, R5-CQ_8 alkyl or R8-CG-8 alkyl;

Ri and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) to (h), wherein Ra and Rb are as defined in the above compound of formula I, and Re and Rd are each Do not represent Η or mountain _4 alkyl, preferably -62- 201041867

Ra, Rb, R. And Rd each represents Η or C丨-4 alkyl'. More preferably, Ra, Rb, Rc and Rd each represent an anthracene or a methyl group, and very preferably Ra, Rb and Rd each represent a hydrazine or a methyl group and R . Representative Η. In another preferred embodiment, the invention relates to a compound of formula I wherein R3 represents -COR4, -CONR4R4, -CO2R4, -so2r4 or -so2nr4r4, preferably - cor4, -conr4r4, -c〇2R4* _s〇2R4, and more preferably -co2r4; 〇R4 represents Cu alkyl or r6-c〇-8 alkyl, preferably Cl-8 or R6-Ci-8 fluorenyl, wherein the Ci.8 In the base group, R6-C〇-8, and R6-Ci-8 alkyl, any alkyl group may be optionally substituted by one or more halogen groups and one of the alkyl chains may be selected from methyl groups. Substituted by -0-; R6 represents C34 cycloalkyl, heterocycloalkyl, aryl or heteroaryl 'preferably C3-8 cycloalkyl, aryl or heteroaryl and more preferably aryl or hetero An aryl group, wherein R6 is optionally independently selected from ci alkyl, halo C -8 alkyl 'halogen, C alkoxy, halo Ci-8 alkoxy, Ci-8 alkylthio a substituent of hydrazine, -CN, C2-4 alkynyl, R5-CG.8 alkyl or r8-c〇-8 alkyl: and R 1 and R 2 together with the nitrogen atom to which they are bonded are selected from a saturated heterocyclic group of (a) or (b), wherein Ra and Rb are as defined in the above formula I, and Re represents hydrazine or Ci-4 alkane Preferably, Ra, Rb and Rc each represent hydrazine or C, -4 alkyl, more preferably Ra, Rb and Re each represent hydrazine or methyl group. More preferably, Ra and Rb each represent hydrazine or Methyl and Rc represent Η 'Very well Ra stands for Η, Rb stands for Η or methyl and R. Representative Η ' and particularly preferably Ra represents Η ' Rb represents a methyl group and Rc represents η. -63- 201041867 In another preferred embodiment, the invention relates to compounds of formula I, wherein R3 represents -COR4'-conr4r4, -co2r4, -so2r4 or -S02NR4R4, preferably -COR4, -CONR4R4, - C02R4 or -so2r4, and more preferably -c O 2 R 4 ; R4 represents c&quot;alkyl or R6-Cg.8 alkyl, preferably Ci-8 alkyl or lU-C&quot;alkyl, wherein In the Cu alkyl group, the R6-Cq-8 alkyl group and the Ra-Cn alkyl group, any alkyl group may be optionally substituted with one or more halogen groups and one methyl group of the alkyl chain may optionally be subjected to -〇-substituted; R6 represents C3_8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably c3-8 cycloalkyl, aryl or heteroaryl and more preferably aryl or heteroaryl Wherein r6 is optionally independently selected from the group consisting of Cu alkyl, halo-Ch 8 alkyl, halogen, Cm alkoxy, halo CU8 alkoxy, Ci-8 alkylthio, -CN, C2- Substituted by alkynyl, R5-C〇.8 alkyl or R8-C〇.8 alkyl: and the sipe 1 and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (a) Wherein Ra and Rb are as defined in the above formula I compounds and represent hydrazine or C,-4 alkyl, preferably Ground Ra, Rb and R. Each represents Η or Cm alkyl, more preferably Ra, Rb and Re each represent Η or methyl, more preferably Ra and Rb each represent Η or methyl and Rc represents Η, and preferably Ra represents That is, Rb represents an anthracene or a methyl group and Rc represents an anthracene, and particularly preferably Ra represents an anthracene, Rb represents a methyl group and Rc represents an anthracene. In another preferred embodiment, the invention relates to a compound of formula I, wherein r3 represents -cor4, -CONR4R4, -CO2R4, -S02R4 or -s〇2nr4r4, preferably - cor4, -conr4r4, -co2r4 or - so2r4 -64- 201041867, and more preferably -co2R4; R4 represents Cm alkyl or R6-CG-8 alkyl, preferably Cu alkyl or R6-Ci_8, wherein the Ci-8, In the R6-C〇-8 and R6_Ci-8 alkyl groups, any alkyl group may be optionally substituted with one or more halo groups and one of the alkyl chains may optionally be methyl-- Instead; r6 represents C3.8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, preferably c3.8 cycloalkyl, aryl or heteroaryl and more preferably aryl or heteroaryl, R wherein R 6 is optionally independently selected from one or more selected from the group consisting of α 8 alkyl, halogen CH 8 , spectrin, Ci 8 methoxy, halogen Ci-8 methoxy, Ci-8 thio, -CN a C2-4 alkynyl group, a R5-CG_8 alkyl group or a R8-C〇-8 alkyl group; and 11! and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of the formula (b) Wherein Ra and Rb are as described above for the compound of formula I, and Re represents hydrazine or Ci.4 alkyl Preferably Ra, Rb and R. Each represents a hydrazine or a Cm alkyl group, more preferably Ra, Rb and R. Each represents Η or methyl, preferably Ra and Rb each represent Η or methyl and Rc represents Η, preferably Ra represents Η, Rb represents Η or methyl and Re represents Η, and particularly preferably Ra Representative Η, Rb represents a methyl group and Rc represents Η. In another preferred embodiment, the invention relates to compounds of formula I, wherein R3 represents -COR4, -CONR4R4, -C02R4, -S02R4 or -S02NR4R4', preferably -COR4, -CONR4R4, -CO2R4 or -so2r4 And more preferably -co2r4; R4 represents a C i -8 alkyl group optionally substituted with one or more halo groups, wherein one methyl group of the alkyl chain is optionally replaced by - Ο-; -65- 201041867

Ri and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of: (i) a heterocyclic group containing two nitrogen atoms and containing no other hetero atom, wherein the heterocyclic group The ring group is optionally substituted by 1 or more C, -4 alkyl groups; and (ii) a heterocyclic group containing 1 nitrogen atom and no other hetero atom, wherein the heterocyclic group is 1 - NRaRb is substituted and optionally substituted with 1 or more Ci-4 alkyl; wherein the heterocyclic group (i) and (ii) are 4 to 7 membered monocyclic, 7 to 8 membered bridged bicyclic or 8 to 12 members fused double rings. In another preferred embodiment, the invention relates to compounds of formula I, wherein R3 represents -COR4, -CONR4R4, -CO2R4'-so2r4 or SO2NR4R4, preferably -COR4, -conr4r4, -co2r4 or -S 〇2R4, and more preferably -co2r4; R4 represents a Chs alkyl group optionally substituted with one or more halo groups, wherein one methyl group of the alkyl chain is optionally replaced by -0-; And R2 and together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) to (h), wherein Ra and Rb are as described in the above formula I, and Re and Rd are each Do not represent hydrazine or C, -4 alkyl group. Preferably, Ra, Rb, Rc and Rd each represent hydrazine or a Ch4 alkyl group, and more preferably, Fla, Rc and Rd each represent hydrazine or methyl group, and are very preferred. The grounds Ra, Rb and Rd each represent a hydrazine or a methyl group and Rc represents hydrazine. In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents -COR4, -CONR4R4', -C02R4, -S02R4 or -66-201041867 s〇2NR4R4, preferably - c〇R4, - Conr4r4,, -co2r4 or - so2r4, and more preferably - co2r4; R4 represents a ci-8 alkyl group optionally substituted by one or more halo groups, wherein one of the alkyl chains is selectively methyl- 0_substitution; and R! and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) or (b) wherein Ra and Rb are as described above for the compound of formula I Meaning, and Re represents 11 or Cm alkyl, preferably Ra, Rb and 〇R. Each represents H or an alkyl group, more preferably Ra, Rb and R. Each represents a hydrazine or a methyl group, more preferably Ra and each represent a hydrazine or a methyl group and Rc represents Η 'very preferably Ra represents η, Rb represents η or methyl and L represents Η ' and particularly preferably Ra represents Η 'Rb stands for methyl and Rc stands for η. In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents -COR4, -CONR4R4', -CO2R4, -so2r4 or -so2nr4r4'' preferably -C〇R4, -CONR4R4,, -co2r4 or -so2r4, and more preferably -co2r4; OR4 represents a C!-8 alkyl group optionally substituted with one or more halo groups, wherein one methyl group of the alkyl chain is optionally via -0- Substituting; and Rule 1 and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (a) wherein Ra and Rb are as defined in the above formula I, and Rc represents hydrazine or alkane Base, preferably Ra, Rb and R. Each represents Η or Cm alkyl, more preferably Ra, Rb and Re each represent Η or methyl, more preferably Ra and Rb each represent Η or methyl and Rc represents Η 'very good Ra represents Η, Rb stands for Η or methyl and R. Representative Η, and preferably Ra represents Η, and Rb represents methyl and R. Representative Η. -67- 201041867 In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents _C0R4, -CONR4R4, -C02R4'-S〇2R4 or -S02NR4R4', preferably -C〇R4,- CONR4R4,, -CO2R4 or -so2r4, and more preferably -C 0 2 R 4 ; R4 represents a C1-8 alkyl group optionally substituted by one or more halo groups, wherein one of the alkyl chains is methyl Alternatively, R1 and R2, together with the nitrogen atom to which they are bonded, form a saturated heterocyclic group of formula (b) wherein Rb is as defined in the above formula I, and R . Represents hydrazine or G.4 alkyl, preferably Ra, Rb and R. Each represents a hydrazine or a Cm alkyl group, more preferably Ra, Rb and R. Each represents Η or methyl, preferably Ra and Rb each represent Η or methyl and Rc represents Η, and preferably Ra stands for Η ' Rb stands for Η or methyl and Re stands for Η, and particularly preferably Ra stands for H' Rb represents a methyl group and 11 (; represents Η. In another preferred system, the invention relates to a compound of formula I, wherein R3 represents -COR4, -conr4r4, -C02R4, -S02R4 or -S02NR4R4, preferably -C〇R4, -CONR4R4, -C02R4 or -SO2R4, and more preferably -C〇2R4; R4 represents R 5 - ci _ 8 alkyl, wherein the alkyl group optionally passes through one or more halogen Substituent and wherein one methyl group of the alkyl chain is optionally substituted by -〇-; r5 represents -conr4'r7, -NR4, COR7, _nr4, co2r7, -NR4 SO2R7, -SO2NR4 R7 '-NR4, CONR4, R7, -CONHSO2R7, -CO2R7, _〇COR7, -SO2R7, -NR4, R_7, -〇H or 1H - four-portion -5-based, preferably -NR4, R7; and -68- 201041867

Rt and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of: (i) a heterocyclic group containing two nitrogen atoms and containing no other hetero atom, wherein the heterocyclic group The cyclic group is optionally substituted by one or more (^-4 alkyl groups; and (ii) a heterocyclic group containing one nitrogen atom and no other hetero atom, wherein the heterocyclic group is via one -NRaRb Substituted and optionally substituted with 1 or more Cm alkyl groups; wherein the heterocyclic groups (i) and (ii) are 4 to 7 membered monocyclic, 7 to 8 membered bridged double rings or 8 to 12 members A fused bicyclic ring. In another preferred embodiment, the invention relates to a compound of formula I, wherein r3 represents -cor4, -CONR4R4, -co2r4, -so2r4 or -so2nr4r4, preferably -cor4, -conr4r4, - Co2r4 or - so2r4, and more preferably -co2r4; R4 represents an alkyl group, wherein the alkyl group is optionally substituted with one or more halo groups and wherein one of the alkyl chains is optionally methylated -〇-replacement;

Rs represents -C〇NR4, R7, -NR4, COR7, -NR4, C02R7, -NR4'S〇2R7, -S02NR4, R7, -NR4, CONR4, R7, -CONHSO2R7, -CO2R7, -〇COR7, -s〇2R7 , -NR4, R7, -OH or 1H-tetrazol-5-yl, preferably -NR4, R7;

Ri and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) to (h) wherein Ra and Rb are as defined in the compound of formula I above and R. And Rd each represents Η or Q-4 alkyl, preferably -69- 201041867

Ra, Rb, Re and Rd each represent an anthracene or a d-4 alkyl group, more preferably Ra, Rb, Rc and Rd each represent η or a methyl group, and very preferably Ra, Rb and Rd each represent Η or Methyl and Rc represent η. In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents -COR4, -CONR4R4, -CO2R4, -SO2R4 or -S02NR4R4" preferably - c〇R4, -CONR4R4, -C02R4 or -SO2R4, and more preferably - co2r4; R4 represents Rs-Ci-s alkyl, wherein the alkyl group is optionally substituted with one or more halo groups and wherein one of the alkyl chains is methyl-selectable Ground replaced by -0;

Rs represents -conr4, r7, -nr4, cor7, -nr4, co2r7, -NR4, SO2R7, -S02NR4, R7, -NR4 CONR4 R? '-CONHSO2R7, -C02R7, -OCOR7, -SO2R7, -NR4, R7, - OH or 1H-tetrazol-5-yl, preferably -NR4, R7;

Ri and R·2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) or (b) wherein Ra and Rb are as defined in the above formula I, and Re represents Or a Cu alkyl group, preferably Ra, Rb and Rc each represent a fluorene or a Cy alkyl group, more preferably Ra, Rb and Re each represent a hydrazine or a methyl group. More preferably, Ra and Rb each represent Η or methyl and Rc represents Η, very preferably Ra stands for Η, Rb stands for Η or methyl and R. Representative Η, and particularly preferably Ra stands for Η, Rb stands for methyl and Rc stands for Η. In another preferred embodiment, the invention relates to a compound of formula I, wherein R; represents -cor4, -CONR4R4', -C02R4, -S02R4 or -S02NR4R4, preferably -COR4, -CONR4R4, -C02R4 or - S〇2r4 -70- 201041867, and more preferably -co2R4; R4 represents an R5-C alkyl group, wherein the alkyl group is optionally substituted with one or more halo groups and wherein one of the alkyl chains is methyl Optional to be replaced by -0-;

Rs represents -CONR4, R7, -NR4 COR7 &gt; -NR4, C02R7, -NR4, S02R7, -S02NR4, R7, -NR4'CONR4, R7, -CONHSO2R7, -C02R7, -OCOR7, -S02R7, -NR4'R7 , -oh or 1H-tetrazole-0 5-yl, preferably -NR4, R7;

Ri and β·2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of the formula (a), wherein Ra and Rb are as defined in the above compound of the formula I, and Re represents Η or (^. 4 alkyl, preferably Ra, Rb and R. Each represents Η or Cm alkyl, more preferably Ra, Rb and R. Each represents Η or methyl, more preferably Ra and Rb each represent Η or methyl and Rc represents Η, preferably Ra represents Η, Rb represents Η or methyl and Rc represents Η, and particularly preferably Ra represents Η, Rb represents methyl and Rc represents Η. 另一In the system, the invention relates to a compound of formula I, wherein R3 represents -COR4, -CONR4R4', -CO2R4'-SO2R4 or -S02NR4R4, preferably -COR4, -CONR4R4, -C02R4 or -S02R4, and more preferably -co2r4; R4 represents Rs-C^.8 alkyl, wherein the alkyl group is optionally substituted with one or more halo groups and wherein one of the alkyl chains is optionally substituted by -? ; r5 represents -conr4'r7, -NR4 COR7 ' -nr4,co2r7, -NR4 SO2R7 ' -S02NR4,R7,-NR4 CONR4 R7 ' -CONHSO2R7 -71 - 201041867 ,-CO2R7,-OCOR7,-S〇2R7,- NR4'r7, ·〇η or 1H_ Four sitting _ 5-base, preferably -NR4, R7;

Ri and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (b) wherein Ra and Rb are as defined in the above formula I, and Re represents deuterium or C!-4 alkane Preferably, Ra, Rb and Re each represent a hydrazine or a Ch alkyl group, more preferably Ra, Rb and r. Each represents η or methyl, preferably Ra and Rb each represent a hydrazine or a methyl group and Rc represents Η, and preferably Ra represents H, and Rb represents hydrazine or methyl and R. Representative Η, and preferably Ra represents Η, Rb represents a methyl group and Rc represents η. In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents -COR4, -CONR4R4', -C02R4, -so2r4 or -S02NR4R4, preferably -COR4, -CONR4R4, -C〇2R4 or -so2r4, and more preferably -co2r4; R4 represents R6-C〇-8 alkyl, preferably R6-C&quot;alkyl, any of which is optionally substituted by one or more halo groups and wherein A methyl group of the alkyl chain is optionally substituted by -0-; R6 represents a C3-8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, preferably a c3-8 cycloalkyl group, an aryl group. Or a heteroaryl group and more preferably an aryl or heteroaryl group, wherein R6 is optionally selected from one or more independently selected from the group consisting of c, -8 alkyl, halogen Ci-8 alkyl, halogen 'Cu alkoxy, halogen Cu alkoxy, C 丨 8 alkylthio, -CN, C 2 . 4 alkynyl, R 5 -C 0 -8 alkyl or R 8 -C 0 - 8 alkyl group; and R, and R2 and together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from the group consisting of: -72- 201041867 (i) a heterocyclic group containing 2 nitrogen atoms and containing no other hetero atom The heterocyclic group is optionally substituted with 1 or more alkyl groups; and (ii a heterocyclic group containing 1 nitrogen atom and containing no other hetero atom, wherein the heterocyclic group is substituted with 1 -NRaRb group and optionally substituted with 1 or more mountain-4 alkyl groups; The heterocyclic groups (i) and (Π) are 4 to 7 membered monocyclic rings, 7 to 8 membered bridged bicyclic rings or 8 to 12 membered fused bicyclic rings. In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents -cor4, -CONR4R4, -C02R4, -so2r4 or -S〇2NR4R4, preferably -COR4, -CONR4R4, -CO2R4 or - so2r4, and more preferably - co2r4; R4 represents R6-Cq-8 alkyl, preferably R6-Cl-8 alkyl, wherein any -alkyl is optionally substituted by one or more halo groups and wherein the alkane One methyl group of the base chain is optionally substituted by -〇-; O R6 represents a c3-8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, preferably a c3-8 cycloalkyl group, an aryl group or a heteroaryl group and more preferably an aryl or heteroaryl group, wherein R6 is optionally selected from one or more independently selected from the group consisting of Cu alkyl, halo 8, halogen, C1-8 alkoxy, halogen Ci_8 Substituted by a base of a Ci-8, a thiol group, a -CN, a C2-4 alkynyl group, an R5-CQ-8 alkyl group or an R8-C〇-8 alkyl group;

Ri and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) to (h), wherein Ra and Rb are as defined in the above formula I, and R e and R d each represents Η or C 1 -4 yard base, preferably -73- 201041867

Ra, Rb, Re and Rd each represent hydrazine or Ci. 4 alkyl, more preferably Ra, Rb, Rc and Rd each represent hydrazine or methyl, and very preferably Ra, Rb and Rd each represent hydrazine or Methyl and Re represents hydrazine. In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents -COR4, -CONR4R4, -C02R4, -SO2R4 or -S02NR4R4, preferably -COR4, -CONR4R4, -C02R4 or -SO2R4 And more preferably - C〇2R4; R4 represents R6-C〇_8 alkyl, preferably R6-CM alkyl, wherein any alkyl group is optionally substituted with one or more halo groups and wherein One methyl group of the alkyl chain is optionally substituted with -〇-; R6 represents a C3-8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, preferably c3.8 cycloalkyl, aryl Or a heteroaryl group and more preferably an aryl or heteroaryl group, wherein the r6 group is optionally selected from one or more independently selected from the group consisting of Cu alkyl, succinyl, halogen, Cl. Substitution of C1-8 alkoxy, Ci_8 thiol, -CN, C2-4, or R5-Cq_8 or R8-Cq-8

Ri and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a) or (b), wherein Ra and Rb are as defined in the above formula I, and Re represents deuterium or Ci-4 alkyl, preferably Ra, Rb and Rc each represent an anthracene or a Cu alkyl group, more preferably Ra, Rb and Rc each represent an anthracene or a methyl group, more preferably Ra and Rb each represent Η or methyl and Rc represents Η, very preferably Ra stands for Η, Rb stands for Η or methyl and R. Representative Η, and particularly preferably Ra stands for Η, and Rb stands for methyl and R. Representative Η. In another preferred embodiment, the invention relates to a compound of formula I, wherein -74- 201041867 R3 represents -COR4, -CONR4R4', -CO2R4, -so2r4 or S02NR4R4, preferably -COR4, -CONR4R4, - C02R4 or - so2r4, and more preferably - co2r4; R4 represents R6-C〇-8 alkyl 'preferably RrCu alkyl' wherein any alkyl group is optionally substituted by one or more halo groups and wherein One methyl group of the alkyl chain may be optionally substituted by -〇-; R6 represents a C3_8 cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, preferably a C3_8 cycloalkyl group, an aryl group or a heterocyclic group. Aryl and more preferably aryl or heteroaryl, wherein R6 is optionally selected from one or more independently selected from the group consisting of Cu alkyl, halo C, -8 alkyl, halogen 'Cu alkoxy, halo cU8 alkoxy a base substitution of a 'Cu alkylthio group, -CN, c2.4 alkynyl group, R5-CG_8 alkyl group or R8-CG-8 alkyl group: and 1 and R2 together with the nitrogen atom to which they are bonded form ( a) a saturated heterocyclic group, wherein Ra and Rb are as defined in the above formula I, and Re represents Η or C! -4 alkyl, preferably Ra, Rb and Rc each represent Η or C ! .4 alkyl, more preferably Ra, Rb and Re Each represents Η or methyl'. More preferably, Ra and Rb each represent fluorene or methyl and Rc represents Η 'Very well Ra stands for Η, Rb stands for Η or methyl and Rc stands for Η, and particularly preferably Ra stands for Η, Rb represents a methyl group and Rc represents Η. In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents -COR4, -CONR4R4, -C02R4, -so2r4 or -S02NR4R4" preferably -COR4, -CONR4R4, -C02R4 or -so2r4 And more preferably - co2r4; R4 represents R6-Cq_8 alkyl, preferably R6_Cl_8 alkyl, any of -75-201041867 alkyl is optionally substituted by one or more halo groups and wherein the alkyl chain One of the methyl groups may alternatively be replaced by 〇-; R6 represents a c3-s cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, preferably a c3-8 cycloalkyl, aryl or hetero Aryl and more preferably aryl or heteroaryl, wherein R6 is optionally selected from - or independently selected from the group consisting of Cu alkyl 'halo C, -8 alkyl, halogen, Cu alkoxy, halo alkoxy Substituents of a base, a Ci.8 alkylthio group, a -CN, a C2.4 alkynyl group, an R5-CG-8 alkyl group or an R8-CQ-8 alkyl group:

Ri and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (b) wherein Ra and Rb are as defined above for the compound of formula I, and Rc represents hydrazine or Cm alkyl, Preferably, Ra, Rb and Re each represent hydrazine or Cm alkyl group. More preferably, Ra, Rb and Re each represent η or methyl group. More preferably, Ra and Rb each represent fluorene or methyl and Re represents Η , very preferably, Ra stands for Η, Rb stands for Η or methyl and Re stands for Η, and particularly preferably Ra stands for Η, Rb stands for methyl and RC stands for Η. Further, the present invention includes all possible combinations of the specific and preferred systems described above. In another preferred embodiment, the invention is directed to a compound of formula I selected from the ones listed in Examples 1 to 77. In another preferred embodiment, the invention relates to a compound of formula I which is capable of being assayed in a Η 4 receptor (such as Example 78) with 〇μ Μ (more preferably 1 μ Μ and particularly preferably 1 1 μ μ). Or 79 describes the inhibition of histamine Η4 receptor activity by more than 50%. The compounds of the invention contain one or more basic nitrogens and are therefore capable of forming salts with the organic -76-201041867 acid or inorganic acid. Examples of such salts include, in particular, inorganic acids (such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid) and organic acids (such as methanesulfonic acid, trifluoromethanesulfonic acid, Ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trans-butenedioic acid, oxalic acid, acetic acid, maleic acid, ascorbic acid, citric acid, lactic acid, tartaric acid, malonic acid, glycolic acid, succinic acid and Salt of propionic acid). The compounds of the present invention may contain one or more acidic protons and may therefore also form salts with bases which are also part of the present invention. Examples of such salts include salts formed with inorganic cations such as sodium, potassium, calcium, magnesium, lithium, aluminum, zinc, and the like, and with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxyalkylamines, and a salt formed by aminic acid, arginine, N-methylglucamine, procaine, and the like. There is no limitation on the type of salt that can be used, provided that the salt is pharmaceutically acceptable for therapeutic purposes. A pharmaceutically acceptable salt is a salt which, in accordance with medical judgment, is suitable for contact with tissues of the human body and other mammals without causing excessive toxicity, irritation, allergic reaction and the like. Pharmaceutically acceptable salts are well known in the art. Salts of the compounds of formula I can be prepared by reacting a salt of a compound of formula I during the final isolation and purification of a compound of the invention or by reacting a compound of formula I with a sufficient amount of the desired acid in a conventional manner. The salt of the compound of formula I can be converted to other salts of the compound of formula I by ion exchange using an ion exchange resin. The compound of formula I and its salts may differ in certain physical properties, but for the purposes of the present invention Words are equivalent. The scope of the invention includes all salts of the compounds of formula I. -77- 201041867 The compound of the present invention may form a complex with a solvent capable of reacting therewith or with a solvent in which precipitation or crystallization can be precipitated. These complexes are referred to as solvates. As used herein, a solvate refers to a complex formed from a solute (a compound of formula I or a salt thereof) and a solvent in a variable stoichiometry. Examples of the solvent include pharmaceutically acceptable solvents such as water, ethanol and the like. The complex formed with water is called a hydrate. The scope of the present invention encompasses solvates of the compounds (or salts thereof) of the present invention, which include hydrates. The compounds of formula I may exist in different physical forms (i.e., amorphous or crystalline). Furthermore, the compounds of the invention can be crystallized in more than one type (i.e., polymorphic). Polymorphs can be distinguished by the different physical properties known in the art, such as X-ray diffraction patterns, melting points or solubility. The scope of the invention encompasses all physical forms of the compounds of formula I, including all polymorphic forms thereof ("polymorphs"). Certain compounds of the invention may exist in the form of several optical isomers and/or several non-image areomers. The non-image isomers can be separated by conventional techniques such as chromatography or fractional crystallization. The optical isomers can be resolved by conventional optical resolution techniques to form optically pure isomers. This resolution can be carried out by using any chiral synthetic intermediate or product of the formula. Optically pure isomers can also be obtained separately by mirror-specific synthesis. The present invention includes all individual isomers and their mixtures (e.g., mixtures of racemic or non-mirromeric isomers) obtained by synthesis or by physical mixing of such isomers. Any of the formulae described herein are also intended to indicate an unlabeled version of the compound and an isotope-labeled version having the structure shown by the formula, wherein only one or more of the atoms are An atom with a selected atomic weight or atomic number. Examples of isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as 2H, 3h, 1 i, 13C, 14C, 15N, 180, 17〇, respectively. 31p, 32p, 35S, 18F, 36CI and 125l. The isotope-labeled compounds are used for metabolic studies (preferably using 14C), reaction kinetic studies (using, for example, 2H or 3H), detection or imaging including drug or substrate tissue distribution assays. Techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), or radioactive treatment of patients. Specifically, compounds labeled with 18F or 11 C are particularly useful for PET or SPECT studies. Further, substitution with heavier isotopes such as deuterium (ie, 2H) may provide certain therapeutic benefits resulting from better metabolic stability (eg, increase in vivo half-life or reduce dosage requirements), and by performing reaction patterns or The method disclosed in the examples and the preparation method described below and using commercially available isotope-labeled reagents instead of the isotope-labeled reactants, generally can be used to prepare the isotope-labeled compounds of the present invention and the like. medicine. The compound of formula I can be obtained by following the methods described below. It will be apparent to those skilled in the art that the precise method for preparing a given compound can vary depending on the chemical structure of the given compound. Further, in some of the following methods, it may be necessary or recommended to protect the reactive group or the unstable group using a conventional protecting group. The nature of such protecting groups and the methods of introducing or removing such protecting groups are well known in the art (see, for example, the literature Greene T.W. and Wuts P.G.M, "Protective Groups in -79- 201041867".

Organic Synthesis", John Wiley &amp; sons, 3rd edition, ι 999. Unless otherwise stated, 'in the following methods, the meaning of the different substituents for the compound of formula I is as described above. Generally speaking From the final step of the synthesis reaction carried out by a compound of formula II or a reactive derivative of a hydrazine compound (i.e., a compound of formula IIB) can be obtained by incorporation of R3 to give a compound of formula I.

Wherein R, and R2 are as defined in the compounds of formula I above and X represents CO or so2. In general, an equivalent reaction can be applied in one or several steps using a typical reaction of organic chemistry and under standard conditions as is conventional. For example, a compound of the formula 1 (wherein R3 represents -COR4) can be conveniently prepared by reacting a compound of the formula π with an acid or an acid chloride of the formula R4_COY (wherein Y is 0H or C1). -80 - 201041867 by reacting a compound of formula II with an isocyanate (r4_NC〇) or an amine formamidine chloride (R4R4'-NCOW 'where W is a leaving group such as, for example, C1 or p-_n〇2_phenoxy) A compound of formula I is prepared (wherein r3 represents _c〇NR4R4,). Alternatively, a compound of formula I can be prepared by reacting a compound of formula II with triphosgene or carbon ruthenium chloride (also known as phosgene) to form compound IIB (wherein X = C〇) and subsequently reacting with an amine of formula NHRA4'. (There is -CONR4R4,).化合物 A compound of formula I (wherein R3 represents -co2r4) can be prepared by reacting a compound of formula 11 with a chloroformate (R4-OCOC1). Alternatively, by reacting a compound of formula II with an R4-OH alcohol (the R4-OH alcohol has been previously reacted with a suitable coupling agent in a suitable solvent such as, for example, prior to carbonyldiimidazole (CDI) in dichloromethane. Reaction (see literature (eg CG Bochet et al. Tetrahedron Lett 42, 2000, 5227)) reaction, reaction with carbon ruthenium chloride or its derivatives (diphosgene or triphosgene) (in solvent such as dichloromethane, In chloroform or dioxane, in the presence of a base such as triethylamine or diisopropylguanidinium and optionally under the catalysis of 4-dimethylaminopyridine, with dichloromethane In the reaction of di(2-pyridyl)carbonate (DPC) (in the presence of a base such as triethylamine) or diamyl sulfonate in methylene chloride (such as a special The compound of formula I (wherein R3 represents -co2r4) can be prepared in the presence of triethylamine. Alternatively, a compound of formula I (wherein Κ·3 series-CO2R4) can be prepared by reacting a compound of formula II with triphosgene or carbon chlorohydrazine to form compound IIB (where x = co) and subsequently reacting with r4-oh alcohol. ). A compound of formula I (wherein R3 represents -S02R4) can be prepared by reacting a compound of formula II with sulfonium chloride (R4-S02C1). A compound of formula I (wherein R3 represents _S〇2NR4R4,) can be prepared by reacting a compound of formula II with amidoxin chloride (R4R4, _ns〇2C1). Alternatively, a compound of formula I (wherein R3 is -SO2NR4R4,) can be prepared by reacting a compound of formula II with thioindigo to form compound IIB (wherein X = S〇2) and subsequently reacting with R4R4'NH amine. The compound of formula II can be produced by reacting a hydroxy derivative of formula IV with an amine of formula III as shown in the reaction scheme below:

Wherein L and R2 are as defined in the compounds of formula I above, P represents a protecting group and R9 represents a leaving group such as a halogen, a triflate or a tosylate. In a suitable solvent (preferably a mixture of acetonitrile or acetonitrile and I,4-dioxane) and a base (preferably -82-201041867 triethylamine) at a temperature between room temperature and reflux temperature. In the presence of a coupling agent such as, for example, p yB 〇p (benzotriazol-1-yl-oxytripyridylpyridinium hexafluorophosphate), the reaction of the compound of formula IV with a compound of formula 111 can be carried out. . Alternatively, by reacting a compound of formula III with a reactive derivative of a compound of formula IV (i.e., a compound of formula IVB, which is prepared by converting a hydroxyl group on a compound of formula IV to a leaving group (such as a halogen, trifluoromethanesulfonate) The compound of formula II can be obtained by reacting an acid ester or a tosylate, preferably chlorine. 〇 Therefore, it can be optionally reacted with a halogenating agent in the presence of a suitable solvent (such as POCl3 (see Journal of Medicinal Chemistry 1 998, 4 1,3 793)) or in a suitable solvent (such as 1,4- The compound of formula IV can be reacted in the presence of dioxane, 1,2-dichloroethane or propionitrile by reaction with a halogenating agent P0CI3/PC15 or a mixture of N,N-dimethylformamide/grass chloride The hydroxyl group is converted to a leaving group such as a halogen, preferably chlorine. The reaction is carried out by heating (preferably at a temperature of from 7 ° C to 140 ° C). Similarly, the hydroxyl group of the compound of formula IV can be converted to the triflate group by reaction with trifluoromethanesulfonic anhydride in the presence of pyridine. The resulting reactive derivative of the compound of formula IV (i.e., the compound of formula IVB) is then reacted with a compound of formula III to form a compound of formula η. The reaction is carried out in a suitable solvent such as ethanol, methanol, butanol, N,N-dimethylformamide, dimethyl hydrazine, tetrahydrofuran or toluene, preferably methanol or ethanol, in the base (which includes In the presence of an organic amine such as triethylamine, N,N-diisopropylethylamine, dimethylaniline and especially diethylaniline, and under heating (preferably at 10 ° C or Performed at reflux temperature). The reaction can be heated by microwave or by microwave irradiation due to the power at which the above temperatures can be reached. -83- 201041867 In general, the piperidinyl group of the compound of formula IV or IVB is protected by (P-based) prior to the reaction of the compound of formula IV with a compound of formula III or a compound of formula IVB with a compound of formula III to avoid the formation of by-products. A subsequent deprotection step is required to generate the hydrazine compound. Any suitable protecting group for the amino functionality can be used, such as, for example, benzyloxycarbonyl. This subsequent deprotection step is carried out under typical conditions such as, for example, hydrogenation with Pd/C in a suitable solvent such as methanol or ethanol. Likewise, the amino substituent of the compound of formula π I can be again protected to avoid the formation of by-products. The amine groups of the compounds of formula IV and IVB can also be protected if necessary. Any suitable protecting group can be used, such as, for example, a tertiary butoxycarbonyl group (Boc). When the amine substituent of the compound of formula IV and / or III and / or IVB is protected, it may be necessary to carry out a deprotection step which is subsequently carried out under typical conditions. Generally, when the amine substituent of the hydrazine compound is protected, the deprotection reaction is carried out on the compound of formula I, often after conversion of the hydrazine compound to the compound of formula I. Thus, when protecting the group B〇c, it can be reacted with a strong acid (such as HCl) and preferably in dichloromethane by a suitable solvent such as 1,4-dioxane, diethyl ether or methanol. The trifluoroacetic acid is reacted to carry out the deprotection reaction. The compound of formula III is commercially available or can be prepared by methods described in the literature. The compound of formula IV can be prepared by reacting a compound of formula V with a phosphonium salt (preferably hydrochloride) as shown in the reaction scheme below: -84- 201041867

Wherein p represents a protecting group. The reaction is carried out in a suitable solvent, preferably ethanol, and in the presence of a base such as potassium carbonate, potassium trisoxide or sodium methoxide, preferably sodium ethoxide. The reaction can be carried out by heating to a suitable temperature (usually between room temperature and reflux temperature) and preferably at reflux temperature. The compound of formula v is commercially available or can be readily prepared from commercially available compounds by conventional methods. Alternatively, as in the reaction scheme shown below, Formula I can be prepared from a derivative of a compound of formula VI by reaction with a compound of formula VII under the same conditions as described for the conversion of a compound of formula IV to a compound of formula 11 Compound: 〇ΝΗ,

+ hnr1r2 ΝΗ〇 nr,r2 wherein R1, R2 and R3 are as defined in the above formula I compounds. The compound of the formula -85- 201041867 VI can be prepared by a method similar to that described for the preparation of the compound of the formula IV. The incorporation of r3 can be carried out by a method similar to that described for the preparation of a compound of formula I from the preparation of a compound of formula II or IIB. Further, some of the present invention may also be obtained by a reaction known in the art of organic chemistry and under standard experimental conditions, by one or more steps, by a suitable functional group conversion reaction, starting from other compounds of formula I. Compound. As stated previously, the compounds of the invention exhibit potent histamine h4 receptor antagonist activity. Thus, the compounds of the invention are expected to be useful in the treatment of diseases in mammals, including humans, via the h4 receptor vector. The h4 receptor-mediated diseases which can be treated or prevented by the compounds of the present invention include, in particular, allergic, immune or inflammatory diseases or pain. Examples of allergic, immune or inflammatory diseases which can be treated or prevented by the compounds of the invention include, but are not limited to, respiratory diseases such as asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD); eye diseases such as allergic rhinoconjunctivitis, dry Eye and cataract; skin diseases such as dermatitis (eg atopic dermatitis), psoriasis, measles and dying; intestinal inflammatory diseases such as ulcerative colitis and Crohn's disease; rheumatoid arthritis Multiple sclerosis; cutaneous lupus; systemic lupus erythematosus; and transplant rejection. Examples of pain symptoms that can be treated or prevented by the compounds of the present invention include, inter alia, inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-operative pain, migraine, cancer pain, visceral pain, osteoarthritis pain, and neuropathy. pain. In a preferred system, the compounds of the invention are used to treat or prevent allergic, immune or inflammatory diseases. In a more preferred system, the compound of the present invention is used for the treatment or prevention of a respiratory disease, an eye disease, a skin disease, an intestinal inflammatory disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, and a whole body selected from the group consisting of respiratory diseases, eye diseases, skin diseases, intestinal diseases, 86-201041867 Allergic, immune or inflammatory disease of lupus erythematosus or transplant rejection. In yet another preferred system, the allergic, immune or inflammatory disease is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataract, dermatitis (eg, different) Position dermatitis), psoriasis, urticaria, jatropha, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus or transplant rejection. In another preferred system, 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 closure Inflammation pain and neuropathic pain. Analysis of the ability of compounds to interact with histamine H4 receptors is well known in the art. For example, H4 receptor binding assays can be used, as described in Example 78. Another useful assay is the GTP [y-35S] binding assay that binds to the cell membrane of the H4 receptor. Functional assays for cells expressing the H4 receptor can also be used, for example, by measuring in the system any cell activity, such as intracellular cAMP amount or Ca2, mediated by a second messenger associated with the H4 receptor. + transfer. In this regard, a highly useful functional assay for the determination of anti-H4 receptor activity is a self-contained autologous egg-like advancement of eosinophils (eg, human eosinophils) as detailed in Example 79. Gated Autofluorescence Forward Scatter assay (GAFS); this analysis is known to the art (see, for example, the literature by Buckland KF et al, 2003 (cited in the above-mentioned prior art section -87 - 201041867) The method disclosed herein is incorporated by reference). In vivo assays useful for testing the activity of the compounds of the invention are also known in the art (see, for example, the above-mentioned prior art section for the various references listed in the in vivo animal model, particularly with peritonitis, pleurisy, Allergic asthmatic, intestinal inflammatory diseases, atopic dermatitis, hypertrophy and pain in vivo models are relevant, all of which are incorporated herein by reference. The selective profile of the compounds of the invention can be tested using a standard histamine receptor binding assay similar to that described in Example 78 using a variety of different histamine receptors. In addition, to test for selectivity to other receptors or ion channels, the corresponding radioligand can be used in accordance with the standard methods reported in the literature (see, for example, the Cerep-Le Bois l'EWque 2008 catalogue and references cited therein). Displacement analysis. In order to select the active compound, the test carried out at 10 μΜ in the test provided in Example 78 must produce an activity which inhibits the H4 receptor by more than 50%. In this analysis, the compound should preferably have an activity of more than 50% inhibition at 1 μΜ (still more preferably 0.1 μΜ). Preferred compounds should also have potent activity in the GAF S assay of Example 79; in this assay, the compound should preferably be at 10 μΜ (more preferably 1 μΜ and still more preferably 1 μΜ) It has an activity of inhibiting more than 5% by weight. Preferred compounds should have a more selective affinity for the Η4 receptor than for other receptors, particularly the Η3 receptor. 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 of -88-201041867. Such excipients must be &quot;acceptable&quot; to be miscible with the other ingredients of the composition and are not deleterious to the recipient. The compounds of the present invention can be administered in the form of any of the pharmaceutical modulators, the nature of which will depend on the nature of the active compound and the route of administration. Any administration route can be used, such as oral, parenteral, nasal, ocular, topical, and rectal administration. In a preferred system, the compounds of the invention are administered orally. In another preferred embodiment, the compounds of the present invention are administered topically. Solid compositions for oral administration include tablets, granules and capsules. In any event, the method of manufacture is based on simple mixing, dry granulation or wet granulation of the active compound with excipients. The excipient can be, for example, a diluent such as lactose, microcrystalline cellulose, mannitol or dibasic calcium phosphate, a binding agent such as, for example, starch, gelatin or polyvinylpyrrolidone, a disintegrating agent such as a carboxy group. Sodium methyl starch or croscarmellose sodium) and a lubricant such as, for example, magnesium stearate, stearic acid or talc. The sputum tablet can be additionally coated with a suitable excipient to achieve the purpose of disintegration and absorption delay of the tablet in the gastrointestinal tract by using conventional techniques, thereby providing a sustained action for a longer period of time' or simply Improve the special sensation or stability of the tablet. The active compound can also be applied to the inert tablet by the use of a natural or synthetic film coating. Soft gelatin capsules are also possible in which the active compound is mixed with water or an oily vehicle such as coconut oil, mineral oil or olive oil. Powders and granules of the oral suspension can be prepared by adding water by mixing the active compound with a dispersing or wetting agent, suspending agent and preservative. Other excipients (such as sweeteners, fragrances, and coloring -89-201041867) may also be added. Liquid forms for oral administration include emulsions, solutions, suspensions, syrups and elixirs containing conventional inert diluents such as purified water, ethanol, sorbitol 'glycerol, polyethylene glycol, and propylene glycol. These compositions may also contain co-adjuvants (such as wetting agents, suspending agents, sweetening, perfuming agents, preservatives, and buffering agents). According to the present invention, a parenteral injectable preparation comprises a sterile solution, suspension or emulsion in a water-soluble or water-insoluble solvent such as propylene glycol, polyethylene glycol or vegetable oil. These compositions may also contain co-adjuvants (such as wetting agents, emulsifying agents, dispersing agents, and preservatives). The compositions may be sterilized by any conventional means or prepared into a sterile solid composition. The sterile solid composition will dissolve in water or any other sterile injectable medium immediately prior to use. It can also be initiated from sterile materials and maintained under sterile conditions throughout the manufacturing process. The compounds of the invention may also be formulated for topical administration to treat conditions which occur in areas or organs accessible through such routes, such as the eye, skin and intestines. Modulators include lotions, lotions, gels, powders, solutions, and patches, wherein the compound is dispersed or dissolved in a suitable vehicle. For nasal or inhalation administration, the compound can be formulated into an aerosol and the compound can be conveniently liberated from the aerosol using a suitable propellant. The dosage form and dosage frequency will depend, inter alia, on the nature and severity of the condition to be treated, the age, general condition and weight of the patient, and the particular compound and route of administration to which it is administered. As an example, a suitable dosage range is from about 0.01 mg/kg to about 100 mg/kg per day, and such doses can be administered in a single dose of -90-201041867 or divided into several doses. The invention will now be illustrated by the following examples. [Embodiment] The following abbreviations are used in the examples:

AcN: acetonitrile EtOAc: ethyl acetate 〇Cone: thick (condensed) DIEA: Ν, Ν-diisopropylethylamine EtOH: ethanol hydrazine: hour BTUH: 0-benzotriazol-1-yl-hydrazine, hydrazine, Ν',Ν'-tetramethyl hexafluorophosphate urethane

MeOH: methanol Min : min Ο M S : mass spectrometry

PyBOP: (benzotriazole-1-yloxypyrrolidinyl hexafluorophosphate) TEA: triethylamine THF: tetrahydrofuran tR: residence time LC-MS: liquid chromatography-mass spectrometry using one of the following methods Determination of LC-MS spectra: Method 1: X-Terra MS C18 column 5 μπχ (100 X 2.1 mm), temperature 30 ° C, flow rate 0.3 5 ml / min, the solution was A = AcN, B = -91 - 201041867 NH4HC〇3 10 mM, gradient 0 minutes A 10%, 1 minute A 90 &lt;) / ◦ and 1 5 minutes A 9 0 %. Method 2: Acquity UPLC BEH C18 column l.7 μιη (2.1 X 50 mm), temperature 40 ° C, flow rate 0.5 0 m 1 /min, elution solution A = AcN, B = NH4HCO3 10 mM, gradient 0 Minutes A 1〇%, 〇·25 minutes A 10%, 3.00 minutes A 90% and 3.75 minutes A %. Reference Example 1 Methyl [(3R)-pyrrolidin-3-yl]aminecarboxylic acid tert-butyl butyl ester (a) [(3R)-1-benzylpyrrolidin-3-yl]methylaminecarboxylic acid tert-butyl A solution of di-tertiary butyl carbonate (II·6 g, 53.〇7 mmol) dissolved in CH2C12 (15 ml) was added to the cooled (3R)_1-knot-N under TC - a solution of methylpyrrolidine-3-amine (10 g, 5 2.55 mmol) in CH2C12 (1 15 ml). The resulting solution was stirred at room temperature for 18 hours. The solvent was evaporated and the crude product was passed. Chromatography (using a hexane/Et0Ac mixture of increasing polarity as the eluent) to give the desired compound (14.5 g, yield 95%) 〇LC-MS (method 1): tR = 9.55 min; m/z = 291 (MH + ) (b) The title compound is heated under reflux with the above compound (1 4 · 5 g, 5 0 _ 1 4 mmol), Pd/C (10%, 50% in water) (3 g) And a solution of ammonium formate (12.7 g, 200.5 mmol) in a mixture of MeOH (3 90 ml) and water (45 ml) for 5 hours. The reaction was filtered over Celite and filtered. Rinse with -92 - 201041867 E t Ο Λ c and Me Ο H. Evaporate the solvent to dryness to generate The title compound (10.6 g, yield 100%). 'H NMR (3 00 MHz, CDC13) δ: 1.38 (s, 9H), 1.72 (m, 1H), 1.96 (m, 1H), 2.53 (s , NH), 2.80 (s, 3H), 2.87 (m, 1H), 2.93 (m, 1H), 3.11 (m, 2H), 4.58 (m, 1H). Reference Example 2 Indole tetrahydroanthracene-3 3-tert-butyl (meth)amine carboxylic acid (a) tert-butyl butyl [1-(diphenylmethyl)tetrahydroindol-3-yl]methylaminecarboxylate, similar to Reference Example 1 Part (a) of the method described, but using 1-(diphenylmethyl)-N-methyltetrahydroindol-3-amine instead of (311)-1-pyringyl-N-methylindole The compound was obtained as a desired compound (3 3 % yield). LC-MS (method 1): tR = 10.14 min; m/z = 3 53 (MH + ) O (b)

The compound obtained above (6.18 g, 17.53 mmol) in MeOH

The solution in (60 ml) and EtOAc (15 ml) was washed with argon. Pd/C% (10%, 5% water) (929 mg) was added and the solution was again purged with argon and stirred under hydrogen for 18 hours. The reaction was filtered through Celite® and the filtrate was washed with EtOAc and MeOH. The solvent was evaporated to dryness to give a mixture of the title compound and 1 equivalent of diphenylmethane (5.66 g) which was used directly in the next step. 4 NMR (3 00 MHz, CD3OD) δ: 1.44 (s, 9H), 2.88 (s, -93- 201041867 3H), 3.56 (m, 2H), 3_71 (m, 2H), 4.75 (m, 1H). Reference Example 3 4 - (2-Amino-6-yl-based ketone--4-yl) vein steep-丨_ residual acid vinegar hydrazine hydrochloride (2.15 g, 22.5 mmol) and ethoxylation Sodium (7.3 g, 2 1 % ethanol gluten solution, 2 2 · 5 halo; 旲 ear) was added to 4 _ ( 3 _ ethoxy _ 3 _ pendant oxypropyl fluorenyl) 峨 steep 1-carboxylic acid benzyl The ester (5. g, 15 mmol) in absolute ethanol (ISO ml) was added and the mixture was heated under reflux - night. The solvent was concentrated to dryness. The residue was diluted with water and the pH was adjusted to 6-7 using 1 N HCl. The suspension was stirred at room temperature for 2 hours. The precipitated solid was filtered and washed with a large portion of water and diethyl ether and dried under vacuum to give the title compound (4.13 g, yield 84%). LC-MS (method 2): tR = 1.51 min; m/z = 329 (MH+). Reference Example 4 a 4-(2-Amino-6-((3R)-3-(tertiarybutoxycarbonyl(methyl)amino)pyrrolidinyl) oxime II--4-) -1 _ decanoic acid ester The compound obtained in Reference Example 3 (2 · 〇g, 6.09 vaole) was heated overnight under reflux, and the amine obtained in Reference Example 1 (195 g, 9·7 mmol), A mixture of PyB OP (4.1 g, 7.9 mmol), TEA (0.9 ml) and acetonitrile (61 ml) was then added a larger amount of the compound obtained in Reference Example 1 (0.61 g) and PyBOP (1.6 g). It was stirred for 2 hours under reflux. The reaction mixture was concentrated to dryness and the residue was diluted with water and ethyl acetate and 2N NaOH solution was added until basic pH. The phase layer was separated and the aqueous phase of -94-201041867 was extracted twice with ethyl acetate. The combined organic phase was washed with a saturated NaCl solution, dried over anhydrous Na 2 SO 4 and concentrated to dryness. The obtained crude product was purified by EtOAc EtOAc (EtOAc:EtOAc) LC-MS (method 2): tR = 2.43 min; m/z 511 (MH+). Reference Examples 4b to 4d 〇 Following the method described in Reference Example 4a but using the corresponding amine instead of the user of Reference Example 1, the following compounds were obtained: Reference Example Name Amine Method (LC-MS) tR (minutes) m/z (MH+) 4b 4-(2-amino-6-(3_(tris-butoxycarbonyl(methyl)amino)tetrahydroindol-1-yl)pyrimidin-4-yl Piperidine-1-carboxylic acid benzyl ester Reference Example 2 2 2.32 497 4c 4-(2-Amino-6-((3R)-3-(tertiarybutoxycarbonylamino)pyrrolidin-1-yl) Pyrimidin-4-yl)piperidine-1-carboxylic acid benzyl ester tert-butyl-[(3R)-pyrrolidin-3-yl]carbamate 2 2.24 497 4d heart (2-amino-6- (4-(Tris-butoxycarbonyl)piperazino-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid benzyl ester piperazine-1-carboxylic acid tert-butyl butyl ester 2 2.41 497 Reference example 5 a (R )· 1 -(2-Amino-6-(piperidin-4-yl)pyrimidin-4-yl)pyrrolidine-3-yl(methyl)carbamic acid tert-butyl butyl ester in H-CubeTM In the unit, use a 10% Pd/C cartridge (70 x 4 mm) at 35 ° C and 1 bar of hydrogen and at a flow rate! „^1/min, the compound of Example 4a (2·46 g, 4.8 mmol) of Me0H (96-95-201041867 m 1) gluten solution was subjected to hydrogenation reaction, after 2 cycles of hydrogenation reaction </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; -4-yl)pyrimidin-4-yl)tetrahydroindol-3-yl(methyl)aminecarboxylic acid tert-butyl butyl ester follows the method described in Reference Example 5a but using the compound of Reference Example 4b Starting material, the title compound was obtained. LC-MS (Method 2): t: = 1 - 35 min; m/z 363 (MH + ). Reference Example 5 c (R)-l-(2-amino-6- Triethyl butyl pyridine 4-(4)pyrimidin-4-yl)pyrrolidin-3-ylcarbamate The M e Ο 令 of the compound of Reference Example 4c (3 5 3 mg, 0·71 mmol) 2 m 1) The solution was reacted with activated carbon (18 mg) and stirred at room temperature for 1 hour. The reaction was filtered through Celite's Celite® and the filtrate was concentrated to dryness. In Me〇H (2 ml) and purged with a gas. Add 10% Pd/C (3 5·3 mg) and The solution was again purged with argon and stirred overnight under hydrogen. The reaction was filtered over Celite® and the filtrate was concentrated to dryness. The residue was diluted with 5% citric acid and The ethyl ester was rinsed twice. The pH of the aqueous phase was adjusted to pH 1 1 with 1N NaOH solution and extracted with ethyl acetate three times. The combined organic phase was dried over anhydrous Na 2 〇 4 and concentrated to dryness to -96 - 201041867 The desired compound was obtained in quantitative yield. LC-MS (method 2): tR = 1.30 min; m/z 3 63 (MH + ). Reference Example 6 4 - (2-amino-6-chloro Pyrimidine-4-yl)piperidine-1 -carboxylic acid benzyl ester Phosphorus chloride (2.1 ml, 22.9 mmol) was added to the compound of Reference Example 3 (5 mg, 1.52 mmol) and tetraethyl A mixture of ammonium chloride (757 mg, 〇4_57 mmol) in acetonitrile (8 ml) and the mixture was heated at 80 ° C for 3 hours and then concentrated to dryness. It was diluted with ethyl acetate and cooled in an ice bath. The pH was adjusted to 9 with concentrated aqueous ammonia. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The organic phase was rinsed with 5% nitric acid solution, and subsequently by naH C Ο 3 saturated aqueous rinse solution. The organic phase was dried and placed over concentrated to dryness to yield a quantitative yield of the target compound over anhydrous Na2S04. LC-MS (method 2): tR = 2.22 min; m/z 347/349 (MH + ) 〇 </ br> </ br> R)-l-Methylpyrrolidin-3-ylaminecarboxylic acid tert-butyl ester Addition of 3 7 % formaldehyde (1.19 m 1,1 4 · 6 mmol) aqueous solution to (R)-pyrrolidine- A solution of 3-tertamine carboxylic acid tert-butyl ester (1.0 g, 5.34 mmol) in MeOH (23 ml) and then slowly sodium hydride (0.61 g, 16.1 mmol). The mixture was allowed to stir overnight at room temperature under argon. The mixed -97-201041867 was concentrated to dryness and the residue was dissolved in CHCI3 and washed successively with brine and NaHC03 sat. The organic phase was dried over Na 2 S 〇 4 and concentrated to dryness to give the title compound (0·85 g, yield 7 9%) 〇'H NMR (300 MHz, CDC13) δ: L43 (s, 9H) , 1.58 (m, 1H), 2.25 (m, 2H), 2.33 (s, 3H), 2.52 (m, 2H), 2.77 (m, 1H), 4.16 (m, 1H), 4.86 (m, NH). (b) Standard compound A solution of 4M HCl in 1,4-dioxane (40 ml) and MeOH (1 ml) was added to the compound obtained in the above step (a) (0.85 g, 4.25 mmol). The mixture was allowed to stir at room temperature for 1 hour. The mixture was concentrated to a dry state. The crude product was dissolved in MeOH and concentrated again to dryness to yield title compound (0.77 g). 'Η NMR (300 MHz, CD30D) 2.15 (m, 1H), 2.55 (m, 1H), 2.91 (s, 3H), 3.15 (m, 1H), 3.3-3.85 (m, 3H), 4.10 (m, 1H). Example 1 4-(2-Amino-6-(1,4-diazinidine-i-yl)pyrimidin-4-yl)piperidine-indole-carboxylic acid benzyl ester was similar to that described in Reference Example 4a. The method was the same as using the compound of Reference Example 3 and 1,4-diazepine as the starting material to give the title compound. LC-MS (method 2): tR = 1 - 59 min; m/z 411 (MH+). -98- 201041867 Example 2 4-(2-Amino-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid benzyl ester The compound of Reference Example 4b (200 mg, 0.4 mmol) was added to HCl (4M 1,4-dioxane solution, 7 ml) and the mixture was stirred at room temperature for 3 hr. The solvent was concentrated to dryness. The residue was dissolved in methanol Q and passed through a sulfonic acid resin Bond eluted SCX-Varian column which had been previously pressed with methanol. Subsequent elution with methanol, the methanol was discarded and eluted with 2N NH3 in MeOH to recover product which was collected and concentrated to dryness. The crude product obtained was purified by silica gel chromatography using a mixture of chloroform/MeOH/NH3 (concentrated) with increasing polarity to afford the title compound (3 0 · 4 mg, yield 19 ° /.) . LC-MS (method 2): tR = 1.65 min; m/z 397 (MH+).实施 Examples 3 to 5 The following compounds were obtained in a manner similar to that described in Example 2 but using the corresponding starting materials': -99- 201041867 Example Name Starting Method (LC-MS) tR ( Minutes) m/z (MH+) 3 4-(2-Amino-6-((3R)-3-(methylamino)pyrrolidin-1 -yl)pyrimidin-4-yl)piperidine-1 - Benzyl Carboxylate Reference Example 4a 2 1.64 411 4 4-(2-Amino-6-((3R)-3-aminopyrrolidin-1-yl)pyrimidin-4-yl)piperidine-1-carboxylate Benzyl benzyl ester Reference Example 4c 2 1.59 397 5 4-(2-Amino-6-(piperidino-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid benzyl ester Reference Example 4d - - 2 --- 1.58 397 Example 6 1-(4-(2-Amino-6-((3R)-3-(methylamino)pyrrolidinyl)Π/密卩定_4_基) Piperidin-1-yl)-3-phenylpropan-1-one

Mixture of 3-phenylpropionic acid (40 mg, 0.27 mmol), btuh (101 mg, 0.27 mmol) and DIEA (52 mg, 0.4 mmol) in DMF (2 ml) at room temperature 1 hour. Subsequently, the compound of Reference Example 5a (100 m g, 0 · 27 mmol) was added and stirred overnight at room temperature. The mixture was concentrated to dryness and the residue was diluted with chloroform. The organic phase was washed with O. SN NaOH solution and a saturated solution of sodium chloride, then dried over Na 2 SO 4 and concentrated to dryness to give a protected precursor product of the Boc type. The crude product was reacted with a 4M HCI solution of EtOAc, &lt;RTI ID=0.0&gt;&gt; The residue was subjected to preparative Η PLC (in which column: X-Bridge Prep C18 5 μηι (19 X 100 mm), flow rate: 20 ml/min, eluent: A = AcN, B = NH4HC〇3 75 mM, Gradient: 〇-100- 201041867 minutes 10% A; 1.0 minutes 10% A; 2.0 minutes 25% A; 7.0 minutes 30% A; 8.0 minutes 90% A) Purification and concentration of the product containing fractions to dryness, The title compound (8.8 mg, yield 8%) was obtained. LC-MS (method 2): tR = 1.50 min; m/z 409 (MH+). Examples 7 to 8 Following the procedure analogous to that described in Example 6 but using the appropriate starting materials, the following compounds were obtained: Example name Starting material method (LC-MS) tR (minutes) m/z ( MH+) 7 1-(4-(2-Amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl)3⁄4, 卩疋-4-yl)岐D疋-1 -yl) hexan-1-one Reference Example 5a and hexanoic acid 2 1.49 375 8 1-(4-(2-amino-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidine Π疋 峨Π ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) Pyrrolidine-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid isobutyl ester DIEA (26 mg, 0.2 mmol) and isobutyl chloroformate (18.1 mg, 0.13 mmol) This was added to a solution of the compound of Example 5a (5 mg, 0.13 mmol) in dichloromethane (2 ml). The mixture was allowed to stir at room temperature for 3 hours and then washed with a saturated solution of NaHCO. Order -101 - 201041867 The organic phase was dried over Na 2 SO 4 and concentrated to dryness to afford a protected precursor product of the Boc type. The crude product was reacted with a solution of 4M EtOAc, EtOAc (EtOAc). The residue was dissolved in methanol and passed through a sulfonic acid resin Bond eluted SCX-Varian column which had been previously pressed with methanol. Subsequent elution with methanol, the methanol was discarded, and the eluted product was recovered from a 2N NH3 MeOH solution which was collected and concentrated to dryness. The crude product thus obtained was purified by silica gel chromatography using a mixture of chloroform / MeOH / NH3 (concentrated) with increasing polarity as a solvent to give the title compound (16.9 mg, yield 34%). LC-MS (method 2): tR = 1.59 min; m/z 377 (MH+). EXAMPLES 0 to 13 Following the procedure analogous to that described in Example 9, but using the appropriate starting materials, the following compounds were obtained: -102- 201041867 Example name starting material method (LC-MS) tR (minutes m/z (MH+) 10 4-(2-Amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidine small carboxylic acid Ester Reference Example 5a and butyl chloroformate 2 1.61 377 11 4-(2-Amino-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-4-yl)piperidine 1-carboxylic acid butyl ester reference example 5b and butyl chloroformate 2 1.64 363 12 4-(2-amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl) Methyl pyrimidin-4-yl)piperidine-1-carboxylate Reference Example 5a and methyl chloroformate 2 1.14 335 13 4-(2-Amino-6-((3R)-3-(methylamino) Ethyl pyrrolidino-l-yl)pyrimidin-4-yl)piperidine-1-carboxylate Reference Example 5a and ethyl chloroformate 2 1.29 349 Example 1 4 4-(2-Amino- 6- ( (3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid 4-(benzyloxy)butyl ester Q 4-(benzyloxy) A solution of butan-1-ol (57.4 11^, 0.32 mmol) in anhydrous dichloromethane (0.5 ml) was added to the previous The cooled by an ice bath carbonyldiimidazole (51.7 mg, 0.32 mmol) of anhydrous dichloromethane. Dioxane (1.3 ml) solution. The ice bath was removed and the mixture was stirred at room temperature for 1 hour. Subsequently, a solution of the compound of Example 5a (100 mg, 〇·27 mmol) in anhydrous dichloromethane (?? The mixture was concentrated to dryness to give the protected precursor compound as Boc. The crude product was dissolved in dichloromethane (1 mL), then cooled in ice-cooled and trifluoroacetic acid ( &lt;RTI ID=0.0&gt;&gt; The mixture was stirred at room temperature for 4 hours and concentrated to dryness. Order -103- 201041867 The residue was subjected to preparative HPLC (in which column: X-Bridge Prep C18 5 μιη (19 x 100 mm), flow rate: 20 ml / min, eluent: A = AcN, B = NH4HC03 75 mM , gradient: 5% minutes 5% A; 2.0 minutes 5% A; 3.0 minutes 35 % A; 8.0 minutes 40% A; 9_0 minutes 80% A; 10.0 minutes 80% A) Purification and concentration of the product containing fractions In the dry state, the title compound (6 8.6 mg, yield 53%) was obtained. LC-MS (method 2): t: = 1.89 min; Example 1 5 to 3 7 Following the procedure similar to that described in Example 14 but using the appropriate starting material, the following compound was obtained: Example name starting material method (LC-MS) tR (min) m/ z (MH+) 15 4-(2-Amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid 3 -(Benzyloxy)propyl ester Reference Example 5a and 3-(benzyloxy)propan-1-ol 2 1.76 469 16 4-(2-Amino-6-((3R)-3-(methylamine) Base) thiazoridin-1-ylpyrimidin-4-yl) piperidine-1-carboxylic acid 3-ethoxypropyl ester Reference Example 5a and 3-ethoxypropan-1-ol 2 1.40 407 17 4 -(2-Amino-6-((3 R)-3-(methylamino)pyrrole-d-yl)pyran-4-yl)piperidine-1-carboxylic acid cyclohexylmethyl ester reference implementation Example 5a and (cyclohexyl)methanol 2 1.96 417 18 4-(2-Amino-6-((3R)-3-(methylamino)-t-thyl-1-yl) chelate hydrazide) Piperidine 1-carboxylic acid (6-methylpyridin-2-yl)methyl ester Reference Example 5a and (6-methylpyridin-2-yl)methanol (1) 2 1.36 426 -104- 201041867 19 4-(2-amine -6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl) phenotypic oxime-l-residual acid (2-methylindole ratio D疋-3- Base) methyl ester reference Example 5a and (2-methylpyridin-3-yl)methanol (1) 2 1.29 426 20 4-(2-amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl) Pyrimidin-4-yl) piperazine-1-carboxylic acid 2-ethoxyethyl ester Reference Example 5a and 2-ethoxyethanol (1) 2 1.29 393 21 4-(2-Amino-6-(( 3R)-3-(Methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid 2-fluorobenzyl ester Reference Example 5a and 2-fluorobenzyl alcohol 2 1.70 429 22 4-(2-Amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid 2-isopropoxy B Esters Reference Example 5a and 2-Isopropoxyethanol 2 1.43 407 23 4-(2-Amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidine-4 -Base) Piperphene 1-carboxylic acid 2-phenoxyethyl ester Reference Example 5a and 2-phenoxyethanol 2 1.70 441 24 4-(2-Amino-6-((3R)-3-( Methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid (pyridin-3-yl)methyl ester Reference Example 5a and (pyridin-3-yl)methanol 2 1.25 412 25 4-(2-Amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid 4-(methylsulfonate Benzyl) benzyl ester reference example 5a and 4-(methylsulfonyl)benzyl Alcohol 2 1.37 489 26 4-(2-Amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl) 峨D疋-1-decanoic acid 2 -(卩比卩疋-2-yl)ethyl ester Reference Example 5a and 2-(pyridin-2-yl)ethanol 2 1.30 426 27 4-(2·Amino-6-((3R)-3-( Methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid 4-(methylsulfonamide) benzyl ester Reference Example 5a and N-(4-(via base armor) Phenyl)methanesulfonamide 2 1.41 504 28 4-(2-amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidin 4-Cyanobenzyl ester of steep-1-carboxylic acid Reference Example 5a and 4-(hydroxymethyl)benzonitrile 2 1.56 436 -105- 201041867 29 4-(2-Amino-6-((3R)-3) -(Methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidine-1 -carboxylic acid imidazo[1,2-a]pyridin-2-ylmethylacetate Reference Example 5a and Imidazo[1,2-a]pyridin-2-ylmethanol 2 1.27 451 30 4-(2-Amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidine 4-yl) piperidine-1-residic acid (tetrahydro-2H-pyran-4-yl)methyl ester Reference Example 5a and (tetrahydro-2H-piperidin-4-yl)methanol 2 1.32 419 31 4-(2-Amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidin-1- Carboxylic acid (1H-benzo[d]imidazol-2-yl)methyl ester Reference Example 5a and (1H-benzo[d]imidazol-2-yl)methanol 2 1.34 451 32 4-(2-Amino- 6-((3R)-3-(Methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid 2-cyclopropylethyl ester Reference Example 5a and 2-ring Propylethanol 2 1.66 389 33 4-(2-Amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidine-1-residic acid (Shame D-but-2-yl)methyl ester Reference Example 5a and (pyridin-2-yl)methanol 2 1.29 412 34 4-(2-Amino-6-((3R)-3-(methylamino) Pyrrolidin-1-ylpyrimidin-4-yl)piperidine-1 -residic acid (disc-4-yl)methyl ester Reference Example 5a and (pyridin-4-yl)methanol 2 1.25 412 35 4- (2-Amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid 3-(pyridin-2-yl) Propyl ester Reference Example 5a and 3-(U-pyridin-2-yl)propanol 2 1.41 440 36 4-(2-Amino-6-((3R)-3-(methylamino)pyrrolidine- 1-yl)pyrimidin-4-yl)piperidin-1-decanoic acid (tetrahydro-2H-piperidin-2-yl)methyl ester Reference Example 5a and (tetrahydro-2H-indol-2-yl) Methanol 2 1.48 419 37 4-(2-Amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidine 4-yl) piperidine-1-carboxylic acid (2,3-dihydrobenzo[b][l,4]dioxan-2-yl)methyl ester Reference Example 5a and 2-hydroxymethyl- 1,4-benzodioxane 2 1.76 469 (1) The deprotection reaction of the Boc group was carried out by substituting 4 M HCl 1,4-dioxane for trifluoroacetic acid. -106- 201041867 Example 3 8 4-(2-Amino-6-((3 R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)-N-benzyl Piperidine-1-carboxamide The DIEA (72 mg, 0.56 mmol) and benzyl isocyanate (70.1 mg, 0::53 mmol) were added to the compound of Reference Example 5a (1 〇〇) Mg, 0.27 mmoles in dichloromethane (3 ml). The mixture was allowed to stir at room temperature for 5 hours and then concentrated to dryness to give a protected precursor compound of the Boc type. The crude product was dissolved in dichloromethane (10 mL) and then cooled in iced water and trifluoroacetic acid (14 ml, 18.5 m. The mixture was stirred at room temperature for 4 hours and concentrated to dryness. The residue was subjected to preparative HPLC (in which column: X-Bridge Prep C18 5 μιη (19 X 100 mm), flow rate: 20 ml/min, eluent: A = AcN, B = NH4HC03 75 mM, gradient: 0 Minute 5% A; 2.0 minutes 5% A; 3.0 minutes 20% A; 8.0 minutes 50% A; 9.0 minutes 〇 80% A; 10.0 minutes 80% A) Purified and concentrated the product containing the fraction to dry state' The title compound (42 mg, yield 39%) was obtained. LC-MS (method 2): t = 1.36 min; m/z 410 (MH+). Example 3 9 4-(2-Amino-6-((3R)-3-(methylamino)pyrrolidine-fluorenyl)pyrimidin-4-yl)-N-butylpiperidine-1- Carboxylamidine followed the procedure described in Example 38 but using butyl isocyanate in place of benzyl isocyanate to give the title compound. -107- 201041867 LC_MS (Method 2): tR = 1.27 min; m/z 376 (MH + ). Example 40 4 - (1 - ( butylsulfonyl) piperidine _ 4 _yl)_ 6 _ (( 3 R) _ 3 _ (methylamino) pyrrolidin-1-yl)pyrimidin-2- The amine was added DIEA (26 mg, 毫. 2 mmol) and 丨-butane sulfonium chloride (2 〇 7 mg, 〇·13 halo) to the compound of Reference Example 5a (50 mg' 0_13 mM). Mole in dichloromethane (2 ml) solution. The mixture was allowed to stir overnight at room temperature and then rinsed with a saturated solution of NaHC.sub.3. The organic phase was dried on a NhSCU and concentrated to dryness to give the protected precursor compound as Boc. The crude product was dissolved in chloroform (5 ml) and then cooled in an ice bath and trifluoroacetic acid ( &lt;RTI ID=0.0&gt;&gt; The mixture was stirred at room temperature for 4 hours and concentrated to dryness. The residue was diluted with water and ethyl acetate. pH was adjusted and separated. The aqueous layer was again extracted with ethyl acetate. The combined organic phase was dried over anhydrous Na.sub.2SO.sub.4 and concentrated to dryness to give the title compound (2 2 · 6 m g, yield 43%). LC-MS (method 2): tR = 1.46 min; m/z 397 (MH+). Example 4 1 to 4 3 Following the procedure described in Example 40 but using the appropriate starting material, the following compound was obtained: -108 - 201041867 Example name starting material method (LC-MS) tR (minutes m/z (MH+) 41 4-(1-( Butyryl)piperidin-4-yl)-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidine- 2-Amine Reference Example 5b and Butasulfonium Chloride 2 1.49 383 42 4-(1-(Benzylsulfonyl)acridin-4-yl)-6-((3R)-3-(methylamino) Pyrrolidin-1-yl)pyrimidine-2-amine Reference Example 5a and benzyl expanded chlorine 2 1.52 431 43 4-(1-(benzylsulfonyl)acridin-4-yl)-6-(3 -(Methylamino)tetrahydroindol-1-yl)pyrimidin-2-amine Reference Example 5b and Benzenesulfonium chloride 2 1.55 417 Example 44 4-(2-Amino-6-((3R) --3-(Methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)-N-butyl-N-methylpiperazin-1-residamine amine TEA (0.1 ml) was added to N - a solution of methyl butylamine (23.2 mg, 0.27 mmol) in anhydrous dichloromethane (2 ml) followed by triphos (31 Q mg, 0.1 1 mmol) of anhydrous dichloromethane (2 ml) In solution. The mixture was stirred at room temperature under nitrogen for 1 hour and then a solution of the compound of Example 5a (100 mg, 0-27 mmol) and TEA (0.1 ml) in anhydrous dichloromethane (2 ml) The resulting mixture was stirred overnight at room temperature. The crude product was rinsed through a 0.5N HCl solution. The acidic aqueous phase was again extracted with dichloromethane. The combined organic phase is dried over Na2SO4 and concentrated to dryness to give a precursor protected by B 〇 c. The crude product was dissolved in dichloromethane (0.6 ml) and then trifluoroacetic acid (3 ml, 4 m. The mixture was stirred at room temperature for 2 hours and concentrated to dryness. The residue was subjected to preparative HPLC (wherein the column: χ-Bridge -109 - 201041867

Prep C18 5 μιη OBD (19 χ 100 mm) column, flow rate: 20 ml/min, eluent: A = AcN, B = NH4HC03 75 mM, gradient: 0 min 5% A; 2.0 min 5% A; 3.0 Minute 25% A; 8.0 minutes 35% A; 9.0 minutes 80% A; 10.0 minutes 80% A) Purification and concentration of the product containing fractions to dryness to give the title compound (1 8.4 mg, yield 18%) Bu-LC-MS (Method 2): tR = 1.50 min; m/z 390 (MH + ). Example 4 5 4-(2-amino-6-((3 R)-3-(methylamino) Pyrrolidin-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid 4-hydroxybutyl ester in a H-CubeTM unit using a 10% Pd/C cartridge (70 x 4 mm) at 50° A solution of the compound of Example 14 (64 mg, 0.13 mmol) in MeOH (3 ml) was hydrogenated under C and 20 bar of hydrogen and at a flow rate of 1 ml/min. Concentrated to dry state and then subjected to preparative HPLC (in which column: X-Bridge Prep C18 5 μιη OBD (19 χ 100 mm) column, flow rate: 20 ml/min, eluent: A = AcN, B = NH4HCO3 75 mM, gradient: 0 minutes 5 % A; 3.0 minutes 1 5 % A; 8.0 minutes 2 5 % A ; 9.0 points 8 0 % A ; 1 0 · 0 min 80 % A ) Purification and concentration of the fractions containing the product to dryness to give the title compound (3 · 7 mg, yield 7%). LC-MS (Method 2 ): tR = 1.15 min; m/z 393 (MH + ). Example 4 6 -110- 201041867 4-(2-amino- 6-((3R)-3-fl-female oxime ratio slightly steeper-1 -based) butyl 4-yl) hydrazine- l- carboxylic acid butyl ester followed by the method described in Example 9 but using the compound of Reference Example 5 c and butyl chloroformate as starting materials, The title compound was obtained. LC-MS (Method 2): tR = 1.55 min; m/z = 363 (MH + ). Example 4 7 to 4 8 〇 类似于 类似于 类似于 类似于 类似于 类似于Starting material, obtaining the desired compound: Example name starting material method (LC-MS) tR (minutes) m/z _勹47 '(Ηphenylsulfonyl)piperidin-4_yl)_6-( 3-(Methylamino)tetrahydroindole-1_yl))pyridin-2-amine Reference Example 5b and phenylsulfonyl chloride 2 1.57 403 48 4-(1-(2-phenylethyl) Sulfhydryl)piperidin-4-yl)-6-(3-(methylamino)tetrahydroindol-1-yl)pyrimidin-2-amine Reference Example 5b and Benzene Sulfosin chloride 2 1.74 431 Examples 49 to 73 Following the procedure similar to that described in Example 14 but using the appropriate starting materials' gave the following compounds: -111 - 201041867 Example name starting material method (LC -MS) tR (min) m/z (MH+) 49 4-(2-Amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidin 4-(methoxycarbonyl) stilbene of pyridine-1-residic acid Reference Example 5a and methyl 4-(hydroxymethyl)benzoate 2 1.64 469 50 4-(2-Amino-6-((3R)- 3-benzyloxyethyl 3-(methylamino)pyrrolidin-1-yl)pyridin-4-yl)piperidine-1-carboxylic acid Reference Example 5a and 2-(benzyloxy)ethanol 2 1.66 455 51 4-(2-Amino-6-((3R)-3-(methylamino)pyrrole-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid cyclopentyl ester reference Example 5a and cyclopentanol 2 1.61 389 52 4-(2-Amino-6-((3R)-3-(methylamino) oxime ratio slightly 1-yl) ridin-4-yl)卩 limb 卩疋-1-hydroxy acid 3-methoxybenzyl ester Reference Example 5a and 3-methoxybenzyl alcohol 2 1.66 441 53 4-(2-Amino-6-((3R)-3-( Methylamino-based succinyl-1-yl)pyridin-4-yl)piperidine-1-carboxylic acid cyclobutyl ester Reference Example 5a and cyclobutanol 2 1.49 3 75 54 4-(2-Amino-6-((3R)-3-(methylamino)pyrrolidindin-1-yl)pyran-4-yl)acridine-1-residual acid 5- (Ethoxycarbonyl) amyl ester Reference Example 5a and 6-hydroxyhexanoic acid ethyl ester (1) 2 1.68 463 55 4-(2-Amino-6-((3R)-3-(methylamino)pyridinium Slightly steep-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid 5-(methoxycarbonyl)pentanyl ester (1) 2 1.57 449 56 4-(2-Amino-6-((3R)-3) -(Methylamino)pyrrolidino-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid cyclopropylmethyl ester Reference Example 5 a and cyclopropylmethanol 2 1.48 375 -112- 201041867 57 4-(2-Amino-6-((3R)-3-(methylamino)pyrrolidine-1-yl)-cheetyl-4·yl)piperidine-1-carboxylic acid cyclopentyl Methyl ester reference example 5a and cyclopentylmethanol 2 1.85 403 58 4-(2-amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl) chelate-4 - phenyl)piperidine-1-carboxylic acid cyclobutylmethyl ester Reference Example 5a and cyclobutylmethanol 2 1.71 389 59 4-(2-Amino-6-((3R)-3-(methylamino)pyridinium Slightly steep-1-yl) domain pyridine-4-yl) hydrazine 2*(methoxy)ethyl ester Reference Example 5a and 3-hydroxybutyl hydroxypropionate (2) 2 1.27 407 60 4-( 2-amino-6-((3R)-3-(methylamino) lyridine-1-yl) chelate -4 yl piperidine-1-carboxylic acid 2-ethylguanidinophenethyl ester Reference Example 5a and N-(2-(2-hydroxyethyl)phenyl)acetamide 2 1.40 482 61 4-( 2-Amino-6-((3R)-3-(methylamino)lahydroidin-1-yl)-c-butyl-4-yl)piperidine-1-carboxylic acid 4-acetamidophenyl Esters Reference Example 5a and N-(4-(2-hydroxyethyl)phenyl)acetamide 2 1.40 482 62 4-(2-Amino-6-((3R)-3-(methylamino) Pyrrolidin-1-yl)pyridin-4-yl)piperidine-1-carboxylic acid 2-ethylguanidinobenzyl ester Reference Example 5a and N-(2-(hydroxymethyl)phenyl)ethyl hydrazine Amine 2 1.37 468 63 4-(2-Amino-6-((3R)-3-(methylamino)-shame-l-yl)-butyl-butyl-4-yl)piperidine-1-carboxylate 3-Ethylaminobenzyl acid ester Reference Example 5a and N-(3-(hydroxymethyl)phenyl)acetamide 2 1.39 468 64 4-(2-Amino-6-((3R)-3) -(Methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid (5-methylisoxazol-3-yl)methyl ester Reference Examples 5a and (5- Methylisoxazol-3-yl)methanol 2 1.38 416 65 4-(2-Amino-6-((3R)-3-aminopyrrolidin-1-yl)pyrimidin-4-yl)piperidine- 1-Residual 4-cyano-esters Reference Example 5c and 4-hydroxymethylbenzonitrile 2 1.50 422 -113- 201041867 66 4-(2-Amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyridin-4-yl)piperidine-1-carboxylic acid 4-methoxybutyl Esters Reference Example 5a and 4-methoxybutan-1-ol 2 1.37 407 67 4-(2-Amino-6-((3R)-3-(methylamino) oxime ratio D-1 2-(cyclohexyloxy)ethyl ester of p-Shen-4-yl)piperidine-1-carboxylic acid Reference Example 5a and 2-(cyclohexyloxy)ethanol 2 1.74 447 68 4-(2- Amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid (U-thiazol-2-yl)methyl ester reference Example 5a and (1,3-oxazol-2-yl)methanol 2 1.26 418 69 4-(2-Amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl Pyrimid-4-yl)piperidine-1-carboxylic acid (2,4-dimethyl-1,3-thiazol-5-yl)methyl ester Reference Example 5a and (2,4-dimethyl-1) , 3-thiazole-5-yl)methanol 2 1.37 446 70 4-(2-Amino-6-((3R)-3-(methylamino)batch-1-yl) spurt) D疋-1-decanoic acid (3-nisoisoxanth-5-yl)methyl ester Reference Example 5a and (3-phenylisoxazol-5-yl)methanol 2 1.78 478 71 4-(2- Amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyridin-4-yl)acridine-1-carboxylic acid (3-methyliso-oxo-5) -base) methyl ester reference implementation 5a and (3-methylisoxazole-5-yl)methanol 2 1.32 416 72 4-(2-amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl) Pyrimidin-4-yl)indole-1-pyruic acid (5-phenylisoxazol-3-yl)methyl ester Reference Example 5a and (5-phenylisoxazol-3-yl)methanol 2 1.81 478 73 4-(2-Amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid (5-cyclopropyl) Isoxazolyl-3-yl)methyl ester Reference Example 5a and (5-cyclopropylisoxazol-3-yl)methanol 2 1.55 442 (1) During the synthesis of the compound of Example 54, the transesterification was carried out using methanol. The reaction resulted in the formation of a mixture of ethyl ester and methyl ester which was isolated by preparative HPLC to give the compounds of Examples 54 and 5, respectively. (2) The Boc deprotection reaction in an acidic matrix causes hydrolysis of the tertiary butyl ester, and methanol is used during the synthesis to cause an esterification reaction, resulting in the formation of a methyl ester. Example 74 4-(2-Amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid 6-hydroxyl The hexyl ester solution of the compound of Example 5 (1 1.8 mg, 0.03 mmol) in THF (0.53 ml) was evaporated. Subsequently, LiAlH4 (1 M in THF, 0.08 ml, 0.08 mmol) was added and the mixture was stirred at &lt;0&gt;C for 2 hours. The reaction was quenched by the addition of 1 aqueous sodium tartrate solution (2 ml). The reaction was diluted with water and chloroform and the layers were separated. The aqueous phase was extracted again with chloroform and the combined organic phases were concentrated to dryness. The residue was subjected to preparative hydrazine HPLC (where column: X-Bridge Prep C18 5 μιη OBD (19 X 100 mm), flow rate: 20 ml/min, eluent: A = AcN, B = NH4HCO3 75 mM, gradient : 0 minutes 5% A; 2.0 minutes 5% A; 3 · 0 minutes 30% Α; 8 · 〇 minutes 40% A; 9.0 minutes 80% Α; 10·0 minutes 80% Α) Purification and product containing The fractions were concentrated to dryness to give the title compound (1 _ 8 4 mg, yield 16%). LC-MS (method 2): tR = 1.31 min; m/z = 421 (MH+). Example 75 -115- 201041867 4 - (2-Amino-6-((3R)-3((methylamino)pyrrolidin-1yl)pyrimidin-4-yl)piperidine-1-carboxylate The acid 4-(hydroxymethyl)benzyl ester was subjected to a procedure similar to that described in Example 47, but using the compound of Example 49 as starting material to give the title compound. LC-MS (method 2): tR = 1.33 min; m/z = 441 (MH+). Example 7 6 4-(2-Amino-6-((3R)-3-(methylamino)-p-[rho]-[j-l-yl][P-denid-4-yl) 1-carboxylic acid (1-methyl-1H-benzo[d]imidazol-2-yl)methyl ester a) 4-(2-amino-6-((3R)-3-(tertiary butoxy) Carbonyl (methyl)amino)pyrrolidine-1-ylpyrimidin-4-yl)piperidine-1-carboxylic acid (1H-benzo[d]imidazol-2-yl)methyl ester (1H-benzene) And [d]imidazol-2-yl)methanol (216 mg, 1_46 mmol) was added to a solution of carbonyldiimidazole (240 mg, 1.46 mmol) in anhydrous dichloromethane (12 ml) and the mixture was Stir at 90 ° C for 90 minutes. Subsequently, the compound of Reference Example 5a (500 mg, 0.27 mmol) was added and the mixture was stirred at 4 ° C for 2 days. The mixture was diluted with dichloromethane and washed with 5% aqueous citric acid. The aqueous phase was extracted again with dichloromethane. The combined organic phase was dried over Na2SO4 and then concentrated to dryness. The crude product was purified by silica gel chromatography eluting with EtOAc (EtOAc: EtOAc). LC-MS (method 2): tR = 2.03 min; m/z = 551 (MH+). b) Subject compound-116- 201041867 Anhydrous potassium carbonate (25 mg, 0.18 mmol) was added to a solution of the compound obtained in step a) (1 mg, 0.18 mmol) in DMF (1.8 ml) and subsequently Methyl iodide (0.01 ml, 0·18 mmol) was added and the mixture was heated overnight at 70 °C. The mixture was concentrated to dryness and the residue was subjected to preparative HPLC (with column: X-Bridge Prep C18 5 μιη OBD (19 χ 100 mm), flow rate: 20 ml/min, eluent: A = AcN , B = NH4HCO3 75 mM, gradient: 0 min 5 % A; 2 · 0 min 0 5% A; 3.0 min 35% A; 8.0 min 45% A; 9.0 min 90% A; 10.0 min 90% A) Purified The fractions containing the product were concentrated to dryness to give a Boc-protected precursor compound (45 mg). The product was dissolved in dichloromethane (0.4 ml) and trifluoroacetic acid (0.2 ml). The reaction was allowed to stir at room temperature for 2 hours and concentrated to dryness. The residue was diluted with water containing a few drops of HCl and ethyl acetate and the layers were separated. The acid aqueous phase was adjusted to pH 10-1 1 with IN NaOH solution and extracted several times with AcOEt. The combined organic phase was dried over Na 2 SO 4 and then dried to dryness to give the title compound (9.3 m g, yield 11.1%). LC-MS (method 2): tR = 1.43 min; m/z = 465 (MH+). Example 7 7 4-(2-Amino-6-(1-methylpyrrolidinyl-(3 R)-3-ylamino)pyrimidin-4-yl)-pyridin-1-carboxylic acid benzyl ester A solution of the compound of Example 6 (0.96 g, EtOAc, EtOAc) The residue was diluted with Et0H (3 - 117 - 201041867 m 1) and DIE A (4 · 8 m 1) and the compound of Reference Example 7 (622 mg, 3.6 mM) and the mixture was allowed to be at 90 ° C Heated overnight. The mixture was concentrated to dryness and the residue was diluted with EtOAc EtOAc &lt The phase layer was separated and the acidic aqueous phase was again flushed through A c Ο E t and then the AcOEt was discarded. The pH of the aqueous phase was adjusted to 1 1 with 0.5 N NaOH solution and extracted several times with AcOEt. The combined organic phase was dried over Na 2 SO 4 and concentrated to dryness. The crude product obtained was subjected to preparative HPLC (wherein column: x_Bridge Prep C18 5 μιη OBD (19 X 100 mm), flow rate: 20 ml/min, eluent: A == AcN, B = NH4HCO3 75 mM, gradient : 〇 minutes 5 % A; 2.0 minutes 5 % A; 3.0 minutes 30 % A; 8.0 minutes 4 % % a; 9.0 minutes 80 % A; 10.0 minutes 8 % A) | tfi ft The product containing the fraction is concentrated To dryness, the title compound (6 3.9 rn g, yield 21%) was obtained. LC.MS (Method 2): tR = 1.69 min; m/z = 411 (MH+). Examples 77b to 7kk followed the procedure described in Example 14 but allowed the mixture of carbonyldiimidazole and the alcohol S,-chloroformin to be 3 $. The mixture obtained after heating for 2 hours and allowing the compound to be added to the compound of Example Sa to be heated by a Pra instrument at 4 Torr gave the following compound. The corresponding starting materials were used in each of the examples. -118- 201041867 Example name Starting material method (LC-MS) tR part clock) m/z (MH+) 77b 4-(2-amino-6-((3R)-3-(methylamino)) Pyrrrolidin-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid benzo[d]thiazol-2-ylmethyl ester Reference Example 5a and benzo[d]thiazol-2-ylmethanol 2 1.65 468 77c 4-(2-Amino-6-((3R)-3-(methylamino)pyrrole-1,yl)pyran-4-yl)piperidine-1-carboxylic acid (6- Chloro-1H-benzo[d]imidazol-2-yl)methyl ester Reference Example 5a and (6-chloro-1H-benzo[d]imidazol-2-yl)methanol 2 1.53 485 77d 4-(2- Amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid (2-methylthiazole-5-yl) Methyl ester reference example 5a and (2-methylthiazol-5-yl)methanol 2 1.36 432 77e 4-(2-amino-6-((3R)-3-(methylamino))-pyrrolidine- 1-yl)pyrimidin-4-yl)piperidin-1-carboxylic acid 3-cyano-ester ester Reference Example 5a and 3-(hydroxymethyl)benzonitrile 2 1.55 436 77f 4-(2-Amino- 6-((3R)-3-(Methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid 4-(1Η-pyrazol-1-yl)benzyl ester reference Example 5a and (4-(1Η-pyrazol-1-yl)phenyl)methanol 2 1.62 477 V7g 4-(2-amine -6-((3R)-3-(methylamino)pyrrole-thyl-1-yl)-1,4-yl) piperazine-1-carboxylic acid (1-methyl-5-phenyl-1H) -indolozol-3-yl)methyl ester Reference Example 5a and (1-methyl-5-phenyl-1H-pyrazol-3-yl)methanol 2 1.69 490 77h 4-(2-Amino-6 -((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid (6-methyl-1H-benzo[d]imidazole-2 -yl)methyl ester reference example 5a and (6-methyl-1H-benzo[d]imidazol-2-yl)methanol 2 1.45 465 77i 4-(2-amino-6-((3R)-3 -(Methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid 3-((1Η-pyrazol-1-yl)methyl)benzyl ester Reference Example 5a and (3-((1Η-pyrazol-1-yl)methyl)phenyl)methanol 2 1.59 491 -119- 201041867 77j 4-(2-Amino-6-((3R)-3-(methylamine) 2-(4-methylthiazole-5-yl)ethyl ester of pyrrolidin-1-ylpyrimidin-4-yl)piperidine-1-carboxylic acid Reference Example 5a and 2-(4-methylthiazole -5-yl)ethanol 2 1.33 446 77k 4-(2-Amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidine-1 -carboxylic acid (6-fluoro-1H-benzo[d]imidazol-2-yl)methyl ester Reference Example 5a and (6-fluoro-1H-benzo[d]imidazol-2-yl)methanol 2 1.45 46 9 Example 771 4-(2-Amino-6-((3R)-3-(methylamino)pyrrolidin-1-yl)pyrimidin-4-yl)piperidine-1-carboxylic acid 2- (4-Fluorophenylamino)ethyl ester a) 4-(2-Amino-6-((3 R)-3-(tertiarybutoxycarbonyl(methyl)amino)pyrrolidin-1 -yl) Pyrimidine-4-yl)piperidine-1 -carboxylic acid 2-bromoethyl ester The compound of Reference Example 5a was reacted with 2-bromoethyl chloroformate to give the title compound. The desired bromine compound and the chlorine compound derived by substituting the chlorine anion are separated. LC-MS (method 2): tR = 2 - 21 min; m/z 485 (MH + ) and (method 1): tR = 2.27 min; m/z 527 (MH+). b) the target compound obtained from the above procedure (100 mg, 0.19 mmol), 4-fluoroaniline (63.2 mg, 0.569 mmol), potassium carbonate (79 mg, 0.569 mmol) and potassium iodide ( A solution of a mixture of 12.59 mg, 0.076 mmol, in DMF (1_9 ml) was stirred at 50 ° C for 18 hours and then stirred for another 18 hours at 8 liters. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was dried over Na 2 SO 4 and concentrated to dryness and -120 - 201041867 by preparative HPLC (where column: X-Bridge Prep C18 5 μπι (19 χ 100 mm), flow rate: 19 ml/min (in The column was diluted to 1 ml/min), the eluent: A = MeOH, B = NH4HC03 30 mM, gradient: 25 minutes 25% A; 3.0 minutes 65% A; 8.0 minutes 80% A; 9.0 minutes 95% A ; 1 0.0 min 9 5 % A) Purification. The title compound (6.6 mg, 7.6% over 2 steps) was obtained after hydrolysis of the Boc group using TFA as described in Example 14 above. ❹ LC-MS (method 2): tR = 1_66 min; m/z 458 (MH + ). Example 7 Binding Competitive Analysis of [3H]-Histamine to Human Histamine H4 Receptor As determined by binding assay, a recombinant CHO recombinant cell line prepared from human histamine H4 receptor (Euroscreen/Perkin-) was used. Cell membrane extract of Elmer). The test compound was extracted with 10 nM [3 H]-histamine and cell membrane at a selected concentration and at a selected concentration of 50 μM Tris-HCl, pH 7.4, 1.25 mM EDTA in a total volume of 250 μM. The material (15 pg) was incubated for 60 minutes in a double repeat. Non-specific binding is defined in the presence of unlabeled histamine (1 μ μΜ). The reaction was terminated by using a vacuum collector (Multiscreen Millipore) in a 96-well groove tray (Multiscreen HTS Millipore) previously immersed in 0.5% polyethylenimine at 〇 °C for 2 hours. The plate was then rinsed at 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, followed by the addition of scintillation fluid and determination using a P-plate scintillation counter. Combined with radiation -121 - 201041867 activity. This assay measures the compounds of Examples 1 to 77k and the compounds exhibit an inhibitory effect on the binding of histamine to the human histamine h4 receptor by more than 50% at a concentration of 1 μ. Example 79 A histamine-induced shape change analysis of human eosinophils (Gated auto fluorescence forward scatter assay (GAFS)). In this analysis, a flow cytometer was used. The histamine-induced shape change of human eosinophils was determined by detecting an increase in cell size (forward scattering, FSC). Preparation of polymorphonuclear leukocytes (PMNL, containing whole blood from healthy human volunteers) Fractions of neutrophils and eosinophils). Briefly, red blood cells are separated by sedimentation in 1.2% dextran (SIGMA) and in the presence of Ficoll-Paque® (Biochrom) The leukocyte-rich fraction (PMNL) was separated from the top layer by centrifugation for 20 minutes at g. The PMNL was resuspended in PBS buffer at a concentration of 1.1 X 106 cells/ml/tube and dissolved in PBS at 37 °C. Test compounds of different concentrations were pretreated for 30 minutes, followed by stimulation with 300 nM histamine (Fluka) for 5 minutes. Finally, polyformaldehyde (final concentration 1% PBS solution) was added to stop the reaction and maintain cell shape The change in cell shape was analyzed by flow cytometry (FACSC a 1 ib ur, BD Biosystems). Based on the eosinophilic white blood cells in PMNL, the autofluorescence was higher than that of neutrophils. - 201041867 Iso-red blood cells (fluorescence channel FL2) in PMNL. Changes in cell shape were monitored by forward scatter signal (FSC). The results were changed by histamine-induced shape for each concentration of test compound. % inhibition. This analysis measures Examples 1 to 5, 7 to 1 1 , 1 3 to 15 , 1 7 , 2 1 to 23, 25, 27, 28, 31, 32, 35, 37' 38, 41, Compounds of 43, 46, 48 to 58, Μ to 67, and 76 to 7 7k and these compounds exhibit a 50% reduction in the shape change of human eosinophils induced by histamine at a concentration of 1 μΜ Inhibition.

-123-

Claims (1)

201041867 VII. Patent application scope: 1 · A compound of formula I nh2 r^v^-^NRlR2 Wherein R1 and r2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group: the saturated heterocyclic group is selected from the group consisting of: (0 heterocyclic group containing 2 nitrogen atoms and containing no other hetero atom) The ring group is optionally substituted with 1 or more c, _4 alkyl groups; and (H) a heterocyclic group containing 1 nitrogen atom and no other hetero atom, wherein the heterocyclic group is 1 -NRaRb Substituted and optionally substituted with 1 or more CL4 alkyl groups; wherein the heterocyclic groups (i) and (ii) are 4 to 7 membered monocyclic, 7 to 8 membered bridged bicyclic or 8 to 12 member thick a bicyclic ring; or R 1 represents hydrazine or C.. 4 alkyl, and R 2 represents a tetrahydroindenyl group, a pyridyl D group, a piperidinyl group or a hydrazinyl group, wherein the R 2 group optionally passes through one or more Ci.4 alkyl substituted; Ra represents hydrazine or Cm alkyl; -124- 201041867 Rb represents hydrazine or Ci_4 alkyl; or Ra and Rb together with the nitrogen atom to which they are bonded, pyrrolidinyl, piperidine A pyridyl or aziridine group, which may be substituted with one or more alkyl groups; R3 represents -COR4, -CONR4R4, -CO2R4'so2nr4r4'; R4 represents Ci.8 alkyl, r5_Ci8 alkyl or R6_c〇8 Ο于Ci-s alkyl, Rs-C&quot;alkyl and R6-C〇.8 alkyl are optionally substituted with 1 or more halo groups and the alkyl chain group is optionally substituted by -0-; R4, representing η or Cb8 alkyl; and optionally R·4 and R·4, bonding formation - C3-5 stretching alkyl alkyl group - optionally substituted by 1 or more C ^ 8 alkyl groups Rs represents -C〇NR4, R7, _NR4, COR7, NR4 SO2R7, -SO2NR4 R7 '-nr4, conr4, r7, _ 〇' -CO2R7 ' -OCOR7 ' -S〇2r7 , _NR4 R7 ' -OH Έ 5- R6 represents a C3·8 cyclodecyl group, a heterocycloalkyl group, an aryl group or an intermediate R6 group, optionally one or more independently selected from the group consisting of Cl 8 alkyl, halogen 'CU alkoxy, halogen (^&quot Alkoxy, -CN, C2.4 alkynyl, R5-CQ_8 alkyl or r8_Cq.8 院&gt; R7 stands for Η, Cu 焼 'c3 8 cycloalkyl-Cw too (: 〇.8 alkyl , wherein the (:1-8 alkyl, (:3_8 cycloalkyl-(:: into tetrahydro D丫唉 is selected via 1-S02R4 or -alkyl, wherein 'one of the bases' -, -C3-5 41C 〇2 R 7 ' - conhso2r7 obtains 1 Η-tetrazole-heteroaryl group, the base of which is substituted with a halogen group of a Cl.8 C 1 - 8 thiol group -&gt;-8 alkyl and aryl ' 125- 201041867 base - Cq - 8 in the base of any of the hospital bases may be optionally substituted with one or more halogen groups, and the C3.8 cycloalkyl and aromatic Any one of the groups optionally selected from C&quot; alkyl, halo Cm alkyl, halogen, d-8 alkoxy, halo Ci-8 alkoxy, Cm alkylthio, - Substituting CN, C2.4 alkynyl or hydroxyCl8 alkyl; and optionally r4 in the R5 group, and r7 bonding to form a _C3.5 alkyl group, the -Cw alkyl group - optionally Substituted with 1 or more Cl.8 alkyl; and R8 represents C3_8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein R8 is optionally optionally substituted with one or more alkyl groups, Halogen C, 1 '8 fen, dentin, Cl-8 decyloxy, halogen Ci-8 alkoxy, Ci-8 thiol, -CN, C2_4 alkynyl or hydroxy Cb8 alkyl group; or The salt of the other. 2. A compound as claimed in claim 1 wherein R3 represents -COR4, -CONR4R4, -C02R4 or -SO2R4. 3. A compound as claimed in claim 2, wherein R3 represents _C Ο 2 R 4 . 4. A compound as claimed in claim 2, wherein R3 represents _S Ο 2 R 4 . 5. The compound of any one of claims 1 to 4, wherein R4 represents C, -8 alkyl or R6_CQ.8 alkyl, wherein the C..8 alkyl and R 6 - C 〇 are In the s-family, any one of the hospital bases may alternatively be substituted with one or more lenyl groups and wherein one of the alkyl chain extensions may alternatively be replaced by - hydrazine. The compound of any one of claims 1 to 4 wherein R 4 represents a Ci-8 alkyl group optionally substituted by one or more halogen groups and wherein one of the alkyl chains The methyl group is optionally replaced by -0. 7. The compound of any one of claims 1 to 4 wherein R4 represents Rs-C^alkyl, wherein the alkyl group is optionally substituted with one or more halo groups and wherein the alkyl chain One of the methyl groups is optionally replaced by -0. The compound of any one of claims 1 to 4 wherein R4 represents R6-C〇_8 alkyl, wherein the alkyl group is optionally substituted with one or more halo groups and wherein A methyl group of the alkyl chain is optionally replaced by -Ο. 9. A compound according to claim 8 wherein R4 represents a 1U-q-8 alkyl group, wherein the alkyl group is optionally substituted with one or more halo groups and wherein one of the alkyl chains is methyl Alternatively, it can be replaced by -Ο. 10. The compound of any one of claims 1 to 4 and 7 wherein R5 represents -NR4, R7. 11. A compound according to claim 1 wherein R7 represents an aryl-cG-8 alkyl group, wherein the alkyl group is optionally substituted with 1 or more halo groups and the aryl group is optionally 1 or A plurality of substituents independently selected from the group consisting of Cbs alkyl, halo CU8 alkyl, halogen, alkoxy, haloCu alkoxy, Cu alkylthio, -CN, C2_ alkynyl or hydroxy C.8 alkyl. 1 2. A compound according to claim 1 wherein R7 represents an aryl-Cm alkyl group, wherein the alkyl group is optionally substituted with 1 or more halo groups and the aryl group is optionally 1 Or multiple independently selected from (^_8 alkyl, -127- 201041867 halogen C!-8), halogen, C1-8 alkoxy, halogen Cl-8 alkoxy 'Cl_8 alkylthio, -CN, C2.4 A compound of the alkynyl group or a hydroxy-Ci 8 alkyl group, wherein the compound of any one of claims 1 to 5 and 8 to 9 wherein R0 represents a C3-8 cycloalkyl group, an aryl group or a heteroaryl group, wherein R6 is optionally one or more independently selected from the group consisting of Cl-8 alkyl, halo-Cu alkyl, halogen 'C&quot; alkoxy, haloCl-8 alkoxy, Cl-8 alkylthio, CN, C2-4 alkyne a compound of the formula R3-CG-8 alkyl or r8-C().8 alkyl. 1 4. The compound of claim 3, wherein r6 represents a C3-8 cycloalkyl group, the C3_8 ring The alkyl group is optionally selected from one or more independently selected from C 丨-8 alkyl, haloalkyl, halogen, c 丨-8 alkoxy, halo alkoxy, (^.8 alkylthio, - CN, C2.4 alkynyl, R5-CG-8 alkyl or R8-C〇.8 base substitution. 1 5 · If applying for The compound of claim 14 wherein R 6 represents a monocyclic C 3-8 cycloalkyl group, optionally selected from one or more independently selected from the group consisting of alkyl, halo-alkyl, halogen, ^_8 alkoxy, halo C, -8 alkoxy, C&quot; alkylthio, -CN, C2_4 alkynyl, 115-fluorene: fluoren-8 alkyl or R8-Cq-8. 6. The compound of claim 13, wherein R6 represents an aryl or heteroaryl group, optionally exemplified by one or more independently selected from C 丨 8 alkyl, halo Ci-8 alkyl, halogen, Ci-8 alkoxy, halo Cm alkoxy, Cm alkylthio '-CN, C2.4 alkynyl, R5-CQ.8 alkyl or R8-C〇.8 alkane Substituting a radical. i. 7. A compound according to claim 16 wherein R6 represents an aryl group optionally substituted by one or more independently selected from C, _8 alkyl, -128- 201041867 Halogen Ci-8 alkyl, halogen, Cu alkoxy, halo Cl-8 alkoxy, Cl-8 alkylthio, -CN, C2.4 alkynyl, R5-CQ-8 or R8-C〇-8 Substituting the base of the yard. 1 8. The compound of claim 17 of the patent 'where Re represents a phenyl group, the phenyl group optionally 1 or more independently selected from the group consisting of Cl_8, halogen ci-8 alkyl, halogen, Cu alkoxy, halogen Ci-s alkoxy, ci-8 alkylthio, -CN, C2-4 alkynyl, R5-C -8 yard base or R8_Cq-8 yard base replaced. 1 9 - The compound of claim 16 wherein R6 represents a heteroaryl group optionally substituted by one or more independently selected from the group consisting of Cl_8, haloalkyl, halogen, Cl-8 Substituent substitution of alkoxy, halo C!-8 alkoxy, Cl-8 alkylthio, -CN, C2.4 alkynyl, R5-CG-8 alkyl or r8-Cq-8 alkyl. The compound of any one of claims 1 to 19 wherein R 1 and R 2 and the nitrogen atom bonded thereto form a saturated heterocyclic thiol group. The saturated heterocyclic group is selected from the group consisting of : (i) a heterocyclic group containing 2 nitrogen atoms and containing no other hetero atom, wherein the heterocyclic group is optionally substituted by 1 or more alkyl groups; and (ii) contains 1 nitrogen atom and is not a heterocyclic ring S' containing any other hetero atom, wherein the heterocyclic group is substituted with 1 -NRaRb group and optionally substituted with 1 or more Cm alkyl groups; wherein the heterocyclic group (i) and (ii) It is a 4 to 7 member single ring, a 7 to 8 member bridged double ring or an 8 to 12 member fused double ring. The compound of claim 2, wherein Ri and together with the nitrogen atom to which they are bonded form a saturated heterocyclic group, the saturated heterocyclic group being selected from the group consisting of: Wherein Rc and Rd each represent a hydrazine or a Cl_4 alkyl group. 2 2. For the compound of claim 21, where Re stands for Η. 23. The compound of claim 21, wherein R1 and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group selected from (a), (b), (e) or (1). 24. A compound according to claim 21 or 22, wherein R1 and R2 together with the nitrogen atom to which they are bonded form a saturated -130-201041867 heterocyclic group selected from (a) or (b). 25. The compound of claim 24, wherein R! and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (a). 26. The compound of claim 24, wherein R! and R2 together with the nitrogen atom to which they are bonded form a saturated heterocyclic group of formula (b). The compound according to any one of claims 1 to 26, wherein Ra and Rb independently represent hydrazine or C!-4 alkyl. 〇 2 8 · A compound of claim 27, wherein Ra and Rb independently represent an anthracene or a methyl group. 2 9 _ A compound of claim 28, wherein Ra represents hydrazine and Rb represents a methyl group. 3 如. For example, the compound of claim 28, wherein Ra and Rb represent hydrazine. The compound of any one of claims 1 to 19 wherein R1 represents hydrazine or C i -4 alkyl, and r2 represents tetrahydroindenyl, pyrrolidinyl, piperidinyl Or a hydrazinyl group, wherein the r2 is optionally substituted with one or more C^4 alkyl groups. And a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, as defined in any one of claims 1-3. 3. A compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3 of the patent application, which is for use in therapy. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease mediated by the histamine-131 - 201041867 H4 receptor. A compound according to claim 34, or a pharmaceutically acceptable salt thereof, wherein the disease caused by the histamine H4 receptor is allergic to an immune or inflammatory disease or pain. Use of a compound according to any one of claims 3 to 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing a disease mediated by histamine H4 receptor . 37. The use of claim 36, wherein the disease mediated by the tissue @receptor is an allergic, immune or inflammatory disease or pain 〇38. A method of preparing a compound of formula I as claimed in claim 1 , which comprises: (1) a compound starting from a compound of formula 11 (or a protected form of the amine group) nh2 HN, / wherein I and R2 are as described in claim 1 (a) when formula I In the case where R3 represents _c〇R4, the compound of formula II is reacted with an acid of the formula R4-COY or a mercapto chloride (wherein the γ system 〇H or C1); or -132- 201041867 (b) when the compound of the formula I is R3 Representative -CONR4R4, when the compound of formula 11 is reacted with an isocyanate of the formula R4-NCO or an amine formazan chloride of the formula R4R4, -NCOW (wherein the W is leaving a group); or (C) when a compound of the formula I represents R3 - CONR4R4, when the compound of formula 11 is reacted with triphosgene or phosgene and subsequently with an amine of the formula NHR4R4; or (d) when R3 represents -C〇2R4 in the compound of formula I, the formula and formula R4-OCOC1 chloroformate reaction; or (e) when R3 represents -C02R4 in the compound of formula I, the hydrazine compound has been previously Reaction with a coupling agent of an alcohol of the formula R4-OH; or (f) when R3 of the compound of the formula I represents -C02R4, the compound of the formula II is reacted with triphosgene or phosgene and subsequently with an alcohol of the formula R4-OH; Or (g) when r3 represents -so2r4 in the compound of formula I, the compound of formula II is reacted with sulfonium chloride of formula R4-so2ci; or (h) when R3 represents -S02NR4R4 in the compound of formula I, formula II The compound is reacted with the amine sulfonium chloride of the formula R4R4, -NS02C1, or (i) when R3 represents -S02NR4R4 in the compound of formula I, the compound of formula II is reacted with sulfonium chloride and subsequently with an amine of the formula NHR4R4; In any of the above (a) to (i), if necessary, any protecting groups which may be present are removed; or (2) the compound of the formula VI is reacted with a compound of the formula (or a protected form of the amine group) -133- 201041867 HNRtRs Wherein R i, R 2 and R 3 are as defined in claim 1 of the patent application, and if necessary, subsequently remove any protecting groups which may be present; or (3) converting the compound of formula I into another form via one or several steps I compound. -134- 201041867 IV. Designated representative map: (1) The designated representative figure of this case is: None (2), the representative symbol of the representative figure is a simple description: None 201041867 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 nh2 N^N i -4-