TW200934783A - Furo[3,2-d]pyrimidine derivatives - Google Patents

Abstract

Furo [3, 2-d] pyrimidine derivatives of formula I, wherein the meanings for the various substituents are as defined in the description. These compounds are useful as H4 receptor antagonists.

Description

200934783 IX. Description of the Invention [Technical Fields of the Invention] The present invention relates to a novel series of furo[3,2-d]pyrimidine derivatives, a process for the preparation thereof, a pharmaceutical composition containing the same, and a medical composition thereof use. [Prior Art] ❹ Histamine is one of the most potent mediators of immediate hypersensitivity reactions, although histamine has been affected by smooth muscle cell contraction, vascular permeability, and gastric acid secretion. Know, but its impact on the immune system has only just begun to be revealed. A few years ago, a new histamine receptor named H4 was selected by several independent research groups (Oda T et al., J CAe/n 2000, 275: 3678 1 -6; Nguyen T et al., Mo/ Φ 2001, 59: 427-33). As with other members of the family, the receptor is a G-protein coupled receptor (GPCR) containing seven transmembrane segments, whereas the H4 receptor is similar to the other three histamine receptors. The homology is low (Oda T et al.), notably its only 35% similarity to the H3 receptor. Although the expression of H3 receptors is restricted to cells of the central nervous system, the expression of H4 receptors is mainly found in cells of the haematopoietic lineage, especially eosinophils, obese cells, basophils, dendritic cells. And T cells (Oda T et al.). The fact that the sputum receptor is highly distributed in the immune system 200934783 cells indicates that this receptor is involved in the immune inflammatory response. Furthermore, this hypothesis can be enhanced by the fact that its gene expression can be modulated by inflammatory stimuli such as interferon, TNFa, and IL-6. However, the H4 receptor is also expressed in other cell types, for example in rheumatoid arthritis (W ojtec ka-L ukasik E et al., Ann Rheum D is 2006, 65 (Suppl II): 129; Ikawa Y ^ A , Biol Pharm Bull 2005, 28 :2016-8) and patients with osteoarthritis (Grzybowska-Kowalczyk A et al, European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, P-11) It is expressed in human synovial cells; it is also expressed in the human gut (Sander LE et al., Gwi 2 006, 5 5 · 498-504). It has been reported that the performance of the Η4 receptor is improved in nasal polyps compared to that in healthy nasal mucosa (J0k\iti Α et al, Cell Biol Int 2007, 31 : 1 3 67-70). ). Recent studies on specific ligands for H4 receptors have helped define the pharmacological properties of this receptor. These studies demonstrate that several histamine-induced reactions in eosinophils, such as chemotaxis, conformational changes, and upregulation of CDllb and CD54 are specifically mediated by the H4 receptor (Ling P et al. , Br J Pharmacol 2004, 142: 161-71;

Buckland KF # Λ , Br J Pharmacol 2003, 1 40 : 1 1 1 7-27 ). Studies have also shown that H4 receptors affect the maturation, interleukin production, and migration of these cells in dendritic cells (Jelinek I et al., 1st Joint Meeting of European National Societies of Immunology, Paris, France, 2006, PA). - 1 25 5 ). In addition, the role of H4 receptors in obese cells has also been studied. Although H4 receptor activation does not trigger fat -6-200934783 fat cell degranulation (degranulati〇n), it releases histamine and other inflammatory mediators (Pr〇inflammatory mediators); The H4 receptor mediates the chemotaxis and calcium movement of obese cells (Honstra CL et al, J Pharmacol Exp Ther 2003, 305: 1 2 1 2-21). As for the T-Polony ball, it is shown that H4 receptor activation triggers T-cell migration and preferentially attracts the Τ- morpha group with inhibitor/regulatory phenotype and function g (Morgan RK et al., American Thoracic ❿ Society Conference, San Diego, USA, 2006, P-536), and modulates activation of CD4+ T cells (Dunford PJ et al, J Immunol 2006, 176: 7062-70). As for the intestine, the distribution of the H4 receptor indicates that it may have a role in the control of peristalsis and gastric acid secretion (Morini G et al., European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, OR-10). The various H4 receptor functions observed in eosinophils, obese cells, and T-cells indicate that this receptor can play an important role in immune inflammatory responses. In fact, H4 receptor antagonists have been used in peritonitis (Thurmond RL et al, J Pharmacol Exp Ther 2004, 3 09: 404-13), thymitis ( Takeshita K ^ X, J Pharmacol Exp Ther 2003, 307: 1 In vivo activity was exhibited in a murine model of 0 7 2-8), and scratches (Bell JK et al., Br J Pharmacol 2004, 1 42 : 3 74-80 ). In addition, H4 receptor antagonists have been used in allergic asthma (Dunford PJ et al., 2006), inflammatory bowel disease (Varga C et al, ugly μr «/ corpse / ι ar / η ac 〇 / 2 0 0 5 , 5 2 2 : 130-8 ), pruritus (Dunford PJ et al., C//n 2007, 119: 176-83), atopic dermatitis (Cowden 200934783 JM et al., /j/Zergy C/ z'" //nwM«o/ 2007; 119 ( 1) : S 2 3 9 (

Abs 9 3 5 ) , American Academy of Allergy, Asthma and

Immunology 2007 AAAAI Annual Meeting, San Diego, USA), eye inflammation (Zampeli E et al., European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, OR-36), edema and hyperalgesia (Coruzzi G et al, In vivo activity was demonstrated in an experimental model of V. 2007, 563: 240-4) and neuropathic pain (Cornart MD et al., J Med Chem. 2008; 51 (20): 6547-57). H4 receptor antagonists are therefore expected to be useful in the treatment or prevention of allergic, immunological, and inflammatory diseases, as well as pain. Therefore, it is desirable to provide novel compounds having H4 receptor antagonist activity and being excellent candidate drugs. In particular, preferred compounds should bind strongly to the histamine H4 receptor but have low affinity for other receptors. In addition to being able to bind to the H4 receptor, these compounds also exhibit good pharmacological activity in an immunoinflammatory in vivo model. In addition, these compounds are capable of reaching the target tissue or organ when administered by a selected route of administration and have advantageous pharmacokinetic properties. Furthermore, these compounds should be non-toxic and have few side effects. SUMMARY OF THE INVENTION One aspect of the invention pertains to a compound of formula I, 200934783

among them:

Rj is Η or NH2; R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group, which may be a 4 to 7 membered monocyclic ring, a 7 to 8 member bridged double ring, or 8 to 8 a 12-membered fused bicyclic ring wherein the heterocyclic group may contain up to two N atoms and is free of any other heteroatoms, and may be optionally selected from one or more substituents independently selected from (^-4 alkyl and NRaBb) Substituted, but the heterocyclic group must contain 2 N atoms or contain 1 N atom and be substituted by one NRaRb group; or R2 is a Ci-4 alkyl group, and R3 is a tetrahydroindenyl group, a pyrrolidinyl group, a piperidinyl group, or a hydrazinyl group, which may be optionally substituted by one or more s.

Ra is hydrazine or Cm alkyl;

Rb is hydrazine or Cl.4 alkyl; or 1 and Rb together with the N atom bonded thereto form a tetrahydroindenyl group, a pyridyl group, a piperidinyl group, or a hydrazinyl group, which may be selectively one or more Substituted by a Cl.4 hospital base; R4 is one or more of two independently selected from the group consisting of fluorene and (^-4 alkyl groups, and optionally on the same carbon atom or on two different carbon atoms The r4 groups may be bonded together to form a _Cl_6 alkyl- group, wherein the (etc.) R4 group may be attached to any available position in the ring of -9-200934783 A; and η is 0, 1, 2, or 3 The invention also relates to salts and solvates of the compounds of formula I. Some of the compounds of formula I may have a palm center such that they have various stereoisomers. The invention also relates to the individual isomers of these stereoisomers and mixture.

The compounds of formula I exhibit a high affinity for the Η4 receptor. Therefore, another aspect of the invention relates to a compound of formula I for use in medicine

R2 and R3 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group which may be a 4 to 7 membered monocyclic ring, a 7 to 8 member bridged bicyclic ring, or an 8 to 12 membered fused bicyclic ring. Wherein the heterocyclic group may contain up to two ν atoms and does not contain any other hetero atom, and may be optionally substituted by one or more substituents independently selected from C 4 ·4 alkyl and NRaBb, but the hetero The ring group must contain 2 N atoms or contain 1 N atom and be substituted by one NRaRb group; or β·2 is Η or Ci-4, and R3 is tetrahydro V fluorenyl, 卩 is slightly steep, a piperidinyl group, or a hydrazinyl group, which may be optionally substituted by one or more Ci.4 alkyl groups-10-200934783;

Ra is hydrazine or Cl. 4 alkyl;

Rb is hydrazine or Cl.4 alkyl; or Ra and Rb together with the N atom bonded thereto form a tetrahydroindenyl group, a pyrrolidinyl group, a piperidinyl group, or a hydrazinyl group, which may be selectively selected by one or more Substituted by a Ci-4 alkyl group; R4 is one or more groups independently selected from the group consisting of hydrazine and C..4 alkyl, and optionally fluorene on the same carbon atom or on two different carbon atoms. The R4 groups can be bonded together to form an alkyl group, wherein the (etc.) R4 group can be attached to any available position in the A ring; and η is 0, 1, 2, or 3. Another aspect of the invention relates to a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable hydrazine salt thereof for the manufacture of a medicament for the treatment of a disease mediated by histamine 114 receptor. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of an allergic, immune, or inflammatory disease or pain. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of an allergic, immunological, or inflammatory disease. Preferably, the allergic, immunological, or inflammatory disease is selected from the group consisting of respiratory diseases, ocular diseases, skin diseases, inflammatory -11 - 200934783 intestinal diseases, rheumatoid arthritis, multiple sclerosis, Skin lupus 'systemic lupus erythematosus, and transplant rejection. More preferably, the allergic, immune, or inflammatory disease is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataract, dermatitis (eg, atopic Dermatitis), psoriasis, urticaria, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus, and transplant rejection. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of pain. Preferably, the pain is selected from the group consisting of inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-operative pain, migraine, cancer pain, visceral pain, osteoarthritis pain, and neuropathic pain. Another aspect of the invention is directed to a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition mediated by the H4 histamine receptor. Another aspect of the invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of an allergic, immune, or inflammatory disease or pain. Another aspect of the invention relates to the treatment of allergies, immunity A compound of formula I, or a pharmaceutically acceptable salt thereof, of a sexual or inflammatory disease. Preferably, the allergic, immunological, or inflammatory disease is selected from the group consisting of respiratory diseases, eye diseases, skin diseases, inflammatory bowel diseases, rheumatoid arthritis, multiple sclerosis, skin lupus, systemic Lupus erythematosus, and transplant rejection. More preferably, the allergic, immune, or inflammatory disease is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), over-12-200934783 sensitizing rhinoconjunctivitis, dry eye, cataract, dermatitis (eg atopic dermatitis), psoriasis, urticaria, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus, and transplant rejection . Another aspect of the invention is directed to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of pain. Preferably, the pain is selected from the group consisting of inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-operative pain, migraine, φ cancer pain, visceral pain, osteoarthritic pain, and neuropathic pain. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of a disease mediated by histamine H4 receptor. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of an allergic, immune, or inflammatory disease or pain. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of an allergic, immune, or inflammatory disease. Compared with CI, the allergic, immune, or inflammatory disease is selected from the group consisting of respiratory diseases, eye diseases, skin diseases, inflammatory bowel diseases, rheumatoid arthritis, multiple sclerosis, and skin lupus. Systemic lupus erythematosus, and transplant rejection. More preferably, the allergic, immune, or inflammatory disease is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataract, dermatitis (eg, atopic) Dermatitis), psoriasis, urticaria, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus, and transplant rejection -13- 200934783 Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of pain. Preferably, the pain is selected from the group consisting of inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-operative pain, migraine, cancer pain, visceral pain, osteoarthritic pain, and neuropathic pain. Another aspect of the invention relates to a method for treating a disease mediated by a histamine H4 receptor to an individual in need thereof, in particular a human, comprising administering to the individual a compound of formula I or a pharmaceutically acceptable compound thereof Salt. Another aspect of the invention relates to a method for treating an allergic, immune, or inflammatory disease or pain in an individual in need thereof, particularly a human, comprising administering to the individual a compound of formula I or a pharmaceutically acceptable compound thereof Accepted salts. Another aspect of the invention relates to a method for treating an allergic, immune, or inflammatory disease in an individual in need thereof, particularly a human, comprising administering to the individual a compound of formula I or a pharmaceutically acceptable compound thereof Salt. Preferably, the allergic, immunological, or inflammatory disease is selected from the group consisting of respiratory diseases, eye diseases, skin diseases, inflammatory bowel diseases, rheumatoid arthritis, multiple sclerosis, skin lupus, systemic Lupus erythematosus, and transplant rejection. More preferably, the allergic, immune, or inflammatory disease is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataract, dermatitis (eg, atopic) Dermatitis), psoriasis, measles, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus, and transplant rejection. Another aspect of the invention relates to a method for treating pain in an individual in need thereof (Eur. 14-200934783, which is a human), comprising administering to the individual a compound of the formula or a pharmaceutically acceptable salt thereof . Preferably, the pain is selected from the group consisting of inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-operative pain, migraine, cancer pain, visceral pain, osteoarthritis pain, and neuropathic pain. A method for the preparation of a compound of formula I as defined above, comprising: Φ (a) reacting a compound of formula 11 with a compound of formula III

Wherein Ri, R2, R3, r4, and η have the definitions defined above; or ❹ (b) reacting a compound of formula IV with a hydrazine compound

Wherein I is a leaving group, and R1, r2, r3, r4, and η have the above definition; or 200934783 (C) converting a compound of formula I to another compound of formula I in one or more steps. In the above definition, the term 匕·4 alkyl means a straight or branched alkyl chain containing from 丨 to 4 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl Base, secondary butyl, and tertiary butyl.

The -Cw alkyl group associated with the group formed by the two R4 substituents on the ring of the compound A of the formula I is a linear or branched alkyl chain having from 1 to 6 carbon atoms. If two R4 substituents bonded together are attached to the same carbon atom of the A ring, the alkyl chain forms a spiro ring system together with the A ring; if the two R4 substituents bonded together are Attached to the different carbon atoms of the A ring, the alkyl chain forms a bridged bicyclic system along with the A ring. The R4 group forming a -Calkyl group can be attached to any available carbon atom on the ring of the compound A of the formula I, as long as the resulting ring system can be obtained chemically and is stable. Examples of -Ci-6 alkyl-formed by two R4 groups on the same carbon atom and thus forming a spiro ring include:

Examples of alkyl groups formed by two R4 groups on different carbon atoms of the A ring and thus forming a bridge include: -16- 200934783

The term "saturated" means a group that does not contain any double bonds or key bonds. A "bridged" bicyclic group means that a double ring system has two shared atoms (bridge ends) connected to three acyclic chains (bridges), so that a rainy bridge with a larger number of atoms forms a main ring, and the atom The smaller number of bridges is the "bridge ©". In the definition of NR2R3, R2 and R3 together with the N atoms bonded to it can form a saturated 4 to 7 member single ring containing up to 2 N atoms and no other heteroatoms. Heterocyclic. Examples thereof include tetrahydroindenyl, pyrrolidinyl, piperidinyl, piperidinyl, and literin. In the definition of NR2R3, R2 and R3 together with the N atom to which they are bonded may form a bridged bicyclic group having 7 to 8 atoms. The bridged bicyclic group may contain up to two N atoms and no other heteroatoms. Examples thereof include 2,5-diindole-bicyclo[2.2.1]heptyl and 2,5-diindole-bicyclo[2.2_2]octyl. In the definition of NR2R3, the term "fused bicyclic" refers to an 8- to 12-membered bicyclic system consisting of two adjacent rings sharing two atoms. The fused bicyclic group may contain up to two N atoms in any available position and does not contain any other heteroatoms. Examples thereof include octahydropyrrolo[3,4-b]pyridinyl, octahydropyrrolo[3,2-c]pyridinyl, octahydropyrrolo[1,2-a]pyridyl, and octahydropyrrole. And [3,4-c]pyrroline group. As described above for NR2R3 in the definition of the compound of formula I, the above three-17-200934783 saturated heterocyclic rings (monocyclic, bridged bicyclic, and fused bicyclic) may be selectively selected by one or more Substituents independently selected from the group consisting of Cl_4 alkyl and NRaRb are substituted 'but if the ring contains only one N atom, the ring must be substituted with one NRaRb group. If a substituent is present, the substituent may be attached to any available position of the ring; if the substituent is an alkyl group, the position on the accessible ring includes an N atom. "Selectively substituted by one or more" means that the group may be substituted by one or more (preferably 1, 2, 3, or 4 'more preferably 1 or 2) substituents, but The group must have a position that is sufficient to be replaced. These substituents may be the same or different ' and may be attached to any available position. In the present specification, the terms "treatment" or "treatment" of a disease refer to a curative treatment of the disease and a palliative treatment or a prophylactic treatment. For the purposes of the present invention, 'beneficial or desirable clinical outcomes include, but are not limited to, reducing or ameliorating one or more symptoms, attenuated disease levels, stable (ie, non-deteriorating) disease states, preventing the occurrence of diseases that are predisposed to the patient Or a disease that does not show symptoms, a delay or slowing of the progression of the disease, an improvement or mitigation of the disease state, and a reduction (partial or total). Those in need of treatment include those who already have the disease or condition as well as those who are predisposed to the disease or condition or who are to be prevented. The invention is thus related to a compound of formula I as defined above. In another embodiment, the invention is directed to a compound of formula I wherein 1 is Η.

In another embodiment, the invention is a compound of formula I 200934783 relating to R, which is ΝΗ2. In another embodiment, the invention is directed to a compound of formula I wherein n is 1, 2, or 3. In another embodiment, the invention is directed to a compound of formula I wherein n is 0, 1, or 2. In another embodiment, the invention is directed to a compound of formula I wherein n is 1 or 2.

φ In another embodiment, the invention relates to compounds of formula I wherein n is 0 or 1. In another embodiment, the invention is directed to a compound of formula I wherein η is zero. In another embodiment, the invention is directed to a compound of formula I wherein η is 1. In another embodiment, the invention is directed to a compound of formula I wherein η is 2.另一 In another embodiment, the invention is a compound of formula I wherein R4 is one or more substituents selected from the group consisting of 11 and 4 alkyl groups. In another embodiment, the invention is directed to a compound of formula I wherein R4 is oxime. In another embodiment, the invention relates to a compound of formula I wherein η is 1, 2, or 3 and R 4 is one or more substituents selected from the group consisting of 11 and Ci. 4 alkyl. In another embodiment The present invention relates to compounds of formula I wherein n is 1, 2, or 3 and R4 is deuterium. -19- 200934783 In another embodiment, the invention relates to a compound of formula I wherein n is 0, 1, or 2 and R4 is one or more substituents selected from the group consisting of hydrazine and (^-4 alkyl) In one embodiment, the invention relates to a compound of formula I wherein n is 0, 1, or 2 and FU is oxime. In another embodiment, the invention relates to η being 1 or 2 and R4 being one or more In a further embodiment, the invention relates to a compound of formula I wherein n is 1 or 2 and R4 is deuterium. The present invention relates to a compound of formula I wherein n is 0 or 1 and R4 is one or more substituents selected from the group consisting of hydrazine and Ci-4 alkyl. In another embodiment, the invention relates to η being 0. Or a compound of formula I wherein R4 is oxime. In another embodiment, the invention is directed to a compound of formula I wherein η is 0 and R4 is one or more substituents selected from the group consisting of hydrazine and Ci-4 alkyl. In another embodiment, the invention relates to a compound of formula I wherein η is 0 and 〜 is Η. In another embodiment, the invention relates to η being 1 and R 4 being one or more selected from the group consisting of <^_4 substituent of formula A of formula I In another embodiment, the invention relates to a compound of formula I wherein η is 1 and is Η. In another embodiment, the invention relates to η being 2 and R 4 being one or more selected from A compound of formula I which is substituted with a C..4 alkyl group. In another embodiment, the invention is directed to a compound of formula I wherein η is 2 and R4 is Η-20-200934783. In another embodiment The present invention relates to a compound of formula I having the following definitions: R2 and R3 together with the N atom bonded thereto form a heterocyclic group selected from the group consisting of the following saturated heterocyclic groups (i) containing 2 N atoms and not containing any other hetero atom a cyclic group wherein the heterocyclic group is optionally substituted by one or more C!-4 alkyl groups; and oxime (ii) a heterocyclic group containing 1 N atom and no other hetero atom, wherein the heterocyclic ring The base is substituted by an NRaRb group and is optionally substituted by one or more Cm alkyl groups; wherein the heterocyclic groups (i) and (ii) can be 4 to 7 membered monocyclic, 7 to 8 Members bridging bicyclic, or 8 to 12-membered fused bicyclic rings; or R2 is 11 or (^-4 alkyl, and r3 is tetrahydroindenyl, pyrrolidinyl, piperidinyl, or hydrazine , which may be optionally substituted by one or more Cl.4 alkyl groups. In another embodiment, the invention relates to the formation of a saturated heterocyclic group by R2 and R3 together with the N atom bonded thereto and the saturated hetero The cyclic group may be a 4 to 7 membered monocyclic, 7 to 8 membered bridged bicyclic, or 8 to 12 membered fused bicyclic compound of formula I wherein the heterocyclic group may contain up to two N atoms and Containing any other hetero atom, and may be optionally substituted by one or more substituents independently selected from the group consisting of Ci-4 alkyl and NRaRb, but the heterocyclic group must contain 2 N atoms or contain 1 N atom and Replaced by an NRaRb group. In another embodiment, the invention relates to a compound of formula I wherein R2 and R3 together with an N atom bonded thereto form a saturated heterocyclic group selected from the group consisting of: - (i) containing 2 N atoms a heterocyclic group free of any other hetero atom, wherein the heterocyclic group is optionally substituted by one or more Cl 4 alkyl groups; and (η) a heterocyclic group containing 1 N atom and no other hetero atom Wherein the heterocyclic group is substituted by an NRaRb group, and may be optionally substituted by - or a plurality of Ci_4 alkyl groups; wherein the heterocyclic groups (i) and (ii) may be 4 to 7 membered monocyclic groups 7 to 8 members are bridged with a double ring or 8 to 12 members with a fused double ring. In another embodiment, the invention is relevant! ^ A compound of formula I independently of Rb or a Ci-4. In another embodiment, the invention is a compound of formula I in which the heart and Rb are independently Η, methyl, or ethyl. In another embodiment, the invention is relevant! ^ A compound of formula I in which Rb is independently Η or methyl. In another embodiment, the invention is directed to a compound of formula I wherein 1 is Η and Rb is Η or C alkyl. In another embodiment, the invention is directed to a compound of formula I wherein 1 is hydrazine and Rb is hydrazine, methyl, or ethyl. In another embodiment, the invention is directed to a compound of formula I wherein 113 is hydrazine and Rb is hydrazine or methyl. In another embodiment, the invention is directed to a compound of formula I wherein Ra is hydrazine and Rb is Cj.4 alkyl. In another embodiment, the invention is directed to a compound of formula I wherein 113 is hydrazine and Rb is methyl or ethyl. -22- 200934783 In another embodiment, the invention is directed to a compound of formula I wherein Ra is fluorene and Rb is methyl. In another embodiment, the invention is directed to a compound of formula I wherein Ra and Rb are deuterium. In another embodiment, the invention relates to a compound of formula I wherein R2 and R3 together with the N atom bonded thereto form a saturated heterocyclic group selected from the group consisting of

Wherein, Ra and Rb have the above definitions for the compound of formula I, and 1 is hydrazine or Ci-4 alkyl, and preferably R. H. In another embodiment, the invention relates to a compound of formula I having the following definition: R2 and R3 together with the N atom bonded thereto form a saturated heterocyclic group selected from (a) to (h), and Ra, Rb, independently of Rc, is η or

Ci·4 alkyl 'better', {, and Rc are independently η or methyl, and more preferably Ra and Rb are independently Η or methyl and Re is Η. -23- 200934783 in another embodiment The present invention relates to a compound of formula I having the following definition: R2 and R3 together with the N atom bonded thereto form a saturated heterocyclic group selected from (a) to (e), wherein 1^ and Rb have the above formula I. The definition of compound I, R. is H or (^.4 alkyl, preferably R. is H. In another embodiment, the invention relates to a compound of formula I having the following definition: R2 and R3, together with the N atom bonded thereto, forms a saturated heterocyclic group selected from (a) to (e), and Ra, Rb, and Rc are independently a fluorene or a Cw alkyl group, and preferably Ra, Rb, and Rc are independently Preferably, Ra and Rb are independently hydrazine or methyl and Re is hydrazine. In another embodiment, the invention relates to a compound of formula I having the following definition: R2 and R3 bonded thereto The N atom forms a saturated heterocyclic group selected from (a) to (d), wherein 113 and Rb have the above-defined definitions for the compound of the formula I, and R is Η or C!-4 alkyl, preferably Re is Η 〇 in another In an embodiment, the invention relates to a compound of formula I having the following definition: R2 and R3 together with a ruthenium atom bonded thereto form a saturated heterocyclic group selected from (a) to (d), and Ra, Rb, and Rc is independently hydrazine or Cm alkyl, preferably Ra, Rb, and Rc are independently hydrazine or methyl, and more preferably, Ra and Rb are independently fluorenyl or methyl and Rc is hydrazine. In another embodiment, The invention relates to a compound of formula I having the following definition: R2 and R3 together with the N atom bonded thereto form a saturated heterocyclic group selected from (a) and (b) wherein 1^ and Rb have the above formula I Said, and R. is Η or C! _4 alkyl, preferably R. is Η -24 - 200934783 In another embodiment, the invention relates to a compound of formula I having the following definition: R2 And R3 together with the N atom bonded thereto form a saturated heterocyclic group selected from (a) and (b), and Ra, Rli, and Rc are independently Η or Cm alkyl, preferably {^, ,, and Rc Independently being hydrazine or methyl, more preferably Ra and Rb are independently hydrazine or methyl and 1 is hydrazine. In another embodiment, the invention relates to a compound of formula I having the following definitions: R2 and R3 The ruthenium atom bonded thereto forms a saturated heterocyclic group selected from (a Φ ) and (b), Ra is H, Rb is 11 or Cu alkyl, and R is Η. In another embodiment, The present invention relates to a compound of formula I having the following definitions: R2 and R3 together with a ruthenium atom bonded thereto form a saturated heterocyclic group selected from (a) and (b), Ra is H, Rb is ruthenium or methyl, and Rc is Η 另一 In another embodiment, the invention relates to a compound of formula I having the following definition: R2 and R3 together with a ruthenium atom bonded thereto form a formula (a) oxime heterocycle

(8) wherein Ra and Rb have the above definitions for the compound of formula I, and 1 is hydrazine or (^_4 alkyl, preferably R. is H. In another embodiment, the invention relates to a compound of formula I There is a heterocyclic ring of -25-200934783, 'Rb' or a methyl group is defined below, and a heterocyclic ring is defined below, which is defined as follows: R2 and R3 together with the N atom forming a bond thereof (a) and Ra, Rb, and R. Independently, it is a hydrazine or a Ci-4 alkyl group. Preferably, Ra and Rc are independently hydrazine or methyl group, and more preferably, the heart and Rb are independently η and R c is Η. In another embodiment, the invention relates to a compound of formula I: R2 and R3 together with a ruthenium atom bonded thereto form (a) Ra is H' Rb is 11 or Ci. 4 alkyl, and Re Why?另一 In another embodiment, the invention relates to a compound of formula I: Rz and R3 together with a ruthenium atom bonded thereto form (a) Ra is Η ' Rb is Η or methyl, and Rc is Η . In another embodiment, the invention is directed to a compound of formula I: R2 and R3 together with a ruthenium atom bonded thereto (b

Ra wherein Ra and Rb have the above definitions for the compound of formula I, and 1^ is Η or Ci. 4 院基* preferably R. In another embodiment, the invention is directed to a compound of formula I having the following definition: R2 and R3 together with the N atom to which they are bonded form a heterocycle of formula (b) and Ra, Rb, and Re are independently 11 Or Cm alkyl, preferably Ra, Rb, and Rc are independently hydrazine or methyl, and more preferably, Ra and Rb are independently -26-200934783 hydrazine or methyl and amp. Why? In another embodiment, the invention is of the formula: wherein R 2 and R — 3 together with a ruthenium atom bonded thereto form (b) heterocycle '1 is H' Rb is only or Cw alkyl And Rc is η. In another embodiment, the invention relates to a compound of formula I having the following definition: R2 and R3 together with a ruthenium atom bonded thereto form a heterocycle of formula (b), and Ra is H'Rb is oxime or methyl, And RjH. 〇 In another embodiment, the invention relates to a compound of formula I having the following definition: Rz and R3 together with the N atom bonded thereto form a heterocyclic ring of formula (c)

Ra

I 广N Rc (c) © wherein ^ is independently or ^Cm alkyl, preferably 1 and Re are independently oxime or methyl'. Preferably, Ra is oxime or methyl and Rc is oxime. In another embodiment, the invention is directed to a compound of formula I having the following definition: R2 and R3 together with a ruthenium atom bonded thereto form a heterocyclic ring of formula (d) -27- 200934783

Ra

(d) wherein Ra is H or Ci·4 alkyl'. Preferably, 1 is H or methyl. In another embodiment, the present invention relates to a compound of formula I having the following definitions: R 2 is a fluorene or Ci_4 ordinal group and R 3 is a tetrahydro gamma thiol group, a succinct steep group, a piperidinyl group, or a hydrazine group. a group which may be optionally substituted by - or a plurality of c 烷基 alkyl groups. 'Better R 2 is Η and R 3 is 1 - methyl-pyro-staple _3 〇. In another embodiment, the present invention is About η is 〇, 1, now 2 and

Ri is a compound of formula I of ΝΗ2. In another embodiment, the invention is directed to a compound of formula I wherein η is hydrazine or hydrazine and is NH2. 1 In another embodiment, the invention is directed to a compound of formula I wherein n is 1 or 2 and & nh2. 1 © In another embodiment, the invention relates to a compound of formula I wherein n is 〇2 and R1 is ΝΗ2. In another embodiment, the present invention relates to a compound of formula I wherein n is 1 day and R 1 is ΝΗ2. In another embodiment, the invention is related! ! A compound of formula I wherein R1 is N Η 2 for 2 days. In another embodiment, the invention relates to η being 〇, 1, 4 2 and -28 - 200934783

Ri is a compound of formula I. In another embodiment, the invention is directed to a compound of formula I wherein n is 0 or 1 and R1 is oxime. In another embodiment, the invention is directed to a compound of formula I wherein n is 0 and 1 is Η. In another embodiment, the invention is directed to a compound of formula I wherein η is 1 and 1 is Η.另一 In another embodiment, the invention is directed to a compound of formula I wherein η is 2 and is Η. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is Ο, 1, or 2;

Ri is Η; and R2 and R3 together with the ruthenium atom to which it is bonded form a saturated heterocyclic group, which may be a 4 to 7 membered monocyclic ring, a 7 to 8 member bridged double ring, © or 8 To a 12-membered fused bicyclic ring wherein the heterocyclic group may contain up to two N atoms and is free of any other heteroatoms, and may be optionally substituted with one or more substituents independently selected from the group consisting of ci-4 alkyl and NRaRb Substituted, but the heterocyclic group must contain 2 N atoms or contain 1 N atom and be substituted by one NRaRb group. In an embodiment, the invention relates to a compound of formula I having the following definitions: 11 is 〇, 1, or 2; R> is Η; and -29-200934783 R2 and R3 together with the N atom bonded thereto are selected from a saturated heterocyclic group: (i) a heterocyclic group containing 2 N atoms and not containing any other hetero atom, wherein the heterocyclic group is optionally substituted by one or more (^.4 alkyl groups; (11) a heterocyclic group containing 1 N atom and not containing any other hetero atom, wherein the heterocyclic group is substituted by one NRaRb group, and may be optionally substituted by - or a plurality of C 4 alkyl groups; The heterocyclic groups (i) and (ii) may be a 4 to 7 monocyclic ring, a 7 to 8 member bridged bicyclic ring, or an 8 to 12 membered fused bicyclic ring. In another embodiment. The present invention relates to a compound of formula I having the following definition: η is 0, 1, or 2;

Ri is Η; and R 2 and R 3 together with the ruthenium atom bonded thereto form a saturated heterocyclic group selected from (a) to (h ) wherein Ra, Rb, and the definitions described above are preferred 'Ra, Rb And Re is independently 1! or Cl-4 alkyl, more preferably ◎ Ra, Rb, and Rc are independently hydrazine or methyl, and more preferably, Ra and Rb are independently hydrazine or methyl and 1 is H. In another embodiment, the invention is of the formula wherein: η is 0, 1, or 2; R1 is Η, and R·2 and R·3 are formed together with a ruthenium atom bonded thereto a saturated heterocyclic group selected from (a) and (b), wherein Ra, Rb, and Re have the above-defined -30-200934783, preferably Ra, Rb, and Re are independently Η or Ci-4 The alkyl group, more preferably Ra, Rb and Rc are independently fluorene or methyl, and more preferably, 1 and Rb are independently hydrazine or methyl and 1 is H. In another embodiment, the invention is of the formula: wherein η is 0, 1, or 2;

Ri is Η; and 形成 forms a heterocyclic ring of formula (a) with the ruthenium 3 and the ruthenium atom bonded thereto, wherein Ra, Rb, and R. Independently, it is a hydrazine or a Cl 4 alkyl group. Preferably, Ra, Rb, and Rc are independently hydrazine or methyl group. Further, Ra and Rb are independently η or methyl and R. Why? In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 0, 1, or 2;

Ri is Η; and Ο R2 and R3 together with the ruthenium atom bonded thereto form a heterocyclic ring of formula (b), wherein Ra, Rb, and Rc are 1L Η or Cl·4, preferably Ra, Rb, and Independently Η or methyl, the better heart and Rb are independently η or methyl and Η. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 0, 1, or 2;

Ri is Η; and R·2 is Η or C μ 垸, and R_3 is tetrahydroindenyl, stiletto-31 - 200934783, piperidinyl or fluorenyl, which may be selectively one or more Substituted by a Ci-4 alkyl group, preferably R2 is fluorene and R3 is 1-methyl-pyrrolidin-3-yl. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 0, 1, or 2;

Ri is ΝΗ2; and R2 and R3 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group which may be a 4 to 7 membered monocyclic ring, a 7 to 8 member bridged double ring, or 8 to 12 members. A fused bicyclic ring wherein the heterocyclic group may contain up to two N atoms and does not contain any other hetero atom, and may be optionally substituted by one or more substituents independently selected from C 1 -4 alkyl and NRaBb However, the heterocyclic group must contain 2 N atoms or contain 1 N atom and be substituted by one NRaRb group. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 0, 1, or 2;

Ri is ΝΗ2; and R2 and R3 together with the ruthenium atom bonded thereto form a saturated heterocyclic group selected from the group consisting of: (i) a heterocyclic group containing 2 ruthenium atoms and no other hetero atom, wherein the heterocyclic group Optionally substituted with one or more Cl 4 alkyl groups; and (Π) a heterocyclic group containing 1 N atom and no other hetero atom, wherein the heterocyclic group is substituted by an NRaRb group, and Optionally substituted by one or more Ci-4 alkyl groups; -32- 200934783 wherein the heterocyclic groups (i), (ii) may be 4 to 7 members, 8 members bridging bicyclic, or 8 to 12 members Fused double ring. In another embodiment, the invention is directed to the following formula I: η is 0, 1, or 2;

Ri is ΝΗ2; and R·2 and R3 together with a ruthenium atom bonded thereto form a saturated heterocyclic group, wherein Ra, Rb, and Re have meanings, preferably Ra, Rb, and R. Independently 11 or Ci-4 Ra, Rb, and Rc are independently hydrazine or methyl, and more preferably hydrazine or methyl and R. Why? In another embodiment, the invention is defined by the formula I below: η is 0, 1, or 2;

Ri is ΝΗ2; and R2 and R·3 together with a ruthenium atom bonded thereto form a saturated heterocyclic group, wherein Ra, Rb, and R. The meanings are preferred, Ra, Rb, and R. Independently Η or Ch, ", Rb, and Rc are independently oxime or methyl, and more preferably 舄Η or methyl and Rc is Η. In another embodiment, the invention is directed to the following formula I: η is 0, 1, or 2;

Ri is NH2; and monocyclic, 7 to the compound have a fixed alkyl group as described above from (a) to (h, and more preferably, the Ra and Rb independent compounds have from (a) to (d above The alkyl group, more preferably, the Ra and Rb independent compounds have -33-200934783 R·2 and R·3 together with the N atom bonded thereto form a saturated heterocyclic group selected from (a) and (b) wherein Ra , Rb, and having the definitions described above 'better Ra, Rb, and Re are independently η or Cm alkyl, more preferably

Ra ' Rb Rc ® ^ H or methyl, and more preferably {^ and Rb are independently hydrazine or methyl and Rc is H. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 0, 1, or 2; ▲ ❹

Ri is ΝΗ2; and R2 and R3 together with the ruthenium atom bonded thereto form a heterocyclic ring of formula (a), wherein Ra, Rb, and R. Independently being hydrazine or Cl-4 alkyl, preferably Ra, Rb, and independently are hydrazine or methyl, more preferably 1 and Rb are independently η or methyl and R c is hydrazine. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 0, 1, or 2; Λ 〇

Ri is ΝΗ2; and R2 and R3 together with the ruthenium atom bonded thereto form a heterocyclic ring of formula (b), wherein Ra, Rb, and R. Independently 11 or Ci.4 alkyl, preferably Ra, Rb, and Rc are independently hydrazine or methyl, more preferably! ^ is independent of Rb as η or methyl and Rc is Η. In another embodiment, the invention relates to a compound of formula I having the following definitions: η is 0, 1, or 2; -34- 200934783 is nh2; and 112 and R3 are formed together with the N atom bonded thereto (c) a heterocyclic ring wherein Ra and Re are independently 11 or Cm alkyl groups, preferably Ra and R. It is independently hydrazine or methyl, and more preferably Ra is hydrazine or methyl and Rc is hydrazine. In another embodiment, the invention relates to a compound of formula 1 having the following definitions: η is 0, 1, or 2; 〇R! is ΝΗ2; and R2 and R3 together with a ruthenium atom bonded thereto ( d) a heterocyclic ring wherein Ra is independently a Cu alkyl group, preferably Ra is a hydrazine or a methyl group. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 0, 1, or 2;

Ri is ΝΗ2; and R2 is Η or Ct-4 alkyl, and R3 is tetrahydroindenyl, pyrrolidinyl®, piperidinyl, or aziridine, which may be optionally substituted by one or more Cm alkyl groups. Substituted 'better R2 is oxime and R3 is 1-methyl-pyrrolidin-3-yl. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 1 or 2;

Ri is ΝΗ2; and R2 and R3 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group which may be a 4 to 7 membered monocyclic ring, a 7 to 8 member bridged double ring, or 8 to 12 members. A fused bicyclic ring wherein the heterocyclic group may contain up to two -35-200934783 N atoms and is free of any other heteroatoms, and may be optionally selected from one or more independently selected from C!.4 alkyl and NRaBb The substituent is substituted, but the heterocyclic group must contain 2 N atoms or contain 1 N atom and be substituted by one NRaRb group. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 1 or 2;

Ri is ΝΗ2; and R2 and R3 together with the ruthenium atom bonded thereto form a saturated heterocyclic group selected from (a) to (h), wherein Ra, Rb, and R. Preferably, Ra, Rb, and Re are independently oxime or Cu alkyl, and more preferably, Ra, Rb, and Rc are independently fluorene or methyl, and more preferably, Ra and Rb are independently Η. Or methyl and Re is H. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 1 or 2;

Ri is ΝΗ2; and R3 together with the ruthenium atom bonded thereto form a saturated heterocyclic group selected from (a) to (e), wherein Ra, Rb, and Re have the above definitions, preferably Ra, Rb And R. Independently, it is a hydrazine or a Cu alkyl group. More preferably, Ra, Rb' and Rc are independently a hydrazine or a methyl group, and more preferably, Ra and Rb are independently a hydrazine or a methyl group and 1 is H. In another embodiment, the invention relates to a compound of formula I having the following definition: -36-200934783 η is 1 or 2; R1 is ΝΗ2; and R2 and R3 together with a ruthenium atom bonded thereto are selected from ( a) to a saturated heterocyclic group of (d), wherein Ra, Rb, and Rc have the above-defined definitions, preferably Ra, Rb, and Re are independently hydrazine or Cl_4 alkyl, more preferably

Ra, Rb, and Rc are independently hydrazine or methyl, and more preferably, 1 and Rb are independently hydrazine or methyl and Re is hydrazine. ❹ In another embodiment, the invention relates to a compound of formula I having the following definition: η is 1 or 2;

Ri is ΝΗ2; and R2 and R3 together with a ruthenium atom bonded thereto form a saturated heterocyclic group selected from (a) and (b) wherein Ra, Rb, and Rc have the definitions described above, preferably Ra, Rb, and R. Independently Η or Cl 4 alkyl, better

Ra, and Re are independently H or methyl, and more preferably, 1 and Rb are independently 〇 or methyl and Rc is H. In another embodiment, the invention is directed to a compound of the formula having the following definition: η is 1 or 2;

Ri is ΝΗ2; and R2 and R3 together with the ruthenium atom bonded thereto form a heterocyclic ring of formula (a), wherein Ra, Rb, and Re are independently Η or C 卜 alkyl, preferably Ra, Rb, and Rc are independent. Preferably, it is Η or methyl, and more preferably, 1 and Rb are independently η or methyl and Rc is Η. -37- 200934783 In another embodiment the invention relates to a compound of formula I having the following definition: η is 1 or 2;

Ri is ΝΗ2; and R2 and R3 together with the ruthenium atom bonded thereto form a heterocyclic ring of formula (b), wherein Ra, Rb, and Rc are independently Η or Cm alkyl, preferably Ra, Rb, and Rc are independently Η Or the methyl 'better 113 and Rb are independently η or methyl and Rc is Η. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 1 or 2;

Ri is ΝΗ2; and r2 and R3 together with the ruthenium atom bonded thereto form a heterocyclic ring of formula (c), wherein Ra and Re are independently Η or CU4 alkyl, preferably Ra and R. Independently Η or methyl, and better Ra is Η or methyl and! 1. H. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 1 or 2;

Ri is ΝΗ2; and R2 and R3 together with the ruthenium atom bonded thereto form a heterocyclic ring of formula (d), wherein Ra is ruthenium or Ch alkyl group, and preferably 1 is η or methyl. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 1 or 2; -38- 200934783

Ri is NH2; and R2 is H or alkyl and R3 is tetrahydroindenyl, pyrrolidinyl, piperidinyl, or aziridine, which may be optionally substituted by one or more Ci-4 alkyl groups, Preferably, R2 is hydrazine and R3 is 1-methyl-pyrrolidin-3-yl. In another embodiment, the invention relates to a compound of formula I having the following definition: η is 0 or 1; φ Ri is ΝΗ2; and R2 and R3 together with a ruthenium atom bonded thereto form a saturated heterocyclic group, The saturated heterocyclic group may be a 4 to 7 membered monocyclic ring, a 7 to 8 membered bridged bicyclic ring, or an 8 to 12 membered fused bicyclic ring, wherein the heterocyclic group may contain up to two N atoms and does not contain any Other heteroatoms, and may be optionally substituted by one or more substituents independently selected from the group consisting of (3^4 alkyl and NRaRb, but the heterocyclic group must contain 2 N atoms or contain 1 N atom and be Substituted by one NRaRb group. G In another embodiment, the invention relates to a compound of formula I having the following definition: η is 0 or 1;

Ri is ΝΗ2; and R2 and R3 together with a ruthenium atom bonded thereto form a saturated heterocyclic group selected from the group consisting of: (i) a heterocyclic group containing 2 N atoms and no other hetero atom, wherein the heterocyclic group Optionally substituted by one or more mountain-4 alkyl; and (H) heterocyclic group containing 1 N atom and free of any other hetero atom, -39- 200934783 wherein the heterocyclic group is ~NRaRb Substituted by a group, and optionally substituted by one or more (^-4 alkyl groups; wherein the heterocyclic groups (1), (H) may be 4 to 7 membered monocyclic, 7 to 8 member bridged Bicyclic, or 8- to 12-membered fused bicyclic. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 0 or 1;

Ri is ΝΗ2; and R2 and R3 together with the ruthenium atom bonded thereto form a saturated heterocyclic group selected from (a) to (h), wherein Ra, Rb, and Re have the above definitions, preferably Ra, Rb, and R. Independently, it is a hydrazine or a Cm alkyl group. More preferably, Rb, and Rc are independently a hydrazine or a methyl group, and more preferably, Ra and Rb are independently a hydrazine or a methyl group and R. Is η. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 0 or 1;

Ri is ΝΗ2; and R2 and R3 together with the ruthenium atom bonded thereto form a saturated heterocyclic group selected from (a) to (d), wherein Ra, Rb, and r. Having the above definitions, 'better Ra, Rb, and independently HS C!-4 alkyl, more preferably Ra, Rb, and Rc are independently fluorene or methyl, and more preferably Ra and Rb are independently Η or methyl and 1^ is H. In another embodiment, the invention relates to a compound of formula I having the following definition: -40-200934783 η is 0 or 1; is νη2; and R2 and R3 together with a ruthenium atom bonded thereto are selected from (a And a saturated heterocyclic group of (b), wherein Ra, Rb, and Re have the above-defined definitions, preferably Ra, Rb, and Re are independently oxime or Cu alkyl, and more preferably Ra, Rb, and R . Independently, it is a hydrazine or a methyl group, and more preferably, Ra and Rb are independently hydrazine or methyl and Rc is H. Q In another embodiment, the invention relates to a compound of formula I having the following definition: η is 0 or 1;

Ri is ΝΗ·2; and R2 and R3 together with the ruthenium atom bonded thereto form a heterocyclic ring of formula (a), wherein Ra, Rb, and R. Independently Η or c丨-4 alkyl, preferably Ra, Rb, and R. Independently oxime or methyl group, 'better' is independently η or methyl and Rc is Η. Ο In another embodiment, the invention relates to a compound of formula I having the following definition: η is 0 or 1;

Ri is ΝΗ2; and R2 and Ra together with the ruthenium atom bonded thereto form a heterocyclic ring of formula (b), wherein Ra, Rb, and independently are 11 or Cm alkyl groups, preferably Ra, Rb, and R. Independently, it is preferably a hydrazine or a methyl group. Further, 1 and Rb are independently η or a methyl group and Rc is Η. In another embodiment, the invention is directed to a compound of formula I having the definition of -41 - 200934783: η is 0 or 1;

Ri is ΝΗ2; and R2 and 113 together with the ruthenium atom bonded thereto form a heterocyclic ring of formula (c) wherein Ra and R are. Independently being hydrazine or Cm alkyl, preferably, Re and Re are independently hydrazine or methyl, and more preferably Ra is hydrazine or methyl and 1 is H. In another embodiment, the invention is directed to a compound of formula 1 having the following definition: η is 0 or 1;

Rj is ΝΗ2; and R2 and R3 together with the ruthenium atom bonded thereto form a heterocyclic ring of formula (d) wherein Ra is independently 11 or Ci-4 alkyl, preferably 1 is oxime or methyl. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 0 or 1;

Ri is ΝΗ2; and R2 is hydrazine or Ci-4 alkyl' and R3 is tetrahydroindenyl, pyrrolidinyl, piperidinyl, or aziridine, which may be selectively selected by one or more Ci-4 Substituted by a group, preferably R2 is oxime and R3 is 1-methyl-pyrrolidin-3-yl. In another embodiment, the invention relates to a compound of formula I having the following definitions: η is 0, R is ΝΗ2; and R2 and R3 together with a ruthenium atom bonded thereto form a saturated heterocyclic group, this -42 - 200934783 The saturated heterocyclic group may be a 4 to 7 membered monocyclic ring, a 7 to 8 member bridged double or an 8 to 12 membered fused bicyclic ring, wherein the heterocyclic group may contain a N atom and does not contain any other hetero atom. And optionally substituted by one or 1L of a substituent selected from the group consisting of C!-4, and NRaRb, but the whisker contains 2 N atoms or contains 1 N atom and is substituted by one group. In another embodiment, the invention is directed to a compound of formula 1 wherein: η is hydrazine;

Ri is ΝΗ2; and R2 and R3 together with the ruthenium atom bonded thereto form a heterocyclic group selected from the group consisting of: (i) a heterocyclic group containing two deuterium atoms and not containing any other hetero atom, wherein the heterocyclic group is optionally Or a plurality of CL4 alkyl groups substituted (ii) a heteroquinone containing 1 N atom and no other hetero atom, wherein the heterocyclic group is substituted by one NRaRb group, and may be optionally substituted with a plurality of Cb4 alkyl groups; Wherein the heterocyclic groups (i), (ii) may be 4 to 7 membered monocyclic 8 member bridged bicyclic rings or 8 to 12 membered fused bicyclic rings. In another embodiment, the invention is directed to a compound of formula I wherein: η is 0;

Ri is ΝΗ2; and R2 and R3 together with the ruthenium atom bonded thereto form a saturated ring group selected from the group consisting of (〇-ring, two more than two monocyclic groups, NRaRb, and a ring group, the nature is one, seven) To a saturated heterocyclic group of (h -43-200934783), wherein Ra, Rb, and Rc have the above definitions, preferably Ra, Rb, and Re are independently C!·4 alkyl' Preferably, Ra, Rb, and Rc are independently hydrazine or methyl, and more preferably, Ra and Rb are independently hydrazine or methyl and Rc is in another embodiment. The present invention has the following definitions in relation to the compound of formula 1 η is 0; R! is ΝΗ2; and R2 and R3 together with the ruthenium atom bonded thereto form a saturated heterocyclic group selected from (a) to (d), wherein Ra, Rb, and Rc have the above Definitions, preferably Ra, Rb, and independently are Η or mountain-4 alkyl, more preferably Ra, Rb, and Rc are independently fluorene or methyl, and more preferably, Ra and Rb are independently fluorenyl or methyl. Rc is H. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 0,

Ri is ΝΗ2; and R2 and R3 together with the ruthenium atom bonded thereto form a saturated heterocyclic group selected from (a) and (b) wherein Ra 'Rb, and Re have the definitions described above, preferably Ra, Rb, and Re are independently Η or Cl-4 alkyl, more preferably

Ra, Rb and Re are independently fluorene or methyl, and more preferably, 1 and Rb are independently hydrazine or methyl and Rc is H. In another embodiment, the invention has the following definitions in the formula: -44 - 200934783 η is 0,

Ri is ΝΗ2; and R2 and R3 together with the ruthenium atom bonded thereto form a heterocyclic ring of formula (a), wherein Ra, Rb, and Rc are independently Η or Ci. 4 alkyl, preferably Ra, Rb, and R. Independently, it is a hydrazine or a methyl group. More preferably, 113 and Rb are independently hydrazine or methyl and Rc is hydrazine. In another embodiment, the invention relates to a compound of formula I having the following definitions: η is 0; R is ΝΗ2; and 112 and 尺3 together with a ruthenium atom bonded thereto form a heterocyclic ring of formula (b) Wherein, Ra, Rb, and Rc are independently 11 or Cw alkyl, preferably Ra, Rb, and R. Independently oxime or methyl, more preferably Ra and Rb are independently oxime or methyl and R. Why? In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 0;

Ri is ΝΗ2; and R2 and R3 together with the ruthenium atom bonded thereto form a heterocyclic ring of formula (c), wherein Ra and R. Independently Η or Ch alkyl, preferably 1^ and R. Independently, it is a hydrazine or a methyl group, and more preferably 113 is a hydrazine or a methyl group and 1 is H. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 0; -45- 200934783

Ri is NH2; and R2 and R3 together with the N atom to which they are bonded form a heterocyclic ring of formula (d) wherein Ra is independently ^1 or C,4 alkyl, preferably 1 is η or methyl. In another embodiment, the invention is directed to a compound of formula I having the following definition: π is 0,

Ri is ΝΗ2; and R2 is fluorene or Cu alkyl, and R3 is tetrahydroindenyl, pyrrolidinyl, piperidinyl, or aziridine' which may be selectively substituted by one or more Ct.4 alkyl groups. Preferably, R2 is hydrazine and R3 is 1-methyl-pyrrolidin-3-yl. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 1;

Ri is ΝΗ2; and R2 and R3 together with the ruthenium atom to which they are bonded form a saturated heterocyclic group which may be a 4 to 7 membered monocyclic ring, a 7 to 8 member bridged double ring, or 8 to 12 members. A fused bicyclic ring wherein the heterocyclic group may contain up to two N atoms and is free of any other heteroatoms, and may be optionally substituted with one or more substituents independently selected from C^-4 alkyl and NRaBb Substituted, but the heterocyclic group must contain 2 N atoms or contain 1 N atom and be substituted by one NRaRb group. In another embodiment, the invention relates to a compound of formula I having the following definition: η is 1; -46- 200934783 R! is NH2; and R·2 and R·3 are formed together with the N atom bonded thereto A saturated heterocyclic group selected from the group consisting of: (i) a heterocyclic group containing 2 N atoms and no other hetero atom, wherein the heterocyclic group is optionally substituted by one or more C!-4 alkyl groups And (ii) a heterocyclic group containing 1 N atom and no other hetero atom, wherein the heterocyclic group is substituted by one NRaRb group, and may be optionally substituted by -Q or a plurality of Cm alkyl groups; Wherein the heterocyclic groups (i), (ii) may be 4 to 7 membered monocyclic, 7 to 8 membered bridged bicyclic, or 8 to 12 membered fused bicyclic. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 1;

Ri is ΝΗ2; and R2 and R·3 together with the N atom bonded thereto form a saturated heterocyclic group selected from (a) to (h eg ), wherein Ra, Rb, and Rc have the definitions described above. Ra, Rb, and R. Independently, the Ci.4 alkyl group is more preferably Ra, Rb, and Rc are independently hydrazine or methyl group, and more preferably 趴 and Rb are independently hydrazine or methyl and R. Why? In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 1;

Ri is ΝΗ2; and R·2 and R3 together with the ruthenium atom bonded thereto form a saturated heterocyclic group selected from (a) to (d-47-200934783) wherein Ra, Rb, and Re have the above definitions Preferably, Ra, Rb, and Re are independently H or CL4 alkyl groups, more preferably Ra, Rb, and RC are independently fluorene or methyl, and more preferably, Ra and Rb are independently hydrazine or methyl and R. Why? In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 1;

Ri is ΝΗ2; and R·2 and R·3 together with the ruthenium atom bonded thereto form a saturated heterocyclic group '(R), Rb, and R selected from (a) and (b). It has the above definitions. Preferably, Ra, Rb, and Re are independently hydrazine or Cl. 4 alkyl groups, more preferably Ra, Rb and R. Independently fluorenyl or methyl, and more preferably, R and Rb are independently hydrazine or methyl and 1 is H. In another embodiment, the invention is directed to a compound of formula I having the following definitions:

η is 1;

Ri is ΝΗ2; and R·2 and F·3 together with the ruthenium atom bonded thereto form a heterocyclic ring of formula (a), wherein Ra, Rb, and independently are Η or c丨_4, preferably Ra, Rb And Rc is independently hydrazine or methyl, more preferably 1" and "is independently hydrazine or methyl and Rc is hydrazine. In another embodiment, the invention relates to a compound of formula I having the following definition: η 1; -48- 200934783 R! is ΝΗ2·; and R2 and R3 together with the ruthenium atom bonded thereto form a heterocyclic ring of formula (b), wherein Ra, Rb, and Rc are independently Η or Cm alkyl, preferably Ra, Rb, and Re alone are oxime or methyl 'better. Ra and Rb are independently oxime or methyl and R. is oxime. In another embodiment, the invention has the following compounds in formula I; Defined by: ❹ η is 1;

Ri is ΝΗ2; and R2 and R3 together with the ruthenium atom bonded thereto form a heterocyclic ring of formula (c), wherein Ra and R. Independently Η or (^_4 alkyl, preferably 1^ and Re are independently oxime or methyl, more preferably 1^ is oxime or methyl and 1 is H. In another embodiment, the invention is With respect to the compound of formula I, the following definitions are defined: η is 1; Ο I is ΝΗ2; and R2 and R3 together with the ruthenium atom bonded thereto form a heterocyclic ring of formula (d), wherein Ra is independently Η or Ci_4, Preferably, Ra is hydrazine or methyl. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 1;

Ri is ΝΗ2; and 'R·2 is Η or C i _4 alkyl' and r3 is tetrahydroindenyl, pyrrolidinyl, piperidinyl, or aziridine' which may be selectively selected by one or more Ci4 Alkyl-49-200934783 Substituted, preferably R2 is deuterium and R3 is 1-methyl-pyrrolidin-3-yl. In another embodiment, the invention is of the formula 1 having the following definition: π is 2,

Ri is NH2; and Rule 2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group which may be a 4 to 7 membered monocyclic ring, a 7 to 8 member bridged double ring, or 8 to 12 A fused bicyclic ring wherein the heterocyclic group may contain up to two N atoms and does not contain any other hetero atom, and may be optionally selected from one or more substituents independently selected from the group consisting of (^.4 alkyl and NRaRb) Substituted, but the heterocyclic group must contain 2 N atoms or contain 1 N atom and be substituted by one NRaRb group. In another embodiment, the invention relates to a compound of formula I having the following definitions : π is 2 » ,

Ri is NH2; and R2 and R3 together with the N atom bonded thereto form a saturated heterocyclic group selected from the group consisting of: (1) a heterocyclic group containing 2 N atoms and no other hetero atom, wherein the heterocyclic group Optionally substituted by one or more CU4 alkyl groups; and (Π) a heterocyclic group containing 1 N atom and no other hetero atom, wherein the heterocyclic group is substituted by an NRaRb group, and Selectively substituted by - or a plurality of 4 alkyl groups; wherein the heterocyclic groups (i), (ii) may be 4 to 7 membered monocyclic, 7 to -50 to 200934783, 8 member bridged bicyclic, or 8 Up to 12 members fused double ring. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 2; R is ΝΗ2; and R2 and R3 together with a ruthenium atom bonded thereto are selected from (a) to (h) a saturated heterocyclic group 'wherein Ra, Rb, and r. It has the above-defined φ 义' preferred Ra, Rb, and R. Independently 11 or (^.4 alkyl, more preferably Ra, Rb, and Rc are independently fluorene or methyl, and more preferably, Ra and Rb are independently fluorene or methyl and Re is H. In another embodiment In the present invention, the invention has the following definitions in the compounds of formula I: η is 2,

Ri is ΝΗ2; and R2 and R3 together with the ruthenium atom bonded thereto form a saturated heterocyclic group selected from (a) to (d 〇) wherein Ra'Rb, and Re have the above definitions, preferably Ra Rb and Re are independently hydrazine or Ci-4 alkyl, more preferably Ra, Rb, and Rc are independently η or methyl, and more preferably, Ra and Rb are independently hydrazine or methyl and Re is H. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 2;

Ri is ΝΗ2; and R2 and R3 together with the ruthenium atom bonded thereto form a saturated heterocyclic group selected from (a) and (b-51 - 200934783), wherein Ra, Rb, and Re have the above definitions, Preferably, Ra, Rb, and Re are independently 11 or Cu alkyl groups. More preferably, Ra, Rb and Rc are independently fluorene or methyl, and more preferably, Ra and Rb are independently hydrazine or methyl and 1 is H. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 2;

Ri is ΝΗ2; and R2 and R3 together with the ruthenium atom bonded thereto form a heterocyclic ring of formula (a), wherein Ra, Rb' and Re are independently oxime or Ci.4 alkyl, preferably Ra, Rb, and Rc are independent More preferably, the group 113 and Rb are independently hydrazine or methyl and R. Why? In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 2;

Ri is ΝΗ2; and R2 and R3 together with the ruthenium atom bonded thereto form a heterocyclic ring of formula (b), wherein Ra, Rb, and Rc are independently 11 or Cu alkyl groups, preferably Ra, Rb, and Rc are independently Η Or methyl, more preferably Ra and Rb are independently hydrazine or methyl and are hydrazine. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 2;

Ri is ΝΗ2; and 200934783 R2 and R3 together with the N atom bonded thereto form a heterocyclic ring of formula (c), wherein Ra and Re are independently 11 or Cm alkyl groups, preferably ^ and Re are independently fluorene or methyl group, The preferred one is Ra or methyl and 1^ is H. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 2;

Ri is ΝΗ2; and 〇 R2 and R3 together with the ruthenium atom bonded thereto form a heterocyclic ring of formula (d) wherein Ra is independently 11 or a Cu alkyl group, and preferably Ra is ruthenium or methyl. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 2;

Ri is ΝΗ2; and is Η or ¢^.4 alkyl, and R3 is tetrahydroindenyl, pyrrolidinyl, piperidinyl, or aziridine, which may be selectively selected by one or more (^_4 alkanes) Substituted by a radical, preferably R2 is hydrazine and R3 is 1-methyl-pyrrolidin-3-yl. In another embodiment, the invention relates to a compound of formula I having the following definition: η is 0 , 1, or 2; R! is ΝΗ2; R2 and R3 together with the ruthenium atom bonded thereto form a saturated heterocyclic group, which may be a 4- to 7-membered monocyclic ring, and a 7 to 8 member bridged double ring. Or an 8- to 12-membered fused bicyclic ring wherein the heterocyclic group may contain up to two N atoms and is free of any other heteroatoms, and may be optionally selected from one or more mono-53-200934783 ^.4 substituted by a substituent of an alkyl group and NRaRb, but the heterocyclic group must contain 2 n atoms or contain 1 N atom and be substituted by one NRaRt group; and R4 is one or more selected from Η And a substituent of the Ci-4 alkyl group, preferably R 4 is hydrazine. In another embodiment, the invention relates to a compound of formula I having the following definitions:

η is 0, 1, or 2;

Ri is ΝΗ2; R2 and R3 together with a ruthenium atom bonded thereto form a saturated heterocyclic group selected from the group consisting of: (i) a heterocyclic group containing 2 N atoms and no other hetero atom, wherein the heterocyclic group may be Selectively replaced by one or more Ci-4 hospital bases; and

(ii) a heterocyclic group containing 1 N atom and no other hetero atom, wherein the heterocyclic group is substituted by one NRaRb group, and may be optionally substituted by one or more C^-4 alkyl groups; Wherein the heterocyclic group (i) '(ii) may be a 4 to 7 membered monocyclic ring, a 7 to 8 member bridged bicyclic ring, or an 8 to 12 membered fused bicyclic ring; and R4 is one or more A substituent selected from the group consisting of hydrazine and a Ci-4 alkyl group, preferably R4 is hydrazine. In another embodiment, the invention relates to a compound of formula I having the following definitions: η is 0, 1, or 2; I is ΝΗ2; -54- 200934783 R2 and R3 together with the N atom bonded thereto From the saturated heterocyclic group of (a) to (h), wherein Ra, Rb, and Rc have the above-defined definitions, preferably Ra, Rb, and R. Independently 11 or Ci.4 alkyl, more preferably Ra, Rb, and Rc are independently hydrazine or methyl, and more preferably, Ra and Rb are independently hydrazine or methyl and 1^ is 11; and R4 is one or A plurality of substituents selected from the group consisting of 11 and G.4 alkyl groups, preferably R4 is hydrazine. φ In another embodiment, the invention relates to a compound of formula I having the following definition: η is 0, 1, or 2;

Ri is ΝΗ2; R2 and R3 together with the ruthenium atom bonded thereto form a saturated heterocyclic group selected from (a) to (d), wherein Ra, Rb, and Rc have the above-defined definitions, preferably Ra, Rb 'And R. Independently being hydrazine or Cm alkyl, more preferably Ra, Rb, and Rc are independently hydrazine or methyl, and more preferably, Ra and Rb are independently hydrazine or methyl and 1 is 11; and R4 is one or more A substituent selected from the group consisting of hydrazine and a Ci-4 alkyl group, preferably R 4 is hydrazine. In another embodiment, the invention is directed to a compound of formula I having the following definition: η is 0, 1, or 2;

Ri is ΝΗ2; R2 and R3 together with the ruthenium atom bonded thereto form a saturated heterocyclic group selected from (a) and (b), wherein Ra, Rb, and R. Having the above-mentioned definition -55-200934783 meaning 'better Ra, Rb' and Re are independently 11 or Cm alkyl, more preferably Ra, Rb and Re are independently fluorene or methyl, and more preferably 1 Rb is independently hydrazine or methyl and Rc is H; and R4 is one or more substituents selected from the group consisting of hydrazine and Q_4 alkyl, preferably R4 is Η 另一 In another embodiment, the invention is related The compound I has the following definition: η is 0, 1, or 2;

Ri is ΝΗ2; R2 and R3 together with the ruthenium atom bonded thereto form a heterocyclic ring of formula (a), wherein Ra, Rb, and Re are independently Η or Cl 4 alkyl, preferably Ra, Rb, and R. Independently being hydrazine or methyl, more preferably 1 and Rb are independently η or methyl and Re is Η; and R4 is one or more substituents selected from fluorene and (^-4 alkyl), preferably R4 is In another embodiment, the invention relates to a compound of formula I having the following definition: η is 0, 1, or 2;

Ri is ΝΗ2; R2 and R3 together with the ruthenium atom bonded thereto form a heterocyclic ring of formula (b), wherein Ra, Rb, and Re are independently Η or C, -4 alkyl, preferably Ra, Rb, and Rc are independent More preferably, it is independently Η or methyl and Re is Η; and R 4 is one or more substituents selected from fluorene and (^-4 alkyl, preferably -56- 200934783 R4 is Η. In another embodiment, the invention relates to a compound of formula I having the following definition: η is 0, 1, or 2;

Ri is ΝΗ2; R2 and R3 together with the ruthenium atom bonded thereto form a heterocyclic ring of formula (c), wherein Ra and R. Independently being hydrazine or Cm alkyl, preferably Ra and Re are independently 〇H or methyl, more preferably Ra is fluorene or methyl and R4 is one or more selected from 11 and C!.4 alkyl Substituent, preferably R4 is Η 另一 In another embodiment, the invention has the following definitions in relation to the compound of formula I: η is 0, 1, or 2;

Ri is ΝΗ2; R2 and R3 together with the ruthenium atom bonded thereto form a heterocyclic ring of formula (d), wherein Ra is independently H or Cu alkyl, preferably Ra is ruthenium or methyl; and R4 is one or more Substituents selected from the group consisting of hydrazine and C, _4 alkyl, preferably R4 is hydrazine. In another embodiment, the invention relates to a compound of formula I having the following definition: η is 0, 1, or 2;

Ri Μ ΝΗ2 ; R·2 is Η or C!-4 alkyl, and r3 is tetrahydroindenyl, thiazolidinyl, piperidinyl, or aziridine' which may be selectively substituted by one or more Cl 4-alkyl-57-200934783 substituted, preferably R2 is hydrazine and R3 is 1-methyl-pyrrolidin-3-yl; and R4 is one or more substituents selected from 11 and (^.4 alkyl) The present invention is intended to cover all possible combinations of the foregoing specific embodiments and preferred embodiments. In another embodiment, the invention relates to Formula I selected from the following Compound: 4-[(3i?)-3-(Methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydrobenzofuro[3,2- 〇pyrimidine- 2-amine; 4-[3-(methylamino)tetrahydroindol-1-yl]-6,7,8,9-tetrahydrobenzofuro[3,2- 〇pyrimidin-2- Amine; 4-[(37?)-3-aminopyrrolidin-1-yl]-6,7,8,9-tetrahydrobenzofuro[3,24]pyrimidin-2-amine; 4-( 3-aminotetrahydroindol-1-yl)-6,7,8,9-tetrahydrobenzofuro[3,24]pyrimidin-2-amine; 4-[( 4aR,7aR )-octahydrogen -6 pyrrolo[3,4-6]pyridine-6-yl]-6,7,8,9-tetrahydrobenzopyrene [3,2 -3) pyrimidine-2-amine; 4-[3-methyl-3-(methylamino)tetrahydroindol-1-yl]-6,7,8,9-tetrahydrobenzofuran [3,24]pyrimidin-2-amine; 4-piped-1-yl-6,7,8,9-tetrahydrobenzofuro[3,2-3]pyrimidin-2-amine; 4-( 1,4 -diazain-1-yl)-6,7,8,9-tetrahydrobenzofuro[3,2-ί/]pyrimidin-2-amine; 4-[ (3i?) -3 -(methylamino)pyrrolidin-1-yl]-6,7,8,9-tetra-58- 200934783 Hydrobenzobenzopyrano[3,2-^n-pyrimidine; 4-[3-(A Amino group) tetrahydroindol-1-yl]-6,7,8,9-tetrahydrobenzofuro[3,2-g?]pyrimidine; 4-(1,4-diazaindole-1 -yl)-6,7,8,9-tetrahydrobenzofuro[3,2-ί/]pyrimidine; 4-[(3i?)-3-(methylamino)pyrrolidin-1-yl -7,8,9,10-tetrahydro-6 ugly-cyclohepta[4,5]furo[3,2-3]pyrimidin-2-amine; φ 4-[3-(methylamino) Tetrahydroindol-1-yl]-7,8,9,10-tetrahydro-6/ί-cyclohepta[4,5]furo[3,2-ίn-pyrimidin-2-amine; 4-[( 311)-3-Aminopyrrolidin-1-yl]-7,8,9,10-tetrahydro-6//-cyclohepta[4,5]furo[3,2- 〇pyrimidin-2- Amine; 4-[3-methyl-3-(methylamino)tetrahydroindol-1-yl -7,8,9,10-tetrahydro-6ii-cyclohepta[4,5]furo[3,2-3]pyrimidin-2-amine» 4-[3-(methylamino)tetrahydroindole唉-1-yl]-7,8-dihydro-6H-cyclopenta[4,5]furo[3,24]pyrimidin-2-amine; 4-[(3i?)-3-(methyl Amino) succinctyl-1-yl-7,8-nitrogen-6//-cyclopenta[4,5]furo[3,24]pyrimidin-2-amine; N4-[( )-1 -(methylpyrrolidin-3-yl)amino-6,7,8,9-tetrahydrobenzofuro[3,2-[]pyrimidine-2,4-diamine; 4-(4-A Kepi 11 and-1-yl)-6,7,8,9-tetrahydrobenzofuran [3,2-pyrimidin-2-amine; (5) -4- (3-methylpiped- 1-yl)-6,7,8,9-tetrahydrobenzofuro[3,2-ί/]pyrimidin-2-amine; and -59- 200934783 4- (4-methylpiperazin-1 -yl)-6,7,8,9-tetrahydrobenzofuro[3,2-d]pyrimidine. In another embodiment, the invention is directed to an H4 receptor binding assay (as described in Example 22), at 10 μΜ, more preferably 1 μΜ, and even more preferably 0·1 μΜ At a concentration, the η4 receptor activity can provide a compound of formula I with a greater than 50% inhibition. The compounds of the present invention contain one or more basic nitrogen atoms and thus form salts with organic or inorganic acids. Examples of such salts include: salts formed with inorganic acids n such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid, or phosphoric acid; and organic acids such as methanesulfonic acid, three Fluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, acetic acid, maleic acid, ascorbic acid, citric acid, lactic acid, tartaric acid, malonic acid, glycolic acid (glycolic acid), succinic acid, and salts formed by propionic acid. The type of salt that can be used is not limited as long as it is pharmaceutically acceptable for medical use. The term "pharmaceutically acceptable salts" refers to salts which are suitable for use in contact with tissues of humans and other mammals, without adverse toxicity, irritation, allergic reactions, etc., according to medical judgment. Pharmaceutically acceptable salts are well known in the art. Salts of the compounds of formula I can be obtained during the final isolation and purification of the compounds of the invention, or can be prepared by conventionally treating the compound of formula I with an amount of the desired acid. The salts of the compounds of formula I can be converted to other salts of the compounds of formula I by ion exchange using ion exchange resins. The compounds of formula I and their salts may differ in some physical properties - 60-200934783, but are identical for the purposes of the present invention. All salts of the compounds of formula I are included within the scope of the invention. The compounds of the present invention may form complexes with the solvent used in the reaction or the solvent used for precipitation or crystallization, and these complexes are referred to as solvates. The term "solvate" as used herein refers to a stoichiometric complex of a solute (a compound of formula I or a salt thereof) with a solvent, and examples of the solvent include pharmaceutically acceptable solvents such as water, ethanol, etc., φ The complex formed with water is called a hydrate. Solvates (including hydrates) of the compounds of the invention (or salts thereof) are embraced within the scope of the invention. The compounds of formula I may take on different physical forms, i.e., amorphous and crystalline. Furthermore, the compounds of the invention may have the ability to crystallize into more than one type, a property known as polymorphism. Polymorphs can be distinguished by various physical properties known in the art, such as X-ray diffraction patterns, melting points, or solubility. All physical forms of the compounds of formula I, including all polymorphs thereof, are intended to be encompassed within the scope of the invention. Among the compounds of the present invention, some may be in the form of several optical isomers and/or several diastereoisomers. The non-image isomers can be separated by conventional techniques such as chromatography or fractional crystallization; optical isomers can be isolated by conventional optical resolution techniques to obtain pure optical isomers (optically pure). Isomers). This isolation step can be performed on any of the palm-forming synthetic intermediates or on the Formula I product. Pure optical isomers can also be prepared individually using mirror-specific synthesis (-61 - 200934783 enantiospecific synthesis). The present invention encompasses all individual isomers and mixtures thereof (e.g., racemic mixtures or mixture of non-image isomers), whether obtained synthetically or by physically mixing them. The compounds of formula I can be prepared by the methods described below. It will be apparent to those skilled in the art that the exact method used to prepare a given compound may vary depending on its chemical structure. In addition, in some of the methods described below, it may be necessary or desirable to protect reactive or labile groups with conventional protecting groups. The nature of these protecting groups and the steps used to introduce or remove such protecting groups are known in the art (for example, reference to Greene TW and Wuts PGM, "Protective Gr〇Ups in 0rganic Synthesis", John Wiley & Sons, Third Edition, 1999). Unless otherwise indicated, otherwise, in the methods described below, the definitions of the different substituents are as defined above for the compounds of formula I. Substantially, the compounds of formula I can be borrowed by the formula π The compound is reacted with a compound of the formula hi to produce 'as shown in the following reaction scheme: -62- 200934783

Wherein R!, R2, R3, R4, and η have the definitions described above for formula I, and r5 is a leaving group such as a halogen atom or a triflate compound of formula II and formula III The reaction between the compounds may be carried out using a coupling agent such as PyBOP (benzotriazol-1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate®) in a suitable solvent (eg, 4-dioxane, tetrahydrofuran, dichloromethane, dimethylformamide, or acetonitrile, preferably acetonitrile, in the presence of a base such as diisopropylethylamine, dimethylaniline, diethyl The reaction is carried out in the case of aniline or triethylamine, preferably triethylamine. This reaction can be carried out at a temperature between room temperature and reflux temperature, preferably room temperature. Alternatively, a compound of formula I can be prepared by a reaction between a compound of formula III and a reactive derivative (IV) of a compound of formula II wherein the reactive derivative (IV) converts the hydroxyl group of the compound oxime to a leaving group. Prepared (e.g., halogen or trifluoromethanesulfonyloxy, preferably chlorine). -63- 200934783 Accordingly, the -OH group of the compound of formula II can be reacted with a halogenating agent such as P〇Cl3 by selective solvent, or can be in a suitable solvent such as 1,4-di n-hexane or 1, The 2-dichloroethane is converted to a leaving group (e.g., a halogen, preferably chlorine) by reaction with a mixture of hydrazine (: 13/? (: 15 or dimethylformamide/grass chloride). The reaction is carried out by heating (preferably at a temperature between 100 ° C and 140 ° C.) Furthermore, in the presence of pyridine, the hydroxyl group of the compound of formula II can be converted by reaction with trifluoromethanesulfonic anhydride. To a trifluoromethanesulfonyloxy group. Next, the resulting reactive derivative (IV) of the compound of formula II is reacted with a compound of formula III to give a compound of formula I. The reaction is carried out in a suitable solvent (e.g., ethanol, methanol, butanol). , dimethylformamide, dimethyl hydrazine, tetrahydrofuran, or toluene, preferably ethanol), in a base (including organic amines such as triethylamine, diisopropylethylamine, dimethylaniline, And diethyl aniline in the presence and heating (preferably at a temperature between 5 〇 and 100 ° C) The heating may be carried out thermally or by means of microwave radiation at a wattage at which the above temperature can be reached. Roughly, between the compounds of the formula II and the formula III or the formula IV and Prior to the reaction between the compounds of III, the amine substituent of the compound of formula III is protected to avoid the formation of by-products. Further, if necessary, the amine group (Ri) of the compound of formula II and formula IV can also be protected. Any suitable protecting group may be employed, such as a tertiary butoxycarbonyl group (Boc). When the amine substituent of the compound of formula II and / or formula III and / or formula IV is protected, a subsequent step of removing the protecting group may be required, It is carried out under standard conditions. -64 - 200934783 Therefore, when the protecting group used is Boc, it can be formed by adding a strong acid (such as HCl) in a suitable solvent such as 1,4-dioxane, diethyl ether or methanol. The solution can be directly removed from the crude product by treatment with trifluoroacetic acid in dichloromethane. The compound of formula III can be obtained commercially or can be prepared by the procedures disclosed in the literature. From the compound of formula V, using the different Φ steps (depending on the nature of substituent I), as shown in the scheme:

Wherein n, R!, and R4 have the definitions described for the compounds of formula I. 1^ is a hydrogen-containing hydrazine compound permeable to a compound of formula V and formamide

The reaction is carried out under appropriate temperature (preferably reflux temperature). The compound of formula II wherein I is NH2 is prepared by reacting a compound of formula V with cyanamide in an acidic medium, preferably HCl, in a suitable solvent, preferably dioxane. This reaction can be carried out by heating at a suitable temperature (preferably, reflux temperature) usually between room temperature and reflux temperature. The resulting foramidine intermediate is subsequently treated with NaOH to give the cyclized compound. The compound of formula V can be prepared according to the reaction scheme shown below: -65- 200934783

Where η and R4 have the definitions described above

The reaction between the compound of formula VI and the compound of formula V11 is carried out using triphenyl scales and diethyl azodicarboxylate (DEAD) in a suitable solvent such as tetrahydrofuran. This reaction can be carried out at a temperature between 〇 ° C and reflux temperature, preferably at room temperature. It is usually necessary to add a base such as NaH to cause a cyclization reaction. Compounds of formula VI are commercially available or can be readily prepared from commercially available compounds by standard procedures (for example, see J. Org Chem 2007, 72, 1431 by F. Fleming et al. and Can J Chem 1 by GK Chip and TR Lynch). 974, 52, 2249 ).

In addition, some of the compounds of the present invention can also be prepared by subjecting a compound of another formula I to a suitable functional group conversion reaction in one or more steps using known reactions in organic chemistry under standard laboratory conditions. As described above, the compounds of the present invention exhibit potent histamine H4 receptor antagonist activity. It is therefore contemplated that the compounds of the invention are useful in the treatment of diseases mediated by the H4 receptor in mammals, including humans. Diseases which can be treated with the compounds of the invention include allergic, immunological, or inflammatory diseases or pain. Examples of allergic, immunological, or inflammatory diseases that may be treated with the compounds of the invention include, but are not limited to, respiratory diseases such as asthma, -66-200934783 allergic rhinitis, and chronic obstructive pulmonary disease (COPD); Eye diseases such as allergic rhinoconjunctivitis, dry eyes, and cataracts; skin diseases such as dermatitis (eg, atopic dermatitis), psoriasis, urticaria, and pruritus; inflammatory bowel diseases such as ulcerative colitis And Crohn's disease; rheumatoid arthritis; multiple sclerosis; cutaneous lupus; systemic lupus erythematosus; and transplant rejection. Examples of pain treatable with the compounds of the invention include inflammatory pain, φ inflammatory hyperalgesia, hyperalgesia, post-operative pain, migraine, cancer pain, visceral pain, osteoarthritic pain, and neuropathic pain. In a preferred embodiment, the compounds of the invention are used to treat allergic, immunological, or inflammatory diseases. In a more preferred embodiment, the compounds of the invention are used to treat an allergic, immunological, or inflammatory disease selected from the group consisting of respiratory diseases, eye diseases, skin diseases, inflammatory bowel diseases, rheumatoid arthritis Arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus, and transplant rejection. In a still further preferred embodiment, the allergic, immunological, or inflammatory disease is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), allergic rhinoconjunctivitis, dry eye, cataract Dermatitis (eg atopic dermatitis), psoriasis, urticaria, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, pimple lupus, systemic lupus erythematosus, And transplant rejection. In another preferred embodiment, the compounds of the invention are used to treat pain, preferably inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-operative pain, migraine, cancer pain, visceral pain, osteoarthritis Pain, -67- 200934783 or neuropathic pain. Analytical methods for determining the ability of a compound to interact with a histamine H4 receptor are known in the art, for example, h4 receptor binding assays can be utilized, as detailed in Example 22. Another useful analytical method is GTP [ γ -35s] binding analysis of membranes exhibiting H4 receptors. Functional assays performed on cells expressing the H4 receptor can also be utilized, for example, to measure any type of second messenger associated with the H4 receptor (eg, intracellular cAMP content or Ca2+ movement). The cellular activity is carried out in a system. Another useful method of functional analysis is the Gated Auto fluorescence Forward Scatter assay (GAFS) performed in eosinophils (e.g., human eosinophils), as is known in the art (e.g., reference to the prior art paragraph above) The method disclosed by Buckland KF et al. in 2003 is incorporated herein by reference. In vivo assays which can be used to test the activity of the compounds of the invention are also known to those skilled in the art (for example, with reference to various literatures listed in the above prior art paragraphs for in vivo animal models, especially with peritonitis, pleurisy, allergies). Literature relating to in vivo models of sexual asthma, inflammatory bowel disease, atopic dermatitis, and pruritus are incorporated herein by reference). In order to select the active compound, the test carried out at 1 〇 μΜ of the compound in the test provided in Example 22 must achieve an inhibitory activity of more than 50% for H4 receptor activity. More preferably, the compound should exhibit a degree of inhibition greater than 50% at 1 μΜ (and even better at 0.1 μΜ). The invention also relates to pharmaceutical compositions comprising a compound of the invention (or a pharmaceutically acceptable salt or solvate thereof -68-200934783) and one or more pharmaceutically acceptable excipients. The excipient must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient of the excipient. The compounds of the present invention can be administered in the form of any pharmaceutical combination, and the nature of these compounds, which are known, will depend on the nature of the active compound and the route of administration. Any route can be used, such as oral, parenteral, nasal, ocular, topical, and rectal administration. Solid compositions for oral administration include lozenges, granules, and capsules. In the case of any of the solid compositions, the method of manufacture is based on simple mixing, dry granulation or wet granulation of the active compound with the excipient. These excipients can be, for example, diluents such as lactose, microcrystalline cellulose, mannitol, or dibasic calcium phosphate; binding agents such as starch, gelatin, or polyvinylpyrrolidone (povidone); A disintegrating agent, such as sodium carboxymethyl starch, or sodium croscarmellose; a hydrazine and a lubricant such as magnesium stearate, stearic acid, or talc. In order to delay the disintegration and absorption of the tablet in the gastrointestinal tract, the tablet may be coated with a suitable excipient by known techniques, thereby providing a sustained action for a longer period of time, or merely improving its sensory properties or stability. The active compound can also be incorporated by means of a natural or synthetic film coating agent applied to the inert particles. Soft gelatin capsules are also possible in which the active compound is mixed with a water or oily vehicle such as coconut oil, mineral oil or olive oil. Powders and granules for the preparation of oral suspensions by addition of water may be obtained by mixing active compounds and dispersing or wetting agents, suspending agents, and preservatives. - Other excipients such as sweet may also be added. Flavoring agents, and coloring agents, liquid forms for oral administration, include generally inert diluents (eg, purified water, ethanol, sorbitol, glycerin, macrogols, and propylene glycol). Emulsions, solutions, suspensions, syrups, and elixirs. The compositions may also contain coadjuvants such as wetting agents, suspending agents, sweeteners, flavoring agents, preservatives, and buffering agents. According to the present invention, the injectable preparation for parenteral administration contains a sterile solution, suspension, or emulsion formed in an aqueous or nonaqueous solvent such as propylene glycol, polyethylene glycol, or vegetable oil. These compositions may also contain adjuvant adjuvants such as wetting agents, emulsifying agents, dispersing agents, and preservatives. They may be sterilized or formed into a sterile solid composition by any known method, and the sterile solid composition is dissolved in water or any sterile injectable medium just prior to use. It is also possible to start with sterile materials and to keep these materials under these conditions throughout all manufacturing processes. The compounds of the invention may also be formulated for topical administration to treat conditions which occur in areas or organs accessible through, for example, the eyes, skin, and intestinal tract. Blends include creams, lotions, gels, powders, solutions, and patches' wherein the compound is dispersed or dissolved in a suitable vehicle. For nasal administration or inhalation, the compound can be formulated into an aerosol which can be conveniently released from the aerosol using a suitable propellant. The dosage and frequency of administration will depend on such factors as the nature and severity of the condition to be treated, the age, general condition, and weight of the patient, as well as the particular composition and route of administration. For example, a suitable dosage range is from about 0.01 mg/kg to about 100 mg/kg per day, and this dose can be administered in a single or divided dose. [Embodiment] The present invention will be described by way of the following examples.实施 Examples The following abbreviations are used in the examples:

AcN: acetonitrile DMF: dimethylformamide EtOAc: ethyl acetate MeOH: methanol ρυβορ: hexafluorophosphate (benzotriazol-1-yl-oxy)tripyrrolidinyl iron ((benzotriazol-l-yloxy) Tripyrrolidinophosphonium hexafluorophosphate ❹ THF THF: tetrachloropyranyl tR: residence time LC-MS: liquid chromatography-mass spectrometry LC-MS spectroscopy is performed by one of the following methods: Method 1: Column X-Terra, MS C18 5 Μιη (100 mm X 2.1 mm), temperature: 3 (TC, flow rate: 0.35 mL/min, extract: A = AcN, B = l〇mM NH4HC03, gradient: 0 min 10% A; 10 -71 - 200934783 Min 90% A ; 15 min 90% A. Method 2: Column Acquity UPLC BEH C18 1_7 μιη (2.1 x 50 mm), temperature: 40 ° C, flow rate: 0.50 mL/min, extract: A = AcN, B = 10 mM NH4HC03, gradient: 〇min 10% A; 0.25 min 10% A; 3.00 min 90% A; 3.75 min 90% A. Reference Example 1 Methyl [(3i〇-pyrrolidin-3-yl) Terephthalic acid tert-butyl butyl ester (a) [( 3Λ ) -1-benzylpyrrolidin-3-yl]methylcarbamic acid tert-butyl butyl ester in () -1-benzylmethyl pyrrolidine 3-amine (10 g, 52.55 mmol) in a solution of 115 mL of CH2C12 and cooled to 〇°c, di-'e"-butyl dicarbonate (1,6) dissolved in 15 mL of CH2C12 g, 53.07 mmol) was added, and the resulting solution was stirred at room temperature for 18 hours. After evaporation of the solvent, the obtained crude product was chromatographed on silica gel, using a hexane/e. The desired compound (14.5 g). , 50.14 mmol ), Pd/C (10%, 50% in water) (3 g), and ammonium formate (12.7 g, 200.5 mmol) in Me Ο Η (390 mM) and water (4 5 m) The solution formed in the mixed 200934783 compound of L) was heated under reflux for 5 hours. After the reaction mixture was filtered through Celite®, the filtrate was washed with EtOAc and MeOH. The solvent was concentrated to dryness to give the title compound (yield: 10%).

XH NMR ( 300 MHz, CDC13) δ : 1.38 ( s, 9 Η) , 1.72 ( m, 1 Η), 1.96 (m, 1 Η), 2.53 ( s, ΝΗ), 2.80 ( s, 3 Η), 2.87 (m , 1H), 2.93 (m, 1H), 3.11 (m, 2H), 4.58 (m, 1H ❸ ) Reference Example 2 Tert-butyl butyl 4-hydroindol-3-yl (meth)carbamate ( a) [1-(Diphenylmethyl)tetrahydroindol-3-yl]methylcarbamic acid tert-butyl butyl ester according to the similar procedure described in part (a) of Reference Example 1, but using 1 -(diphenylmethyl)-iV-methyltetrahydroindol-3-amine instead of G benzyl-V-methylpyrrolidine-3-amine gave the desired compound (yield: 73%). LC-MS (method 1): tR = 10.14 min; m/z = 353 (ΜΗ+). (b) title compound A solution of the compound obtained above (6.18 g, 17.53 mmol) in 60 mL MeOH and 15 mL EtOAc was washed with argon. Then, Pd/C (10%, 50% in water) (929 mg) was added, and the solution was again washed with argon and stirred under H2 atmosphere for 18 hours. Reaction mixture -73- 200934783 After filtration through Celite®, the filtrate was washed with EtOAc and MeOH and evaporated to dryness. !H NMR (300 MHz, CD3〇D) δ: 1.44 (s, 9Η), 2.88 (s, 3Η), 3.56 (m, 2Η), 3.71 (m, 2Η), 4.75 (m, 1Η). Reference Example 3 (4d, 7ai?)-octahydro-1pyrrolo[3,4-6]pyridine-1-carboxylic acid tert-butyl butyl ester (a) (4aR,7aR) ·6-benzyl eight Hydrogen-1 ugly-pyrrolo[3,4-indolyl]pyridine-1-carboxylic acid tert-butyl ester in (U?)-6-benzyloctahydropyrrolo[3,4-6]pyridine dihydrochloride (0.9 g '3.1 1 mmol) in a solution of 9 mL of CH2C12, dissolved in 2 mL of CH2C12 in triethylamine (0.95 mL, 6.84 mmol) and di(tri-butyl) dicarbonate (0.75 g, 3.42 mmol) was added. The resulting solution was stirred overnight at room temperature. The solvent was evaporated, and the obtained crude product was purified by chromatography eluting with EtOAc EtOAc (EtOAc) LC-MS (method 2): tR = 2.94 min; m/z = 317 (MH+). (b) title compound A solution of a part of the obtained compound (0.79 g, 2.49 mmol) in 10 mL of MeOH was washed with argon. Next, Pd/C (10%, 50% in water) (157 mg) was added, and the solution was again washed with argon-74-200934783 and stirred overnight in an atmosphere of 1:1. After the reaction mixture was filtered through Celite®, the filtrate was washed with Me 〇H, and the solvent was concentrated to dryness to give the desired compound of 丨 丨 丨 , , , , , LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC LC = 1.29 min ; m/z = 227 ( MH+ ). REFERENCE EXAMPLE 4 三Methyl(3-methyltetrahydroindol-3-yl)carbamic acid tert-butyl butyl ester (Ο[1-(diphenylmethyl)-3-methyltetrahydroindole) -3-yl]methylaminocarbamic acid tert-butyl ester according to the similar procedure described in part a) of Reference Example 1, but using 1-(diphenylmethyl)-iV, 3-dimethyl Instead of (3/?)-1-benzyl-indole-methylpyrrolidin-3-amine, the tetrahydroindol-3-amine is obtained in a full yield of the desired compound. *H NMR ( 3 00 MHz, CDC13) δ : 1.53 ( s, 12Η) , 2.59 ( s, ❹ 3H ), 2.89 ( m, 2H ), 3.16 ( m, 2H ), 4.30 ( s, 1H ), 7.17 ( m, 1H), 7.26 (m, 2H), 7.42 (m, 1H). (b) title compound A solution of a portion of the obtained compound (6.06 g, 16.5 mmol) in EtOAc (EtOAc) Then Pd/C (10%) (814 mg) was added, the solution was washed again with argon and stirred overnight under H2. After the reaction mixture was filtered through Celite®, the filtrate was washed with EtOAc and MeOH. The solvent was concentrated to dryness to give -75-200934783 4.55 g. !H NMR ( 300 MHz, CDCb) δ : 1.45 ( s, 12 Η) , 2.67 ( s, 3 Η), 3.28 (m, 1 Η), 3.61 (m, 1 Η), 3.87 (m, 1 Η), 4.00 (m, lH). Reference Example 5 (3Λ)-1-methylpyrrolidine-3-amine dihydrochloride (a) (3Λ) 1-methylpyrrolidin-3-ylaminocarbamic acid tert-butyl ester in a (3Λ)-Pyrrolidin-3-ylaminocarbamic acid tert-butyl butyl ester (1. g, 5.34 mmol) in a solution of 23 mL of MeOH, 3 7% aqueous formaldehyde solution (1.19 mL, 14.6 mmol) Then, sodium borohydride (0.61 g, 16.1 mmol) was slowly added. The resulting mixture was stirred overnight at room temperature under an argon atmosphere. The solvent was evaporated, the crude product was taken in CH.sub.3, washed with brine and then washed with sat. NaHC03. The organic phase was dried (Na2SO4) and evaporated to dryness. !H NMR ( 300 MHz, CDC13 ) δ : 1.43 ( 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) the title compound

Mix a mixture of the compound obtained in part a) (0.85 g, 4.25 mmol), a 1,4- hexane solution (40 mL) with a concentration of HCl of 4 、, and MeOH 200934783 (1 mL) at room temperature 1 After an hour, the resulting mixture was concentrated to dryness. The obtained crude product was dissolved in EtOAc (EtOAc m. lU NMR (3 00 MHz, CD3〇D) δ : 2.15 ( m, 1Η) , 2.55 ( m, 1H), 2.91 (s, 3H), 3.15 (m, 1H), 3.3-3.85 (m, 3H), 4.10 ( m, 1 H ). ❹ Reference Example 6 Ethyl 3-amino-4,5,6,7-tetrahydrobenzofuran-2-carboxylate in triphenylphosphine (29.9 g, 114 mmol) in 500 mL THF To form a solution cooled to 0 ° C, slowly add a toluene solution (5 2 · 2 mL, 1 14 mmol) with a concentration of 40% azodicarboxylate, and ethyl acetate (10.8 mL, 114 mmol), and 2-ketocyclohexanecarbonitrile (10 g '81·3 mmol). The resulting solution was stirred at room temperature for 20 hours, then 50% sodium hydride (1 1 g, 229 mmol) was added and the mixture was stirred at room temperature for 5 hours. The reaction mixture was cooled to 0 ° C, and a pH 7.8 phosphate buffer (Na 2 HP 04 / KH 2 P.sub.4) solution (3 75 mL) was added. The aqueous solution obtained by evaporation of THF was extracted with EtOAc. The organic phase was dried over NaaSCU and concentrated to dryness. The obtained crude product was chromatographed on silica gel using hexane / Et0Ac mixture with increasing polarity to give 8.5 g of the desired compound (yield: 5%). LC-MS (method 2): tR = 1.97 min; m/z = 210 (MH+). REFERENCE EXAMPLE 7 -77- 200934783 2-Amino-6,7,8,9-tetrahydrobenzofuro[3,2-rf]pyrimidin-4-ol in a compound obtained from Reference Example 6 (3.6 g, 17.4 mmol) of cyanamide (2.9 g > 69.5 mmol) was added to the solution formed in 1,4-two-mouth (52 mL), and then the concentration of HC1 was slowly added to 4 A solution of hydrazine in 1,4-dioxane (35 mL). The resulting suspension was stirred at room temperature for 2 hours and then stirred under reflux for 20 hours. The solvent was evaporated, 2M NaOH (87 mL) was then weighed and the mixture was warmed under reflux for 6 hours. The reaction mixture was neutralized with 3 Μ H C1, and the resulting precipitate was collected by filtration, washed with EtOAc 20 and dried to give the title compound (yield: 8%). LC-MS (method 2): t r = 1. 1 7 mi η; m/z = 2 0 6 (MH+). REFERENCE EXAMPLE 8 6,7,8,9-Tetrahydrobenzofuro[3,2-3]pyrimidin-4-ol The compound obtained in Reference Example 6 (1.4 g, 6.7 mmol) and formamide The mixture (24 mL) was stirred at 1701: for 24 hours. The reaction mixture was poured into H20, and the obtained precipitate was collected by filtration, washed with cold and dried to give the desired compound (yield: 71%). LC-MS (method 2): tR = 1.23 min; m/z = 191 (MH+). Reference Example 9 2-ketocycloheptanenitrile in a suspension containing tertiary potassium butoxide (6.17 g, 55·mmol) and THF (200934783 50 mL) and heated under reflux, A solution of 6-dicyanohexane (5.0 g, 36.7 mmol) in THF (25 mL) was added dropwise. The reaction mixture was cooled to room temperature, 10% H.sub.2SO.sub.4 (50 mL) was added and the mixture was stirred at room temperature overnight. After the mixture was diluted with water and EtOAc, aq. The organic extracts were combined and dried over anhydrous Na.sub.2.sub.4 and concentrated to dry. The obtained crude product was purified by vacuum distillation (yield: 5 mmHg), and the product was collected to give the title compound (yield: 24%). LC-MS (method 2): tR = 1.37 min; m/z = 138 (MH+). REFERENCE EXAMPLE 10 Ethyl 3-amino-5,6,7,8-tetrahydro-4//-cyclohepta[0]furan-2·carboxylate analogous steps as described in Reference Example 6 The title compound was obtained in the title compound (yield: 41%). ❹ LC-MS (Method 2): tR = 2.18 min; m/z = 224 (MH+) Reference Example 1 1 2-amino-7,8,9,l-tetrahydro-6i/-cycloheptane [4,5]furo[3,2-4]pyrimidin-4-ol, according to a similar procedure as described in Reference Example 7, but with the title compound of Reference Example 10 as the starting product, The title compound was obtained in quantitative yield. LC-MS (method 2): tR = 14 min; m/z = 22 (MH+). -79- 200934783 Reference Example 1 2 2-Amino-5,6-dihydro-4H-cyclopenta[b]furan-2-carboxylic acid ethyl ester at -78 °C from diisopropylamine (6.8 mL, 48.11 mmol) n-butyllithium (1.6 M in hexanes; 30 mL, 48.11 mmol) was added dropwise in a solution of tetrahydrofuran (80 mL). The reaction mixture was stirred at -78 °C for 1 hour. A solution of 2-ketocyclopentanenitrile (5 g, 45.82 mmol) in tetrahydrofuran (10 mL) was added, then warmed to room temperature and stirred overnight. The precipitated solid was collected by vacuum filtration, washed with diethyl ether and dried to give a white powder. Diethyl chloromalonate (8.9 mL, 54.98 mmol) was added dropwise to a solution of this powder in DMF ( 184 mL). The reaction mixture was stirred overnight at room temperature and diluted with water (500 mL). After the organic extracts were combined, dried over Na 2 SO 4 filtered, and the filtrate was concentrated to dryness to give an orange syrup. This orange syrup was dissolved in ethanol (210 mL), which was added with di-bicyclobicyclo[ 4.3.0] 壬-5-ene (6.2 mL, 50.4 mmol). The mixture was stirred at room temperature overnight. The solution was concentrated to dryness. EtOAc m. It is a light brown oil. LC-MS (method 2): tR = 1.81 min; m/z 196 (MH+). Reference Example 13 200934783 2-Amino-7,8-dihydro-6 ugly-cyclopenta[4,5]furo[3,2-d]pyridin-4-ol According to Reference Example 7 The titled compound was obtained in a similar step to afford the title compound. LC-MS (method 2): tR = 0.96 min; m/z = 192 (MH+). φ Example 1 4-[(3i?)-3-(Methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydrobenzofuro[3,2-αpyrimidine- 2-Amine (〇(7?)-1-(2-amino-6,7,8,9-tetrahydrobenzofuro[3,2-3]pyrimidin-4-yl)pyrrolidine-3- A suspension of the base (methyl) carbamic acid tert-butyl ester in the suspension of the compound obtained in Reference Example 7 (1 g, 4.88 mmol) in 1,4-dioxane (50 mL) Ethylamine (12.5 mL) <RTI ID=0.0>>&&&&&&&&&&&&&&&&&& After the crude product was partitioned between methylene chloride and 0.5N EtOAc, EtOAc (EtOAc)EtOAc. The extract was extracted to give 1 _ 1 2 g of the desired compound (yield: 59%). LC-MS (method 2): tR = 2.38 min; m/z 388 (MH+) b) 200934783

A mixture of the compound obtained in part a) (1·12 g, 2.88 mmol), 4 M HCl in i,4-dioxane (49 mL), and MeOH (25 mL) was stirred at room temperature 3 Hour, then concentrate to dryness. After the crude product obtained is partitioned between dichloromethane and 1 N NaOH, the organic phase is

Na^O4 was dried <RTI ID=0.0> and </ RTI> </ RTI> <RTI ID=0.0> LC-MS (method 2): tR = 1.40 min; m/z 288 (MH+).实施 Example 2-17 &amp; analogous steps as described in Example 1, but using the appropriate starting materials, respectively, to give the following compounds: Example Compound Name Starting Material Method (LC-MS) tR(min) m /z (MIT) 2 4-[3-(Methylamino)tetrahydroindol-1-yl]-6,7,8,9-tetrahydrobenzofuro[3,2-pyrimidine-2 -Amine Reference Example 7, 2 2 1.41 274 3 4-[(3i?)-3-Aminopyrrolidin-1 -yl]-6,7,8,9-tetrahydrobenzofuran ρ,2 -pyrimidin-2-amine Reference Example 7 and pyrrolidin-3-yl]carbamic acid tert-butyl butyl ester 2. 1.29 274 4 4-(3-Aminotetrahydroinden-1-yl)-6 ,7,8,9-tetrahydrobenzofuro[3,2-c/J pyrimidin-2-amine Reference Example 7 and tetrahydroindol-3-ylaminocarbamic acid tert-butyl butyl 2 1.26 260 5 4-[(4α/?,7α/?)-octahydro-6//-pyrrolo[3,4-0]pyridine-6-yl]-6,7,8,9-tetrahydrobenzofuran And [3,2-£/]pyrimidine-2-amine Reference Example 7, 3 (" 2 1.53 314 6 4-[3-methyl-3-(methylamino)tetrahydroindole-1- -6,7,8,9-tetrahydrobenzofuran [3,2-4 pyridin-2-amine Reference Example 7, 4 (" 2 1.51 288 -82- 200934783 7 4-Pipe &gt;1-base-6,7,8,9-four Benzofurandpyrimidin-2-amine Reference Example 7 and _ Series 1** tert-butyl phthalate (*) 2 1.26 274 8 4·(1,4-diazepine&gt;1-yl)- 6,7,8,9-tetrahydrobenzofuran, 2-4 pyrimidin-2-amine Reference Example 7 and 1,4-diazonium-1-carboxylic acid tert-butyl acrylate (*) 2 1.35 288 9 4-[(3Λ)·3-(Methylamino)pyrrolidin-1-yl]-6,7,8,9-tetrahydrobenzofuro[3,24-pyrimidine Reference Example 8 ,1(**) 2 1.50 273 10 4-[3-(Methylamino)tetrahydroindol-1-yl]-6,7,8,9-tetrahydrobenzofuran [3,2- Θ 陡 steep reference example 8, 2 (**) 2 1.47 259 11 4-( 1,4-diazepine &gt; 1-yl)-6,7,8,9-tetrahydrobenzofuran [ 3,2 pyrimidine reference example 8 and 1,4-diazepine*1-carboxylic acid tertiary butyl ester (**) 2 1.33 273 12 4-[(3 and)-3-(methylamino group Pyrrolidin-1-yl]-7,8,9,10-tetrahydro-6//-cyclohepta[4,5]furanindole, 2-ί/]pyrimidin-2-amine Reference Example 11 , 1 (material) 2 1.57 302 13 4-[3-(methylamino)tetrahydroindole-1.yl]-7,8,9,10-tetrahydro-6 ugly-cyclohepta [4,5 ] furo[3,2-4pyrimidin-2-amine Reference Example U, 2 (Material) 2 1.59 288 14 4-[(3R)-3-Aminopyrrolidin-1-yl] -7,8,9,10-tetrahydro-6 ugly-cyclohepta[4,5]furan P,24 pyridin-2-amine Reference Example 11 and [(3R)-pyrrolidine-3- Tertiary butyl carbazate 2 1.45 288 15 4-[3-methyl-3·(methylamino)tetrahydroindol-1-yl]-7,8,9,10-tetrahydro- 6/f-cyclohepta[4,5]furo[3,2 is pyrimidine-2-amine Reference Example 11, 4 (**) (***^ 2 1.68 302 16 4-[3·( Methylamino)tetrahydroindol-1-yl]-7,8-dihydro-6/f-cyclopenta[4,5]furo-P,2-piperidin-2-amine Reference Example 13, 2(**)(***) 2 1.28 260 17 4-[(3/?)-3-(Methylamino)pyrrolidin-1-yl]-7,8-dihydro-6 ugly-ring Pent [4,5]furo[3,2-pyrimidin-2-amine Reference Example 13, 1 (**) (***) 2 1.28 274 (*) This reaction is at 1:1 It was carried out in a mixture of AcN-l, 4-second. (*) This reaction is carried out in AcN. (***) This reaction is carried out at 8 (TC). -83-200934783 Example 18-21 Similar steps as described in Example 1, a), However, using the appropriate starting materials and using a mixture of 1:1 AcN-l,4-dioxane as solvent, the following compounds are obtained: Example Compound name starting material method (LC-MS) tR(min) m/z (MIT) 18 N4-[(3i?)-l-Methylpyrrolidin-3-yl]amino-6,7,8,9-tetrahydrobenzofuran ρ,2-ί/] pyrimidine-2 , 4-Diamine Reference Example 7, 5 2 1.32 288 19 4-(4-Methylpiperidin-1 -yl)-6,7,8,9-tetrahydrobenzofuran, 2- ί/]pyrimidine-2-amine Reference Example 7 and 1-methylpiperidin 2 1.63 288 20 (5)-4-(3-methylpipenfrl-yl)-6,7,8,9- Tetrahydrobenzofuran [3,2-4pyrimidin-2-amine Reference Examples 7 and 2 1.40 288 21 4-(4·methylpiped-1 -yl)-6,7,8,9- Tetrahydrobenzofuran P,2-d]pyrimidine Reference Example 8 and 1-methylindole 2 1.72 273 (*" This reaction was carried out in AcN. Example 22 [3H]-histamine on human tissue Binding competition analysis of the amine H4 receptor for this binding analysis Membrane extracts prepared from stable CHO recombinant cell lines expressing human histamine H4 receptor (Euroscreen / Perkin_E; lmer). Test compounds at selected concentrations (two sets) together with 1 〇nM [3H]-tissue The amine and 15 pg of membrane extract were incubated for 60 minutes at 25 ° C in a total volume of 250 μί containing 50 mM Tris-HCl, pH 7.4, 1.25 mM EDTA. Under 100 μΜ unlabeled histamine Define non-specific binding. 96-well plates (Multiscreen HTS Millipore) that have been immersed in 0.5% polyethylenimine solution for 2 hours at -84-200934783 〇 °C. The reaction was stopped by filtration using a vacuum collector (Multiscreen Millipore). Then, the 96-well plate was washed with 50 mM Tris (pH 7.4), 1.25 mM EDTA at 50 °C, and the filter was at 50-60 °C. The cells were dried over the 1 hour period, then scintillation fluid was added and the bound radioactivity was determined using a 5-plate scintillation counter. The compounds of Examples 1 to 21 were tested in this analysis. As a result, when tested at a concentration of 1 μΜ, all of the compounds showed a degree of inhibition of more than 50% for the case of histamine-binding human Η4 receptor. -85-

Claims (1)

200934783 X. Patent application scope 1 · A compound of formula I Wherein: Ri is Η or NH2; R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group which may be a 4 to 7 membered monocyclic ring, a 7 to 8 member bridged double ring, or a tuned bicyclic ring of 8 to 12 members, wherein the heterocyclic group may contain up to two N atoms and does not contain any other hetero atom, and may be optionally selected from one or more independently selected from the group consisting of ί^·4 alkyl and NRaRb Substituted by a substituent, but the heterocyclic group must contain 2 N atoms or contain 1 N atom and be substituted by one NRaRb group; 〇 or R 2 is Η or CL 4 alkyl, and R 3 is tetrahydroindenyl, Pyrrolidinyl, piperidinyl, or aziridine, optionally substituted by one or more Cl.4 alkyl; Ra is hydrazine or Cr4 alkyl; Rb is hydrazine or Cu alkyl; or Ra and Rb Forming a tetrahydroindenyl group, a pyrrolidinyl group, a piperidinyl group, or a hydrazinyl group together with the N atom bonded thereto, which may be optionally substituted by one or more Cl 4 alkyl groups; -86- 200934783 R4 is one or a plurality of groups independently selected from the group consisting of fluorene and CU4 alkyl groups, and two R4 groups selectively on the same carbon atom or on two different carbon atoms may be bonded together And -Ci-6 alkyl-, wherein the (etc.) R4 group can be attached to any available position in the A ring; and η is 0, 1, 2, or 3: or a salt thereof. 2. For example, the scope of patent application is 〇 3. If the scope of patent application is 4. The scope of patent application is where η is 0, 1, or 2. 5. If the scope of the patent application is η, where η is 0 or 1. 6. If the scope of the patent application is η, where η is 0. φ 7. As in the scope of the patent application, where η is 1. 8. If the scope of the patent application is η, where η is 2. A compound of the formula 1, wherein Ri is a compound of ΝΗ1, wherein 1^ is H. A compound according to any one of items 1 to 3, a compound of any one of items 1 to 3, a compound of any one of items 1 to 3, a compound of any one of items 1 to 3, and 1 to 3 A compound according to any one of claims 1 to 8, wherein R4 is one or more substituents selected from the group consisting of 11 and Ci-4 alkyl. 10. The compound of claim 9, wherein R4 is Η 〇1 1. The compound of any one of claims 1 to 1 to claim 87-200934783, wherein R2 and R3 are bonded thereto The N atom forms a saturated heterocyclic group and the saturated heterocyclic group may be a 4 to 7 membered monocyclic ring, a 7 to 8 membered bridged bicyclic ring, or an 8 to 12 membered fused bicyclic ring, wherein the heterocyclic group may contain Up to two N atoms and free of any other heteroatoms, and optionally substituted by one or more substituents independently selected from the group "alkyl and NRaRb, but the heterocyclic group must contain 2 N atoms or Containing 1 N atom and being substituted by a NRaRb group. 1 2 The compound of any one of the claims 1 to 1 wherein R 2 and R 3 together with the N atom bonded thereto form a saturation selected from the group consisting of Heterocyclyl: (i) a heterocyclic group containing 2 N atoms and free of any other hetero atom, wherein the heterocyclic group is optionally substituted by one or more Cl-4 alkyl groups; and (Π) a heterocyclic group containing 1 N atom and no other hetero atom, wherein the heterocyclic group is substituted by an NRaRb group, and Selectively substituted by one or more Ci-4, wherein the heterocyclic groups (i), (ii) may be 4 to 7 membered monocyclic, 7 to 8 membered bridged, or 8 to 12 The compound of any one of the above-mentioned items of the present invention, wherein R 2 and R 3 together with the \ atom bonded thereto form a saturated heterocyclic group selected from the group consisting of: -88 - 200934783 Wherein Re is a hydrazine or a Ch alkyl group. 14. A compound as claimed in claim 13 wherein R is. The compound of claim 13 or claim 14, wherein R 2 φ and R 3 together with the N atom bonded thereto form a saturated heterocyclic group selected from (a) to (e). A compound according to claim 13 or claim 14, wherein R2 and R3 together with the N atom bonded thereto form a saturated heterocyclic group selected from (a) to (d). A compound according to claim 13 or claim 14, wherein R2 and R3 together with the N atom bonded thereto form a saturated heterocyclic group selected from (a) and (b). 18. A compound according to claim 13 or 14 wherein R2 and R3 together with the N atom to which they are bonded form a saturated heterocyclic group of formula (a). The compound of claim 13 or 14, wherein R2 and R3 together with the N atom bonded thereto form a saturated heterocyclic group of the formula (b). 20. A compound according to claim 13 or 14, wherein R2 and Rs together with the N atom to which they are bonded form a saturated heterocyclic group of formula (c). A compound according to claim 13 wherein R2 and R3 together with the N atom bonded thereto form a saturated heterocyclic group of the formula (d). The compound according to any one of claims 1 to 19, wherein Ra and Rb are independently 11 or (^.4 alkyl. 23) The compound of claim 22, wherein Ra and Rb are independent 24. The compound of claim 23, wherein 1 is Η and Rb is Η or methyl. 25 A compound according to any one of claims 1 to 10 Wherein R2 is hydrazine or &lt;^-4 alkyl, and r3 is tetrahydroindenyl, pyrrolidinyl, piperidinyl, or aziridine' which may be optionally substituted by one or more Cl-4 alkyl groups 26. A compound according to claim 25, wherein r2 is η and R3 is 1-methyl·lalyzol-3-yl. 2 7. The compound of claim 1 is selected from the group consisting of 4-[(3/〇-3-(Methylamino)pyrrolidinyl]-6,7,8,9-tetrahydrobenzofuro[3,2-ί/]pyrimidine-2-amine 4-[3-(Methylamino)tetrahydroindole-indoleyl]-6,7,8,9-tetrahydrobenzofuro[3,2-ί/]pyrimidin-2-amine; 4-[(3i?)-3-aminopyrrolidine-yl]-6,7,8,9-tetrahydrobenzofuran 200934783 m-[3,2-d]pyrimidin-2- 4-(3-Aminotetrahydroindol-1-yl)-6,7,8,9-tetrahydrobenzofuro[3,2- 〇pyrimidin-2-amine; 4-[ ( 4aR ,7aR)-octahydro-6i/-pyrrolo[3,4-6]pyridin-6-yl]-6,7,8,9-tetrahydrobenzofuro[3,24]pyrimidin-2-amine 4-[3-Methyl-3-(methylamino)tetrahydroindol-1-yl]-6,7,8,9-tetrahydrobenzofuro[3,2-ί/]pyrimidine -2-amine; ^ 4_piped-1·yl-6,7,8,9-tetrahydrobenzofuro[3,2-pyrimidin-2-amine; 4-(1,4-dinitrogen)咩-1-yl)-6,7,8,9-tetrahydrobenzofuro[3,2-3]pyrimidin-2-amine; 4-[(3Λ)-3-(methylamino)pyrrole Pyridin-1-yl]-6,7,8,9-tetrahydrobenzofuro[3,2-rf]pyrimidine; 4-[3-(methylamino)tetrahydroindole-1-yl] -6,7,8,9-tetrahydrobenzofuro[3,2-d]pyrimidine; 〇4-( 1,4-diazin-1-yl)·6,7,8,9-tetra Hydrobenzofuro[3,2-pyrimidine; 4-[(3Λ)-3-(methylamino)pyrrolidin-1-yl]-7,8,9,10-tetrahydro-6/f- Cyclohepta[4,5]furo[3,2-ί/]pyrimidin-2-amine; 4-[3-(methylamino)tetrahydroindole-1-yl]_7,8,9,10 - tetrahydro-6 ugly - cycloglycol [4, 5] furo[3,2-p-pyrimidin-2-amine; 4-[(3R)·3-aminopyrrolidin-1-yl]-7,8,9,10-tetrahydro-6// -cyclohepta[4,5]furo[3,2-3]pyrimidin-2-amine; 4-[3-methyl-3-(methylamino)tetrahydroindol-1-yl]- 91 - 200934783 7,8,9,10·tetrahydro-6i/-cyclohepta[4,5]furo[3,2-3]pyrimidine-2-amine t 4-[3_(methylamino)tetra Hydroquinone-1-yl]-7,8-dihydro-6//-cyclopenta[4,5]furo[3,2- 〇pyrimidin-2-amine; 4-[ (3J?) - 3-(methylamino)pyrrolidine·byl]_7,8-dihydro 6 ugly-cyclopenta[4,5]furo[3,2-rf]pyrimidin-2-amine; N4-[ (3Λ )-1-(methylpyrrolidin-3-yl)armament_6,7,8,9-tetrahydrobenzofuro[3,2- 〇pyrimidine-2,4-diamine; 0 4- (4-methylpipen-1-yl)-6,7,8,9-tetrahydrobenzofuro[3.2- 〇pyrimidin-2-amine; (5) -4-(3-methylperazine Plung-1-yl)-6,7,8,9-tetrahydrobenzofuro[3,2-ί/]pyrimidin-2-amine; and 4-(4-methylpiped-1-yl) -6,7,8,9-tetrahydrobenzofuro[3.2-d]pyrimidine; or a salt thereof. 28. A pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, of any one of claims 1 to 27, and one or more pharmaceutically acceptable excipients. 29. Use of a compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 27, for the manufacture of a medicament for the treatment of a disease mediated by histamine H4 receptor . 30. The use of claim 29, wherein the disease mediated by the histamine H4 receptor is an allergic, immunological, or inflammatory disease&apos; or pain. The compound of the formula I according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, is used for medical treatment. 32. A compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 27, for use in the treatment of a disease mediated by the group &lt;-artamine H4@body. 33. A compound of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 27, for use in the treatment of an allergic, immunological or inflammatory disease, or pain. 34. A method for the preparation of a compound of formula I of claim 1 comprising: (a) reacting a compound of formula II with a compound of formula III Wherein Ri ' R2, R3, R4, and η are as defined in claim 1; or (b) reacting a compound of formula IV with a compound of formula III -93 - 200934783 Wherein R5 is a leaving group, and Ri, R2, R3, R4, and η are as defined in item 1 of the patent application; or (c) converting a compound of formula I to another compound of formula I in one or more steps. -94- 200934783 VII. Designated representative map: (1) The representative representative of the case is: No (2), the symbol of the representative figure is simple: no flaw. 8. If there is a chemical formula in this case, please reveal the best display invention. Characteristic chemical formula: Ri