TW200951136A

TW200951136A - Furo[3,2-d]pyrimidine derivatives

Info

Publication number: TW200951136A
Application number: TW098108440A
Authority: TW
Inventors: Gonzalez Elena Carceller; Fuentes Eva Maria Medina; Bernado Marina Virgili; Via Josep Marti
Original assignee: Palau Pharma Sa
Priority date: 2008-03-17
Filing date: 2009-03-16
Publication date: 2009-12-16
Also published as: WO2009115496A1; PE20091958A1; AR070928A1

Abstract

Furo[3,2-d]pyrimidine derivatives of formula I, wherein the meaning of the different substituents are those indicated in the description. These compounds are useful as histamine H4 receptor antagonists.

Description

200951136 六、發明說明：【發明所屬之技術領域】本發明是有關新系列的呋喃並〔3，2-d〕嘧啶衍生物、其製備方法、含有這些化合物的藥學組成物、及其在醫療上的用途。【先前技術】組織胺是立即性高過敏反應（immediate hypersensitivity reactions )的最強效媒介物（mediators )之一，雖然組織胺對於平滑肌細胞收縮、血管穿透性、以及胃酸分泌的影響已眾所皆知，但其對於免疫系統的影響是到目前才剛開始被揭露出來。200951136 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to a novel series of furo[3,2-d]pyrimidine derivatives, a process for preparing the same, a pharmaceutical composition containing the same, and medical treatment thereof the use of. [Prior Art] 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.

數年前，有一種被命名爲H4之新的組織胺受體分別被幾個獨立進行的硏究團體所選殖出來（〇da T等人，JA few years ago, a new histamine receptor named H4 was selected by several independent research groups (〇da T et al., J).

Biol Chem 2000，275 : 3 678 1 -6; Nguyen T 等人，MolBiol Chem 2000, 275: 3 678 1 -6; Nguyen T et al., Mol

Pharmacol 200 1，5 9: 427-3 3 )。如同其家族的其他成員一般，該受體是一種含有7個跨膜段的G-蛋白質耦合受體（G-protein coupled 受體，GPCR )，然而該 H4 受體與其他三種組織胺受體的相似性（homology )低（Oda T 等人），顯著的是其與H3受體僅有35%的相似性。儘管 H3受體的表現侷限於中樞神經系統的細胞，但H4受體的表現主要被發現於造血譜系（haematopoietic lineage)的細胞，尤其是嗜酸性球、肥胖細胞、嗜鹼性球、樹狀細胞、以及T細胞（Oda T等人）。H4受體高度分佈在免疫系 -5- 200951136 統細胞裡的事實，爲此受體與免疫發炎反應有關。再者，此一假設可從其基因表現可被發炎性刺激物如干擾素、 TNFot、及IL-6所調節的事實而強化。不過，該h4受體也在其他類型的細胞裡表現，例如在取自患有類風濕性關節炎（Wojtecka-Lukasik E 等人，Ann Rheum Dis 2006，65 (Suppl II) : 129; Ikawa Y 等人，Biol Pharm Bull 2005, 28: 2016-8)和骨關節炎（Grzybowska-KowalczykA 等人 ,European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007，P-11)之患者的人類滑膜細胞裡表現；也在人類腸道裡表現（Sander LE等人，Gut 2006，55: 498-504)。已有人提出報告指出，H4受體的表現在鼻息肉組織裡相較於在健康者鼻黏膜裡而言有所提高（J0kiiti A 等人，Cell Biol Int 2007，31 : 1 367-70 )。近來有關H4受體特定配體的硏究已經幫忙界定出此受體的藥理性質。這些硏究證明，在嗜酸性球裡有數種由組織胺引發的反應如趨化性、構形（conformational )變化以及CD1 lb與CD54的調升是特別由該H4受體所媒介 (Ling P 等人，Br J Pharmacol 2004, 1 42 ： 16 1-71; Buckl 及 KF 等人，Br J Pharmacol 2003, 140 ： 1 1 17-27 )。硏究也顯示，H4受體在樹狀細胞中會影響這些細胞的成熟、細胞介素生成、及遷移（Jelinek I等人，1st Joint Meeting of European National Societies of Immunology, Paris, France, 2006, PA- 1 25 5 )。此外，H4受體在肥胖細胞裡的角色也已有硏究。雖然H4受體活化並不會引發肥胖細胞 -6- 200951136 去顆粒作用（d e g r a n u 1 a t i ο π ) ’但會釋出組織胺和其他促發炎媒介物（Pr〇inflammatory mediators):再者’硏究顯示，H4受體會媒介肥胖細胞的趨化性和鈣移動（ Hofstra CL 等人，J Pharmacol Exp Ther 2003，305 : 1 212-21)。至於T-啉巴球’硏究顯示H4受體活化會引發 T-細胞遷移並且會優先吸引具有抑制因子/調節性表型和功會g 的 T -啉巴球群（Morgan RK 等人，American Thoracic ‘ S 〇 c i e t y C ο nf e r e nc e，S an D i e g o, U S A，2 0 0 6，P - 5 3 6 )，並且調節CD4 + T細胞的活化（Dunford PJ等人，J Immunol 2006，176: 7062-70)。至於腸，H4受體的分佈爲其對於蠕動和胃酸分泌的控制可能有其角色（Morini G等人， European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, OR-10)。在嗜酸性球、肥胖細胞、和T-細胞中所觀察到的各種H4受體功能爲此受體在免疫發炎反應中可扮演重要角 φ 色。事實上，H4受體拮抗劑已在腹膜炎（Thurmond RL 等人，J Pharmacol Exp Ther 2004，3 09 ： 404- 1 3 )、胸腺炎（Takeshita K 等人，J Pharmacol Exp Ther 2003，307: 1072-8 )、和抓傷（Bell JK 等人，Br J Pharmacol 2004,1 42 : 3 74-80 )的鼠類模型中顯現出活體內活性。此外，H4受體拮抗劑已在過敏性氣喘（Dunford PJ等人， 2006 )、發炎性腸疾病（Varga C 等人，Eur J Pharmacol 2005, 522 ： 130-8)、搔癢症（Dunford PJ 等人，J Allergy Clin Immunol 2007，1 1 9 : 1 7 6-83 )、異位性皮膚炎（ 200951136Pharmacol 200 1,5 9: 427-3 3 ). 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 associated with three other histamine receptors. The homology is low (Oda T et al.), notably because it is only 35% similar 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 H4 receptor is highly distributed in the immune system -5-200951136 cells, is related to 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, TNFot, and IL-6. However, the h4 receptor is also expressed in other cell types, for example, from rheumatoid arthritis (Wojtecka-Lukasik E et al, Ann Rheum Dis 2006, 65 (Suppl II): 129; Ikawa Y, etc. Human, Biol Pharm Bull 2005, 28: 2016-8) and human synovial cells in patients with osteoarthritis (Grzybowska-KowalczykA et al., European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, P-11) Performance; also manifested in the human gut (Sander LE et al, Gut 2006, 55: 498-504). It has been reported that the expression of H4 receptors is elevated in nasal polyps compared to those in healthy nasal mucosa (J0kiiti A et al, Cell Biol Int 2007, 31: 1 367-70). 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, such as chemotaxis, conformational changes, and upregulation of CD1 lb and CD54 in eosinophils are specifically mediated by the H4 receptor (Ling P et al. Human, Br J Pharmacol 2004, 1 42 : 16 1-71; Buckl and KF et al, Br J Pharmacol 2003, 140 : 1 1 17-27 ). 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 obese cells-6-200951136 to degranulate (degranu 1 ati ο π ) 'but releases histamine and other inflammatory mediators (Pr〇inflammatory mediators): It is shown that the H4 receptor mediates chemotaxis and calcium movement of obese cells (Horstra CL et al, J Pharmacol Exp Ther 2003, 305: 1 212-21). As for T-Polonyballs, the study showed that H4 receptor activation triggers T-cell migration and preferentially attracts T-morpha globules with inhibitory/regulatory phenotypes and g-functions (Morgan RK et al., American Thoracic 'S 〇ciety C ο nf ere nc e, S an D iego, USA, 2 0 0 6, P - 5 3 6 ), 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 may have its 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 can play an important role in the immunoinflammatory response for this receptor. In fact, H4 receptor antagonists have been found in peritonitis (Thurmond RL et al, J Pharmacol Exp Ther 2004, 3 09: 404-13), thymitis (Takeshita K et al, J Pharmacol Exp Ther 2003, 307: 1072- In vivo activity was exhibited in a murine model of 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, Eur J Pharmacol 2005, 522: 130-8), pruritus (Dunford PJ et al. , J Allergy Clin Immunol 2007, 1 1 9 : 1 7 6-83 ), atopic dermatitis (200951136)

Cowden JM 等人，J Allergy Clin Immunol 2007; 119 ( 1) :S239 ( Abs 9 3 5 ) ，American Academy of Allergy,Cowden JM et al, J Allergy Clin Immunol 2007; 119 (1): S239 (Abs 9 3 5 ), American Academy of Allergy,

Asthma 及 Immunology 2 0 0 7 A AAAI Annual Meeting, San Diego, USA )、眼部發炎（Zampeli E 等人，European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, OR-36 )、水腫與痛覺過敏（Asthma and Immunology 2 0 0 7 A AAAI Annual Meeting, San Diego, USA ), eye inflammation (Zampeli E et al., European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, OR-36), edema and hyperalgesia (

Coruzzi G 等人，Eur J Pharmacol 2007，5 63 : 240-4 )、以及神經病性疼痛（Cowart MD等人，J Med Chem. 2008; 51 (20) : 6547-57 )的實驗模型中顯現出活體內活性。因此預期H4受體拮抗劑可用於治療或預防過敏性、免疫性、與發炎性之疾病，以及疼痛。所以，想要提供具有H4受體拮抗劑活性且爲優良候選藥物的新穎化合物。詳言之，較佳的化合物應能強力結合組織胺H4受體，但對其他受體的親和性低。除了能夠結合H4受體之外，這些化合物在免疫發炎的活體內疾病模型中還要能顯現出良好的藥理活性。此外，這些化合物在經由選定的投藥途徑投藥時要能到達目標組織或器官，並具備有利的藥物動力學性質（pharmacokinetic properties)。再者，這些化合應無毒且副作用少。【發明內容】本發明之一方面係關於一種式I化合物： 200951136Coruzzi G et al, Eur J Pharmacol 2007, 5 63: 240-4), and experimental models of neuropathic pain (Cowart MD et al, J Med Chem. 2008; 51 (20): 6547-57) showed alive In vivo activity. 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 immunoinflammatory in vivo disease models. In addition, these compounds are capable of reaching the target tissue or organ when administered via a selected route of administration and possess 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: 200951136

❹ 其中：❹ Where:

Ri 爲 Η 或 NH2 ; R2與R3連同與其鍵結的N原子形成飽和雜環基，此飽和雜環基可爲4至7員單環、7至8員橋接雙環、或8至12 員稠合雙環’其中該雜環基可含有至多兩個N原子且不含任何其他雜原子，而且可選擇性被一或多個獨立選自 Cu院基及NRaRb之取代基所取代，惟該雜環基含有2個 φ N原子且不被NRaRb基所取代，或者含有1個N原子且被一個NRaRb基所取代；或者R·2爲Η或Cl-4烷基，且爲氮雜環丁烷基、吡咯陡基、峨陡基或氮雜環庚烷基，其可選擇性被一或多個 c 1 · 4院基所取代；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 an 8 to 12 member fused ring. 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 the group consisting of Cu and NRab, except the heterocyclic group. Containing 2 φ N atoms and not substituted by NRaRb group, or containing 1 N atom and substituted by one NRaRb group; or R·2 is Η or Cl-4 alkyl, and is azetidinyl, Pyrrole steep, anthracene or azepanyl, which may be optionally substituted by one or more c 1 . 4 hospital groups;

Ra爲H或C1.4烷基；Ra is H or C1.4 alkyl;

Rb爲H或Cl-4烷基；Rb is H or Cl-4 alkyl;

Ra及Rb —起與所連接之氮原子形成氮雜環丁烷基、口比基、哌啶基或氮雜環庚烷基，其可選擇性被一或多 -9- 200951136 個C 1 ·4院基所取代； Κ·4 爲· (1 ) c〗.8烷基； (2 ) C3-8環烷基-CQ.6烷基； (3 )芳基-CQ.6烷基；其中’在基團（1)至（3)中之任何烷基可選擇性經一或多個鹵素原子取代，及C3-8環烷基可選擇性經一或多個獨立地選自Ci.4烷基、鹵素及芳基之取代基取代； ❹ (4 )式（i )之基團Ra and Rb together with the nitrogen atom to be bonded form azetidinyl, alkyl, piperidinyl or azepanyl, which may be selectively one or more -9- 200951136 C 1 · 4 substituted by the base; Κ·4 is · (1) c 〗 8. Alkyl; (2) C3-8 cycloalkyl-CQ.6 alkyl; (3) aryl-CQ.6 alkyl; 'Any alkyl group in the groups (1) to (3) may be optionally substituted by one or more halogen atoms, and the C3-8 cycloalkyl group may be optionally independently selected from Ci. 4 via one or more. Substituted by a substituent of an alkyl group, a halogen, and an aryl group; ❹ (4) a group of the formula (i)

(5)式（ii)之基團：(5) Group of formula (ii):

00 ； R5爲H、鹵素、Cu烷基或CN; R6及R7係各自獨立地選自Η及Cl·4院基’及另外地或R 7基團中之一者可爲芳基或C 3 - 8環院基-C 〇 _ 6院基’及另外地在相同C原子上之R6基團及R7基團可連接而與該C原子一起形成C3_8環院基； -10- 200951136 R_8爲選自Cl-8垸基、C3-8環院基-C〇_6院基及芳基-C〇-4 烷基之基團，其中任何烷基可選擇性經一或多個鹵素原子取代，且c3.8環烷基可選擇性經一或多個獨立地選自Cl_4 烷基、鹵素及芳基之取代基取代； R9爲4-至7-員飽和單環雜環，其包含一個雜原子或選自〇、S、SO及S02之基團，且不包含任何其他另外的雜原子，其中該環可藉由任何可用之C原子連接至該分子之· 其餘部分，其中R9可選擇性經獨立地選自Ci-4烷基及鹵素之一或多個基團取代； X 爲 0、S、so 或 so2 ; n爲1、2或3 ; p爲〇、1或2 ;及芳基爲苯基，其選擇性經獨立地選自 Cl.4烷基、鹵素、 Cl-4院氧基、Ci-4鹵院基、Ci-4鹵院氧基、CN及NH2之一或多個基團取代。本發明亦關於式I化合物之鹽和溶劑化物。一些式I化合物可具有可造成各種立體異構物之對掌中心。本發明關於各個這些立體異構物及其混合物。式I化合物對於組織胺H4受體顯示高親和性。因此，本發明另一方面係關於用於治療之式I化合物 -11 - 20095113600; R5 is H, halogen, Cu alkyl or CN; R6 and R7 are each independently selected from the group consisting of fluorene and Cl.4, and additionally or one of the R7 groups may be aryl or C3. - 8 ring hospital base - C 〇 _ 6 yard base ' and additionally the R 6 group and the R 7 group on the same C atom can be joined to form a C3_8 ring courtyard with the C atom; -10- 200951136 R_8 is selected a group derived from a Cl-8 fluorenyl group, a C3-8 ring-based group -C〇_6, and an aryl-C〇-4 alkyl group, wherein any alkyl group may be optionally substituted by one or more halogen atoms, And the c3.8 cycloalkyl group is optionally substituted with one or more substituents independently selected from the group consisting of a C 4 alkyl group, a halogen group, and an aryl group; R 9 is a 4- to 7-membered saturated monocyclic heterocyclic ring containing a hetero An atom or a group selected from the group consisting of ruthenium, S, SO, and S02, and excluding any other additional hetero atom, wherein the ring may be attached to the remainder of the molecule by any available C atom, wherein R9 is optional Substituted independently of one or more groups selected from the group consisting of Ci-4 alkyl and halogen; X is 0, S, so or so2; n is 1, 2 or 3; p is 〇, 1 or 2; and aryl Is a phenyl group whose selectivity is independently selected from Cl. 4 alkane Substituted by one or more groups of a halogen group, a halogen, a Cl-4 alkoxy group, a Ci-4 halogen compound group, a Ci-4 halogen compound, and a CN and NH2. 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 which can cause various stereoisomers. The present invention is directed to each of these stereoisomers and mixtures thereof. The compounds of formula I show high affinity for histamine H4 receptors. Accordingly, another aspect of the invention relates to a compound of formula I for use in therapy -11 - 200951136

R!爲 Η 或 NH2 ; R2與R3連同與其鍵結的N原子形成飽和雜環基，此飽和雜環基可爲4至7員單環、7至8員橋接雙環、或8 至12員稠合雙環’其中該雜環基可含有至多兩個n原子且不a任何其他雜原子，而且可選擇性被一或多個獨立選自Q-4院基及NRaRb之取代基所取代，但該雜環基含有2 個N原子且不被NRaRb基所取代，或者含有i個N原子且被一個NRaRb基所取代；或者R2爲Η或C!.4烷基，且爲氮雜環丁烷基、吡咯陡基、哌陡基或氮雜環庚院基，其可選擇性被一或多個 C!-4烷基所取代；R! 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 an 8 to 12 member thick a bicyclic ring wherein the heterocyclic group may contain up to two n atoms and not any other hetero atom, and may be optionally substituted by one or more substituents independently selected from the group consisting of Q-4 and NRaB, but The heterocyclic group contains 2 N atoms and is not substituted by the NRaRb group, or contains i N atoms and is substituted by one NRaRb group; or R 2 is fluorene or C..4 alkyl, and is azetidinyl a pyrrole steep group, a piperazine group or an azepine group, which may be optionally substituted by one or more C!-4 alkyl groups;

Ra爲Η或Cm烷基；Ra is hydrazine or Cm alkyl;

Rb爲Η或C ! ·4院基；或者R2爲Η或烷基’及Rs爲氮雜環丁烷基、吡咯 D定基、哌啶基或氮雜環庚烷基’其可選擇性經一或多個 -12- 200951136 C!-4烷基取代； R 4爲· (1) Ci-8 烷基； (2 ) C3-8環烷基-Co-6烷基； (3)方基- c〇_6垸基，其中，在基團（1)至（3)中，任何烷基可選擇性經一或多個鹵素原子取代，及C3_8環烷基可選擇性經獨立地選自Ci-4烷基、鹵素及芳基之一或多個取代基取代； (4 )式（i )之基團Rb is Η or C 4 · 4 yards; or R 2 is Η or alkyl ' and Rs is azetidinyl, pyrrole D-based, piperidinyl or azepanyl' which is selectively Or a plurality of -12- 200951136 C!-4 alkyl substitutions; R 4 is (1) Ci-8 alkyl; (2) C3-8 cycloalkyl-Co-6 alkyl; (3) square group- a c〇_6 fluorenyl group, wherein, in the groups (1) to (3), any alkyl group may be optionally substituted with one or more halogen atoms, and the C3_8 cycloalkyl group may be optionally independently selected from Ci Substituting one or more substituents of -4 alkyl, halogen and aryl; (4) a group of formula (i)

(5)式（ii)之基團(5) Group of formula (ii)

R5爲Η、鹵素、Cm烷基或CN ; R6及R7係各自獨立地選自11及Ci.4烷基，及另外地R6 或R7基團中之一者可爲芳基或C3-8環烷基- C〇-6烷基，及另外地在相同C原子上之R6基圑及R7基團可連接與該 C原子一起形成C3.8環烷基； -13- 200951136 β·8爲選自Ci.8院基、C3-8環院基- C〇_6院基及方基- C〇-4 烷基之基團，其中任何烷基可選擇性經一或多個鹵素原子取代，且C3-8環烷基可選擇性經一或多個獨立地選自Ct.4 烷基、鹵素及芳基之取代基取代；尺9爲4-至7-員飽和單環雜環，其包含一個雜原子或選自0、S、SO及S〇2之基團，且不包含任何其他另外的雜原子，其中該環可藉由任何可用之C原子連接至該分子之其餘部分，其中R9可選擇性經獨立地選自CL4烷基及鹵素之一或多個基團取代； X 爲 0、S、SO 或 S〇2 ; η爲1、2或3 ; Ρ爲0、1或2 ;及芳基爲苯基，其選擇性經獨立地選自烷基、鹵素、R5 is hydrazine, halogen, Cm alkyl or CN; R6 and R7 are each independently selected from 11 and Ci.4 alkyl, and additionally one of the R6 or R7 groups may be aryl or C3-8 ring An alkyl-C〇-6 alkyl group, and additionally an R6 group fluorene and an R7 group on the same C atom may be bonded to form a C3.8 cycloalkyl group together with the C atom; -13- 200951136 β·8 is selected a group derived from a Ci.8, a C3-8 ring, a C-1-6, and a aryl-C〇-4 alkyl group, wherein any alkyl group may be optionally substituted with one or more halogen atoms, And the C3-8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from the group consisting of Ct.4 alkyl, halogen and aryl; Rule 9 is a 4- to 7-membered saturated monocyclic heterocycle, Containing a hetero atom or a group selected from the group consisting of 0, S, SO, and S〇2, and excluding any other additional hetero atom, wherein the ring may be attached to the remainder of the molecule by any available C atom, wherein R9 may be optionally substituted with one or more groups independently selected from the group consisting of a CL4 alkyl group and a halogen; X is 0, S, SO or S〇2; η is 1, 2 or 3; Ρ is 0, 1 or 2 And the aryl group is a phenyl group, the selectivity of which is independently selected from an alkyl group, a halogen ,

Cu烷氧基、Cu鹵烷基、Cu4鹵烷氧基、CN及ΝΗ2之 —或多個基團取代。本發明另一方面是有關一種藥學組成物，其包含式I 化合物或其藥學上可接受之鹽以及一或多種藥學上可接受的賦形劑。本發明另一方面是有關式I化合物或其藥學上可接受之鹽於製造一種用來治療由組織胺Η4受體所媒介之疾病之醫藥的用途。本發明另一方面是有關式I化合物或其藥學上可接受之鹽於製造一種用來治療過敏性、免疫性、或發炎性疾病或疼痛之醫藥的用途。 -14- 200951136 本發明另一方面是有關式I化合物或其藥學上可接受之鹽於製造一種用來治療過敏性、免疫性、或發炎性疾病之醫藥的用途。較佳者，該過敏性、免疫性、或發炎性疾病係選自呼吸系統疾病、眼部疾部、皮膚疾病、發炎性腸疾病、類風濕性關節炎、多發性硬化症、皮膚狼瘡、全身性紅斑性狼瘡、及移植排斥。更佳者，該過敏性、免疫性、或發炎性疾病係選自氣喘、過敏性鼻炎、慢性阻塞性肺 0 疾病（COPD)、過敏性鼻結膜炎、乾眼、白內障、皮膚炎（如異位性皮虜炎）、牛皮癬、蓴麻疹、搔癢症、潰瘍性結腸炎、Crohn氏症、類風濕性關節炎、多發性硬化症、皮膚狼瘡、全身性紅斑性狼瘡、及移植排斥。本發明另一方面是有關式I化合物或其藥學上可接受之鹽於製造一種用來治療或預防疼痛之醫藥的用途。較佳者’該疼痛係選自發炎性疼痛、發炎性痛覺過敏、痛覺過敏 '手術後疼痛、偏頭痛、癌症疼痛、內臟痛、骨關節炎 ❹ 疼痛、及神經病性疼痛。本發明另一方面是有關用於治療或預防由H4組織胺受體所媒介之疾病的式I化合物或其藥學上可接受之鹽。本發明另一方面是有關用於治療或預防過敏性、免疫性、或發炎性疾病或疼痛之式I化合物或其藥學上可接受之鹽。本發明另一方面是有關用於治療或預防過敏性、免疫性、或發炎性疾病之式I化合物或其藥學上可接受之鹽。較佳者’該過敏性、免疫性、或發炎性疾病係選自呼吸系 -15- 200951136 統疾病、眼部疾病、皮膚疾病、發炎性腸疾病、類風濕性關節炎、多發性硬化症、皮膚狼瘡、全身性紅斑性狼瘡、及移植排斥。更佳者，該過敏性、免疫性、或發炎性疾病係選自氣喘、過敏性鼻炎、慢性阻塞性肺疾病（C0PD ) 、過敏性鼻結膜炎、乾眼、白內障、皮膚炎（如異位性皮虜炎）、牛皮癬、蓴麻疼、搔癢症、潰瘍性結腸炎、Cu-alkoxy, Cu haloalkyl, Cu4 haloalkoxy, CN and ΝΗ2 - or a plurality of groups are substituted. Another aspect of the invention is directed to a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease mediated by histamine Η4 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, immunological, or inflammatory disease or pain. -14- 200951136 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 bowel diseases, rheumatoid arthritis, multiple sclerosis, skin lupus, and whole body. 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, ectopic Sexual gingivitis), 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 or prevention 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 a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease mediated by the H4 histamine receptor. Another aspect of the invention is a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of an allergic, immunological, or inflammatory disease or pain. Another aspect of the invention is a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of an allergic, immunological, or inflammatory disease. Preferably, the allergic, immunological, or inflammatory disease is selected from the group consisting of respiratory system -15-200951136 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 (C0PD), allergic rhinoconjunctivitis, dry eye, cataract, dermatitis (eg, atopic) Pipiitis), psoriasis, castor pain, pruritus, ulcerative colitis,

Crohn氏症、類風濕性關節炎、多發性硬化症、皮膚狼瘡、全身性紅斑性狼瘡、及移植排斥。 U 本發明另一方面是有關用於治療或預防疼痛的式I化合物或其藥學上可接受之鹽。較佳者，該疼痛係選自發炎性疼痛、發炎性痛覺過敏、痛覺過敏、手術後疼痛、偏頭痛、癌症疼痛、內臟痛、骨關節炎疼痛、及神經病性疼痛〇本發明另一方面是有關式I化合物或其藥學上可接受之鹽於治療由組織胺H4受體所媒介之疾病的用途。Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus, and transplant rejection. U Another aspect of the invention is a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention 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. Use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of a disease mediated by histamine H4 receptor.

本發明另一方面是有關式I化合物或其藥學上可接受 U 之鹽於治療或預防過敏性、免疫性、或發炎性疾病或疼痛之用途。本發明另一方面是有關式I化合物或其藥學上可接受之鹽於治療或預防過敏性、免疫性、或發炎性疾病之用途。較佳者’該過敏性、免疫性、或發炎性疾病係選自呼吸系統疾病、眼部疾病、皮膚疾病、發炎性腸疾病、類風濕性關節炎、多發性硬化症、皮膚狼瘡、全身性紅斑性狼瘡、及移植排斥。更佳者，該過敏性、免疫性、或發炎性疾 -16- 200951136 病係選自氣喘、過敏性鼻炎、慢性阻塞性肺疾病（C〇PD )、過敏性鼻結膜炎、乾眼、白內障、皮膚炎（如異位性皮膚炎）、牛皮癣、尋麻疹、搔癢症、潰瘍性結腸炎、 Crohn氏症、類風濕性關節炎、多發性硬化症、皮膚狼瘡、全身性紅斑性狼瘡、及移植排斥。本發明另一方面是有關式I化合物或其藥學上可接受之鹽於治療或預防疼痛之用途。較佳者，該疼痛係選自發 φ 炎性疼痛、發炎性痛覺過敏、痛覺過敏、手術後疼痛、偏頭痛、癌症疼痛、內臟痛、骨關節炎疼痛、及神經病性疼痛。本發明另一方面是有關一種用於對有需要的個體（較佳爲人類）治療或預防由組織胺H4受體所媒介之疾病的方法，包括對該個體投予式I化合物或其藥學上可接受之鹽。本發明另一方面是有關一種用於對有需要的個體（較 Φ 佳爲人類）治療或預防過敏性、免疫性、或發炎性疾病或疼痛之方法，包括對該個體投予式I化合物或其藥學上可接受之鹽。本發明另一方面是有關一種用於對有需要的個體（較佳爲人類）治療或預防過敏性、免疫性、或發炎性疾病之方法，包括對該個體投予式I化合物或其藥學上可接受之鹽。較佳者，該過敏性、免疫性、或發炎性疾病係選自呼吸系統疾病、眼部疾病、皮膚疾病、發炎性腸疾病、類風濕性關節炎、多發性硬化症、皮虜狼瘡、全身性紅斑性狼 -17- 200951136 瘡、及移植排斥。更佳者，該過敏性、免疫性、或發炎性疾病係選自氣喘、過敏性鼻炎、慢性阻塞性肺疾病（ COPD )、過敏性鼻結膜炎、乾眼、白內障、皮膚炎（如異位性皮膚炎）、牛皮癬、奪麻疹、搔癢症、潰瘍性結腸炎、Crohn氏症、類風濕性關節炎、多發性硬化症、皮膚狼瘡、全身性紅斑性狼瘡、及移植排斥。Another aspect of the invention is the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of an allergic, immune, or inflammatory disease or pain. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of an allergic, immunological, or inflammatory disease. 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, immunological, or inflammatory disease-16-200951136 is selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease (C〇PD), allergic rhinoconjunctivitis, dry eye, cataract, Dermatitis (eg atopic dermatitis), psoriasis, hives, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus, and transplantation Rejection. Another aspect of the invention is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of pain. 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 or preventing a disease mediated by a histamine H4 receptor for an individual in need thereof, preferably a human, comprising administering to the individual a compound of formula I or a pharmaceutical thereof Acceptable salt. Another aspect of the invention relates to a method for treating or preventing an allergic, immune, or inflammatory disease or pain in an individual in need thereof, which comprises administering a compound of formula I or A pharmaceutically acceptable salt thereof. Another aspect of the invention relates to a method for treating or preventing an allergic, immune, or inflammatory disease in an individual in need thereof, preferably a human, comprising administering to the individual a compound of formula I or a pharmaceutical thereof Acceptable 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, cutaneous lupus, whole body Sexual lupus wolf-17- 200951136 Sore, and transplant rejection. More preferably, 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, measles, pruritus, ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus, and transplant rejection.

本發明另一方面是有關一種用於對有需要的個體（較佳爲人類）治療或預防疼痛之方法，包括對該個體投予式 I化合物或其藥學上可接受之鹽。較佳者，該疼痛係選自發炎性疼痛、發炎性痛覺過敏、痛覺過敏、手術後疼痛、偏頭痛、癌症疼痛、內臟痛、骨關節炎疼痛、及神經病性疼痛。本發明另一方面係關於一種製備如上定義之式I化合物之方法，其包括： (a)使式II化合物與式ΠΙ化合物（或其經胺基保護形式）反應，Another aspect of the invention relates to a method for treating or preventing pain in an individual in need thereof, preferably a human, comprising administering to the individual a compound of formula I 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, osteoarthritic pain, and neuropathic pain. Another aspect of the invention relates to a process for the preparation of a compound of formula I as defined above, which comprises: (a) reacting a compound of formula II with a hydrazine compound (or an amine protected form thereof),

RiRi

hnr2r3 -18Hnr2r3 -18

III 200951136 其中Ri、R2、R3、r4及R5具有如上所述之意義，若需要 ’接著移除任何可能存在之保護基；或 (b)使式IIB化合物與式ill化合物（或其經胺基保護形III 200951136 wherein Ri, R2, R3, r4 and R5 have the meanings indicated above, if it is desired to 'subsequently remove any protecting groups which may be present; or (b) the compound of formula IIB and the compound of formula ill (or its amine group) Protective shape

❹ 其中Rw爲離去基，及Ri、R2、R3、R4及R5具有如上所述之意義’若需要，接著移除任何可能存在之保護基；或 (c) 當式I化合物中之尺5爲鹵素時，使式〗化合物（或其經胺基保護形式），其中R5爲Η，與鹵化劑反應，若需要，接著移除任何可能存在之保護基；或 (d) 當式I化合物中 R5爲CN時，使式I化合物（或其經胺基保護形式），其中R5爲鹵素，與氰化劑反應，若需要，接著移除任何可能存在之保護基；或 (e) 在一或多個步驟中將式I化合物轉變成另一式I化合物。在前述定義中，名稱C^y烷基意指包含X至y個碳原子之直鏈或分支烷基鏈。所以，（^_8烷基意指包含1至 8個碳原子之直鏈或分支烷基鏈。C!-4烷基意指包含1至 -19- 200951136 4個碳原子之直鏈或分支烷基鏈，且包括甲基、乙基、丙基' 異丙基、丁基、異丁基、第二丁基及第三丁基。名稱CG烷基指烷基不存在。Wherein Rw is a leaving group, and Ri, R2, R3, R4 and R5 have the meanings as described above, if necessary, then removing any protecting groups which may be present; or (c) when the compound of formula I is 5 In the case of a halogen, a compound of formula (or an amine-protected form thereof) wherein R5 is hydrazine, reacts with a halogenating agent, and if necessary, removes any protecting groups which may be present; or (d) when a compound of formula I When R5 is CN, a compound of formula I (or an amine-protected form thereof) wherein R5 is a halogen, reacts with a cyanating agent, and if necessary, removes any protecting groups which may be present; or (e) at one or The compound of formula I is converted to another compound of formula I in a number of steps. In the foregoing definition, the name C^y alkyl means a straight or branched alkyl chain containing X to y carbon atoms. Thus, (^_8 alkyl means a straight or branched alkyl chain containing from 1 to 8 carbon atoms. C!-4 alkyl means a straight or branched alkane containing from 1 to -19 to 200951136 4 carbon atoms Base chains and include methyl, ethyl, propyl 'isopropyl, butyl, isobutyl, second butyl and tert-butyl. The name CG alkyl means that the alkyl group is absent.

Ci-4鹵烷基係指經一或多個可相同或不同之鹵素原子 (即氟、氯、溴或碘）取代Ci_4烷基之一或多個氫原子所產生之基團。其例子包括三氟甲基、氟甲基、1-氯乙基、2 -氯乙基、1·氣乙基、2 -氣乙基、2 -漠乙基、2 -确乙基、2，2,2-三氟乙基、五氟乙基、3-氟丙基、3-氯丙基、 2,2,3,3-四氟丙基' 2,2,3,3,3-五氟丙基、七氟丙基、4-氟丁基及九氟丁基。The Ci-4 haloalkyl group means a group produced by substituting one or more hydrogen atoms of the Ci_4 alkyl group with one or more halogen atoms which may be the same or different (i.e., fluorine, chlorine, bromine or iodine). Examples thereof include a trifluoromethyl group, a fluoromethyl group, a 1-chloroethyl group, a 2-chloroethyl group, a 1 gas group, a 2-oxyethyl group, a 2-diethyl group, a 2-ethyl group, and 2, 2,2-Trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 2,2,3,3-tetrafluoropropyl' 2,2,3,3,3-five Fluoropropyl, heptafluoropropyl, 4-fluorobutyl and nonafluorobutyl.

Ci-4烷氧基係指式¢:,.4烷基-〇-，其中烷基部分具有如上定義之相同意義。此名稱因此包括甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、異丁氧基、第二丁氧基及第三丁氧基。The Ci-4 alkoxy group is a formula: ..4 alkyl-oxime-, wherein the alkyl moiety has the same meaning as defined above. This name thus includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, second butoxy and tributoxy.

Ci_4齒院氧基係指經一或多個可相同或不同之_素原子（即氟、氯、溴或碘）取代C!·4烷氧基之一或多個氫原子所產生之基團。其例子包括三氟甲氧基、氟甲氧基、1-氯乙氧基、2-氯乙氧基、1-氟乙氧基、2-氟乙氧基、 2-溴乙氧基、2-碘乙氧基、2,2,2-三氟乙氧基 '五氟乙氧基、氟丙氧基、3_氯丙氧基、2,2,3,3-四氟丙氧基、 2，2,3,3,3-五氣丙氧基' 七氣丙氧基、4 -氣丁氧基及九氟丁氧基。 C3·8環院基（爲一基團或C3_8環院基- C〇_6院基之一. 部分）係關於具有3至8個碳原子之飽和碳環，其可爲單 -20- 200951136 環或橋接雙環基。其例子包括環丙基、環丁基、環戊基、環己基、環庚基、環辛基、雙環[2.2.1]庚烷基及雙環 [2.2.2]辛烷基。名稱C3_8環烷基-(：〇.6烷基包括C3_8環烷基及（：3_8環院基- Ci.6院基。 c3 環烷基-C! ^烷基係指以一或多個可相同或不同之c3.8環烷基取代Ch6烷基之一或多個氫原子所產生之基團。較佳地，Cu烷基經一或兩個c3_8環烷基取代，及更佳地，其經一個C3-8環烷基取代。C3-8環烷基可取代烷基之碳原子上的氫原子或者相同碳原子上之兩個氫原子（在該情況下，c3_8環烷基與烷基分享相同碳原子），如以下例子所示基團：Ci_4 is a group derived from one or more hydrogen atoms which may be substituted by one or more hydrogen atoms which may be the same or different atomic atoms (ie, fluorine, chlorine, bromine or iodine). . Examples thereof include trifluoromethoxy, fluoromethoxy, 1-chloroethoxy, 2-chloroethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2-bromoethoxy, 2 -iodoethoxy, 2,2,2-trifluoroethoxy 'pentafluoroethoxy, fluoropropoxy, 3-chloropropoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentapropoxy' heptapropoxy, 4-oxetoxy and nonafluorobutoxy. C3·8 ring courtyard base (which is a group or C3_8 ring yard base - one of the C〇_6 yard bases. Part) is a saturated carbon ring with 3 to 8 carbon atoms, which can be single-20- 200951136 Ring or bridged bicyclic groups. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl and bicyclo[2.2.2]octyl. The name C3_8 cycloalkyl-(:〇.6 alkyl includes C3_8 cycloalkyl and (:3_8 ring-yard-Ci.6). c3 cycloalkyl-C!^alkyl means one or more The same or different c3.8 cycloalkyl group is substituted with one or more hydrogen atoms of the Ch6 alkyl group. Preferably, the Cu alkyl group is substituted by one or two c3_8 cycloalkyl groups, and more preferably, It is substituted by a C3-8 cycloalkyl group. The C3-8 cycloalkyl group can replace a hydrogen atom on a carbon atom of an alkyl group or two hydrogen atoms on the same carbon atom (in this case, a c3_8 cycloalkyl group and an alkane The base shares the same carbon atom), as shown in the following example:

2-環丙基丁基其中在C原子上之1個Η 原子經環丙基取代之丁基2-cyclopropylbutyl group wherein one of the oximes on the C atom is substituted with a cyclopropyl group.

其中在相同C原子上2個Η 原子經環丙代之丁基 C3-8環烷基烷基之例子包括：環丙基甲基、環丁基甲基、環戊基甲基、環己基甲基、環庚基甲基、環辛基甲基、雙環[2.2.1]庚烷基甲基、二環丙基甲基、（1-甲基-環丙基）甲基、（1-乙基-環丙基）甲基、（1-環戊基甲基-環丙基）甲基、2-環丙基乙基、2-環丁基乙基、2-環戊基乙基、2-環己基乙基、2,2-二環丙基-乙基、2-環己基-2-環丙基-乙基、2- ( 1-甲基-環丙基）乙基、1-環丙基-卜 -21 - 200951136 甲基乙基、1-環丙基乙基、1-環丁基乙基、1-環戊基乙基、1-環己基乙基、3-環丙基丙基、3-環丁基丙基、3-環戊基丙基、3-環己基丙基、1-環丙基-2-甲基丙基、4-環丙基丁基、3-環丙基丁基、2-環丙基丁基、1-環丙基丁基、4-環丁基丁基、4-環戊基丁基、4-環己基丁基、5-環丙基戊基、及6-環丙基己基。在式I化合物之定義中，C3_8環烷基可選擇性經一或多個獨立地選自 Ci.4烷基、鹵素及芳基之基團取代，該取代基可相同或不同且可在C3_8環*院基之任何可用的碳原子上，包括環鍵結至分子之其餘部分的碳。名稱芳基-C^y烷基包括芳基及芳基-C^y烷基。芳基-C^-y烷基係指烷基之氫原子經芳基取代所產生之基團。當y是4時，芳基-Cm烷基之例子包括苄基，1-苯基乙基、2-苯基乙基、1-苯基-1-甲基乙基、3-苯基丙基、4-苯基丁基及2-苯基-1-甲基丙基，其中苯基可如上文芳基定義中所述般選擇性經取代。在R4之定義中，關於（1)至（3)之定義及R8之定義中，任何烷基可選擇性經一或多個鹵素基團取代。此係指在R4及Rs中形成C3-8環烷基-CQ_6烷基之部分的Cj-8 烷基及C〇.6烷基，及在R4中形成芳基-CG-6烷基之部分的 C〇.6烷基，以及在R8形成芳基-C〇-4烷基之部分的CG-4烷基。如上所述，R9爲4-至7-員飽和單環雜環，其包含一個雜原子或選自〇、S、SO及S02之基團且不包含任何其 -22- 200951136 他另外之雜原子。該雜環可經由任何可用之C原子連接至分子之其餘部分。R9環之例子包括：Examples of the butyl C3-8 cycloalkylalkyl group in which two fluorene atoms are cyclized on the same C atom include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, Cycloheptylmethyl, cyclooctylmethyl, bicyclo[2.2.1]heptylmethyl, dicyclopropylmethyl, (1-methyl-cyclopropyl)methyl, (1-ethyl- Cyclopropyl)methyl, (1-cyclopentylmethyl-cyclopropyl)methyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-ring Hexylethyl, 2,2-dicyclopropyl-ethyl, 2-cyclohexyl-2-cyclopropyl-ethyl, 2-(1-methyl-cyclopropyl)ethyl, 1-cyclopropyl -卜-21 - 200951136 Methyl ethyl, 1-cyclopropylethyl, 1-cyclobutylethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 3-cyclopropylpropyl, 3-cyclobutylpropyl, 3-cyclopentylpropyl, 3-cyclohexylpropyl, 1-cyclopropyl-2-methylpropyl, 4-cyclopropylbutyl, 3-cyclopropyl , 2-cyclopropylbutyl, 1-cyclopropylbutyl, 4-cyclobutylbutyl, 4-cyclopentylbutyl, 4-cyclohexylbutyl, 5-cyclopropylpentyl, and 6-Cyclopropylhexyl. In the definition of a compound of formula I, the C3_8 cycloalkyl group may be optionally substituted by one or more groups independently selected from the group consisting of Ci. 4 alkyl, halo and aryl, which may be the same or different and may be at C3_8 Any available carbon atom of the ring base includes carbon bonded to the remainder of the molecule. The name aryl-C^y alkyl includes aryl and aryl-C^y alkyl. The aryl-C^-y alkyl group means a group in which a hydrogen atom of an alkyl group is substituted with an aryl group. When y is 4, examples of the aryl-Cm alkyl group include a benzyl group, a 1-phenylethyl group, a 2-phenylethyl group, a 1-phenyl-1-methylethyl group, and a 3-phenylpropyl group. 4-phenylbutyl and 2-phenyl-1-methylpropyl, wherein the phenyl group is optionally substituted as described in the definition of aryl above. In the definition of R4, with respect to the definitions of (1) to (3) and the definition of R8, any alkyl group may be optionally substituted with one or more halogen groups. This means a Cj-8 alkyl group and a C〇.6 alkyl group which form a C3-8 cycloalkyl-CQ-6 alkyl group in R4 and Rs, and a part which forms an aryl-CG-6 alkyl group in R4. A C.6 alkyl group, and a CG-4 alkyl group which forms a part of an aryl-C〇-4 alkyl group at R8. As described above, R9 is a 4- to 7-membered saturated monocyclic heterocyclic ring which contains a hetero atom or a group selected from the group consisting of ruthenium, S, SO and S02 and does not contain any of its other heteroatoms from -22 to 200951136. . The heterocyclic ring can be attached to the remainder of the molecule via any available C atom. Examples of R9 rings include:

任何r9環可選擇性經一或多個獨立地選自烷基及鹵素（如上所述）之基團取代，且該取代基可在環上之任何可用之位置。鹵素基團或其縮寫鹵基係指氟、氯、溴或碘。作爲烷基、環烷基或芳基之取代基的較佳鹵素原子爲氟及氯，更佳爲氟。相關於Rs之較佳_素原子爲氟及氯’更佳爲氯〇名稱“飽和”意指不含任何雙鍵或參鍵的基團。 “橋接（的）雙環”基團意指雙環狀系統有兩個共用原子（橋頭）連接三條非環狀鏈（橋），使得原子數目較多 -23- 200951136 的兩個橋形成主環，而原子數目較少的橋即爲該「橋」。在NR2R3的定義中，112與R3連同與其鍵結的N原子可形成含有至多2個N原子且不含其他雜原子的飽和4 至7員單環雜環。其例子包括：氮雜環丁烷基、吡咯啶基、哌啶基、哌畊基及升哌畊基。在NR2R3之定義中，R2與R3連同與其鍵結的N原子可形成7-至8-員的橋接雙環基。該雙環基可含有至多兩個N原子且不含任何其他雜原子。其例子包括2,5-二氮雜-雙環〔2.2.1〕庚烷基以及2,5-二氮雜-雙環〔2.2.2〕辛烷基。在NR2R3的定義中，名稱“稠合雙環”基團是指由共用兩個原子的相鄰兩環所組成的8-至12-員雙環系統。該雙環基團可含有至多兩個Ν原子在任何可用位置，且不含· 任何其他雜原子。其例子包括八氫吡咯並[3,4-b]吡啶基、八氫吡咯並[3,2-c]吡啶基、八氫-吡咯並[l，2-a]吡_基及八氫吡咯並[3,4-c]吡咯啉基。如以上就式I化合物定義中的NRZR3所述者，上述三種飽和雜環（單環、橋接雙環、及稠合雙環）可選擇彳生被 —或多個獨立地選自C^4烷基和NRaRb的基團所取代，前提爲雜環基包含兩個N原子且未被NRaRb的基團取代，或者包含一個N原子且被一個NRaRb基所取代。所以，若雜環包含一個N原子，則該環必須被一個NRaRb基取代，且另外可選擇性地經一或多個C!_4烷基取代。若該環包含兩個N原子，其可選擇性經一或多個（^.4院基 200951136 取代’但不被任何NRaRb基取代。取代基，若存在，可位於該環之任何可用位置上，包括取代基爲Cl_4烷基之情況下在N原子上。當式I化合物中η爲2或3或者p爲2時，因此在該化合物中有超過一個R6基團及超過一個r7基團，、及 R·7各自獨立地選自如上所示式I化合物之定義中可能的意義，因此這些基團可相同或不同。 φ “選擇性被一或多個…取代，’意指基團可被—或多個（較佳爲1、2、3、或4個，更佳爲〗、2或3個及更佳爲1 或2個）取代基所取代，但該基團須具有足夠可被取代的位置。這些取代基可相同或相異，且可接在任何可用位置上。本說明書中，“治療”係指排除、降低或改善疾病的原因或結果。基於本發明的目的，治療包括（但不限於）減輕或改善或排除疾病之一或多種症狀；疾病程度的減弱； φ 穩定（即非惡化）的疾病狀態；疾病進程的延遲或減慢；疾病狀態的改善或緩和；以及疾病的減輕（部份或全部）〇此處所使用之“預防”意指預防一個體之疾病的發生，該個體傾向於或具有風險因素，但仍未呈現疾病徵兆。預防也包括在一先前罹患該疾病之個體再度出現該疾病。本發明因此關於定義於上文之式I化合物。在另一實施態樣中，本發明關於式I化合物，其中 R!是 NH2。 -25- 200951136 在另一實施態樣中，本發明關於式I化合物，其中 R2及R3 —起與所連接之氮原子形成選自如下之飽和雜環基： (i)包含2個N原子且不包含任何其他雜原子之雜環基，其中該雜環基可選擇性經一或多個Cl_4烷基取代；及 (U)包含1個N原子且不包含任何其他雜原子之雜環基 ’其中該雜環基經一個NRaRb基團取代且可選擇性經—或多個烷基取代；其中該雜環基（i)及（ii)可爲4-至7-員單環、7-至8-員橋接雙環或8-至12-員稠合雙環；或者R·2爲Η或Cu烷基，R3爲氮雜環丁烷基、吡咯淀基、脈啶基或氮雜環庚烷基，其可選擇性經一或多個 C I - 4院基取代。在另一實施態樣中，本發明關於式I化合物，其中 R2及R3—起與所連接之氮原子形成飽和雜環基，其可爲 4_至7、員單環、7·至8-員橋接雙環或8-至12-員稠合雙環 ’其中該雜環基可包含高至兩個N原子且不含任何其他雜原子’及可選擇性經—或多個獨立地選自Ci4烷基及 NRaRb之取代基取代，惟該雜環基係包含2個N原子且不經NRaRb基團取代，或者包含1個N原子且經一個NRaRb 基團取代。在另一實施態樣中，本發明關於式丨化合物，其中 R2 & R3 —起與所連接之氮原子形成選自如下之飽和雜環基： -26- 2〇〇951136 (1)包含·5 , 2個N原子且不包含任何其他雜原子之雜環基一、中該雜Tea # 環基可選擇性經一或多個C!_4烷基取代；及 C 11 ) 曰1個N原子且不包含任何其他雜原子之雜環基其中該雜環基經—個NRaRb基團取代且可選擇性經—或多個CN4烷基取代；其中該雜環基（i)及（Π)可爲4_至7_員單環、7_至8_ 員橋接雙環或8-至12-員稠合雙環。〇在另一實施態樣中’本發明關於式I化合物，其中Ra 及Rb獨立地爲Η或CU4烷基。在另一實施態樣中’本發明關於式Ϊ化合物，其中，其中尺3及Rb獨立地爲H、甲基或乙基。在另一實施態樣中，本發明關於式丨化合物，其中Ra 及Rb獨立地爲Η或甲基。在另一實施態樣中，本發明關於式I化合物，其中Ra 及Rb爲Η。 Ο 在另—實施態樣中’本發明關於式I化合物，其中Ra 爲H，Rb爲Η或Cu烷基。在另一實施態樣中’本發明關於式I化合物，其中Ra 爲H，Rb爲Η、甲基或乙基。在另一實施態樣中，本發明關於式I化合物，其中Ra 爲H，Rb爲Η或甲基。在另一實施態樣中，本發明關於式I化合物，其中Ra 爲H ’ Rb爲C1.4院基。在另一實施態樣中，本發明關於式I化合物，其中Ra -27- 200951136 爲H，Rb爲甲基或乙基。在另一實施態樣中，本發明關於式I化合物，其中Ra 爲Η，Rb爲甲基。在另一實施態樣中，本發明關於式I化合物，其中 R2及R3 —起與所連接之氮原子形成選自如下之飽和雜環基：Any r9 ring may be optionally substituted with one or more groups independently selected from the group consisting of alkyl and halo (as described above), and the substituent may be at any available position on the ring. Halogen group or its abbreviation halo means fluorine, chlorine, bromine or iodine. Preferred halogen atoms as the substituent of the alkyl group, the cycloalkyl group or the aryl group are fluorine and chlorine, and more preferably fluorine. Preferably, the atomic atom associated with Rs is fluorine and chlorine. More preferably, the name "saturated" means a group which does not contain any double bond or bond. "Bridged" bicyclic" group means that the bicyclic system has two shared atoms (bridge ends) connected to three non-cyclic chains (bridges), so that the number of atoms is larger - 23-200951136 of the two bridges form the main ring, The bridge with a small number of atoms is the "bridge." In the definition of NR2R3, 112 and R3 together with the N atom to which they are bonded may form a saturated 4 to 7 membered monocyclic heterocyclic ring containing up to 2 N atoms and no other heteroatoms. Examples thereof include azetidinyl, 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 7- to 8-membered bridged bicyclic group. The bicyclic group may contain up to two N atoms and does not contain any other heteroatoms. Examples thereof include 2,5-diaza-bicyclo[2.2.1]heptyl and 2,5-diaza-bicyclo[2.2.2]octyl. In the definition of NR2R3, the name "fused bicyclic" group refers to an 8- to 12-membered bicyclic ring system consisting of two adjacent rings sharing two atoms. The bicyclic group may contain up to two deuterium atoms at any available position and does not contain any other heteroatoms. Examples thereof include octahydropyrrolo[3,4-b]pyridinyl, octahydropyrrolo[3,2-c]pyridyl, octahydro-pyrrolo[l,2-a]pyrryl and octahydropyrrole. And [3,4-c]pyrrolyl. As described above for NRZR3 in the definition of the compound of formula I, the above three saturated heterocyclic rings (monocyclic, bridged bicyclic, and fused bicyclic) may be selected from the group consisting of - or independently selected from C^4 alkyl groups and The group of NRaRb is substituted, provided that the heterocyclic group contains two N atoms and is not substituted by the group of NRaRb, or contains one N atom and is substituted by one NRaRb group. Therefore, if the heterocyclic ring contains an N atom, the ring must be substituted with an NRaRb group and additionally optionally substituted with one or more C!_4 alkyl groups. If the ring contains two N atoms, it may be optionally substituted by one or more (^.4 yards 200951136) but not by any NRaRb group. Substituents, if present, may be located at any available position in the ring. , in the case where the substituent is a C 4 alkyl group, on the N atom. When η is 2 or 3 or p is 2 in the compound of formula I, thus there is more than one R 6 group and more than one r 7 group in the compound. And R.sup.7 are each independently selected from the meanings as defined above for the definition of the compound of formula I, such that these groups may be the same or different. φ "selectivity is replaced by one or more of," meaning a group Substituted by one or more (preferably 1, 2, 3, or 4, more preferably, 2 or 3 and more preferably 1 or 2) substituents, but the group must have sufficient Substituted positions. These substituents may be the same or different and may be attached to any available position. In the present specification, "treatment" refers to the cause or result of eliminating, reducing or ameliorating a disease. For the purposes of the present invention, treatment Including (but not limited to) alleviating or ameliorating or eliminating one or more symptoms of the disease Degree of disease reduction; φ stable (ie non-deteriorating) disease state; delayed or slowed progression of the disease; improvement or mitigation of disease state; and reduction of disease (partial or total) “ "prevention" used here Means to prevent the occurrence of a disease in which the individual tends to or has a risk factor but still does not present a symptom of the disease. Prevention also includes recurrence of the disease in an individual who has previously suffered from the disease. The present invention is therefore defined above In another embodiment, the invention relates to a compound of formula I, wherein R! is NH2. -25- 200951136 In another embodiment, the invention relates to a compound of formula I, wherein R2 and R3 are And a saturated heterocyclic group selected from the group consisting of: (i) a heterocyclic group containing 2 N atoms and not containing any other hetero atom, wherein the heterocyclic group may be selectively subjected to one or more a C1-4 alkyl group; and (U) a heterocyclic group containing 1 N atom and no other hetero atom, wherein the heterocyclic group is substituted with one NRaRb group and optionally substituted with - or a plurality of alkyl groups;The heterocyclic group (i) and (ii) may be a 4- to 7-membered monocyclic, 7- to 8-membered bridged bicyclic or 8- to 12-membered fused bicyclic ring; or R·2 is ruthenium or Cu. Alkyl, R3 is azetidinyl, pyrrolazolyl, cytidine or azepanyl, which may be optionally substituted by one or more CI-4. In another embodiment The present invention relates to a compound of formula I, wherein R2 and R3 together form a saturated heterocyclic group with the nitrogen atom to which they are attached, which may be 4 to 7 members, a single 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 does not contain any other hetero atom' and may be optionally substituted with a plurality of substituents independently selected from Ci4 alkyl and NRaRb However, the heterocyclic group contains 2 N atoms and is not substituted by the NRaRb group, or contains 1 N atom and is substituted by one NRaRb group. In another embodiment, the present invention is directed to a compound of the formula wherein R2 & R3 together with the nitrogen atom to which they are attached form a saturated heterocyclic group selected from the group consisting of -26- 2〇〇951136 (1) 5 , a heterocyclic group of 2 N atoms and containing no other hetero atom, wherein the heteroTea # ring group may be optionally substituted by one or more C!_4 alkyl groups; and C 11 ) 曰 1 N atom And a heterocyclic group which does not contain any other hetero atom, wherein the heterocyclic group is substituted by an NRaRb group and may be optionally substituted by a plurality of CN4 alkyl groups; wherein the heterocyclic group (i) and (Π) may be It is a 4_ to 7_ member single ring, a 7_ to 8_ member bridged double ring or an 8- to 12-membered fused double ring. 〇 In another embodiment, the invention relates to compounds of formula I, wherein Ra and Rb are independently hydrazine or CU4 alkyl. In another embodiment, the invention is directed to a hydrazone compound, wherein ampule 3 and Rb are independently H, methyl or ethyl. In another embodiment, the invention is directed to a compound of the formula wherein Ra and Rb are independently hydrazine or methyl. In another embodiment, the invention is directed to a compound of formula I, wherein Ra and Rb are deuterium. Ο In another embodiment </RTI> The invention relates to compounds of formula I, wherein Ra is H and Rb is deuterium or Cu alkyl. In another embodiment, the invention relates to a compound of formula I, wherein Ra is H and Rb is deuterium, methyl or ethyl. In another embodiment, the invention is directed to a compound of formula I, wherein Ra is H and Rb is deuterium or methyl. In another embodiment, the invention is directed to a compound of formula I, wherein Ra is H' Rb is a C1.4 building. In another embodiment, the invention is directed to a compound of formula I, wherein Ra-27-200951136 is H and Rb is methyl or ethyl. In another embodiment, the invention is directed to a compound of formula I, wherein Ra is hydrazine and Rb is methyl. In another embodiment, the invention is directed to a compound of formula I, wherein R2 and R3 together with the nitrogen atom to which they are attached form a saturated heterocyclic group selected from the group consisting of:

其中Ra及Rb具有上文所述式I化合物中之意義，R。爲 Η或Cm烷基，較佳爲Η或甲基，更佳爲H，Rd爲Η或 Ch4烷基，更佳爲Η或甲基。在另一實施態樣中，本發明關於式I化合物，其中 R2及R3 —起與所連接之氮原子形成選自（a)至（h)之飽和雜環基，Ra、Rb、R。及Rd獨立地爲Η或Cm烷基， -28- 200951136 較佳地’ Ra、Rb、Rc及Rd獨立地爲Η或甲基，更佳地， Ra、Rb及Rd獨立地爲Η或甲基，及Rc爲Η。在另一實施態樣中，本發明關於式I化合物，其中 R2及Ra—起與所連接之氮原子形成選自（a) 、（b)、 (c) 、（d) 、（f) 、（g)及（h)之飽和雜環基，Ra 及Rb具有上文所述式I化合物中之意義，R。爲^^或¢^-4 院基，較佳爲Η或甲基，更佳爲Η，Rd爲Η或G-4烷基，較佳爲Η或甲基。在另一實施態樣中，本發明關於式I化合物，其中 R2及R3 —起與所連接之氮原子形成選自（a) 、（b)、 (c) 、( d) 、（f) 、（g)及（h)之飽和雜環基，Ra 、Rb、Rc及Rd獨立地爲H或Cu烷基，較佳地Ra、Rb 、Rc及Rd獨立地爲H或甲基，更佳地Ra、Rb及Rd獨立地爲H或甲基，及Rc爲11。在另一實施態樣中，本發明關於式I化合物，其中尺2及R3 一起與所連接之氮原子形成選自（a) 、（b)、 (e)及（f)之飽和雜環基，及Ra及Rb具有上文所述式 I化合物中之意義’ Rc爲Η或Ci“院基’較佳爲Η或甲基，更佳爲Η，及Rd爲Η或Cm烷基，較佳爲Η或甲基〇在另一實施態樣中，本發明關於式I化合物，其中尺2及r3 —起與所連接之氮原子形成選自（a) 、（b)、 (e )及（f)之飽和雜環基’及Ra、Rb、Re及Rd獨立地爲Η或Ci-4燒基’較佳地Ra、Rb、Rc及Rd獨立地爲Η -29- 200951136 或甲基，及更佳地Ra'Rb及Rd獨立地爲H或甲基，及 Rc 爲 Η。在另一實施態樣中，本發明關於式1化合物，其中 112及R3 —起與所連接之氮原子形成選自（a)及（b)之飽和雜環基，其中Ra及Rb具有如上所述式1化合物中之意義，及爲11或（：1-4烷基’更佳地Rc爲H。在另一實施態樣中，本發明關於式I化合物’其中 R2及R3 —起與所連接之氮原子形成選自（a)及（b)之飽和雜環基，及Ra、Rb及Re獨立地爲Η或Cm烷基，較佳地Ra、Rb及獨立地爲Η或甲基，及更佳地118及 Rb獨立地爲Η或甲基，及Rc爲11。在另一實施態樣中，本發明關於式I化合物，其中尺2及R3 —起與所連接之氮原子形成選自（a)及（b)之飽和雜環基，Ra爲H，Rb爲Η或CL4烷基，及Re爲Η 〇在另一實施態樣中，本發明關於式I化合物，其中 R2及R3 —起與所連接之氮原子形成選自（a)及（b)之飽和雜環基，^爲！^“爲Η或甲基，及Rc爲11。在另一實施態樣中，本發明關於式I化合物，其中 R2及R3 —起與所連接之氮原子形成選自（a)及（b)之飽和雜環基，R a爲Η ’ R b爲甲基，及Rc爲Η。在另一實施態樣中，本發明關於式I化合物，其中 R2及R3 —起與所連接之氮原子形成選自（a)及（b)之飽和雜環基，及Ra、Rb及Re爲Η。 -30- 200951136 在另一實施態樣中，本發明關於式I化合物，其中 R2及R3 —起與所連接之氮原子形成式（a)之飽和雜環基Wherein Ra and Rb have the meaning of the compound of formula I above, R. The hydrazine or Cm alkyl group is preferably hydrazine or methyl group, more preferably H, and Rd is hydrazine or a C4 alkyl group, more preferably hydrazine or methyl group. In another embodiment, the invention is directed to a compound of formula I, wherein R2 and R3 together with the nitrogen atom to which they are attached form a saturated heterocyclic group selected from (a) to (h), Ra, Rb, R. And Rd is independently hydrazine or Cm alkyl, -28-200951136 preferably 'Ra, Rb, Rc and Rd are independently hydrazine or methyl, and more preferably, Ra, Rb and Rd are independently hydrazine or methyl , and Rc is Η. In another embodiment, the invention relates to a compound of formula I, wherein R2 and Ra together with the nitrogen atom to which they are attached are selected from (a), (b), (c), (d), (f), The saturated heterocyclic groups of (g) and (h), Ra and Rb have the meanings of the compounds of formula I above, R. Preferably, it is hydrazine or methyl, more preferably hydrazine, and Rd is hydrazine or G-4 alkyl, preferably hydrazine or methyl. In another embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with the nitrogen atom to which they are attached are selected from (a), (b), (c), (d), (f), (g) and (h) a saturated heterocyclic group, and Ra, Rb, Rc and Rd are independently H or a C alkyl group, preferably Ra, Rb, Rc and Rd are independently H or a methyl group, more preferably Ra, Rb and Rd are independently H or methyl and Rc is 11. In another embodiment, the invention relates to a compound of formula I, wherein ampule 2 and R3 together with the nitrogen atom to which they are attached form a saturated heterocyclic group selected from (a), (b), (e) and (f) And Ra and Rb have the meanings in the compounds of formula I above. 'Rc is Η or Ci. The "base" is preferably hydrazine or methyl, more preferably hydrazine, and Rd is hydrazine or Cm alkyl, preferably. In another embodiment, the invention relates to a compound of formula I, wherein ampule 2 and r3 together with the nitrogen atom to which they are attached are selected from (a), (b), (e) and ( f) the saturated heterocyclic group 'and Ra, Rb, Re and Rd are independently hydrazine or Ci-4 alkyl group'. Preferably, Ra, Rb, Rc and Rd are independently Η-29- 200951136 or methyl, and More preferably, Ra'Rb and Rd are independently H or methyl, and Rc is oxime. In another embodiment, the invention is directed to a compound of formula 1, wherein 112 and R3 together with the nitrogen atom to which they are attached From the saturated heterocyclic group of (a) and (b), wherein Ra and Rb have the meanings of the compound of the formula 1 as described above, and are 11 or (: 1-4 alkyl 'more preferably Rc is H. In one embodiment, the invention relates to Formula I Wherein R2 and R3 together form a saturated heterocyclic group selected from (a) and (b) with the nitrogen atom to be bonded, and Ra, Rb and Re are independently fluorene or Cm alkyl, preferably Ra, Rb And independently hydrazine or methyl, and more preferably 118 and Rb are independently hydrazine or methyl, and Rc is 11. In another embodiment, the invention is directed to a compound of formula I, wherein amp 2 and R3 are Forming a saturated heterocyclic group selected from (a) and (b) with a nitrogen atom to be bonded, Ra is H, Rb is hydrazine or CL4 alkyl, and Re is Η 另一 In another embodiment, the present invention With respect to the compound of formula I, wherein R2 and R3 together with the nitrogen atom to which they are attached form a saturated heterocyclic group selected from (a) and (b), which is Η or methyl, and Rc is 11. In another embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with the nitrogen atom to which they are attached form a saturated heterocyclic group selected from (a) and (b), and R a is Η ' R b is Methyl, and Rc are oxime. In another embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with the nitrogen atom to which they are attached form a saturated heterocyclic group selected from (a) and (b) , and Ra, Rb and Re are Η In another embodiment -30-200951136 aspect, the present invention compounds of formula I, wherein R2 and R3 - starting with the nitrogen of attachment form a saturated heterocyclic group of formula (a) of

Ra\ /Rb NRa\ /Rb N

⑻ 其中Ra及Rb具有上文所述式I化合物中之意義，及Rc 爲H或CU4烷基，及更佳地R。爲η。在另一實施態樣中，本發明關於式I化合物，其中 R2及R3 —起與所連接之氮原子形成式（a)之飽和雜環基 ’及Ra、Rb及Re獨立地爲Η或（^_4烷基，較佳地Ra、 φ Rb及R。獨立地爲Η或甲基，及更佳地Ra及Rb獨立地爲 Η或甲基，及Rc爲H。在另一實施態樣中，本發明關於式I化合物，其中 R2及R3 —起與所連接之氮原子形成式（a)之飽和雜環基，Ra爲H，Rb爲11或Cu烷基，及R。爲H。在另一實施態樣中，本發明關於式I化合物，其中 112及R3 —起與所連接之氮原子形成式（a)之飽和雜環基，1爲11，1115爲11或甲基，及11<:爲11。在另一實施態樣中，本發明關於式I化合物’其中 -31 - 200951136 R2及R3 —起與所連接之氮原子形成式（a)之飽和雜環基 ,Ra爲Η，Rb爲甲基，及Rc爲Η。在另一實施態樣中，本發明關於式I化合物，其中 R2及R3 —起與所連接之氮原子形成式（b)之飽和雜環基，(8) wherein Ra and Rb have the meanings of the compounds of formula I above, and Rc is H or CU4 alkyl, and more preferably R. Is η. In another embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with the nitrogen atom to which they are attached form a saturated heterocyclic group of formula (a) and Ra, Rb and Re are independently Η or ( ^_4 alkyl, preferably Ra, φ Rb and R. independently hydrazine or methyl, and more preferably Ra and Rb are independently hydrazine or methyl, and Rc is H. In another embodiment The present invention relates to a compound of formula I, wherein R2 and R3 together with a nitrogen atom to be bonded form a saturated heterocyclic group of formula (a), Ra is H, Rb is 11 or a Cu alkyl group, and R is H. In another embodiment, the invention relates to a compound of formula I, wherein 112 and R3 together with a nitrogen atom to which they are attached form a saturated heterocyclic group of formula (a), 1 is 11, 1115 is 11 or methyl, and 11 <;: is 11. In another embodiment, the invention relates to a compound of formula I wherein -31 - 200951136 R2 and R3 together form a saturated heterocyclic group of formula (a) with a nitrogen atom to be bonded, Ra is Η Rb is a methyl group, and Rc is Η. In another embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with a nitrogen atom to be bonded form a saturated heterocyclic group of formula (b)

其中Ra及Rb具有上文所述式I化合物中之意義，及Rc 爲Η或C^-4烷基，更佳地R。爲Η。在另一實施態樣中’本發明關於式I化合物，其中 R2及R3 —起與所連接之氮原子形成式（b)之飽和雜環 ❹ 基，及Ra、Rb及R。獨立地爲Η或（^_4烷基，較佳地Ra 、Rb及R。獨立地爲Η或甲基，及更佳地1及Rb獨立地爲Η或甲基，及Rc爲H。在另一實施態樣中’本發明關於式I化合物，其中 R2及R3 —起與所連接之氮原子形成式（b)之飽和雜環基’ Ra爲H’ 爲Η或Ci-4院基，及Re爲H。在另一實施態樣中，本發明關於式I化合物，其中 R2及R3 —起與所連接之氮原子形成式（b)之飽和雜環 -32- 200951136 基，Ra爲H’ Rb爲Η或甲基，及Re爲Η。在另一實施態樣中’本發明關於式I化合物，其中 R2及R3 —起與所連接之氮原子形成式（b)之飽和雜環基，Ra爲Η ’ Rb爲甲基，及Rc爲Η。在另一實施態樣中，本發明關於式I化合物，其中 R2及R3 —起與所連接之氮原子形成式（b)之飽和雜環基，及Ra、Rb及Re爲Η。 φ 在另一實施態樣中’本發明關於式I化合物，其中 R2爲Η或<^-4烷基，及R3爲氮雜環丁烷基、吡咯啶基、哌啶基或氮雜環庚烷基，其可選擇性經一或多個Cl-4烷基取代。在另一實施態樣中，本發明關於式I化合物，其中 R2爲Η及R3爲1-甲基-吡咯啶-3-基。在另一實施態樣中，本發明關於式I化合物，其中爲： _ ( 1 ) C 1 _ 8 院基； (2) C3.8環烷基-CG.6烷基； (3 )芳基-CQ.6烷基；其中，在基團（1)至（3)中，任何烷基可選擇性經一或多個鹵素原子取代，C3-8環烷基可選擇性經—或多個獨立地選自Ci-4烷基、鹵素及芳基之取代基取代；或 (4 )式（i )之基團 -33- 200951136Wherein Ra and Rb have the meanings as defined above for the compound of formula I, and Rc is Η or C^-4 alkyl, more preferably R. Why? In another embodiment, the invention is directed to a compound of formula I, wherein R2 and R3 together with a nitrogen atom to which they are attached form a saturated heterocyclic fluorenyl group of formula (b), and Ra, Rb and R. Independently hydrazine or (^_4 alkyl, preferably Ra, Rb and R. independently hydrazine or methyl, and more preferably 1 and Rb are independently hydrazine or methyl, and Rc is H. In one embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with the nitrogen atom to which they are attached form a saturated heterocyclic group of formula (b) 'Ra' is H', or a Ci-4, and Re is H. In another embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with the nitrogen atom to which they are attached form a saturated heterocyclic ring of formula (b)-32-200951136, Ra is H' Rb is hydrazine or methyl, and Re is hydrazine. In another embodiment, the invention relates to a compound of formula I, wherein R2 and R3 together with a nitrogen atom to be bonded form a saturated heterocyclic group of formula (b), Ra is Η ' Rb is methyl, and Rc is Η. In another embodiment, the invention relates to a compound of formula I, wherein R 2 and R 3 together with the attached nitrogen atom form a saturated heterocyclic ring of formula (b) And R, Rb and Re are Η. φ In another embodiment, the invention relates to a compound of formula I, wherein R 2 is hydrazine or < 4 alkyl, and R 3 is azetidinyl, Pyrrolidinyl Piperidinyl or azepanyl, which may be optionally substituted by one or more Cl-4 alkyls. In another embodiment, the invention relates to compounds of formula I, wherein R2 is hydrazine and R3 is 1 -Methyl-pyrrolidin-3-yl. In another embodiment, the invention is directed to a compound of formula I, wherein: _(1)C1-8-8; (2) C3.8 cycloalkyl- CG.6 alkyl; (3) aryl-CQ.6 alkyl; wherein, in the groups (1) to (3), any alkyl group may be optionally substituted by one or more halogen atoms, C3-8 The cycloalkyl group may be optionally substituted with one or more substituents independently selected from the group consisting of Ci-4 alkyl, halogen and aryl; or (4) a group of formula (i) -33- 200951136

在另一實施態樣中，本發明關於式I化合物，其中 R4爲： (1 ) C 1 . 8 院基；In another embodiment, the invention is directed to a compound of formula I, wherein R4 is: (1) C 1.8 .

(2) C3-8環院基- C〇-6院基；其中，在基團（1 )及（2 )中，任何烷基可選擇性經一或多個鹵素原子取代，C3_8環烷基可選擇性經一或多個獨立地選自C^4烷基、鹵素及芳基之取代基取代； (3 )式（i )之基團(2) C3-8 ring-based base - C〇-6-based base; wherein, in the groups (1) and (2), any alkyl group may be optionally substituted by one or more halogen atoms, C3_8 cycloalkyl Optionally substituted with one or more substituents independently selected from C^4 alkyl, halogen and aryl; (3) a group of formula (i)

(4)式（ii)之基團(4) Group of formula (ii)

在另一實施態樣中，本發明關於式I化合物，其中 R4爲： -34- 200951136 (1 ) C丨-8烷基； (2) C3.8環烷基-C().6烷基；或 (3 )芳基-C〇.6烷基；其中，在基團（1)至（3)中，任何烷基可選擇性經一或多個鹵素原子取代，及c38環烷基可選擇性經—或多個獨立地選自Cl·4烷基、鹵素及芳基之取代基取代。在另一實施態樣中，本發明關於式〗化合物，其中扁^ R 4爲 Ο (1 ) Cm烷基； (2) C3_8環烷基_C()_6烷基；及 (3) 芳基- C!.6院基；其中’在基團（1)至（3)中，任何烷基可選擇性經一或多個齒素原子取代，及c3 8環烷基可選擇性經—或多個獨立地選自C!.4烷基、鹵素及芳基之取代基取代。在另一實施態樣中，本發明關於式I化合物，其中 φ R4爲Cl·8院基或C3·8環烷基-C()_6烷基；其中烷基可選擇性經一或多個園素原子（較佳氟）取代，C3 8環烷基可選擇性經一或多個獨立地選自cl-4烷基、鹵素（較佳氟）及芳基之取代基取代。在另一實施態樣中’本發明關於式I化合物，其中尺4爲C!·8烷基或C：3·8環烷基_Cq_6烷基。在另一實施態樣中，本發明關於式〗化合物，其中 R4爲C2_8烷基或c：3.8環烷基-Cm烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代，C38環烷基可選 -35- 200951136 擇性經一或多個獨立地選自Cl4烷基、鹵素（較佳氟）及芳基之取代基取代。在另一實施態樣中’本發明關於式I化合物，其中 R4爲C2_8烷基或c3-8環烷基-c。^烷基。在另一實施態樣中’本發明關於式I化合物，其中 R·4爲C2_8烷基或C3.8環烷基，較佳爲c2 4烷基或（^3 6環烷基’及更佳爲乙基、異丙基、第三丁基或環丙基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代，C3.8 環烷基可選擇性經一或多個獨立地選自Ci.4烷基、鹵素 (較佳氟）及芳基之取代基取代。在另一實施態樣中，本發明關於式I化合物，其中 R4爲C2.8烷基或C3·8環烷基，更佳爲c2 4烷基或c3 6環烷基。在另一實施態樣中，本發明關於式I化合物，其中 R4爲乙基、異丙基、第三丁基或環丙基。在另一實施態樣中，本發明關於式I化合物，其中 R4爲Cn-8烷基，較佳爲C2_8烷基，更佳爲C2_4烷基選擇性經一或多個鹵素原子（較佳氟）取代。在另一實施態樣中’本發明關於式I化合物，其中 114爲Cu烷基’較佳爲C2_8烷基，更佳爲c2.4烷基。在另一實施態樣中’本發明關於式Ϊ化合物，其中 R4爲乙基、異丙基或第三丁基。在另一實施態樣中’本發明關於式Ϊ化合物，其中 BU爲C3.8環烷基-Co-6烷基，其中烷基可選擇性經—或多 -36- 200951136 個鹵素原f (較佳氟）取代，c3.8環烷基可選擇性經-或 #«立地選自C14烷基、鹵素（較佳氟）及芳基之取代基取代。在另一實施態樣中，本發明關於式I化合物，其中爲c3.8環烷基烷基。在另一實施態樣中，本發明關於式I化合物，其中 R4爲摄综數 ΛIn another embodiment, the invention relates to a compound of formula I, wherein R4 is: -34- 200951136 (1) C丨-8 alkyl; (2) C3.8 cycloalkyl-C().6 alkyl Or (3) aryl-C〇.6 alkyl; wherein, in the groups (1) to (3), any alkyl group may be optionally substituted by one or more halogen atoms, and the c38 cycloalkyl group may be Optionally, it is substituted with one or more substituents independently selected from the group consisting of Cl. 4 alkyl, halogen and aryl. In another embodiment, the present invention is directed to a compound of the formula wherein: R 4 is Ο (1 ) Cm alkyl; (2) C 3-8 cycloalkyl _C() -6 alkyl; and (3) aryl - C!.6院; where 'in the groups (1) to (3), any alkyl group may be optionally substituted with one or more dentate atoms, and the c3 8 cycloalkyl group may be optionally-- or A plurality of substituents independently selected from C..4 alkyl, halogen and aryl are substituted. In another embodiment, the invention relates to a compound of formula I, wherein φ R4 is Cl 8 or a C 3 ·8 cycloalkyl-C()-6 alkyl; wherein the alkyl group is optionally one or more The C3 8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from the group consisting of a cl-4 alkyl group, a halogen (preferably fluorine), and an aryl group. In another embodiment, the invention is directed to a compound of formula I, wherein the rule 4 is C!.8 alkyl or C:3.8 cycloalkyl-Cq-6 alkyl. In another embodiment, the invention is directed to a compound of formula wherein R 4 is C 2-8 alkyl or c: 3.8 cycloalkyl-Cm alkyl; wherein the alkyl group is selectively capable of passing one or more halogen atoms (preferably fluorine) Substituted, C38 cycloalkyl optionally -35- 200951136 is optionally substituted with one or more substituents independently selected from the group consisting of a C4 alkyl group, a halogen (preferably fluorine), and an aryl group. In another embodiment, the invention relates to a compound of formula I, wherein R4 is C2-8 alkyl or c3-8 cycloalkyl-c. ^Alkyl. In another embodiment, the invention relates to a compound of formula I, wherein R.sup.4 is C2_8 alkyl or C3.8 cycloalkyl, preferably c2 4 alkyl or (^3 6 cycloalkyl) and more preferably Is an ethyl group, an isopropyl group, a tert-butyl group or a cyclopropyl group; wherein the alkyl group is optionally substituted by one or more halogen atoms (preferably fluorine), and the C3.8 cycloalkyl group may be selectively passed through one or more Substituents independently selected from the group consisting of Ci.4 alkyl, halo (preferably fluorine) and aryl. In another embodiment, the invention is directed to a compound of formula I, wherein R4 is C2.8 alkyl or C3 An 8-cycloalkyl group, more preferably a c2 4 alkyl group or a c3 6 cycloalkyl group. In another embodiment, the invention relates to a compound of formula I, wherein R4 is ethyl, isopropyl, tert-butyl or Cyclopropyl. In another embodiment, the invention relates to a compound of formula I, wherein R4 is Cn-8 alkyl, preferably C2-8 alkyl, more preferably C2_4 alkyl is selected via one or more halogen atoms (preferably fluorine) is substituted. In another embodiment, the invention relates to a compound of formula I, wherein 114 is a Cu alkyl group, preferably a C2-8 alkyl group, more preferably a c2.4 alkyl group. In the sample The invention relates to a compound of the formula wherein R4 is ethyl, isopropyl or tert-butyl. In another embodiment, the invention relates to a compound of the formula wherein BU is C3.8 cycloalkyl-Co-6 alkane a group wherein the alkyl group is optionally substituted with - or more than - 36 - 200951136 halogens of the original f (preferably fluorine), and the c3.8 cycloalkyl group is optionally selected from - or from the C14 alkyl group, halogen ( Substituents of preferred fluoro) and aryl groups. In another embodiment, the invention relates to compounds of formula I, wherein is c3.8 cycloalkylalkyl. In another embodiment, the invention relates to Compound I, where R4 is the number of photosΛ

3_S iS Μ：基i烷基，其中烷基可選擇性經一或多個_素原+ f齡： $寸· V蚁彳圭氟）取代，c38環烷基可選擇性經一或多個獨立地彳p自p ^ H Cl-4烷基、鹵素（較佳氟）及芳基之取代基取代。在努一實施態樣中，本發明關於式I化合物，其中 R4爲C3.8環烷基_Cq i烷基。在另一實施態樣中，本發明關於式I化合物，其中 R4爲C3 β摄控龙· Β 基’較佳爲C3_6環烷基，及更佳爲環丙基 /、選擇性經〜或多個獨立地選自C14烷基、鹵素（較佳氣）及芳基之取代基取代。在另一實施態樣中，本發明關於式I化合物，其中 R4爲C3-8環烷基，較佳爲（：3_6環烷基。在另一實施態樣中，本發明關於式I化合物，其中 R·4爲環汽基。在另一實施態樣中，本發明關於式I化合物，其中 R4爲芳基_Cq.6烷基，其中烷基可選擇性經一或多個原子（較佳氟）取代。在另一實施態樣中，本發明關於式I化合物，其中 -37- 200951136 R4爲芳基-CG_2烷基’其中烷基可選擇性經一或多個齒素原子（較佳氟）取代。在另—實施態樣中，本發明關於式I化合物，其中 R4爲芳基-Cl.6烷基，其中烷基可選擇性經—或多個鹵素原子（較佳氟）取代。〃在另—實施態樣中’本發明關於式I化合物，其中 R4爲芳基。 '3_S iS Μ: yl i-alkyl, wherein the alkyl group is optionally substituted by one or more _ primogens + f age: $ inch · V ant 彳氟 )), c38 cycloalkyl can be selectively passed one or more Separately, 彳p is substituted with a substituent of p ^ H Cl-4 alkyl, halogen (preferably fluorine) and aryl. In one embodiment, the invention is directed to a compound of formula I, wherein R4 is C3.8 cycloalkyl-Cq ialkyl. In another embodiment, the invention is directed to a compound of formula I, wherein R4 is C3[beta]-controlled guanyl- thiol, preferably C3-6 cycloalkyl, and more preferably cyclopropyl/, selective via ~ or more Substituents which are independently selected from the group consisting of a C14 alkyl group, a halogen (preferably gas) and an aryl group. In another embodiment, the invention relates to a compound of formula I, wherein R4 is C3-8 cycloalkyl, preferably (3-6 cycloalkyl). In another embodiment, the invention is directed to a compound of formula I, Wherein R.sup.4 is a cycloalcohol group. In another embodiment, the present invention is directed to a compound of formula I, wherein R4 is aryl-Cq.6 alkyl, wherein the alkyl group is selectively one or more atoms (more In another embodiment, the present invention is directed to a compound of formula I, wherein -37-200951136 R4 is aryl-CG_2alkyl' wherein the alkyl group is selectively capable of passing one or more dentate atoms (compare In another embodiment, the invention relates to a compound of formula I, wherein R4 is aryl-Cl.6 alkyl, wherein the alkyl group may be optionally substituted with one or more halogen atoms (preferably fluorine) Substituted. 〃 In another embodiment, the invention relates to a compound of formula I, wherein R4 is aryl.

在另一實施態樣中，本發明關於式I化合物，其中 R4爲式（i)之基團。在另一實施態樣中，本發明關於式I化合物，其中 R4爲式（i)之基團，X爲〇。在另一實施態樣中，本發明關於式I化合物，其中 R4爲式（ϋ )之基團。在另一實施態樣中，本發明關於式I化合物，其中 R5爲H、鹵素或Cl_8烷基。In another embodiment, the invention is directed to a compound of formula I, wherein R4 is a group of formula (i). In another embodiment, the invention is directed to a compound of formula I, wherein R4 is a group of formula (i) and X is deuterium. In another embodiment, the invention is directed to a compound of formula I, wherein R4 is a group of formula (ϋ). In another embodiment, the invention is directed to a compound of formula I, wherein R5 is H, halo or Cl-8 alkyl.

在另一實施態樣中，本發明關於式I化合物，其中 Rs爲Η、鹵素或Cl_2烷基。在另一實施態樣中’本發明關於式I化合物，其中尺5爲H、鹵素、Ci.2烷基或CN。在另一實施態樣中’本發明關於式I化合物，其中 R5爲Η、鹵素或CN，更佳爲Η、氯或CN。在另一實施態樣中，本發明關於式I化合物，其中 R5爲Η或鹵素，更佳爲Η或氯。在另一實施態樣中’本發明關於式I化合物，其中 -38 200951136In another embodiment, the invention is directed to a compound of formula I, wherein Rs is hydrazine, halogen or Cl 2 alkyl. In another embodiment, the invention is directed to a compound of formula I, wherein the rule 5 is H, halogen, Ci. 2 alkyl or CN. In another embodiment, the invention is directed to a compound of formula I, wherein R5 is deuterium, halogen or CN, more preferably deuterium, chlorine or CN. In another embodiment, the invention is directed to a compound of formula I, wherein R5 is deuterium or halogen, more preferably deuterium or chlorine. In another embodiment, the invention relates to a compound of formula I, wherein -38 200951136

Rs爲鹵素或CN，更佳爲氯或CN。在另一實施態樣中，本發明關於式I R5 爲 Η。在另一實施態樣中，本發明關於式I Rs爲鹵素。在另一實施態樣中，本發明關於式I R5爲氯。在另一實施態樣中’本發明關於式I R5 爲 CN。在另一實施態樣中’本發明關於式I R6及R7各自獨立地選自Η及Cl_4烷基， R7之一者可爲芳基或C3_8環烷基_cG_6烷基在另一實施態樣中，本發明關於式Ϊ L及R7各自獨立地選自Η及Cl_4烷基，2 C原子上之Re基團及R7基團可連接一起奠 C 3 - 8環院基。在另一實施態樣中’本發明關於式I R6及R7各自獨立地選自Η及d_4烷基。在另一實施態樣中，本發明關於式I R6及R·7各自獨立地選自Η及甲基。在另一實施態樣中，本發明關於式I Re或R7基團中之一者爲C3.8環烷基-Cq_6^ 在另一實施態樣中’本發明關於式I R·6或R·7基團中之一者爲芳基。化合物，其中化合物，其中化合物，其中化合物，其中化合物，其中且另外地β·6或 Ο 化合物，其中之另外地在相同丨該C原子形成化合物，其中化合物，其中化合物，其中芒基。化合物，其中 -39- 200951136 在相同c 原子形在 X爲（在爲1或在爲0或在 Rg爲；〇在 R 8爲在 R 8爲個園素多個獨代基取在 R 8爲個鹵素多個獨代基取另一實施態樣中’本發明關於式I化合物，其中在原子上之Re基團及R7基團係彼此連接一起與該C 成C3.8環烷基。另一實施態樣中，本發明關於式I化合物，其中 )。另一實施態樣中，本發明關於式I化合物，其中 n 2 〇另一實施態樣中，本發明關於式I化合物，其中 p 1 〇 © 另一實施態樣中’本發明關於式I化合物，其中選擇性經一或多個鹵素原子（較佳氟）之Cb8烷基另一實施態樣中，本發明關於式I化合物，其中 Cl-8烷基。另一實施態樣中，本發明關於式I化合物，其中 C3-8環烷基-Co.6烷基’其中烷基可選擇性經一或多原子（較佳氟）取代，c3.8環烷基可選擇性經〜或 ^ Μ地選自<^_4院基、鹵素（較佳氟）及芳基之取代。另一實施態樣中，本發明關於式I化合物，其中 C3-8環烷基-Co-i烷基’其中烷基可選擇性經一或多原子（較佳氟）取代，C3-8環烷基可選擇性經〜或 ΛΙ地選自d_4院基、鹵素（較佳氟）及芳基之取代。 -40- 200951136 在另一實施態樣中，本發明關於式I化合物，其中 Κ·8爲C3-8環院基- C〇.i院基。在另一實施態樣中，本發明關於式I化合物，其中 R8爲C3_8環烷基，其選擇性經一或多個獨立地選自Cu4 烷基、圖素（較佳氟）及芳基之取代基取代。在另一實施態樣中，本發明關於式I化合物，其中 Κ·8爲C3-8環院基。在另一實施態樣中，本發明關於式I化合物，其中 R8爲芳基-Co-4烷基，其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代。在另一實施態樣中，本發明關於式I化合物，其中 R8爲芳基-Co.!烷基。在另一實施態樣中，本發明關於式I化合物，其中 r8爲芳基。在另一實施態樣中，本發明關於式I化合物，其中 1爲NH2，及115爲H、鹵素或Ci.2烷基。在另一實施態樣中，本發明關於式I化合物，其中Rs is halogen or CN, more preferably chlorine or CN. In another embodiment, the invention is in the formula I R5 is Η. In another embodiment, the invention is directed to a halogen of formula I Rs. In another embodiment, the invention is based on formula I R5 being chlorine. In another embodiment, the invention is directed to Formula I R5 is CN. In another embodiment, the present invention is independently selected from the group consisting of hydrazine and Cl 4 alkyl, and one of R 7 may be aryl or C 3-8 cycloalkyl _cG-6 alkyl in another embodiment. In the present invention, the formulae Ϊ L and R7 are each independently selected from the group consisting of hydrazine and a Cl 4 alkyl group, and the Re group and the R 7 group at the 2 C atom may be bonded together to form a C 3 - 8 ring. In another embodiment, the invention is independently selected from the group consisting of hydrazine and d_4 alkyl with respect to formula I R6 and R7. In another embodiment, the invention is independently selected from the group consisting of hydrazine and methyl, with respect to formula I R6 and R.7. In another embodiment, the invention is directed to C3.8 cycloalkyl-Cq_6^ as one of the groups of formula I Re or R7. In another embodiment, the invention relates to formula IR·6 or R· One of the 7 groups is an aryl group. A compound, wherein the compound, wherein the compound, wherein the compound, wherein the compound, and additionally the β·6 or oxime compound, wherein additionally the same 丨, the C atom form a compound, wherein the compound, wherein the compound, wherein the awning group. a compound in which -39- 200951136 is in the same c atomic form at X (in the case of 1 or at 0 or in Rg; 〇 in R 8 is at R 8 as a monolithic multiple of the mononucleic group taken at R 8 The present invention relates to a compound of the formula I in which the Re group and the R7 group at the atom are bonded to each other together with the C to form a C3.8 cycloalkyl group. In one embodiment, the invention is directed to a compound of formula I, wherein). In another embodiment, the invention relates to a compound of formula I, wherein n 2 〇 in another embodiment, the invention relates to a compound of formula I, wherein p 1 〇© in another embodiment, the invention relates to a compound of formula I In another embodiment in which a Cb8 alkyl group is selected via one or more halogen atoms (preferably fluorine), the invention is directed to a compound of formula I, wherein Cl-8 is alkyl. In another embodiment, the invention relates to a compound of formula I, wherein C3-8 cycloalkyl-Co.6 alkyl' wherein alkyl is optionally substituted with one or more atoms (preferably fluorine), c3.8 ring The alkyl group may be optionally selected from the group consisting of <^_4, a halogen group (preferably fluorine) and an aryl group. In another embodiment, the invention relates to a compound of formula I, wherein C3-8 cycloalkyl-Co-ialkyl' wherein alkyl is optionally substituted with one or more atoms, preferably fluoro, C3-8 ring The alkyl group may be optionally selected from the group consisting of d_4, a halogen (preferably fluorine) and an aryl group. -40- 200951136 In another embodiment, the invention is directed to a compound of formula I, wherein Κ·8 is a C3-8 ring-based group - C〇.i. In another embodiment, the invention relates to a compound of formula I, wherein R8 is C3_8 cycloalkyl, the selectivity of which is selected from one or more independently selected from the group consisting of Cu4 alkyl, moieties (preferably fluorine) and aryl Substituent substitution. In another embodiment, the invention is directed to a compound of formula I, wherein Κ·8 is a C3-8 ring hospital. In another embodiment, the invention is directed to a compound of formula I, wherein R8 is aryl-Co-4 alkyl, wherein the alkyl group is optionally substituted with one or more halogen atoms, preferably fluoro. In another embodiment, the invention is directed to a compound of formula I, wherein R8 is aryl-Co.! alkyl. In another embodiment, the invention is directed to a compound of formula I, wherein r8 is aryl. In another embodiment, the invention is directed to a compound of formula I, wherein 1 is NH2, and 115 is H, halo or Ci. 2 alkyl. In another embodiment, the invention is directed to a compound of formula I, wherein

Ri爲NH2，及R5爲H、鹵素或CN，更佳爲H、氯或CN 〇在另一實施態樣中，本發明關於式I化合物，其中 L爲NH2，及R5爲Η或鹵寒，更佳爲Η或氯。在另一實施態樣中，本發明關於式I化合物，其中 Ri爲ΝΗ2，及R5爲鹵素或CN，更佳爲氯或CN。在另一實施態樣中，本發明關於式I化合物，其中 -41 - 200951136 R!爲NH2及R5爲Η。在另一實施態樣中’本發明關於式I化合物，其中 I爲NH2及R5爲鹵素。在另一實施態樣中’本發明關於式I化合物，其中 Ri爲NH2及Rs爲氯。在另一實施態樣中，本發明關於式I化合物，其中 Ri 爲 NH2 及 R5 爲 CN。在另一實施態樣中，本發明關於式I化合物，其中：Ri is NH2, and R5 is H, halogen or CN, more preferably H, chlorine or CN 〇 In another embodiment, the invention is directed to a compound of formula I wherein L is NH2 and R5 is hydrazine or halogenated, More preferably bismuth or chlorine. In another embodiment, the invention is directed to a compound of formula I, wherein Ri is ΝΗ2, and R5 is halo or CN, more preferably chloro or CN. In another embodiment, the invention is directed to a compound of formula I, wherein -41 - 200951136 R! is NH2 and R5 is deuterium. In another embodiment, the invention relates to compounds of formula I, wherein I is NH2 and R5 is halogen. In another embodiment, the invention is directed to a compound of formula I, wherein Ri is NH2 and Rs is chloro. In another embodiment, the invention is directed to a compound of formula I, wherein Ri is NH2 and R5 is CN. In another embodiment, the invention is directed to a compound of formula I, wherein:

Ri 爲 NH2 ; R5爲Η、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN ;及 R2及R3 —起與所連接之氮原子形成飽和雜環基，其可爲4-至7-員單環、7-至8-員橋接雙環或8_至！2-員稠合雙環’其中該雜環基可包含高至兩個N原子且不含任何其他雜原子’及可選擇性經一或多個獨立地選自Ci-4烷基及NRaRb之取代基取代，惟雜環基包含兩個 n原子且不經NRaRb基團取代’或者包含一個n原子且經一個 NRaRb基團取代。在另—實施態樣中，本發明關於式I化合物，其中：Ri is NH2; R5 is fluorene, halogen or CN, preferably halogen or CN, more preferably chlorine or CN; and R2 and R3 together form a saturated heterocyclic group with the nitrogen atom to which it is attached, which may be 4- to 7-member single ring, 7- to 8-member bridged double ring or 8_ to! 2-membered fused bicyclic ring 'wherein the heterocyclic group may contain up to two N atoms and free of any other hetero atom' and may be optionally substituted by one or more independently selected from Ci-4 alkyl and NRaRb The base is substituted, except that the heterocyclic group contains two n atoms and is not substituted by the NRaRb group ' or contains one n atom and is substituted with one NRaRb group. In another embodiment, the invention is directed to a compound of formula I, wherein:

Ri 爲 NH2 ; R5爲Η、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN ;及 R2及R3 —起與所連接之氮原子形成選自如下之飽和雜環基： -42- 200951136 (〇包含兩個N原子且不包任何其他雜原子之雜環基，其中該雜環基可選擇性經一或多個Ci4烷基取代；及 (ii)包個N原子且不包任何其他雜原子之雜環基，其中該雜環基經一個NRaRb基團取代且可選擇性經一或多個C!_4烷基取代；其中該雜環基（i)及（ii )可爲4-至7_員單環、7_ 至8-員橋接雙環或8_至i2_員稠合雙環。在另一實施態樣中’本發明關於式〗化合物，其中： Ri 爲 NH2 ;Ri is NH2; R5 is fluorene, halogen or CN, preferably halogen or CN, more preferably chlorine or CN; and R2 and R3 together with the nitrogen atom to which they are attached form a saturated heterocyclic group selected from: -42 - 200951136 (heterocyclic group containing two N atoms and not including any other hetero atom, wherein the heterocyclic group may be optionally substituted by one or more Ci4 alkyl groups; and (ii) a N atom is not included a heterocyclic group of any other hetero atom, wherein the heterocyclic group is substituted by an NRaRb group and may be optionally substituted by one or more C!-4 alkyl groups; wherein the heterocyclic groups (i) and (ii) may be 4- to 7_membered monocyclic, 7- to 8-membered bicyclic or 8- to i2-fused fused bicyclic ring. In another embodiment, the invention relates to a compound of the formula wherein: Ri is NH2;

Rs爲Η、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN ;及 R2爲Η或C^4烷基’及R3爲氮雜環丁烷基、吡咯啶基、哌啶基或氮雜環庚烷基’其可選擇性經一或多個Cl_4 烷基取代。在另一實施態樣中，本發明關於式I化合物，其中： Ri 爲 NH2 ;Rs is hydrazine, halogen or CN, preferably halogen or CN, more preferably chlorine or CN; and R2 is hydrazine or C^4 alkyl' and R3 is azetidinyl, pyrrolidinyl, piperidinyl Or azacycloheptyl' which may be optionally substituted by one or more Cl-4 alkyl groups. In another embodiment, the invention relates to a compound of formula I, wherein: Ri is NH2;

Rs爲Η、鹵素或CN，較佳爲鹵素或Cn，更佳爲氯或CN ;及 R2及R3 —起與所連接之氮原子形成選自（a)至（h )之飽和雜環基，其中Ra及Rb具有上文所述式I化合物中之意義，及Rc及Rd獨立地爲11或Ci_4院基。在另一實施態樣中’本發明關於式I化合物，其中： Ri 爲 NH2 ; R5爲Η、鹵素或CN，較佳爲鹵素或CN，更佳爲氯 -43- 200951136 或CN ;及 R2及R3 —起與所連接之氮原子形成選自（a)至（h )之飽和雜環基，及Ra、Rb、R。及Rd獨立地爲11或Cu 烷基，較佳地Ra、Rb ' Re及Rd獨立地爲Η或甲基。在另一實施態樣中，本發明關於式I化合物，其中： R !爲 Ν Η 2 ; R5爲Η、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN ;及 R2及R3 —起與所連接之氮原子形成選自（a) 、（b )、(c) 、 ( d) 、 ( f) 、（g)及（h)之飽和雜環基，其中Ra及Rb具有上文所述式I化合物中之意義，及Rc 及Rd獨立地爲Η或（^.4烷基。在另一實施態樣中’本發明關於式I化合物，其中：Rs is deuterium, halogen or CN, preferably halogen or Cn, more preferably chlorine or CN; and R2 and R3 together with the nitrogen atom to be bonded form a saturated heterocyclic group selected from (a) to (h), Wherein Ra and Rb have the meanings of the compounds of formula I above, and Rc and Rd are independently 11 or Ci_4. In another embodiment, the invention relates to a compound of formula I, wherein: Ri is NH2; R5 is deuterium, halogen or CN, preferably halogen or CN, more preferably chloro-43-200951136 or CN; and R2 and R3 together with the nitrogen atom to be bonded forms a saturated heterocyclic group selected from (a) to (h), and Ra, Rb, R. And Rd is independently 11 or Cu alkyl, preferably Ra, Rb 'Re and Rd are independently hydrazine or methyl. In another embodiment, the invention relates to a compound of formula I, wherein: R is Ν Η 2 ; R 5 is fluorene, halogen or CN, preferably halogen or CN, more preferably chlorine or CN; and R 2 and R 3 And a saturated heterocyclic group selected from the group consisting of (a), (b), (c), (d), (f), (g) and (h), wherein Ra and Rb have The meaning of the compounds of formula I as described herein, and Rc and Rd are independently oxime or (^.4 alkyl. In another embodiment, the invention relates to a compound of formula I, wherein:

Ri 爲 ΝΗ2 ; R5爲Η、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN ;及 R2及R3 —起與所連接之氮原子形成選自（a) 、( b )、（c) 、（d) 、（f) 、（g)及（h)之飽和雜環基，及Ra、Rb、R。及Rd獨立地爲H或Cm烷基，較佳地 Ra、Rb、Rc及Rd獨立地爲Η或甲基。在另一實施態樣中，本發明關於式I化合物，其中：Ri is ΝΗ2; R5 is fluorene, halogen or CN, preferably halogen or CN, more preferably chlorine or CN; and R2 and R3 together with the nitrogen atom to be bonded are selected from (a), (b), ( c), (d), (f), (g) and (h) saturated heterocyclic groups, and Ra, Rb, R. And Rd is independently H or Cm alkyl, preferably Ra, Rb, Rc and Rd are independently hydrazine or methyl. In another embodiment, the invention is directed to a compound of formula I, wherein:

Ri 爲 ΝΗ2 ; R5爲Η、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN ;及 -44 - 200951136 R2及R3 —起與所連接之氮原子形成選自（a) 、（b )、（e)及（f)之飽和雜環基，其中118及Rb具有上文所述式I化合物中之意義，及R。及Rd獨立地爲Η或（^.4 烷基。在另一實施態樣中，本發明關於式I化合物，其中： R!爲 ΝΗ2 ; R5爲Η、鹵素或CN，較佳爲鹵素或CN，更佳爲氯赢或CN ;及 Φ R2及R3—起與所連接之氮原子形成選自（a) 、（b )、（e)及（f)之飽和雜環基，及Ra、Rb、Re及Rd獨立地爲Η或C!-4烷基，較佳地Ra、Rb、Re及Rd獨立地爲Η或甲基》在另一實施態樣中，本發明關於式I化合物，其中： I 爲 ΝΗ2 ; R5爲Η、鹵素或CN，較佳爲鹵素或CN，更佳爲氯 φ 或CN ;及 R2及R3 —起與所連接之氮原子形成選自（a)及（b )之飽和雜環基’其中Ra及Rb具有上文所述式】化合物中之意義’及Re爲Η或Cm烷基，較佳地Re爲η。在另一實施態樣中，本發明關於式I化合物，其中：Ri is ΝΗ2; R5 is fluorene, halogen or CN, preferably halogen or CN, more preferably chlorine or CN; and -44 - 200951136 R2 and R3 together with the nitrogen atom to be bonded are selected from (a), ( The saturated heterocyclic group of b), (e) and (f) wherein 118 and Rb have the meanings of the compounds of formula I above, and R. And Rd is independently hydrazine or (^.4 alkyl. In another embodiment, the invention relates to a compound of formula I, wherein: R! is ΝΗ2; R5 is hydrazine, halogen or CN, preferably halo or CN More preferably, it is chlorine or CN; and Φ R2 and R3 together with the nitrogen atom to be bonded form a saturated heterocyclic group selected from (a), (b), (e) and (f), and Ra, Rb And Re and Rd are independently hydrazine or C!-4 alkyl, preferably Ra, Rb, Re and Rd are independently hydrazine or methyl. In another embodiment, the invention relates to a compound of formula I, wherein : I is ΝΗ2; R5 is fluorene, halogen or CN, preferably halogen or CN, more preferably chloro φ or CN; and R2 and R3 together with the nitrogen atom to be bonded are selected from (a) and (b) The saturated heterocyclic group 'wherein Ra and Rb have the meanings in the compound of the above formula' and Re is Η or Cm alkyl, preferably Re is η. In another embodiment, the invention relates to Compound I, wherein:

Ri 爲 ΝΗ2 ;Ri is ΝΗ2 ;

Rs爲Η、鹵素或CN’較佳爲鹵素或CN，更佳爲氯或CN ;及 R2及R3 —起與所連接之氮原子形成選自（a)及（b -45- 200951136 )之飽和雜環基，及Ra、Rb及R。獨立地爲Η或Cu烷基，較佳地Ra、Rb及Re獨立地爲Η或甲基，更佳地Ra 及Rb獨立地爲Η或甲基’及r。爲η，又更佳地113爲Η ，Rb爲甲基，及Rc爲Η。在另一實施態樣中’本發明關於式I化合物，其中： R!爲 ΝΗ2 ; R5爲Η、鹵素或CN’較佳爲鹵素或CN，更佳爲氯或CN ;及 R2及R3 —起與所連接之氮原子形成式（a)之飽和雜環基’其中Ra及Rb具有上文所述式I化合物中之意義，及Re爲烷基，及更佳地R。爲η。在另一實施態樣中，本發明關於式I化合物，其中：Rs is hydrazine, halogen or CN' is preferably halogen or CN, more preferably chlorine or CN; and R2 and R3 together with the nitrogen atom to be bonded form a saturation selected from (a) and (b -45- 200951136) Heterocyclic groups, and Ra, Rb and R. Independently, it is a hydrazine or a Cu alkyl group. Preferably, Ra, Rb and Re are independently hydrazine or methyl group, and more preferably Ra and Rb are independently hydrazine or methyl group and r. It is η, and more preferably 113 is Η, Rb is a methyl group, and Rc is Η. In another embodiment, the invention relates to a compound of formula I, wherein: R! is ΝΗ2; R5 is oxime, halogen or CN' is preferably halogen or CN, more preferably chlorine or CN; and R2 and R3 together The saturated heterocyclic group of formula (a) is formed with a nitrogen atom to be bonded, wherein Ra and Rb have the meanings of the compounds of formula I above, and Re is an alkyl group, and more preferably R. Is η. In another embodiment, the invention is directed to a compound of formula I, wherein:

Ri 爲 NH2 ; R5爲Η、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN ;及 R2及R3 —起與所連接之氮原子形成式（a)之飽和雜環基’其中Ra、Rb及Re獨立地爲η或Cm烷基，及較佳地Ra、Rb及R。獨立地爲Η或甲基，及更佳地Ra及Rb 獨立地爲Η或甲基，及R。爲η，又更佳地113爲H，Rb爲甲基及Re爲Η。在另一實施態樣中，本發明關於式I化合物，其中：Ri is NH2; R5 is deuterium, halogen or CN, preferably halogen or CN, more preferably chlorine or CN; and R2 and R3 together form a saturated heterocyclic group of formula (a) with the attached nitrogen atom. Ra, Rb and Re are independently η or Cm alkyl, and preferably Ra, Rb and R. Independently hydrazine or methyl, and more preferably Ra and Rb are independently hydrazine or methyl, and R. It is η, and more preferably 113 is H, Rb is a methyl group and Re is a hydrazine. In another embodiment, the invention is directed to a compound of formula I, wherein:

Ri 爲 ΝΗ2 ; R5爲Η、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN ;及 -46- 200951136 R2及R3 —起與所連接之氮原子形成式（b)之飽和雜環基，其中Ra及Rb具有上文所述式I化合物中之意義，及R。爲Η或Ci-4院基’及更佳地Re爲H。在另一實施態樣中，本發明關於式I化合物，其中：Ri is ΝΗ2; R5 is fluorene, halogen or CN, preferably halogen or CN, more preferably chlorine or CN; and -46- 200951136 R2 and R3 together form a saturated impurity of formula (b) with the attached nitrogen atom a cyclic group wherein Ra and Rb have the meanings of the compounds of formula I above, and R. It is a Η or Ci-4 yard base' and preferably Re is H. In another embodiment, the invention is directed to a compound of formula I, wherein:

Ri 爲 NH2 ; R5爲Η、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN ;及 φ R2及R3 —起與所連接之氮原子形成式（b)之飽和雜環基，其中Ra、Rb及Re獨立地爲11或Cm烷基，及較佳地Ra、Rb及R。獨立地爲Η或甲基，及更佳地Ra及 Rb獨立地爲Η或甲基，及11。爲H，又更佳地Ra爲H，Rb 爲甲基及Rc爲Η。在另一實施態樣中，本發明關於式I化合物，其中：Ri is NH2; R5 is deuterium, halogen or CN, preferably halogen or CN, more preferably chlorine or CN; and φ R2 and R3 together form a saturated heterocyclic group of formula (b) with the nitrogen atom to be bonded, Wherein Ra, Rb and Re are independently 11 or Cm alkyl, and preferably Ra, Rb and R. Independently hydrazine or methyl, and more preferably Ra and Rb are independently hydrazine or methyl, and 11. It is H, and more preferably Ra is H, Rb is a methyl group and Rc is a hydrazine. In another embodiment, the invention is directed to a compound of formula I, wherein:

Ri 爲 ΝΗ2 ; 爲鹵素，更佳爲氯；及 φ R2及R3 —起與所連接之氮原子形成飽和雜環基，其可爲4-至7_員單環、7_至8_員橋接雙環或8_至12_員稠合雙環’其中該雜環基可包含高至兩個N原子且不含任何其他雜原子，及可選擇性經一或多個獨立地選自d ·4烷基及NRaRb之取代基取代，惟雜環基包含兩個n原子且不經NRaR_b基團取代，或包含—個n原子且經一個NRaRb 基團取代。在另一實施態樣中，本發明關於式I化合物，其中： R1 爲 NH2 ; -47- 200951136Ri is ΝΗ2; is halogen, more preferably chlorine; and φ R2 and R3 together form a saturated heterocyclic group with the nitrogen atom to be bonded, which can be 4- to 7-membered single-ring, 7- to 8-member bridge Bicyclic or 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 independently selected from d. 4 alkanes by one or more The substituent is substituted with a substituent of NRaRb, except that the heterocyclic group contains two n atoms and is not substituted by the NRaRb group, or contains one n atom and is substituted with one NRaRb group. In another embodiment, the invention is directed to a compound of formula I, wherein: R1 is NH2; -47- 200951136

Rs爲鹵素，更佳爲氯；及 R·2及R3 —起與所連接之氮原子形成選自如下之飽和雜環基： (1)包含兩個N原子且不含任何其他雜原子之雜環基，其中該雜環基可選擇性經一或多個烷基取代；及 (U)包含一個N原子且不含任何其他雜原子之雜環基，其中該雜環基經一個NRaRb基團取代及可選擇性經一或多個烷基取代；其中該雜環基（i)及（ii)可爲4-至7·員單環、7-至8-員橋接雙環或8_至12-員稠合雙環。在另一實施態樣中，本發明關於式I化合物，其中：Rs is a halogen, more preferably chlorine; and R.2 and R3 together with a nitrogen atom to be bonded form a saturated heterocyclic group selected from the group consisting of: (1) a hetero atom containing two N atoms and no other hetero atom a cyclic group wherein the heterocyclic group is optionally substituted with one or more alkyl groups; and (U) a heterocyclic group containing one N atom and no other hetero atom, wherein the heterocyclic group is via an NRaRb group Substituted and optionally substituted by one or more alkyl groups; wherein the heterocyclic groups (i) and (ii) may be 4- to 7-membered monocyclic, 7- to 8-membered bridged double rings or 8 to 12 - Member fused double ring. In another embodiment, the invention is directed to a compound of formula I, wherein:

Ri 爲 NH2 ; R5爲鹵素，更佳爲氯；及 R2爲Η或q·4烷基，及R3爲氮雜環丁烷基、吡咯啶基、哌啶基或氮雜環庚烷基，其可選擇性經—或多個Cl_4 烷基取代。在另一實施態樣中’本發明關於式I化合物，其中：Ri is NH2; R5 is halogen, more preferably chlorine; and R2 is hydrazine or q.4 alkyl, and R3 is azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, It may be optionally substituted with - or a plurality of Cl_4 alkyl groups. In another embodiment, the invention relates to a compound of formula I, wherein:

Ri 爲 NH2 ; R5爲鹵素，更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自（a)至（h )之飽和雜環基’其中113及Rb具有上文所述式！化合物中之意義，及Rc及Rd獨立地爲Η或¢:^4烷基。在另一實施態樣中’本發明關於式I化合物，其中：Ri is NH2; R5 is halogen, more preferably chlorine; and R2 and R3 together with a nitrogen atom to be bonded form a saturated heterocyclic group selected from (a) to (h) wherein 113 and Rb have the above formula! The meaning of the compound, and Rc and Rd are independently Η or ¢: ^4 alkyl. In another embodiment, the invention relates to a compound of formula I, wherein:

Ri 爲 ΝΗ2 ; 200951136 R5爲鹵素，更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自（a)至（h )之飽和雜環基，及Ra、Rb、Re及Rd獨立地爲Η或Ci-4 烷基，較佳地Ra、Rb、Rc及Rd獨立地爲Η或甲基。在另一實施態樣中，本發明關於式I化合物，其中： R 1 爲 Ν Η 2 ; R5爲鹵素，更佳爲氯；及 φ 尺2及R3 —起與所連接之氮原子形成選自（a) 、（b )、（c) 、（d) 、（f) 、（g)及（h)之飽和雜環基，其中Ra及Rb具有上文所述式I化合物中之意義，及Rc 及Rd獨立地爲11或Cu烷基。在另一實施態樣中，本發明關於式I化合物，其中：Ri is ΝΗ2; 200951136 R5 is halogen, more preferably chlorine; and R2 and R3 together with the nitrogen atom to be bonded form a saturated heterocyclic group selected from (a) to (h), and Ra, Rb, Re and Rd Independently hydrazine or Ci-4 alkyl, preferably Ra, Rb, Rc and Rd are independently hydrazine or methyl. In another embodiment, the invention relates to a compound of formula I, wherein: R 1 is Ν Η 2 ; R 5 is halogen, more preferably chloro; and φ 尺 2 and R 3 together with the nitrogen atom to which they are attached are selected from (a), (b), (c), (d), (f), (g) and (h), wherein Ra and Rb have the meanings of the compounds of formula I above, and Rc and Rd are independently 11 or Cu alkyl. In another embodiment, the invention is directed to a compound of formula I, wherein:

Ri 爲 NH2 ; R5爲鹵素，更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自（a) 、（b φ ) 、（Ο 、（d) 、（f) 、（g)及（h)之飽和雜環基 ’及Ra、Rb、Rc及Rd獨立地爲H或Ci-4烷基，較佳地 Ra ^ Rb、Rc及Rd獨立地爲Η或甲基。在另一實施態樣中，本發明關於式I化合物，其中： R1 舄 NH2 ; 舄鹵素，更佳爲氯；及尺2及R3 —起與所連接之氮原子形成選自（a) 、（b )、（e)及（f)之飽和雜環基，其中Ra&Rb具有上文所述式I化合物中之意義，及R。及、獨立地爲Η或C!-4 -49- 200951136 烷基。在另一實施態樣中，本發明關於式I化合物，其中： R1 爲 N Η 2 ; R5爲鹵素，更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自（a) 、（b )、（e )及（f)之飽和雜環基，及Ra、Rb、Re及Rd獨立地爲Η或（^-4烷基，較佳地Ra、Rb、Re及Rd獨立地爲Η或甲基。在另一實施態樣中，本發明關於式I化合物，其中：Ri is NH2; R5 is halogen, more preferably chlorine; and R2 and R3 together with the nitrogen atom to be bonded are selected from (a), (b φ ), (Ο, (d), (f), (g And (h) a saturated heterocyclic group ' and Ra, Rb, Rc and Rd are independently H or a Ci-4 alkyl group, preferably Ra^Rb, Rc and Rd are independently a hydrazine or a methyl group. In one embodiment, the invention is directed to a compound of formula I, wherein: R1 舄NH2; oxime halogen, more preferably chloro; and quaternary 2 and R3 together with the attached nitrogen atom are selected from (a), (b) And a saturated heterocyclic group of (e) and (f), wherein Ra&Rb has the meaning of the compound of formula I above, and R. and, independently, Η or C!-4 -49- 200951136 alkyl In another embodiment, the invention relates to a compound of formula I, wherein: R1 is N Η 2 ; R 5 is halogen, more preferably chloro; and R 2 and R 3 together with the nitrogen atom to which they are attached are selected from (a And the saturated heterocyclic group of (b), (e) and (f), and Ra, Rb, Re and Rd are independently Η or (^-4 alkyl, preferably Ra, Rb, Re and Rd are independently The ground is hydrazine or methyl. In another embodiment, the invention relates to the formula I Object, where:

Ri 爲 ΝΗ2 ; R5爲鹵素，更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自（a)及（b )之飽和雜環基，其中Ra及Rb具有上文所述式I化合物中之意義，及Rc爲Η或Cm烷基，較佳地Re爲Η。在另一實施態樣中，本發明關於式I化合物，其中： R1 爲 Ν Η 2 ; R5爲鹵素，更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自（a)及（b )之飽和雜環基，及Ra、Rb及Re獨立地爲Η或C,.4烷基，較佳地Ra、Rb及R。獨立地爲Η或甲基，更佳地Ra 及Rb獨立地爲Η或甲基，及R。爲η，又更佳地1^爲Η ，Rb爲甲基及爲Η。在另一實施態樣中，本發明關於式I化合物，其中： R!爲 ΝΗ2 ; 200951136Ri is ΝΗ2; R5 is halogen, more preferably chlorine; and R2 and R3 together with the nitrogen atom to be bonded form a saturated heterocyclic group selected from (a) and (b), wherein Ra and Rb have the above The meaning of the compound of formula I, and Rc is hydrazine or Cm alkyl, preferably Re is hydrazine. In another embodiment, the invention relates to a compound of formula I, wherein: R1 is Ν Η 2 ; R 5 is halogen, more preferably chloro; and R 2 and R 3 together with the attached nitrogen atom are selected from (a) And the saturated heterocyclic group of (b), and Ra, Rb and Re are independently hydrazine or C, .4 alkyl, preferably Ra, Rb and R. Independently hydrazine or methyl, more preferably Ra and Rb are independently hydrazine or methyl, and R. It is η, and more preferably 1^ is Η, and Rb is a methyl group and a hydrazine. In another embodiment, the invention is directed to a compound of formula I, wherein: R! is ΝΗ2; 200951136

Rs馬鹵素，更佳爲氯；及 R2及R3 —起與所連接之氮原子形成式（a)之飽和雜環基’其中Ra及Rb具有上文所述式I化合物中之意義’ 及R。爲Η或Cl_4烷基，及更佳地Re爲η。在另一實施態樣中，本發明關於式I化合物，其中： Ri 舄 ΝΗ2 ;Rs horse halogen, more preferably chlorine; and R2 and R3 together with the nitrogen atom to be bonded form a saturated heterocyclic group of formula (a) wherein Ra and Rb have the meanings of the compounds of formula I above and R . It is Η or Cl_4 alkyl, and more preferably Re is η. In another embodiment, the invention is directed to a compound of formula I, wherein: Ri 舄 ΝΗ 2 ;

Rs爲鹵素，更佳爲氯；及 Φ R2及r3 —起與所連接之氮原子形成式（a)之飽和雜環基’其中Ra、Rb及R。獨立地爲山-4烷基，及較佳地Ra ’ Rb及Re獨立地爲Η或甲基，及更佳地Ra及Rb 獨立地爲Η或甲基及Re爲Η，又更佳地Ra爲H，Rb爲甲基及R。爲Η。在另一實施態樣中，本發明關於式I化合物，其中： Ri 爲 ΝΗ2 ; 尺5爲_素，更佳爲氯；及 ❷ R2及R3 —起與所連接之氮原子形成式（b)之飽和雜環基’其中Ra及Rb具有上文所述式I化合物中之意義，及R。爲Η或Ci-4烷基，及更佳地R。爲Η。在另一實施態樣中，本發明關於式I化合物，其中： Ri 爲 ΝΗ2 ; R5爲鹵素，更佳爲氯；及尺2及R3 —起與所連接之氮原子形成式（b)之飽和雜環基’其中Ra、Rb及Rc獨立地爲11或Cm烷基，及較佳地Ra、Rb及Re獨立地爲Η或甲基，及更佳地Ra及 -51 - 200951136Rs is a halogen, more preferably chlorine; and Φ R2 and r3 together form a saturated heterocyclic ring of formula (a) with a nitrogen atom to be bonded, wherein Ra, Rb and R. Independently being a mountain-4 alkyl group, and preferably Ra 'Rb and Re are independently hydrazine or methyl group, and more preferably Ra and Rb are independently hydrazine or methyl and Re is hydrazine, and more preferably Ra For H, Rb is methyl and R. Why? In another embodiment, the invention relates to a compound of formula I, wherein: Ri is ΝΗ2; 尺5 is _, more preferably chloro; and ❷ R2 and R3 together form a formula (b) with the attached nitrogen atom Saturated heterocyclic group 'wherein Ra and Rb have the meanings of the compounds of formula I above, and R. It is a hydrazine or a Ci-4 alkyl group, and more preferably R. Why? In another embodiment, the invention is directed to a compound of formula I, wherein: Ri is ΝΗ2; R5 is halogen, more preferably chloro; and ampule 2 and R3 together form a saturation of formula (b) with the attached nitrogen atom. Heterocyclyl' wherein Ra, Rb and Rc are independently 11 or Cm alkyl, and preferably Ra, Rb and Re are independently hydrazine or methyl, and more preferably Ra and -51 - 200951136

Rb獨立地爲Η或甲基及11。爲Η，又更佳地1^爲H，Rb 爲甲基及R。爲Η。在另一實施態樣中，本發明關於式I化合物，其中： R!爲 ΝΗ2 ; R·4爲Ci_8烷基或Cm環烷基_C().6烷基，較佳爲Cl_8 院基或Cl8環烷基-(：〇_!烷基，更佳爲C2_8烷基或C3 8環院基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代’ c：3_8環烷基可選擇性經—或多個獨立地選自Ci 4烷基、鹵素（較佳氟）及芳基之取代基取代；又更佳地r4 爲乙基、異丙基、第三丁基或環丙基； R5爲H、鹵素或CN’較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成飽和雜環基，其可爲4-至7-員單環、7-至8-員橋接雙環或8_至12_員稠合雙環，其中該雜環基可包含高至兩個N原子且不含任何其他雜原子’及可選擇性經—或多個獨立地選自Ci4烷基及NRaRb之取代基取代，惟雜環基包含兩個n原子且不經NRaRb基團取代，或包含—個N原子且經一個NRaRb 基團取代。在另一實施態樣中’本發明關於式I化合物，其中：Rb is independently hydrazine or methyl and 11. Preferably, 1^ is H, and Rb is methyl and R. Why? In another embodiment, the invention relates to a compound of formula I, wherein: R! is ΝΗ2; R·4 is Ci-8 alkyl or Cm cycloalkyl-C().6 alkyl, preferably Cl_8 or Cl8 cycloalkyl-(:〇_!alkyl, more preferably C2_8 alkyl or C3 8 ring; wherein the alkyl group may be optionally substituted by one or more halogen atoms (preferably fluorine) 'c:3_8 ring The alkyl group may be optionally substituted with or a plurality of substituents independently selected from the group consisting of Ci 4 alkyl, halogen (preferably fluorine) and aryl; more preferably, r4 is ethyl, isopropyl, butylene Or cyclopropyl; R5 is H, halogen or CN' is preferably halogen or CN, more preferably chlorine or CN, more preferably chlorine; and R2 and R3 together form a saturated heterocyclic group with the nitrogen atom to which they are attached , which may be a 4- to 7-membered monocyclic, 7- to 8-membered bicyclic or 8- to 12-membered fused bicyclic ring wherein the heterocyclic group may contain up to two N atoms and does not contain any other a hetero atom 'and optionally substituted with - or a plurality of substituents independently selected from the group consisting of Ci4 alkyl and NRaRb, except that the heterocyclic group contains two n atoms and is not substituted by the NRaRb group, or contains one N atom and Substituted by a NRaRb group. In another embodiment, the invention relates to a compound of formula I, wherein:

Ri 爲 NH2 ; 尺4爲Cu烷基或C3_8環烷基-Co-6烷基，較佳爲Ci-8 院基或c：3_8環烷基—cw烷基’更佳爲c2 8烷基或C3 8環院基；其中烷基可選擇性經一或多個鹵素原子（較佳氟） -52- 200951136 取代，Cs-8環烷基可選擇性經一或多個獨立地選自Cl 4烷基、鹵素（較佳氟）及芳基之取代基取代；又更佳地r4 爲乙基、異丙基、第三丁基或環丙基； R5爲H、鹵素或CN，較佳爲鹵素或Cn，更佳爲氯或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自如下之飽和雜環基： (i)包含兩個N原子且不含任何其他雜原子之雜環基，其中該雜環基可選擇性經一或多個Ci.4烷基取代；及 (Π)包含一個N原子且不含任何其他雜原子之雜環基，其中該雜環基經一個NRaRb基團取代及可選擇性經一或多個（^_4烷基取代；其中該雜環基（i)及（ii)可爲4_至7 -員單環、7-至8-員橋接雙環或8-至12-員稠合雙環。在另一實施態樣中，本發明關於式I化合物，其中：Ri is NH2; Rule 4 is Cu alkyl or C3_8 cycloalkyl-Co-6 alkyl, preferably Ci-8 or C:3-8 cycloalkyl-cw alkyl is more preferably c2 8 alkyl or C3 8 ring-based; wherein the alkyl group is optionally substituted by one or more halogen atoms (preferably fluorine) -52- 200951136, and the Cs-8 cycloalkyl group may be optionally selected from one or more independently selected from Cl 4 Substituted with a substituent of an alkyl group, a halogen (preferably fluorine) and an aryl group; more preferably, r4 is an ethyl group, an isopropyl group, a tert-butyl group or a cyclopropyl group; and R5 is H, halogen or CN, preferably Halogen or Cn, more preferably chlorine or CN, more preferably chlorine; and R2 and R3 together with a nitrogen atom to be bonded form a saturated heterocyclic group selected from the group consisting of: (i) containing two N atoms and not containing a heterocyclic group of any other hetero atom, wherein the heterocyclic group is optionally substituted by one or more Ci.4 alkyl groups; and (Π) a heterocyclic group containing one N atom and no other hetero atom, wherein The heterocyclic group is substituted by an NRaRb group and optionally substituted by one or more (^-4 alkyl groups; wherein the heterocyclic groups (i) and (ii) may be 4_ to 7-membered monocyclic, 7 - to 8-member bridged double ring or 8- to 12-member fused The ring In another aspect of the embodiment, the present invention relates to compounds of formula I, wherein:

Ri 爲 NH2 ; R4爲Cy烷基或C3.8環烷基-C〇_6烷基，較佳爲Cl 8 烷基或C3·8環烷基-Co.!烷基，更佳爲C2_8烷基或c3_8_ 烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代’ C3-8環烷基可選擇性經一或多個獨立地選自Cl4^ 基、鹵素（較佳氟）及芳基之取代基取代；又更佳地爲乙基、異丙基、第三丁基或環丙基； R5爲H、鹵素或CN，較佳爲鹵素或CN，更佳爲氣或CN ’又更佳爲氯；及 -53- 200951136 R2爲11或烷基，及r3爲氮雜環丁烷基、吡咯啶基、哌啶基或氮雜環庚烷基，其可選擇性經一或多個Ci.4 烷基取代。在另一實施態樣中，本發明關於式I化合物，其中：Ri is NH2; R4 is a Cy alkyl group or a C3.8 cycloalkyl-C〇_6 alkyl group, preferably a C8 alkyl group or a C3.8 cycloalkyl-Co.! alkyl group, more preferably a C2_8 alkane. Or a c3_8_alkyl group; wherein the alkyl group is optionally substituted by one or more halogen atoms (preferably fluorine), the 'C3-8 cycloalkyl group is optionally optionally one or more selected from the group consisting of Cl4^, halogen ( Substituted with a preferred fluoro) and aryl substituent; more preferably ethyl, isopropyl, tert-butyl or cyclopropyl; R5 is H, halogen or CN, preferably halogen or CN, more preferably Or gas is more preferably chlorine; and -53- 200951136 R2 is 11 or alkyl, and r3 is azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, which Optionally substituted with one or more Ci.4 alkyl groups. In another embodiment, the invention is directed to a compound of formula I, wherein:

Ri 爲 NH2 ; R4爲Cu烷基或C3-8環烷基-Cq.6烷基，較佳爲Cl_8 烷基或C3_8環烷基-CG_i烷基’更佳爲C2-8烷基或（：3.8環烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代’ C3-8環院基可選擇性經一或多個獨立地選自c!-4院基、鹵素（較佳氟）及芳基之取代基取代；又更佳地R4 爲乙基、異丙基、第三丁基或環丙基； R5爲H、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自（a)至（h )之飽和雜環基，其中Ra及Rb具有上文所述式I化合物中之意義，及及Rd獨立地爲11或Cu烷基。在另一實施態樣中’本發明關於式I化合物，其中：Ri is NH2; R4 is Cu alkyl or C3-8 cycloalkyl-Cq.6 alkyl, preferably Cl-8 alkyl or C3-8 cycloalkyl-CG_i alkyl is more preferably C2-8 alkyl or (: a 3.8 cycloalkyl group; wherein the alkyl group is optionally substituted with one or more halogen atoms (preferably fluorine), the 'C3-8 ring-based group may be optionally selected from one or more independently selected from the c!-4 yard, Halogen (preferably fluorine) and substituents of aryl are substituted; more preferably R4 is ethyl, isopropyl, tert-butyl or cyclopropyl; R5 is H, halogen or CN, preferably halogen or CN More preferably, it is chlorine or CN, and more preferably chlorine; and R2 and R3 together with the nitrogen atom to be bonded form a saturated heterocyclic group selected from (a) to (h), wherein Ra and Rb have the above The meaning of the compounds of formula I, and Rd is independently 11 or Cu alkyl. In another embodiment, the invention relates to compounds of formula I, wherein:

Ri 爲 NH2 ; R4爲Ci.8院基或C3.8環院基- CQ.6院基，較佳爲Ci-8 嫁基或C3·8環烷基- Cq^烷基，更佳爲C2_8烷基或（：3_8環嫁基；其中院基可選擇性經一或多個鹵素原子（較佳氟）取代’ C3.8環烷基可選擇性經一或多個獨立地選自Ci 4烷基、鹵素（較佳氟）及芳基之取代基取代；又更佳地R4 爲乙基、異丙基、第三丁基或環丙基； -54- 200951136 R5爲Η、鹵素或CN，較佳爲鹵素或cN，更佳爲氯或CN，又更佳爲氯；及 R2及R·3 —起與所連接之氮原子形成選自（a)至（h )之飽和雜環基’及Ra、Rb、Rc及、獨立地爲η或C1-4 垸基，較佳地Ra、Rb、Rc及Rd獨立地爲Η或甲基。在另一實施態樣中’本發明關於式I化合物，其中： R1 爲 Ν Η 2 ; R·4爲Ci.8院基或C3·8環院基- CG_6院基，較佳爲Ci·8 烷基或C3.8環烷基-Cm烷基，更佳爲c2.8院基或C3·8環烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代，C3_8環院基可選擇性經一或多個獨立地選自Cl-4院基、鹵素（較佳氟）及芳基之取代基取代；又更佳地R4 爲乙基、異丙基、第三丁基或環丙基； R·5爲H、鹵素或CN’較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自（a) 、（b )、（c) 、（d) 、（f) 、（g)及（h)之飽和雜環基 ’其中Ra及Rb具有上文所述式I化合物中之意義，及Rc 及Rd獨立地爲Η或Ci-4烷基。在另一實施態樣中’本發明關於式I化合物，其中：Ri is NH2; R4 is Ci.8 yard base or C3.8 ring yard base - CQ.6 yard base, preferably Ci-8 graft base or C3·8 cycloalkyl-Cq^ alkyl group, more preferably C2_8 An alkyl or (: 3-8 ring-graft group; wherein the pendant group is optionally substituted by one or more halogen atoms (preferably fluorine). The 'C3.8 cycloalkyl group is optionally independently selected from Ci 4 by one or more Substituted with a substituent of an alkyl group, a halogen (preferably fluorine) and an aryl group; more preferably, R4 is an ethyl group, an isopropyl group, a tert-butyl group or a cyclopropyl group; -54- 200951136 R5 is an anthracene, a halogen or a CN Preferably, it is halogen or cN, more preferably chlorine or CN, and more preferably chlorine; and R2 and R.3 together with the nitrogen atom to be bonded form a saturated heterocyclic group selected from (a) to (h) And Ra, Rb, Rc and, independently, η or C1-4 fluorenyl, preferably Ra, Rb, Rc and Rd are independently hydrazine or methyl. In another embodiment, the invention relates to Compound I, wherein: R1 is Ν Η 2 ; R·4 is Ci.8 or C3·8 ring-based CG_6, preferably Ci·8 alkyl or C3.8 cycloalkyl-Cm More preferably, it is a c2.8 or a C3·8 cycloalkyl group; wherein the alkyl group may be selectively passed through one or more halogen atoms (preferably Alternatively, the C3_8 ring may be optionally substituted with one or more substituents independently selected from the group consisting of Cl-4, halogen (preferably fluorine) and aryl; more preferably, R4 is ethyl or isopropyl. Or a tributyl or cyclopropyl group; R.5 is H, halogen or CN' is preferably halogen or CN, more preferably chlorine or CN, more preferably chlorine; and R2 and R3 are linked to The nitrogen atom forms a saturated heterocyclic group selected from (a), (b), (c), (d), (f), (g), and (h) wherein Ra and Rb have the formula I described above The meaning of the compound, and Rc and Rd are independently hydrazine or Ci-4 alkyl. In another embodiment, the invention relates to a compound of formula I, wherein:

Ri 爲 NH2 ; R4爲Ci-8院基或C3-8環院基- C〇.6垸基，較佳爲C1-8 烷基或C3-8環烷基-Cm烷基，更佳爲c2_8烷基或（^^環烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟） -55- 200951136 取代，c3-8環烷基可選擇性經一或多個獨立地選自Cu烷基、鹵素（較佳氟）及芳基之取代基取代；又更佳地R4 爲乙基、異丙基、第三丁基或環丙基； 115爲H、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自（a) 、（b )、（c ) 、（ d ) 、（ f) 、（ g )及（h )之飽和雜環基，及113、111>、尺。及1^獨立地爲11或€：丨_4烷基，較佳地 Ra、Rb、及Rd獨立地爲Η或甲基。在另一實施態樣中，本發明關於式I化合物，其中： R i 爲 Ν Η 2 ; 尺4爲Ci.8烷基或C3.8環烷基-CQ.6烷基，較佳爲Cm 烷基或C3_8環烷基-Co.!烷基，更佳爲C2_8烷基或C3-8環院基；其中院基可選擇性經一或多個_素原子（較佳氟）Ri is NH2; R4 is Ci-8 or C3-8 ring-based - C〇.6 fluorenyl, preferably C1-8 alkyl or C3-8 cycloalkyl-Cm alkyl, more preferably c2_8 An alkyl group or a cycloalkyl group; wherein the alkyl group is optionally substituted by one or more halogen atoms (preferably fluorine) -55- 200951136, and the c3-8 cycloalkyl group may be optionally independently or one or more independently Substituted with a substituent selected from the group consisting of Cu alkyl, halogen (preferably fluorine) and aryl; more preferably R4 is ethyl, isopropyl, tert-butyl or cyclopropyl; 115 is H, halogen or CN, Preferably, it is halogen or CN, more preferably chlorine or CN, and more preferably chlorine; and R2 and R3 together with the nitrogen atom to be bonded are selected from (a), (b), (c), (d) And (f), (g) and (h) a saturated heterocyclic group, and 113, 111 >, a ruler, and 1^ independently of 11 or €: 丨_4 alkyl, preferably Ra, Rb, and Rd is independently hydrazine or methyl. In another embodiment, the invention relates to a compound of formula I, wherein: R i is Ν Η 2 ; 尺 4 is Ci.8 alkyl or C3.8 cycloalkyl-CQ .6 alkyl, preferably Cm alkyl or C3_8 cycloalkyl-Co.! alkyl, more preferably C2-8 alkyl or C3-8 ring courtyard; The base may be selectively passed through one or more atoms (preferably fluorine)

取代，c3.8環烷基可選擇性經一或多個獨立地選自Ci-4烷基、鹵素（較佳氟）及芳基之取代基取代；又更佳地R4 Q 爲乙基、異丙基、第三丁基或環丙基； R5爲H、鹵素或CN，較佳爲齒素或CN，更佳爲氯或CN，又更佳爲氯；及 R2及Κ·3 —起與所連接之氮原子形成選自（a) 、（b )、（e)及（f)之飽和雜環基，其中Ra及Rb具有上文所述式I化合物中之意義，及Re及Rd獨立地爲11或烷基。在另一實施態樣中，本發明關於式I化合物，其中： -56- 200951136Substituting, the c3.8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from the group consisting of Ci-4 alkyl, halogen (preferably fluorine) and aryl; more preferably, R4 Q is ethyl, Isopropyl, tert-butyl or cyclopropyl; R5 is H, halogen or CN, preferably dentate or CN, more preferably chlorine or CN, more preferably chlorine; and R2 and Κ·3 And a saturated heterocyclic group selected from (a), (b), (e) and (f), wherein Ra and Rb have the meanings of the compound of formula I above, and Re and Rd Independently 11 or alkyl. In another embodiment, the invention is directed to a compound of formula I, wherein: -56- 200951136

Ri 爲 NH2 ; R·4爲Ci.8院基或C3_8環院基- C〇_6院基，較佳爲Ci.8 院基或C3_8環院基- Cq.i院基，更佳爲C2_8院基或C3.8環院基；其中院基可選擇性經一或多個鹵素原子（較佳氟）取代，c3-8環烷基可選擇性經一或多個獨立地選自Cl.4烷基、鹵素（較佳氟）及芳基之取代基取代；又更佳地R4 爲乙基、異丙基、第三丁基或環丙基；Ri is NH2; R·4 is Ci.8 yard base or C3_8 ring yard base - C〇_6 yard base, preferably Ci.8 yard base or C3_8 ring yard base - Cq.i yard base, more preferably C2_8 a hospital base or a C3.8 ring hospital base; wherein the courtyard group is optionally substituted with one or more halogen atoms (preferably fluorine), and the c3-8 cycloalkyl group may be optionally selected from one or more independently selected from Cl. Substituted with a substituent of 4 alkyl, halogen (preferably fluorine) and aryl; more preferably R4 is ethyl, isopropyl, tert-butyl or cyclopropyl;

Rs爲Η、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自（a) 、（b )、（e)及（f)之飽和雜環基，及113、1111、11。及11<)獨立地爲11或Cu烷基，較佳地Ra、Rb、Re及Rd獨立地爲Η或甲基。在另一實施態樣中，本發明關於式I化合物，其中：Rs is deuterium, halogen or CN, preferably halogen or CN, more preferably chlorine or CN, and more preferably chlorine; and R2 and R3 together with the nitrogen atom to be bonded are selected from (a), (b) And saturated heterocyclic groups of (e) and (f), and 113, 1111, and 11. And 11 <) independently of 11 or Cu alkyl group, preferably Ra, Rb, Re and Rd are independently fluorene or methyl. In another embodiment, the invention is directed to a compound of formula I, wherein:

Ri 爲 ΝΗ2 ; R4爲Ci.g院基或C3-8環院基- C〇-6院基，較佳爲Ci-8 烷基或C3-8環烷基-Cm烷基，更佳爲C2_8烷基或C3-8環烷基：其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代，C3-8環烷基可選擇性經一或多個獨立地選自Cl.4烷基、鹵素（較佳氟）及芳基之取代基取代；又更佳地R4 爲乙基、異丙基、第三丁基或環丙基； R5爲H、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自（a)及（b -57- 200951136 )之飽和雜環基，其中Ra及Rb具有上文所述式I化合物中之意義，及Re爲11或Ci-4烷基’較佳地R。爲Η。在另一實施態樣中，本發明關於式I化合物，其中： R!爲 ΝΗ2 ; R4爲Cu烷基或c3.8環烷基-Cfl-6烷基，較佳爲Cm 烷基或c3_8環烷基-Cm烷基，更佳爲C2_s烷基或（：3_8環烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代，C3_8環烷基可選擇性經一或多個獨立地選自C! -4烷基、鹵素（較佳氟）及芳基之取代基取代；又更佳地R4 爲乙基、異丙基、第三丁基或環丙基； R5爲H、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自（a)及（b )之飽和雜環基，及Ra、Rb及Re獨立地爲11或Cm烷基’較佳地Ra、Rb及獨立地爲Η或甲基，更佳地Ra 及Rb獨立地爲Η或甲基，及Re爲Η，又更佳地113爲Η ，Rb爲甲基，及Rc爲Η。在另一實施態樣中，本發明關於式I化合物，其中： R!爲 ΝΗ2 ; 尺4爲Ci-8烷基或C3_8環烷基-CQ.6烷基，較佳爲C" 烷基或C3.8環烷基-(：〇_!烷基，更佳爲c2.8烷基或C3-8環烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代’ c3_8環烷基可選擇性經一或多個獨立地選自Cl4烷基、鹵素（較佳氟）及芳基之取代基取代；又更佳地r4 -58- 200951136 爲乙基、異丙基、第二丁基或環丙基； R5爲H、鹵素或CN，較佳爲鹵素或CN’更佳爲氯或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成式（a)之飽和雜環基，其中Ra及Rb具有上文所述式I化合物中之意義’ 及R。爲Η或Cm烷基，及更佳地R。爲Η。在另一實施態樣中，本發明關於式I化合物，其中：Ri is ΝΗ2; R4 is Ci.g or C3-8 ring-based - C〇-6, preferably Ci-8 alkyl or C3-8 cycloalkyl-Cm alkyl, more preferably C2_8 An alkyl group or a C3-8 cycloalkyl group: wherein the alkyl group is optionally substituted by one or more halogen atoms (preferably fluorine), and the C3-8 cycloalkyl group may be optionally selected from one or more independently selected from Cl. Substituted with a substituent of 4 alkyl, halogen (preferably fluorine) and aryl; more preferably R4 is ethyl, isopropyl, tert-butyl or cyclopropyl; R5 is H, halogen or CN, preferably a halogen or CN, more preferably chlorine or CN, more preferably chlorine; and R2 and R3 together with a nitrogen atom to be bonded form a saturated heterocyclic group selected from (a) and (b-57-200951136), Wherein Ra and Rb have the meanings as defined above for the compound of formula I, and Re is 11 or Ci-4 alkyl' preferably R. Why? In another embodiment, the invention relates to a compound of formula I, wherein: R! is ΝΗ2; R4 is Cu alkyl or c3.8 cycloalkyl-Cfl-6 alkyl, preferably Cm alkyl or c3-8 ring An alkyl-Cm alkyl group, more preferably a C2_s alkyl group or a (:3-8 cycloalkyl group; wherein the alkyl group may be optionally substituted by one or more halogen atoms (preferably fluorine), and the C3_8 cycloalkyl group may be selectively subjected to one Or a plurality of substituents independently selected from C! -4 alkyl, halogen (preferably fluorine) and aryl; more preferably R4 is ethyl, isopropyl, tert-butyl or cyclopropyl; R5 is H, halogen or CN, preferably halogen or CN, more preferably chlorine or CN, more preferably chlorine; and R2 and R3 together with the nitrogen atom to be bonded are selected from (a) and (b) a saturated heterocyclic group, and Ra, Rb and Re are independently 11 or Cm alkyl ' preferably Ra, Rb and independently fluorenyl or methyl, more preferably Ra and Rb are independently hydrazine or methyl, And Re is Η, and more preferably 113 is Η, Rb is methyl, and Rc is Η. In another embodiment, the invention is directed to a compound of formula I, wherein: R! is ΝΗ2; and ruler 4 is Ci- 8-alkyl or C3_8 cycloalkyl-CQ.6 alkyl, preferably C" Or a C3.8 cycloalkyl-(: 〇-! alkyl group, more preferably a c2.8 alkyl group or a C3-8 cycloalkyl group; wherein the alkyl group may be selectively passed through one or more halogen atoms (preferably fluorine) Substituting 'c3_8 cycloalkyl" may be optionally substituted by one or more substituents independently selected from the group consisting of Cl4 alkyl, halogen (preferably fluorine) and aryl; more preferably, r4-58-200951136 is ethyl, Isopropyl, t-butyl or cyclopropyl; R5 is H, halogen or CN, preferably halogen or CN' is preferably chlorine or CN, more preferably chlorine; and R2 and R3 are linked to The nitrogen atom forms a saturated heterocyclic group of the formula (a), wherein Ra and Rb have the meanings ' and R in the compound of the formula I above, are hydrazine or Cm alkyl, and more preferably R. In another embodiment, the invention is directed to a compound of formula I, wherein:

Ri 爲 ΝΗ2 ; 尺4爲Cu烷基或C3_8環烷基-C〇-6烷基，較佳爲Ci-8 烷基或C3.8環烷基-Cm烷基，更佳爲C2_8烷基或C3.8環烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代，C3.8環烷基可選擇性經一或多個獨立地選自Cu烷基、鹵素（較佳氟）及芳基之取代基取代；又更佳地R4 爲乙基、異丙基、第三丁基或環丙基； R5爲H、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成式（a)之飽和雜環基，其中Ra、Rb及Rc獨立地爲Η或Cu烷基，及更佳地Ra ' Rb及Re獨立地爲Η或甲基，及更佳地Ra及Rb 獨立地爲Η或甲基，及1^爲Η，又更佳地Ra爲H，Rb爲甲基，及Rc爲Η。在另一實施態樣中，本發明關於式I化合物，其中：Ri is ΝΗ2; 尺4 is Cu alkyl or C3_8 cycloalkyl-C〇-6 alkyl, preferably Ci-8 alkyl or C3.8 cycloalkyl-Cm alkyl, more preferably C2-8 alkyl or a C3.8 cycloalkyl group; wherein the alkyl group is optionally substituted by one or more halogen atoms (preferably fluorine), and the C3.8 cycloalkyl group is optionally independently selected from the group consisting of Cu alkyl, halogen Substituting (preferably fluorine) and aryl substituents; more preferably R4 is ethyl, isopropyl, tert-butyl or cyclopropyl; R5 is H, halogen or CN, preferably halogen or CN, More preferably, it is chlorine or CN, and more preferably chlorine; and R2 and R3 together form a saturated heterocyclic group of the formula (a) with a nitrogen atom to be bonded, wherein Ra, Rb and Rc are independently hydrazine or Cu alkyl group. And, more preferably, Ra ' Rb and Re are independently hydrazine or methyl, and more preferably Ra and Rb are independently hydrazine or methyl, and 1 is hydrazine, and more preferably Ra is H, and Rb is A Base, and Rc is Η. In another embodiment, the invention is directed to a compound of formula I, wherein:

Ri 爲 ΝΗ2 ; R·4爲Ci-8院基或C3-8環院基- 院基，較佳爲Cl-8 -59- 200951136 烷基或C3-8環烷基-Cou烷基，更佳爲c2.8烷基或（：3-8環烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代，C3-8環烷基可選擇性經一或多個獨立地選自C!-4烷基、鹵素（較佳氟）及芳基之取代基取代；又更佳地R4 爲乙基、異丙基、第三丁基或環丙基； R5爲H、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成式（b)之飽和雜環基，其中Ra及Rb具有上文所述式I化合物中之意義，及Re爲Η或Cm烷基，及更佳地Rc爲η。在另一實施態樣中，本發明關於式I化合物，其中：Ri is ΝΗ2; R·4 is Ci-8 or C3-8 ring-based base, preferably Cl-8-59-200951136 alkyl or C3-8 cycloalkyl-Cou alkyl, more preferably Is c2.8 alkyl or (: 3-8 cycloalkyl; wherein the alkyl group is optionally substituted by one or more halogen atoms (preferably fluorine), and the C3-8 cycloalkyl group may be selectively passed through one or more Substituted independently from a substituent of C!-4 alkyl, halogen (preferably fluorine) and aryl; more preferably R4 is ethyl, isopropyl, tert-butyl or cyclopropyl; R5 is H Halogen or CN, preferably halogen or CN, more preferably chlorine or CN, more preferably chlorine; and R2 and R3 together with a nitrogen atom to form a saturated heterocyclic group of formula (b), wherein Ra And Rb has the meaning of a compound of formula I as described above, and Re is Η or Cm alkyl, and more preferably Rc is η. In another embodiment, the invention relates to a compound of formula I, wherein:

Ra 爲 ΝΗ2 ; R4爲Ci-8院基或C3-8環院基- C〇-6院基，較佳爲Ci-8 烷基或C3-8環烷基-Co-!烷基，更佳爲C2-8烷基或（：3_8環烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代，C3·8環院基可選擇性經一或多個獨立地選自C!-4院基、鹵素（較佳氟）及芳基之取代基取代；又更佳地r4 爲乙基、異丙基、第三丁基或環丙基； R5爲H、鹵素或CN，較佳爲_素或CN，更佳爲氯或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成式（b)之飽和雜環基，其中Ra、Rb及Rc獨立地爲11或Cu院基，及更佳地Ra、Rb及R。獨立地爲Η或甲基，及更佳地Ra及 Rb獨立地爲Η或甲基’及Rc爲Η，又更佳地Ra爲η，Rb -60- 200951136 爲甲基，及Rc爲Η。在另一實施態樣中，本發明關於式I化合物，其中：Ra is ΝΗ2; R4 is Ci-8 or C3-8 ring-based - C〇-6, preferably Ci-8 alkyl or C3-8 cycloalkyl-Co-! alkyl, more preferably Is a C2-8 alkyl group or a (:3-8 cycloalkyl group; wherein the alkyl group is optionally substituted by one or more halogen atoms (preferably fluorine), and the C3.8 ring-based group may be independently selected by one or more independently Substituted from a substituent of C!-4, a halogen (preferably fluorine) and an aryl group; more preferably, r4 is ethyl, isopropyl, tert-butyl or cyclopropyl; R5 is H, halogen Or CN, preferably _ or CN, more preferably chlorine or CN, more preferably chlorine; and R2 and R3 together with the nitrogen atom to be bonded form a saturated heterocyclic group of formula (b), wherein Ra, Rb and Rc are independently 11 or Cu, and more preferably Ra, Rb and R. independently, hydrazine or methyl, and more preferably Ra and Rb are independently hydrazine or methyl' and Rc is hydrazine. More preferably, Ra is η, Rb-60-200951136 is methyl, and Rc is Η. In another embodiment, the invention is directed to a compound of formula I, wherein:

Rj 爲 ΝΗ2 ; R4爲Cm烷基，較佳爲Cm烷基，更佳爲C2 4院基 :其可選擇性經一或多個鹵素原子（較佳氟）取代；又更佳地R4爲乙基、異丙基或第三丁基；Rj is ΝΗ2; R4 is Cm alkyl, preferably Cm alkyl, more preferably C4 4: it may be optionally substituted by one or more halogen atoms (preferably fluorine); more preferably R4 is B Base, isopropyl or tert-butyl;

Rs爲H、鹵素或CN’較佳爲鹵素或CN，更佳爲氯 φ 或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成飽和雜環基，其可爲4-至7-員單環、7-至8-員橋接雙環或8_至ι2_員稠合雙環，其中該雜環基可包含高至兩個N原子且不含任何其他雜原子，及可選擇性經一或多個獨立地選自Cl_4院基及NRaRb之取代基取代，惟雜環基包含兩個n原子且不經NRaRb基圑取代，或包含—個n原子且經—個NRaRt 基團取代。 ® 在另一實施態樣中’本發明關於式I化合物，其中：Rs is H, halogen or CN' is preferably halogen or CN, more preferably chlorine φ or CN, still more preferably chlorine; and R2 and R3 together with a nitrogen atom to form a saturated heterocyclic group, which may be 4- to 7-membered monocyclic, 7- to 8-membered bicyclic or 8- to i- 2 fused bicyclic ring wherein the heterocyclic group may contain up to two N atoms and does not contain any other heteroatoms, and Optionally substituted with one or more substituents independently selected from the group consisting of Cl_4 and NRaRb, except that the heterocyclic group contains two n atoms and is not substituted by the NRaRb group, or contains one n atom and passes through an NRaRt Replacement of the group. ® In another embodiment, the invention relates to a compound of formula I, wherein:

Ri 爲 NH2 ; 尺4爲Cm烷基’較佳爲C2_8烷基，更佳爲c2 4烷基 :其可選擇性經一或多個鹵素原子（較佳氟）取代；又更佳地R4爲乙基、異丙基或第三丁基； R5爲H、鹵素或CN’較佳爲鹵素或CN，更佳爲氯或CN ’又更佳爲氯：及 R2及R3 —起與所連接之氮原子形成選自如下之飽和雜環基： -61 - 200951136 (i) 包含雨個N原子且不含任何其他雜原子之雜環基，其中該雜環基可選擇性經一或多個C! _4烷基取代；及 (ii) 包含一個N原子且不含任何其他雜原子之雜環基，其中該雜環基經一個NRaRb基團取代且可選擇性經—或多個Q-4烷基取代；其中該雜環基（i)及（ii)可爲4-至7_員單環、7_ 至8-員橋接雙環或8-至12-員稠合雙環。Ri is NH2; Rule 4 is Cm alkyl ' preferably C2-8 alkyl, more preferably c2 4 alkyl: it may be optionally substituted by one or more halogen atoms (preferably fluorine); more preferably R4 is Ethyl, isopropyl or tert-butyl; R5 is H, halogen or CN' is preferably halogen or CN, more preferably chlorine or CN' and more preferably chlorine: and R2 and R3 are bonded to The nitrogen atom forms a saturated heterocyclic group selected from the group consisting of: -61 - 200951136 (i) a heterocyclic group containing a rain atom of N and not containing any other hetero atom, wherein the heterocyclic group may be selectively passed through one or more C a _4 alkyl group; and (ii) a heterocyclic group containing one N atom and no other hetero atom, wherein the heterocyclic group is substituted by one NRaRb group and optionally via - or a plurality of Q-4 alkanes a base substitution; wherein the heterocyclic group (i) and (ii) may be a 4- to 7-membered monocyclic ring, a 7- to 8-membered bicyclic ring or an 8- to 12-membered fused bicyclic ring.

在另一實施態樣中，本發明關於式I化合物，其中：In another embodiment, the invention is directed to a compound of formula I, wherein:

Ri 爲 NH2 ; 尺4爲Cu院基’較佳爲C2_8院基，更佳爲c2_4院基 :其可選擇性經一或多個鹵素原子（較佳氟）取代；又更佳地R4爲乙基、異丙基或第三丁基； R·5爲H、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及Ri is NH2; Ruler 4 is a Cu-based base, preferably a C2_8 yard base, more preferably a c2_4 yard base: it may be selectively substituted by one or more halogen atoms (preferably fluorine); and more preferably R4 is B. Or isopropyl or tert-butyl; R. 5 is H, halogen or CN, preferably halogen or CN, more preferably chlorine or CN, more preferably chlorine;

h爲Η或Cm烷基，及R3爲氮雜環丁烷基、啦略淀基、哌啶基或氮雜環庚烷基，其可選擇性經—或多個* 烷基取代。在另一實施態樣中’本發明關於式I化合物，其中： Ri 爲 nh2 ; 尺4爲Ci·8烷基，較佳爲C2_8烷基，更佳爲院基 ;其可選擇性經一或多個鹵素原子（較佳氟）取代·又更佳地R4爲乙基、異丙基或第三丁基； R·5爲H、鹵素或CN’較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及 -62- 200951136 * R2及R3 —起與所連接之氮原子形成選自（ v这）至（h )之飽和雜環基’其中Ra及Rb具有上τ m迎式1化合物中之意義，及R。及Rd獨立地爲Η或Ci-4院基。在另一實施態樣中，本發明關於式I化合物， . 中· R1 爲 NH2 ; 尺4爲Cu院基，較佳爲C2.8院基，更佳爲p …L2-4院基 :其可選擇性經一或多個鹵素原子（較佳氟）取代.又更 φ 佳地R4爲乙基、異丙基或第三丁基；h is hydrazine or Cm alkyl, and R3 is azetidinyl, lyophile, piperidinyl or azepanyl, which may be optionally substituted with one or more *alkyl groups. In another embodiment, the invention relates to a compound of formula I, wherein: Ri is nh2; the rule 4 is Ci.8 alkyl, preferably C2-8 alkyl, more preferably a hospital base; More than one halogen atom (preferably fluorine) is substituted. Further preferably R4 is ethyl, isopropyl or tert-butyl; R.5 is H, halogen or CN' is preferably halogen or CN, more preferably chlorine. Or CN, more preferably chlorine; and -62- 200951136 * R2 and R3 together with the nitrogen atom to be bonded form a saturated heterocyclic group selected from (v) to (h) where Ra and Rb have an upper τ The meaning of m in the formula 1 compound, and R. And Rd is independently a Η or Ci-4 yard. In another embodiment, the invention is directed to a compound of formula I, wherein R1 is NH2; and ruler 4 is a Cu-based, preferably C2.8, and more preferably p...L2-4. Optionally substituted by one or more halogen atoms (preferably fluorine). Further φ preferably R4 is ethyl, isopropyl or tert-butyl;

Rs爲H、鹵素或CN’較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自（a)至 )之飽和雜環基’及Ra、Rb、R<；及^獨立地爲η或匸14 烷基，較佳地Ra、Rb、Rc及Rd獨立地爲η或甲基。在另一實施態樣中，本發明關於式ϊ化合物，其中： 1 爲 ΝΗ2 ; φ R4爲Cu烷基，較佳爲C2.8烷基，更佳爲C2 4院基 ;其可選擇性經一或多個鹵素原子（較佳氟）取代；又更佳地R4爲乙基、異丙基或第三丁基；Rs is H, halogen or CN' is preferably halogen or CN, more preferably chlorine or CN, and more preferably chlorine; and R2 and R3 together with the nitrogen atom to be bonded form a saturation selected from (a) to The heterocyclic group 'and Ra, Rb, R'; and ^ are independently η or 匸14 alkyl, preferably Ra, Rb, Rc and Rd are independently η or methyl. In another embodiment, the present invention is directed to a compound of the formula: wherein: 1 is ΝΗ2; φ R4 is a Cu alkyl group, preferably a C2.8 alkyl group, more preferably a C4 4 building group; Substituted with one or more halogen atoms (preferably fluorine); more preferably R4 is ethyl, isopropyl or tert-butyl;

Rs爲H、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自（a) 、（b )、（c) 、（d) 、（f) 、（g)及（h)之飽和雜環基 ’其中Ra及Rb具有上文所述式！化合物中之意義，及Rc 及Rd獨立地爲Η或（^_4烷基。 -63- 200951136 在另一實施態樣中’本發明關於式I化合物，其中： R1 爲 N Η 2 ; 尺4爲Ci·8烷基，較佳爲C2.8烷基，更佳爲c2 4院基 :其可選擇性經一或多個鹵素原子（較佳氟）取代；又更佳地R4爲乙基、異丙基或第三丁基；Rs is H, halogen or CN, preferably halogen or CN, more preferably chlorine or CN, and more preferably chlorine; and R2 and R3 together with the nitrogen atom to be bonded are selected from (a), (b) , (c), (d), (f), (g) and (h) of a saturated heterocyclic group wherein Ra and Rb have the formula described above! The meaning of the compound, and Rc and Rd are independently Η or (^_4 alkyl. -63- 200951136 In another embodiment, the invention relates to a compound of formula I, wherein: R1 is N Η 2 ; Ci.8 alkyl, preferably C2.8 alkyl, more preferably c2 4: it may be optionally substituted by one or more halogen atoms (preferably fluorine); more preferably R4 is ethyl, Isopropyl or tert-butyl;

Rs爲H、鹵素或CN’較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及 R·2及R3 —起與所連接之氮原子形成選自（a) 、( b )、（c) 、（d) 、（f) 、（g)及（h)之鮑和雜環基 ’及Ra、Rb、Re及Rd獨立地爲H或Ci-4烷基，較佳地 Ra、Rb、R。及Rd獨立地爲Η或甲基》在另一實施態樣中，本發明關於式I化合物，其中： R!爲 ΝΗ2 ; R·4爲Ci_8院基’較佳爲院基，更佳爲C24院基 :其可選擇性經一或多個鹵素原子（較佳氟）取代；又更佳地R4爲乙基、異丙基或第三丁基； R·5爲H、鹵素或CN’較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自（a) 、（b )、（e)及（f)之飽和雜環基’其中Ra及Rb具有上文所述式I化合物中之意義，及1及〜獨立地爲^或Ci-4 烷基。在另一實施態樣中，本發明關^式I化合物，其中：Rs is H, halogen or CN' is preferably halogen or CN, more preferably chlorine or CN, and more preferably chlorine; and R.2 and R3 together with the nitrogen atom to be bonded are selected from (a), ( b), (c), (d), (f), (g) and (h) abalone and heterocyclic group ' and Ra, Rb, Re and Rd are independently H or Ci-4 alkyl, preferably Ground Ra, Rb, R. And Rd is independently hydrazine or methyl. In another embodiment, the invention relates to a compound of formula I, wherein: R! is ΝΗ2; R·4 is Ci_8 院基' preferably preferred as a hospital base, more preferably C24 House base: it may be optionally substituted by one or more halogen atoms (preferably fluorine); more preferably R4 is ethyl, isopropyl or tert-butyl; R·5 is H, halogen or CN' Preferably, it is halogen or CN, more preferably chlorine or CN, and more preferably chlorine; and R2 and R3 together with the nitrogen atom to be bonded are selected from (a), (b), (e) and (f) Saturated heterocyclic group 'wherein Ra and Rb have the meanings as defined in the compounds of formula I above, and 1 and ~ are independently ^ or Ci-4 alkyl. In another embodiment, the invention relates to a compound of formula I, wherein:

Ri 爲 NH2 ; 200951136 尺4爲Cu院基’較佳爲C2-8院基，更佳爲c 2 - 4 基 ;其可選擇性經一或多個鹵素原子（較佳氟）取代.又更佳地R4爲乙基、異丙基或第三丁基； R5爲Η、鹵素或CN’較佳爲鹵素或尺佳爲氧或CN，又更佳爲氯；及 R·2及R3 —起與所連接之氮原子形成選自（a) 、（b )、（e)及（f)之飽和雜環基，及Ra、Rb、Re及Rd獨 φ 立地爲Η或Ci-4烷基’較佳地Ra、Rb、Re及％獨立地爲H或甲基。在另一實施態樣中’本發明關於式I化合物，其中. R!爲 ΝΗ2 ; R·4爲C!-8烷基’較佳爲C2·8院基，更佳爲^ ;^甘 2 - 4阮碁 :其可選擇性經一或多個鹵素原子（較佳氟）取代；又更佳地R4爲乙基、異丙基或第三丁基； R·5爲Η、鹵素或CN’較佳爲齒素或CN，吏佳爲氯 φ 或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自（a)及（b )之飽和雜環基’其中Ra及Rb具有上文所述式I化合物中之意義’及Rc爲Η或Ci.4院基，較佳地^爲只。在另一實施態樣中’本發明關於式I化合物，其中： R!爲 NH2 ; 尺4爲Cm烷基’較佳爲C2_8烷基，更佳爲c24院基 ;其可選擇性經一或多個鹵素原子（較佳氟）取代；又更佳地R4爲乙基、異丙基或第三丁基； -65- 200951136 R5爲Η、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自（a)及（b )之飽和雜環基，及Ra、Rb及R。獨立地爲11或Cu院基，較佳地Ra、Rb及R。獨立地爲Η或甲基，更佳地Ra 及Rb獨立地爲Η或甲基’及1^爲Η，又更佳地1爲Η ，Rb爲甲基，及Rc爲Η。在另一實施態樣中，本發明關於式I化合物，其中：Ri is NH2; 200951136 Ruler 4 is a Cu-based base, preferably a C2-8 yard base, more preferably a c 2 - 4 base; it can be selectively substituted by one or more halogen atoms (preferably fluorine). Preferably, R4 is ethyl, isopropyl or tert-butyl; R5 is hydrazine, halogen or CN' is preferably halogen or preferably is oxygen or CN, more preferably chlorine; and R.2 and R3 Forming a saturated heterocyclic group selected from (a), (b), (e), and (f) with the nitrogen atom to be bonded, and Ra, Rb, Re, and Rd are independently Η or Ci-4 alkyl' Preferably, Ra, Rb, Re and % are independently H or methyl. In another embodiment, the invention relates to a compound of formula I, wherein R is ΝΗ2; R·4 is C!-8 alkyl is preferably C2·8, more preferably ^; - 4阮碁: which may be optionally substituted by one or more halogen atoms (preferably fluorine); more preferably R4 is ethyl, isopropyl or t-butyl; R·5 is deuterium, halogen or CN 'preferably dentate or CN, preferably chloro φ or CN, more preferably chlorine; and R 2 and R 3 together with the nitrogen atom to be bonded form a saturated heterocyclic group selected from (a) and (b) Wherein, Ra and Rb have the meanings in the compounds of formula I above and Rc is Η or Ci. 4, preferably ^. In another embodiment, the invention relates to a compound of formula I, wherein: R! is NH2; the rule 4 is Cm alkyl group, preferably C2-8 alkyl group, more preferably c24 hospital base; Substituted with a plurality of halogen atoms (preferably fluorine); more preferably R4 is ethyl, isopropyl or tert-butyl; -65- 200951136 R5 is hydrazine, halogen or CN, preferably halogen or CN, more preferably It is preferably chlorine or CN, and more preferably chlorine; and R2 and R3 together with the nitrogen atom to be bonded form a saturated heterocyclic group selected from (a) and (b), and Ra, Rb and R. Independently 11 or Cu, preferably Ra, Rb and R. Independently, it is a hydrazine or a methyl group. More preferably, Ra and Rb are independently hydrazine or methyl group and 1 is hydrazine, and more preferably 1 is hydrazine, Rb is a methyl group, and Rc is hydrazine. In another embodiment, the invention is directed to a compound of formula I, wherein:

Ri 爲 ΝΗ2 ; R4爲Cm烷基，較佳爲C2-8烷基，更佳爲c2_4烷基 :其可選擇性經一或多個鹵素原子（較佳氟）取代；又更佳地R4爲乙基、異丙基或第三丁基； R·5爲H、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及 R·2及R·3 —起與所連接之氮原子形成式（a)之飽和雜環基’其中Ra及Rb具有上文所述式I化合物中之意義，及Re爲Η或Cm烷基，及更佳地R。爲η。在另一實施態樣中，本發明關於式I化合物，其中：Ri is ΝΗ2; R4 is Cm alkyl, preferably C2-8 alkyl, more preferably c2_4 alkyl: it may be optionally substituted by one or more halogen atoms (preferably fluorine); more preferably R4 is Ethyl, isopropyl or tert-butyl; R·5 is H, halogen or CN, preferably halogen or CN, more preferably chlorine or CN, more preferably chlorine; and R·2 and R·3 And a saturated heterocyclic group of formula (a) wherein Ra and Rb have the meanings of the compounds of formula I above, and Re is hydrazine or Cm alkyl, and more preferably R. Is η. In another embodiment, the invention is directed to a compound of formula I, wherein:

Ri 爲 ΝΗ2 ; R·4爲C!-8院基，較佳爲C2·8院基，更佳爲c2.4院基 :其可選擇性經一或多個鹵素原子（較佳氟）取代；又更佳地R4爲乙基、異丙基或第三丁基； R·5爲H、鹵素或CN’較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及 200951136 R2及R3 —起與所連接之氮原子形成式（a)之飽和雜環基，其中Ra、Rb及Re獨立地爲Η或Ci-4烷基，及更佳地Ra、Rb及獨立地爲Η或甲基，及更佳地Ra及Rb 獨立地爲Η或甲基，及R。爲Η，又更佳地Ra爲H，Rb爲甲基，及Rc爲Η。在另一實施態樣中，本發明關於式I化合物，其中：Ri is ΝΗ2; R·4 is C!-8 yard base, preferably C2·8 yard base, more preferably c2.4 yard base: it can be selectively substituted by one or more halogen atoms (preferably fluorine) More preferably, R4 is ethyl, isopropyl or tert-butyl; R.5 is H, halogen or CN' is preferably halogen or CN, more preferably chlorine or CN, and more preferably chlorine; 200951136 R2 and R3 together with a nitrogen atom to be bonded form a saturated heterocyclic group of formula (a), wherein Ra, Rb and Re are independently hydrazine or Ci-4 alkyl, and more preferably Ra, Rb and independently It is hydrazine or methyl, and more preferably Ra and Rb are independently hydrazine or methyl, and R. Preferably, Ra is H, Rb is methyl, and Rc is deuterium. In another embodiment, the invention is directed to a compound of formula I, wherein:

Ri Μ ΝΗ2 ； φ R4爲Cu烷基，較佳爲C2_8烷基，更佳爲c2-4烷基 :其可選擇性經一或多個鹵素原子（較佳氟）取代；又更佳地R4爲乙基、異丙基或第三丁基； R·5爲H、鹵素或CN’較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成式（b)之飽和雜環基’其中Ra及Rb具有上文所述式I化合物中之意義 ’及R。爲Η或Cy烷基，及更佳地R。爲η。 φ 在另一實施態樣中，本發明關於式I化合物，其中：Ri Μ ΝΗ 2 ; φ R4 is a Cu alkyl group, preferably a C 2-8 alkyl group, more preferably a c2-4 alkyl group: it may be optionally substituted by one or more halogen atoms (preferably fluorine); more preferably R 4 Is ethyl, isopropyl or tert-butyl; R.5 is H, halogen or CN' is preferably halogen or CN, more preferably chlorine or CN, more preferably chlorine; and R2 and R3 together The nitrogen atom to be bonded forms a saturated heterocyclic group of formula (b) wherein Ra and Rb have the meanings 'and R' in the compounds of formula I above. It is a hydrazine or a Cy alkyl group, and more preferably R. Is η. φ In another embodiment, the invention is directed to a compound of formula I, wherein:

Ri 爲 ΝΗ2 ; R4爲Cl·8院基’較佳爲C2.8院基，更佳爲c2_4院基 ;其可選擇性經一或多個鹵素原子（較佳氟）取代；又更佳地R4爲乙基、異丙基或第三丁基。 R·5爲H、鹵素或CN，較佳爲齒素或CN，更佳爲氯或CN，又更佳爲氯；及 RZ及R3 —起與所連接之氮原子形成式（b)之飽和雜環基，其中Ra、Rb及Rc獨立地爲Η或ClM院基，及 -67- 200951136 更佳地Ra、Rb及R。獨立地爲Η或甲基，及更佳地Ra及 Rb獨立地爲Η或甲基’及Rc爲Η ’又更佳地Ra爲Η ’ Rb 爲甲基，及Rc爲Η ° 在另一實施態樣中’本發明關於式I化合物’其中： Ri 爲 ΝΗ2 ; R4爲C3-8環烷基-Co-6烷基，較佳爲C3_8環烷基-Co.i 烷基，更佳爲c3.8環烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代，C3.8環烷基可選擇性經一或多個獨立地選自CL4烷基、鹵素（較佳氟）及芳基之取代基取代；又更佳地R4爲環丙基； R5爲H、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成飽和雜環基，其可爲4·至7-員單環、7-至8-員橋接雙環或8-至12-員稠合雙環’其中該雜環基可包含高至兩個N原子且不含任何其他雜原子’及可選擇性經—或多個獨立地選自Ci4烷 1 & NRaRb之取代基取代，惟雜環基包含兩個n原子且不經NRaRb基團取代，或包含一個N原子且經一個NRaRb 基團取代。在另一實施態樣中，本發明關於式〗化合物，其中：爲 NH2 ; R4爲Cm環烷基_C()_6烷基，較佳爲c38環烷基_c〇i k基’更佳爲C3-8環烷基；其中烷基可選擇性經一或多原子（較佳氟）取代，C3_8環烷基可選擇性經一或 • 68 - 200951136 多個獨立地選自Cl *烷基、鹵素（較佳氟）及芳基之取代基取代：又更佳地r4爲環丙基；Ri is ΝΗ2; R4 is Cl·8 yard base 'preferably C2.8 yard base, more preferably c2_4 yard base; it may be selectively substituted by one or more halogen atoms (preferably fluorine); more preferably R4 is ethyl, isopropyl or tert-butyl. R·5 is H, halogen or CN, preferably dentate or CN, more preferably chlorine or CN, and more preferably chlorine; and RZ and R3 together form a saturation of formula (b) with the attached nitrogen atom. Heterocyclyl, wherein Ra, Rb and Rc are independently fluorene or ClM, and -67-200951136 more preferably Ra, Rb and R. Independently hydrazine or methyl, and more preferably Ra and Rb are independently hydrazine or methyl ' and Rc is Η ' and more preferably Ra is Η ' Rb is methyl, and Rc is Η ° in another implementation In the aspect, the invention relates to the compound of the formula I wherein: Ri is ΝΗ2; R4 is C3-8 cycloalkyl-Co-6 alkyl, preferably C3_8 cycloalkyl-Co.i alkyl, more preferably c3 .8 cycloalkyl; wherein the alkyl group is optionally substituted by one or more halogen atoms, preferably fluoro, and the C3.8 cycloalkyl group is optionally independently selected from the group consisting of CL4 alkyl, halogen ( Preferably, the fluorine is substituted with a substituent of the aryl group; more preferably, R4 is a cyclopropyl group; R5 is H, halogen or CN, preferably halogen or CN, more preferably chlorine or CN, and more preferably chlorine; And R2 and R3 together form a saturated heterocyclic group with the nitrogen atom to which they are attached, which may be a 4 to 7-membered monocyclic ring, a 7- to 8-membered bicyclic ring or an 8- to 12-membered fused bicyclic ring. The heterocyclic group may contain up to two N atoms and does not contain any other hetero atom 'and may be optionally substituted with - or a plurality of substituents independently selected from Ci4 alkane 1 & NRaRb, except that the heterocyclic group contains two n atoms and not substituted by NRaRb groups And contains a N atom or a substituted a NRaRb group. In another embodiment, the invention is directed to a compound of the formula wherein: is NH2; R4 is Cm cycloalkyl-C()-6 alkyl, preferably c38 cycloalkyl-c〇ikyl' is more preferably a C3-8 cycloalkyl group; wherein the alkyl group is optionally substituted by one or more atoms (preferably fluorine), and the C3_8 cycloalkyl group may be optionally selected from one or more of the group; Substituent substitution of halogen (preferably fluorine) and aryl: more preferably r4 is cyclopropyl;

Rs爲H、鹵素或CN，較佳爲鹵素或cN，更佳爲氯或CN ’又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自如下之飽和雜環基： (I) 包含兩個N原子且不含任何其他雜原子之雜環基， φ 其中該雜環基可選擇性經一或多個Ci-4烷基取代；及 (II) 包含一個N原子且不含任何其他雜原子之雜環基，其中該雜環基經一個NRaRb基團取代及可選擇性經—或多個Cl-Ο烷基取代；其中該雜環基（i)及（ii)可爲4-至7_員單環、7_ 至8-員橋接雙環或8-至12-員稠合雙環。在另一實施態樣中，本發明關於式I化合物，其中： Ri 爲 NH2 ; Φ R4爲C3.8環烷基-CG_6烷基，較佳爲c3.8環烷基-C(Ki 院基’更佳爲C3·8環烷基；其中烷基可選擇性經—或多個鹵素原子（較佳氟）取代，C3_8環烷基可選擇性經—或多個獨立地選自（^_4烷基、鹵素（較佳氟）及芳基之取代基取代；又更佳地R4爲環丙基； R5爲H、鹵素或CN，較佳爲鹵素或CN，更佳爲氣或CN，又更佳爲氯；及 R2爲11或Cw烷基，及R3爲氮雜環丁烷基、吡咯D定基、哌啶基或氮雜環庚烷基，其可選擇性經一或多個Cl 1 * 4 -69- 200951136 烷基取代。在另一實施態樣中’本發明關於式I化合物，其中： R1 爲 NH2 ; R4爲C3_8環烷基-C〇-6烷基，較佳爲C3-8環烷基-CQ. ^烷基，更佳爲C3.8環烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代，C38環烷基可選擇性經一或多個獨立地選自山·4烷基、鹵素（較佳氟）及芳基之取代基取代；又更佳地R4爲環丙基； ~ ❹ R5爲H、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN ’又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自（a)至（h )之飽和雜環基，其中Ra及Rb具有上文所述式I化合物中之意義，及Re及Rd獨立地爲11或C^4烷基。在另一實施態樣中，本發明關於式I化合物，其中：Rs is H, halogen or CN, preferably halogen or cN, more preferably chlorine or CN' is more preferably chlorine; and R2 and R3 together with the nitrogen atom to which they are attached form a saturated heterocyclic group selected from the group consisting of: (I) a heterocyclic group containing two N atoms and not containing any other hetero atom, wherein φ is optionally substituted by one or more Ci-4 alkyl groups; and (II) contains one N atom and a heterocyclic group which does not contain any other hetero atom, wherein the heterocyclic group is substituted by an NRaRb group and optionally substituted by a plurality of Cl-decyl groups; wherein the heterocyclic group (i) and (ii) It can be a 4- to 7-membered single-ring, 7- to 8-membered bicyclic or 8- to 12-membered fused bicyclic. In another embodiment, the invention relates to a compound of formula I, wherein: Ri is NH2; Φ R4 is C3.8 cycloalkyl-CG-6 alkyl, preferably c3.8 cycloalkyl-C (Ki) More preferably, it is a C3·8 cycloalkyl group; wherein the alkyl group is optionally substituted with or a plurality of halogen atoms (preferably fluorine), and the C3_8 cycloalkyl group may be optionally selected from - or independently selected from (^_4) Substituted with a substituent of an alkyl group, a halogen (preferably fluorine) and an aryl group; more preferably R4 is a cyclopropyl group; R5 is H, halogen or CN, preferably halogen or CN, more preferably gas or CN, More preferably chlorine; and R2 is 11 or Cw alkyl, and R3 is azetidinyl, pyrrole D-butyl, piperidinyl or azepanyl, optionally via one or more Cl 1 * 4 -69- 200951136 Alkyl substitution. In another embodiment, the invention relates to a compound of formula I, wherein: R1 is NH2; R4 is C3_8 cycloalkyl-C〇-6 alkyl, preferably C3- 8-cycloalkyl-CQ.^alkyl, more preferably C3.8 cycloalkyl; wherein the alkyl group may be optionally substituted by one or more halogen atoms (preferably fluorine), and the C38 cycloalkyl group may be selectively subjected to one Or a plurality of independently selected from the group consisting of a mountain alkyl group and a halogen ( Substituted with a substituent of a fluoro group and an aryl group; more preferably R4 is a cyclopropyl group; ~ ❹ R5 is H, halogen or CN, preferably halogen or CN, more preferably chlorine or CN' and more preferably chlorine And R2 and R3 together with the nitrogen atom to be bonded form a saturated heterocyclic group selected from (a) to (h), wherein Ra and Rb have the meanings of the compounds of formula I above, and Re and Rd are independent The ground is 11 or C^4 alkyl. In another embodiment, the invention is directed to a compound of formula I, wherein:

Ri Μ ΝΗ2 ；Ri Μ ΝΗ 2 ;

R4爲C3-8環烷基-CG.6烷基，較佳爲c3-8環烷基- QR4 is C3-8 cycloalkyl-CG.6 alkyl, preferably c3-8 cycloalkyl-Q

Cod烷基，更佳爲C3-8環烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代，C3_8環烷基可選擇性經一或多個獨立地選自烷基、鹵素（較佳氟）及芳基之取代基取代；又更佳地R4爲環丙基； R5爲Η、鹵素或CN，較佳爲_素或CN，更佳爲氯或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自（a)至（h )之飽和雜環基’及Ra、Rb、Re及1^獨立地爲}1或C!-4 -70- 200951136 院基’較佳地Ra、Rb、Rc及Rd獨立地爲Η或甲在另一實施態樣中，本發明關於式ί化合物 R 1爲ΝΗ〗； R4爲C3-8環烷基-CG.6烷基，較佳爲C3_i Co-!院基’更佳爲C3-8環烷基；其中烷基可選或多個鹵素原子（較佳氟）取代，C3-8環院基經一或多個獨立地選自（^—4院基、鹵素（較佳基之取代基取代；又更佳地R4爲環丙基； R5爲H、鹵素或CN’較佳爲鹵素或CN，或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自（ )、（c) 、（d) 、（f) 、（g)及（h)之飽，其中Ra及Rb具有上文所述式I化合物中之意及Rd獨立地爲Η或（^-4烷基。在另一實施態樣中’本發明關於式I化合物 Ri 爲 NH2 ; R4爲C3-8環烷基-CG_6烷基，較佳爲c3-! Co·!烷基’更佳爲C3-8環烷基；其中烷基可選或多個鹵素原子（較佳氟）取代，C3.8環烷基經一或多個獨立地選自Ci_4烷基、鹵素（較佳基之取代基取代；又更佳地R4爲環丙基； R_5爲H、齒素或CN，較佳爲齒素或CN，或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自（基。，其中： i環烷基-擇性經一可選擇性氟）及芳更佳爲氯 a) > ( b 和雜環基義，及Rc ，其中： ί壞屍基-擇性經一可選擇性氟）及芳更佳爲氯 a) 、（ b -71 - 200951136 )、(C ) 、( d) 、（f) 、（g)及（h)之飽和雜環基，及Ra、Rb、Rc及Rd獨立地爲H或¢^-4烷基，較佳地 Ra、Rb、Rc及Rd獨立地爲η或甲基。在另一實施態樣中，本發明關於式I化合物，其中： R!爲 ΝΗ2 ; β·4爲C3-8環院基- C〇-6院基，較佳爲C3.8環院基_More preferably, the Cd alkyl group is more preferably a C3-8 cycloalkyl group; wherein the alkyl group is optionally substituted by one or more halogen atoms (preferably fluorine), and the C3_8 cycloalkyl group may be optionally independently selected from one or more Substituting alkyl, halogen (preferably fluorine) and aryl substituents; more preferably R4 is cyclopropyl; R5 is deuterium, halogen or CN, preferably _ or CN, more preferably chloro or CN, More preferably, it is chlorine; and R2 and R3 together with the nitrogen atom to be bonded form a saturated heterocyclic group selected from (a) to (h) and Ra, Rb, Re and 1^ are independently 1 or C. !-4 -70- 200951136 院基' Preferably Ra, Rb, Rc and Rd are independently Η or A. In another embodiment, the invention relates to the formula ί compound R 1 is ΝΗ〗; R4 is C3- An 8-cycloalkyl-CG.6 alkyl group, preferably a C3_i Co-! institute group' is more preferably a C3-8 cycloalkyl group; wherein the alkyl group is optionally substituted with a plurality of halogen atoms (preferably fluorine), C3- The 8-ring hospital base is preferably selected from one or more of (^-4), halogen (substituted substituents; more preferably R4 is cyclopropyl; R5 is H, halogen or CN'. Halogen or CN, or CN, more preferably chlorine; and R2 and R3 The nitrogen atom is formed to be selected from the group consisting of ( ), (c), (d), (f), (g) and (h), wherein Ra and Rb have the meaning of the compound of formula I described above and Rd is independent The ground is hydrazine or (^-4 alkyl. In another embodiment, the present invention relates to the compound of formula I, Ri is NH2; R4 is C3-8 cycloalkyl-CG-6 alkyl, preferably c3-! Co· More preferably, the alkyl group is a C3-8 cycloalkyl group; wherein the alkyl group is optionally substituted with a plurality of halogen atoms (preferably fluorine), and the C3.8 cycloalkyl group is independently selected from the group consisting of Ci-4 alkyl groups, Halogen (substituent substituent substituted; more preferably R4 is cyclopropyl; R_5 is H, dentate or CN, preferably dentate or CN, or CN, more preferably chlorine; and R2 and R3 And the nitrogen atom to be bonded is formed from (base, wherein: i cycloalkyl-selective via a selective fluorine) and aryl is more preferably chlorine a) > (b and heterocyclic meaning, and Rc , wherein: ί 尸基 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - (h) a saturated heterocyclic group, and Ra, Rb, Rc and Rd are independently H or ¢^-4 alkyl, Preferably, Ra, Rb, Rc and Rd are independently η or methyl. In another embodiment, the invention relates to a compound of formula I, wherein: R! is ΝΗ2; β·4 is C3-8 ring-based- C〇-6 yard base, preferably C3.8 ring yard base _

Co-!烷基，更佳爲C3-8環烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代，C3.8環烷基可選擇性 Q 經一或多個獨立地選自 C! ·4烷基、鹵素（較佳氟）及芳基之取代基取代；又更佳地R4爲環丙基； R5爲H、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自（a) 、（b )、（e)及（f)之飽和雜環基，其中113及111)具有上文所述式I化合物中之意義，及R。及Rd獨立地爲11或Cj.4 烷基。 ❹ 在另一實施態樣中，本發明關於式I化合物，其中：Co-!alkyl, more preferably C3-8 cycloalkyl; wherein the alkyl group may be optionally substituted by one or more halogen atoms (preferably fluorine), and the C3.8 cycloalkyl group may be selectively Q through one or more Substituents which are independently selected from C. 4 alkyl, halogen (preferably fluorine) and aryl; more preferably R4 is cyclopropyl; R5 is H, halogen or CN, preferably halogen or CN More preferably, it is chlorine or CN, and more preferably chlorine; and R2 and R3 together with the nitrogen atom to be bonded form a saturated heterocyclic group selected from (a), (b), (e) and (f), Wherein 113 and 111) have the meanings of the compounds of formula I above, and R. And Rd is independently 11 or Cj.4 alkyl. ❹ In another embodiment, the invention is directed to a compound of formula I, wherein:

Ri 爲 NH2 ; Κ·4爲C3-8環院基_Cq-6院基，較佳爲C3-8環院基-Co-i烷基，更佳爲C3.8環烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代，C3.8環烷基可選擇性經一或多個獨立地選自C 4烷基、鹵素（較佳氟）及芳基之取代基取代；又更佳地R4爲環丙基； R5爲H、鹵素或CN，較佳爲鹵素或CN，更佳爲氯 -72- 200951136 或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自（a) 、（b )、（e)及（f)之飽和雜環基，及Ra、Rb、Re及〜獨立地爲Η或Ci.4烷基，較佳地Ra、Rb、R。及Rd獨立地爲Η或甲基。在另一實施態樣中，本發明關於式I化合物，其中：Ri is NH2; Κ·4 is C3-8 ring-based _Cq-6, preferably C3-8 ring-based-Co-i alkyl, more preferably C3.8 cycloalkyl; Optionally substituted with one or more halogen atoms (preferably fluorine), the C3.8 cycloalkyl group may be optionally selected from one or more independently selected from the group consisting of C 4 alkyl, halogen (preferably fluorine) and aryl. Substituent substitution; more preferably R4 is cyclopropyl; R5 is H, halogen or CN, preferably halogen or CN, more preferably chloro-72-200951136 or CN, more preferably chlorine; and R2 and R3 And forming a saturated heterocyclic group selected from (a), (b), (e) and (f) with the nitrogen atom to be bonded, and Ra, Rb, Re and 〜 are independently Η or Ci. 4 alkyl Preferably, Ra, Rb, R. And Rd is independently hydrazine or methyl. In another embodiment, the invention is directed to a compound of formula I, wherein:

Ri 爲 ΝΗ2 ; Κ·4爲〇3·8環院基-C〇-6院基，較佳爲C3.8環垸基-C 〇 - i烷基，更佳爲C 3 _ 8環烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代，C3-8環烷基可選擇性經一或多個獨立地選自CiM烷基、鹵素（較佳氟）及芳基之取代基取代；又更佳地R4爲環丙基； R5爲H、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自（a)及（b φ )之飽和雜環基，其中Ra及Rb具有上文所述式I化合物中之意義，及爲11或Cm烷基，及較佳地rc爲H。在另一實施態樣中，本發明關於式I化合物，其中： R1 爲 NH2 ; R4爲C3-8環烷基-C〇-6烷基，較佳爲c3.8環烷基-Co-i烷基，更佳爲C3-8環烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代，C3-8環烷基可選擇性經一或多個獨立地選自Ci.4烷基、鹵素（較佳氟）及芳基之取代基取代；又更佳地r4爲環丙基.； -73- 200951136 R5爲Η、鹵素或CN’較佳爲_素或CN，更佳爲氯或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成選自（a)及（b )之飽和雜環基，及Ra、Rb及1^獨立地爲Cm烷基，較佳地Ra、Rb及R。獨立地爲Η或甲基，更佳地Ra 及Rb獨立地爲Η或甲基，及Re爲η，又更佳地Ra爲Η ，Rb爲甲基，及Rc爲Η。在另一實施態樣中，本發明關於式I化合物，其中： _ R!爲 ΝΗ2 ; 尺4爲（：3-8環烷基-(：().6烷基，較佳爲（：3.8環烷基-Co.!烷基，更佳爲C3-8環烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代，C3-8環烷基可選擇性經一或多個獨立地選自（^_4烷基、鹵素（較佳氟）及芳基之取代基取代；又更佳地R4爲環丙基；爲Η、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及 ❿ R2及R3 —起與所連接之氮原子形成式（a)之飽和雜環基’其中Ra及Rb具有上文所述式I化合物中之意義，及Re爲Η或Cu烷基，及更佳地Re爲Η。在另一實施態樣中，本發明關於式I化合物，其中：Ri is ΝΗ2; Κ·4 is 〇3·8 ring-yard-C〇-6, preferably C3.8 cyclodecyl-C 〇-i alkyl, more preferably C 3 -8 cycloalkyl Wherein the alkyl group is optionally substituted by one or more halogen atoms (preferably fluorine), and the C3-8 cycloalkyl group may be optionally selected from one or more independently selected from the group consisting of CiM alkyl, halogen (preferably fluorine) and Substituted by a substituent of an aryl group; more preferably R4 is a cyclopropyl group; R5 is H, halogen or CN, preferably halogen or CN, more preferably chlorine or CN, more preferably chlorine; and R2 and R3 - And a saturated heterocyclic group selected from (a) and (b φ ), wherein Ra and Rb have the meanings of the compound of formula I above, and are 11 or Cm alkyl, and Good land rc is H. In another embodiment, the invention relates to a compound of formula I, wherein: R1 is NH2; R4 is C3-8 cycloalkyl-C〇-6 alkyl, preferably c3.8 cycloalkyl-Co-i More preferably, the alkyl group is more preferably a C3-8 cycloalkyl group; wherein the alkyl group is optionally substituted by one or more halogen atoms (preferably fluorine), and the C3-8 cycloalkyl group is optionally independently selected by one or more Substituted from a substituent of Ci. 4 alkyl, halogen (preferably fluorine) and aryl; more preferably, r4 is cyclopropyl.; -73- 200951136 R5 is hydrazine, halogen or CN' is preferably _ or More preferably, it is chlorine or CN, and more preferably chlorine; and R2 and R3 together with the nitrogen atom to be bonded form a saturated heterocyclic group selected from (a) and (b), and Ra, Rb and 1^ Independently Cm alkyl, preferably Ra, Rb and R. Independently hydrazine or methyl, more preferably Ra and Rb are independently hydrazine or methyl, and Re is η, more preferably Ra is Η, Rb is methyl, and Rc is Η. In another embodiment, the invention is directed to a compound of formula I, wherein: _ R! is ΝΗ 2 ; 尺 4 is (: 3-8 cycloalkyl-(:().6 alkyl, preferably (:3.8) a cycloalkyl-Co.! alkyl group, more preferably a C3-8 cycloalkyl group; wherein the alkyl group is optionally substituted by one or more halogen atoms (preferably fluorine), and the C3-8 cycloalkyl group is selectively One or more substituents independently selected from (^-4 alkyl, halogen (preferably fluorine) and aryl; more preferably R4 is cyclopropyl; oxime, halogen or CN, preferably halogen or More preferably, it is chlorine or CN, and more preferably chlorine; and ❿ R2 and R3 together with a nitrogen atom to be bonded form a saturated heterocyclic group of formula (a) wherein Ra and Rb have the formula I described above The meaning of the compound, and Re is hydrazine or Cu alkyl, and more preferably Re is hydrazine. In another embodiment, the invention relates to a compound of formula I, wherein:

Ri 爲 ΝΗ2 ; R4爲C3_8環烷基-CQ_6烷基，較佳爲C3-8環烷基-Co-i烷基，更佳爲C3-8環烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代，C3-8環烷基可選擇性 -74- 200951136 經一或多個獨立地選自 Cij烷基、鹵素（較佳氟）及芳基之取代基取代；又更佳地R4爲環丙基； R5爲H、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及 R2及R3—起與所連接之氮原子形成式（a)之飽和雜環基，其中Ra、Rb及Re獨立地爲11或Cm烷基，及更佳地Ra、Rb及R。獨立地爲Η或甲基，及更佳地Ra及Rb 獨立地爲Η或甲基，及Re爲Η，又更佳地1爲H，Rb爲甲基，及Rc爲Η。在另一實施態樣中，本發明關於式I化合物，其中： Ri 爲 ΝΗ2 ; Κ·4爲C3-8環焼基- 院基，較佳爲C3-8環院基-Co-i烷基，更佳爲C3-8環烷基；其中烷基可選擇性經一或多個歯素原子（較佳氟）取代，c3.8環烷基可選擇性經一或多個獨AA地選自Ci-4院基、鹵素（較佳氣）及芳基之取代基取代；又更佳地R4爲環丙基；Ri is ΝΗ2; R4 is C3_8 cycloalkyl-CQ_6 alkyl, preferably C3-8 cycloalkyl-Co-i alkyl, more preferably C3-8 cycloalkyl; wherein the alkyl group may be selectively passed through one or Substituted by a plurality of halogen atoms (preferably fluorine), the C3-8 cycloalkyl group is optionally -74-200951136 substituted with one or more substituents independently selected from the group consisting of Cij alkyl, halogen (preferably fluorine) and aryl More preferably, R4 is cyclopropyl; R5 is H, halogen or CN, preferably halogen or CN, more preferably chlorine or CN, more preferably chlorine; and R2 and R3 together with the attached nitrogen The atom forms a saturated heterocyclic group of the formula (a), wherein Ra, Rb and Re are independently 11 or Cm alkyl groups, and more preferably Ra, Rb and R. It is independently hydrazine or methyl, and more preferably Ra and Rb are independently hydrazine or methyl, and Re is hydrazine, more preferably 1 is H, Rb is methyl, and Rc is hydrazine. In another embodiment, the invention relates to a compound of formula I, wherein: Ri is ΝΗ2; Κ·4 is C3-8 cyclodecyl-homolyl, preferably C3-8 ring-based-Co-ialkyl More preferably, it is a C3-8 cycloalkyl group; wherein the alkyl group is optionally substituted by one or more halogen atoms (preferably fluorine), and the c3.8 cycloalkyl group is selectively selected by one or more independent AA Substituted from a substituent of Ci-4, halogen (preferably gas) and aryl; more preferably R4 is cyclopropyl;

Rs爲H、鹵素或CN，較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成式（b)之飽和雜環基，其中Ra及Rb具有上文所述式I化合物中之意義，及R。爲11或Cu烷基，及更佳地R。爲η。在另一實施態樣中，本發明關於式I化合物，其中： R!爲 NH2 ; R4爲C3-8環院基- CG-6院基，較佳爲c3-8環院基- -75- 200951136 C0-i烷基，更佳爲C3.8環烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代，C3_8環烷基可選擇性經一或多個獨立地選自C1·4院基、鹵素（較佳氟）及芳基之取代基取代；又更佳地R4爲環丙基； R_5爲H、鹵素或CN’較佳爲鹵素或CN，更佳爲氯或CN，又更佳爲氯；及 R2及R3 —起與所連接之氮原子形成式（b)之飽和雜環基，其中Ra、Rb及Re獨立地爲11或Cm烷基，及更佳地Ra、Rb及R。獨立地爲Η或甲基，及更佳地1^及 Rb獨立地爲Η或甲基’及Re爲η，又更佳地113爲H，Rb 爲甲基，及Rc爲Η。在另一實施態樣中，本發明關於式丨化合物，其中： R]爲 ΝΗ2 ;Rs is H, halogen or CN, preferably halogen or CN, more preferably chlorine or CN, more preferably chlorine; and R2 and R3 together with a nitrogen atom to form a saturated heterocyclic group of formula (b) Wherein Ra and Rb have the meanings of the compounds of formula I above, and R. Is 11 or Cu alkyl, and more preferably R. Is η. In another embodiment, the invention is directed to a compound of formula I, wherein: R! is NH2; R4 is C3-8 ring-based CG-6, preferably c3-8 ring-based -75- 200951136 C0-i alkyl, more preferably C3.8 cycloalkyl; wherein the alkyl group is optionally substituted by one or more halogen atoms (preferably fluorine), and the C3_8 cycloalkyl group may be optionally substituted by one or more Substituted from a substituent of C1·4, a halogen (preferably fluorine) and an aryl group; more preferably R4 is a cyclopropyl group; R_5 is H, halogen or CN' is preferably halogen or CN, more preferably a chlorine or CN, more preferably chlorine; and R2 and R3 together with a nitrogen atom to be bonded to form a saturated heterocyclic group of the formula (b), wherein Ra, Rb and Re are independently 11 or Cm alkyl, and More preferably Ra, Rb and R. Independently hydrazine or methyl, and more preferably 1 and Rb are independently hydrazine or methyl' and Re is η, more preferably 113 is H, Rb is methyl, and Rc is hydrazine. In another embodiment, the invention is directed to a hydrazone compound, wherein: R] is ΝΗ2;

Rs爲Η或鹵素；尺4爲Cn院基或Cl8環烷基_C().6烷基，較佳爲c2_8 烷基或C3_8環烷基- Co.i烷基；其中烷基可選擇性經一或多個齒素原子（較佳氟）取代，C38環烷基可選擇性經或多個獨立地選自C1.4烷基、鹵素（較佳氟）及芳基之取代基取代；及汉2及R3 —起與所連接之氮原子形成飽和雜環基，其 ^爲4-至7-員單環、7_至8_員橋接雙環或8_至12_員稠合雙環’其中該雜環基可包含高至兩個N原子且不含任何、他雜原子’及可選擇性經—或多個獨立地選自Cl"烷基及NRaRb之取代基取代’惟雜環基包含兩個n原子且 -76 - 200951136 不經NRaRb基團取代，或包含—個N原子且經—個NRaRb 基團取代。在另一實施態樣中’本發明關於式I化合物，其中：Rs is hydrazine or halogen; ft 4 is Cn or C8 cycloalkyl-C().6 alkyl, preferably c2-8 alkyl or C3-8 cycloalkyl-Co.i alkyl; wherein alkyl is optional Substituted by one or more dentate atoms (preferably fluorine), the C38 cycloalkyl group may be optionally substituted with or a plurality of substituents independently selected from the group consisting of C1.4 alkyl, halogen (preferably fluorine) and aryl; And Han 2 and R3 together form a saturated heterocyclic group with the nitrogen atom to be bonded, which is a 4- to 7-membered monocyclic ring, a 7- to 8-membered bridged double ring or an 8 to 12-membered fused double ring. Wherein the heterocyclic group may contain up to two N atoms and does not contain any, its hetero atom 'and optionally may be-- or a plurality of substituents independently selected from Cl" alkyl and NRaRb substituted 'unheterocyclic group Containing two n atoms and -76 - 200951136 is not substituted by the NRaRb group, or contains -N atoms and is substituted with -NRaRb groups. In another embodiment, the invention relates to a compound of formula I, wherein:

Ri 爲 NH2 ;Ri is NH2 ;

Rs爲Η或鹵素；以爲Cu院基或C3-8環烷基_Cq-6烷基，較佳爲c2-8 烷基或（：3·8環烷基-Co-,烷基；其中烷基可選擇性經—或 0 多個鹵素原子（較佳氟）取代，c3.8環烷基可選擇性經一或多個獨立地選自4烷基、鹵素（較佳氟）及芳基之取代基取代；及 R·2爲11或Ci.4烷基，及汉3爲氮雜環丁烷基、吡咯啶基、哌啶基或氮雜環庚烷基’其可選擇性經一或多個C1_4 院基取代。在另一實施態樣中’本發明關於式I化合物，其中： Ri 爲 nh2 ; 〇 r5爲Η或鹵素；汉4爲Cu烷基或C3-8環烷基_cQ6烷基，較佳爲c2_8 院基或C3_8環烷基-Co-!烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代，C3-8環烷基可選擇性經 —或多個獨立地選自Cl-4烷基、鹵素（較佳氟）及芳基之取代基取代；及汉2及R3 —起與所連接之氮原子形成選自（a)至（h )之飽和雜環基，其中^及Rb具有上文所述式I化合物中之意義，及Rc及。獨立地爲11或Ci-4烷基。 -77- 200951136 在另一實施態樣中，本發明關於式I化合物，其中： R!爲 NH2 ; R5爲Η或鹵素；汉4爲C!.8烷基或C3.8環烷基-CG.6烷基，較佳爲C2_8 烷基或c3-8環烷基-Cod烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代，C3.8環烷基可選擇性經 —或多個獨立地選自山烷基、鹵素（較佳氟）及芳基之取代基取代；及 R2及R3 —起與所連接之氮原子形成選自（a)至（h )之飽和雜環基，及Ra、Rb、R。及Rd獨立地爲Η或Ci-4 烷基，較佳地Ra、Rb、Rc及Rd獨立地爲Η或甲基。在另一實施態樣中，本發明關於式I化合物，其中： R!爲 ΝΗ2 ; Κ·5爲Η或鹵素； R4爲Cu烷基或C3-8環烷基-CQ_6烷基，較佳爲c2-8 烷基或C3-8環烷基-Co.!烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代，C3_8環烷基可選擇性經 —或多個獨立地選自Ci·4烷基、鹵素（較佳氟）及芳基之取代基取代；及 R2及R3 —起與所連接之氮原子形成選自（a)及（b )之飽和雜環基，其中1及Rb具有上文所述式I化合物中之意義，及Rc爲^1或烷基，較佳地Rc爲Η。在另一實施態樣中’本發明關於式1化合物，其中： R 1 爲 Ν Η 2 ; 200951136 R5爲Η或鹵素； R4爲Cu烷基或c3_8環烷基-Cq_6烷基，較佳爲c2.8 烷基或C3_8環烷基-Co.i烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代，C3_8環烷基可選擇性經一或多個獨立地選自0^_4烷基、鹵素（較佳氟）及芳基之取代基取代；及 R2及R3 —起與所連接之氮原子形成選自（a)及（b φ )之飽和雜環基，及Ra、Rb及R。獨立地爲11或Ci-4烷基’較佳地Ra、Rb及Re獨立地爲η或甲基，更佳地Ra 及Rb獨立地爲Η或甲基’及Re爲η，又更佳地Ra爲Η ’ Rb爲甲基，及Re爲Η。在另一實施態樣中’本發明關於式Ϊ化合物，其中： R!爲 ΝΗ2 ; R5爲Η或鹵素； R4爲Ci-8院基或C3-8環院基-C〇_6院基，較佳爲C2-8 Φ 院基或環院基- Cq^院基；其中烷基可選擇性經—或多個鹵素原子（較佳氟）取代，C3_8環烷基可選擇性經一或多個獨_LL地選自Ci_4焼基、鹵素（較佳氟）及芳基之取代基取代；及 R2及R3 —起與所連接之氮原子形成式（a)之飽和雜環基’其中1及Rb具有上文所述式Ϊ化合物中之意義，及1^爲11或Cu烷基，及更佳地Re爲H。在另一實施態樣中’本發明關於式I化合物，其中：Rs is hydrazine or halogen; is a Cu-based or C3-8 cycloalkyl-Cq-6 alkyl group, preferably a c2-8 alkyl group or a (:3.8 cycloalkyl-Co-, alkyl group; The group may be optionally substituted with - or more than 0 halogen atoms (preferably fluorine), and the c3.8 cycloalkyl group may be optionally selected from one or more independently selected from the group consisting of a 4-alkyl group, a halogen (preferably fluorine) and an aryl group. Substituted by a substituent; and R·2 is 11 or Ci.4 alkyl, and Han 3 is azetidinyl, pyrrolidinyl, piperidinyl or azepanyl' which is selectively Or a plurality of C1_4 substituents. In another embodiment, the invention relates to a compound of formula I, wherein: Ri is nh2; 〇r5 is hydrazine or halogen; and Han 4 is Cu alkyl or C3-8 cycloalkyl _ a cQ6 alkyl group, preferably a c2_8 or a C3-8 cycloalkyl-Co-! alkyl group; wherein the alkyl group may be optionally substituted by one or more halogen atoms (preferably fluorine), and the C3-8 cycloalkyl group may be optionally selected. Substituting - or a plurality of substituents independently selected from the group consisting of Cl-4 alkyl, halogen (preferably fluorine) and aryl; and Han 2 and R 3 together with the nitrogen atom to be bonded are selected from (a) to a saturated heterocyclic group of (h), wherein R and Rb have the formula The meaning of the compound, and Rc and independently are 11 or Ci-4 alkyl. -77- 200951136 In another embodiment, the invention relates to a compound of formula I, wherein: R! is NH2; R5 is Η Or halogen; Han 4 is C..8 alkyl or C3.8 cycloalkyl-CG.6 alkyl, preferably C2-8 alkyl or c3-8 cycloalkyl-Cod alkyl; wherein alkyl is selective Substituted by one or more halogen atoms (preferably fluorine), the C3.8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from the group consisting of an alkylene group, a halogen (preferably fluorine) and an aryl group; And R2 and R3 together with the nitrogen atom to be bonded form a saturated heterocyclic group selected from (a) to (h), and Ra, Rb, R. and Rd are independently a hydrazine or a Ci-4 alkyl group, preferably The Ra, Rb, Rc and Rd are independently hydrazine or methyl. In another embodiment, the invention relates to a compound of formula I, wherein: R! is ΝΗ2; Κ·5 is hydrazine or halogen; R4 is cumane Or a C3-8 cycloalkyl-CQ-6 alkyl group, preferably a c2-8 alkyl group or a C3-8 cycloalkyl-Co.! alkyl group; wherein the alkyl group may be selectively passed through one or more halogen atoms (more Substituted by a good fluorine, the C3_8 cycloalkyl group may be optionally selected from - or independently selected from Ci. a substituent of a 4-alkyl group, a halogen (preferably fluorine) and an aryl group; and R2 and R3 together with a nitrogen atom to be bonded form a saturated heterocyclic group selected from (a) and (b), wherein 1 and Rb Having the meaning of the compound of formula I above, and Rc is ^1 or alkyl, preferably Rc is Η. In another embodiment, the invention relates to a compound of formula 1, wherein: R 1 is Ν Η 2; 200951136 R5 is hydrazine or halogen; R4 is Cu alkyl or c3_8 cycloalkyl-Cq-6 alkyl, preferably c2.8 alkyl or C3-8 cycloalkyl-Co.i alkyl; wherein alkyl is optional Substituted by one or more halogen atoms (preferably fluorine), the C3_8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from the group consisting of 0^_4 alkyl, halogen (preferably fluorine) and aryl; And R2 and R3 together with the nitrogen atom to be bonded form a saturated heterocyclic group selected from (a) and (b φ ), and Ra, Rb and R. Independently 11 or Ci-4 alkyl' preferably Ra, Rb and Re are independently η or methyl, more preferably Ra and Rb are independently Η or methyl ' and Re is η, and more preferably Ra is Η ' Rb is methyl, and Re is Η. In another embodiment, the invention relates to a compound of the formula, wherein: R! is ΝΗ2; R5 is hydrazine or halogen; and R4 is a Ci-8 or a C3-8 ring-based C-1-6. Preferably, it is a C2-8 Φ yard or a ring-based base - a Cq^ group; wherein the alkyl group may be optionally substituted with or a plurality of halogen atoms (preferably fluorine), and the C3_8 cycloalkyl group may be selectively passed through one or more a substituent selected from the group consisting of a Ci_4 fluorenyl group, a halogen (preferably fluorine) and an aryl group; and R2 and R3 together with a nitrogen atom to be bonded to form a saturated heterocyclic group of the formula (a) And Rb has the meaning of the above formula compound, and 1 is 11 or Cu alkyl group, and more preferably Re is H. In another embodiment, the invention relates to a compound of formula I, wherein:

Ri 爲 NH2 ; -79- 200951136Ri is NH2; -79- 200951136

Rs爲Η或鹵素； R4爲Cu烷基或c3-8環烷基-cQ.6烷基，較佳爲c2-8 烷基或C3_8環烷基-CQ. 1烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代，C3_8環烷基可選擇性經一或多個獨立地選自C!-4烷基、鹵素（較佳氟）及芳基之取代基取代；及 R2及R3—起與所連接之氮原子形成式（a)之飽和雜環基，其中Ra、Rb及Re獨立地爲Η或Cm烷基，及更佳地Ra、Rb及Re獨立地爲Η或甲基，及更佳地Ra及Rb 獨立地爲Η或甲基，及R。爲Η，又更佳地Ra爲H，Rb爲甲基，及Rc爲Η。在另一實施態樣中，本發明關於式I化合物，其中：Rs is hydrazine or halogen; R4 is Cu alkyl or c3-8 cycloalkyl-cQ.6 alkyl, preferably c2-8 alkyl or C3-8 cycloalkyl-CQ. 1 alkyl; Substituted by one or more halogen atoms (preferably fluorine), the C3_8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from C!-4 alkyl, halogen (preferably fluorine) and aryl. Substituting; and R2 and R3 together with a nitrogen atom to be bonded to form a saturated heterocyclic group of formula (a), wherein Ra, Rb and Re are independently fluorene or Cm alkyl, and more preferably Ra, Rb and Re are independently The ground is hydrazine or methyl, and more preferably Ra and Rb are independently hydrazine or methyl, and R. Preferably, Ra is H, Rb is methyl, and Rc is deuterium. In another embodiment, the invention is directed to a compound of formula I, wherein:

Rj Μ νη2 ； R5爲Η或鹵素；爲Ci-8院基或匚3_8環院基_C〇_6垸基，較佳爲C2-8 烷基或C3.8環烷基烷基；其中烷基可選擇性經一或多個鹵素原子（較佳氟）取代，C3_8環烷基可選擇性經一或多個獨立地選自C1.4院基、齒素（較佳氟）及芳基之取代基取代；及及R3 —起與所連接之N原子形成式（b)之飽和雜環基，其中Ra及Rb具有上文所述式I化合物中之意義，及Re爲Η或Cu烷基’及更佳地R。爲Η。在另一實施態樣中’本發明關於式1化合物，其中：Rj Μ νη2 ; R5 is hydrazine or halogen; is a Ci-8 or a 匚3_8 ring-based _C〇_6 fluorenyl group, preferably a C2-8 alkyl group or a C3.8 cycloalkylalkyl group; The group may be optionally substituted by one or more halogen atoms (preferably fluorine), and the C3_8 cycloalkyl group may be optionally selected from one or more independently selected from the group consisting of C1.4, dentate (preferably fluorine) and aryl. Substituent substitution; and R3 together with the N atom to be bonded form a saturated heterocyclic group of formula (b) wherein Ra and Rb have the meanings of the compounds of formula I above, and Re is hydrazine or cumane Base 'and better R. Why? In another embodiment, the invention relates to a compound of formula 1, wherein:

Ri 爲 ΝΗ2 ; 200951136 R5爲Η或圖素；尺4爲Cu院基或c3-8環烷基_Cq_6烷基，較佳爲c2-8 烷基或C3-8環烷基-cQ.i烷基；其中烷基可選擇性經—或多個鹵素原子（較佳氟）取代，C3.8環烷基可選擇性經一或多個獨立地選自C^-4烷基、鹵素（較佳氟）及芳基之取代基取代；及 R2及R3 —起與所連接之N原子形成式（b)之飽和 ^ 雜環基’其中Ra、Rb及R。獨立地爲11或Ci.4烷基，較佳地Ra、Rb及R。獨立地爲Η或甲基，更佳地Ra及Rb獨立地爲Η或甲基，及r_。爲η，及又較佳地Ra爲h，Rb爲甲基，及Rc爲Η。再者’本發明包括上述特定及較佳實施例之所有可能的組合。在一另外之實施態樣中，本發明關於選自實施例！ _ 4 6之式I化合物。 φ 在一另外之實施態樣中’本發明關於式I化合物，其在1 ΟμΜ下（較佳在1 μΜ及甚至更佳在〇· 1 μΜ下，如實施例47或48中所述Η4受體分析中）對於η4受體活性提供超過5 0 %抑制效果。本發明化合物含有一或多個鹼性氮原子，因此可與有機酸或無機酸形成鹽類。這些鹽類的例子包括：與無機酸如氫氯酸、氫溴酸、氫碘酸、硝酸、過氯酸、硫酸、或磷酸所形成的鹽類；以及與有機酸如甲烷磺酸、三氟甲烷擴酸、乙烷磺酸、苯磺酸、對甲苯磺酸、反丁烯二酸、草酸 -81 - 200951136 、乙酸、順丁烯二酸、抗壞血酸、檸檬酸、乳酸、酒石酸、丙一酸、經乙酸（glycolic acid) 、丁二酸、及丙酸所形成的鹽類。可用的鹽類其類型並無限制，只要其於醫療目的使用時爲藥學上可接受者。「藥學上可接受之鹽」一詞是指根據醫學判斷適合用於與人類和其他哺乳動物的組織接觸而無不良毒性、刺激性、過敏性反應等的鹽類。藥學上可接受之鹽在此技術領域中是爲人熟知的。式I化合物的鹽類可在本發明化合物的最終單離與純化期間獲得’或者可以習用方式藉足量想要用的酸對式I 化合物進行處理而製得。利用離子交換樹脂，可使式I化合物的鹽類藉離子交換而轉化爲式I化合物的其他鹽類。式I化合物與其鹽類可能在一些物理性質上有所不同 ’但就本發明的目的而言卻是相同的。式I化合物的所有鹽類均包含在本發明的範圍內。本發明化合物可能會與反應所用的溶劑或用來沈澱或結晶化的溶劑形成複合物（complexes)，這些複合物係稱爲溶劑合物。文中所用「溶劑合物」一詞是指溶質（式 I化合物或其鹽類）與溶劑所形成化學計量不定的複合物，溶劑的例子包括藥學上可接受的溶劑，如水、乙醇等，而與水所形成的複合物則稱爲水合物。本發明化合物（或其鹽類）的溶劑合物（包括水合物）均包含在本發明的範圍內。式I化合物可呈不同的物理型式，即非晶形與結晶型 -82- 200951136 。再者，本發明化合物可能具有能結晶成多於一種型式的能力，即稱爲多晶型（polymorphism)的特性。多晶型可藉此技術領域中已知的各種物理性質來區別，例如X射線繞射圖案、熔點、或溶解度。式I化合物的所有物理型式（包括其所有多晶型（polymorphs ))均包含在本發明之範圍內。本發明化合物中，有的化合物可呈數種光學異構物及 /或數種非鏡像異構物（diastereoisomers)。非鏡像異構物可藉習用技術如層析法或分段結晶法來分離；而光學異構物則可藉習用光學離析（optical resolution)技術加以離析，而得到純光學異構物（optically pure isomers) 。此離析步驟可對任何對掌性合成中間物施行或對式I 產物施行。純光學異構物也可利用鏡像特異性合成法（ enantiospecific synthesis)而個別製得。本發明涵蓋所有個別異構物及其混合物（例如消旋混合物或非鏡像異構物混合物），不論是以合成方式取得或是藉物理方式將它們混合而得者。式I化合物可藉以下所述方法製得。對熟習此技術者明顯易知的是，用來製備既定化合物的確實方法可能視其化學結構而異。此外，在以下所述某些方法中，可能必須或者建議以習用保護基將反應性或不穩定的基團加以保護。這些保護基的本質以及用來將這些保護基導入或去除的步驟均爲此技術領域中已知者（例如參考 Greene T.W.與 Wuts P.G.M 的著作 “Protective Groups in Organic -83- 200951136Ri is ΝΗ2; 200951136 R5 is Η or pixel; rule 4 is Cu-based or c3-8 cycloalkyl-Cq_6 alkyl, preferably c2-8 alkyl or C3-8 cycloalkyl-cQ.i alkane a group; wherein the alkyl group is optionally substituted with or a plurality of halogen atoms (preferably fluorine), and the C3.8 cycloalkyl group is optionally independently selected from C^-4 alkyl, halogen (more Substituents of the fluoro group and the aryl group; and R2 and R3 together with the N atom to be bonded form a saturated heterocyclic group of the formula (b) wherein Ra, Rb and R. Independently 11 or Ci.4 alkyl, preferably Ra, Rb and R. Independently hydrazine or methyl, more preferably Ra and Rb are independently hydrazine or methyl, and r_. It is η, and further preferably Ra is h, Rb is a methyl group, and Rc is Η. Further, the present invention includes all possible combinations of the specific and preferred embodiments described above. In a further embodiment, the invention is directed to an embodiment selected from! _ 4 6 of the compound of formula I. φ In a further embodiment, the invention relates to a compound of formula I which is under 1 ΟμΜ (preferably at 1 μΜ and even more preferably at 〇 1 μΜ as described in Example 47 or 48) In the bulk assay, more than 50% inhibition was provided for η4 receptor activity. 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 with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid, or phosphoric acid; and organic acids such as methanesulfonic acid, trifluorocarbon Methane acid expansion, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid-81 - 200951136, acetic acid, maleic acid, ascorbic acid, citric acid, lactic acid, tartaric acid, propionic acid a salt formed by acetic acid, succinic acid, and 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 salt" means a salt which is suitable for use in contact with human and other mammalian tissues according to medical judgment without adverse toxicity, irritation, allergic reaction and the like. Pharmaceutically acceptable salts are well known in the art. Salts of the compounds of formula I can be obtained during the final isolation and purification of the compounds of the invention or can be prepared by 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' 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., and The complex formed by 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 be in different physical forms, i.e., amorphous and crystalline -82-200951136. 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 embraced 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 product of formula I. Pure optical isomers can also be prepared individually using 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 these protecting groups are known in the art (for example, reference to Greene T.W. and Wuts P.G.M "Protective Groups in Organic -83- 200951136

Synthesis”，John Wiley & Sons，第三版，1 999 )。除非另有指明，否則在以下所述方法中’不同取代基的定義係如以上就式I化合物所述之定義。大致而言，式I化合物可藉式II化合物與式III化合物的反應而製得，如以下流程圖所示：Synthesis", John Wiley & Sons, 3rd edition, 1 999. Unless otherwise indicated, the definition of 'different substituents' in the methods described below is as defined above for the compounds of formula I. The compound of formula I can be prepared by reacting a compound of formula II with a compound of formula III, as shown in the following scheme:

其中RrRrRrIU及n5具有以上有關式I所述之定義，而Rio爲離去基’如鹵素、甲院磺醯氧基（mesylate )、甲苯磺醯氧基（tosylate )或三氟甲烷磺醯氧基（ triflate )。式II化合物與式ΠΙ化合物之間的反應可利用耦合劑如PyBOP (六氟磷酸苯並***-1-基-氧基三吡咯啶基鐵， -84- 200951136 benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate)，於適當溶劑（如 1，4 -二嚷院、四氫呋喃、二氯甲烷、N，N-二甲基甲醯胺、乙腈或其混合物，較佳爲乙腈或乙腈/二噁烷之混合物）中，在有鹼（如 N，N-二異丙基乙基胺、二甲基苯胺、二乙基苯胺、三乙胺或1,8-二氮雜雙環並[5.4.0]十一碳-7-烯（DBU)，較佳爲三乙胺）情況下進行。此反應可在介於室溫與迴流溫度之間的溫度（較佳加熱）下進行。或者，式I化合物可藉式III化合物與式II化合物的反應性衍生物（ΠΒ )之間的反應製得，其中該反應性衍生物（ΠΒ)是將化合物II裡的羥基轉化成離去基（如鹵素、甲烷磺醯氧基、甲苯磺醯氧基或三氟甲烷磺醯氧基）而製得的。式II化合物的-0H基可在選擇性有適當溶劑，選擇性有鹼如氯化四乙基銨、二異丙基乙基胺或二乙基苯胺的情況下，透過與鹵化劑如P〇Cl3的反應；或者可在適當溶劑如1,4-二噁烷或1,2-二氯乙烷裡透過與P〇Cl3/PCl5或 N，N-二甲基甲醯胺/草醯氯混合物的反應，而轉化成離去基（如鹵素，較佳爲氯）。此反應是藉加熱（較佳係在介於100 °C與140 °c之間的溫度下）進行。此外，在吡啶存在下，式II化合物的羥基可藉與三氟甲烷磺酸酐反應而轉化成三氟甲烷磺醯氧基。在適當溶劑如二氯甲烷中，在鹼如三乙胺或吡啶存在下，式π化合物的羥基可藉與對_ 甲苯磺醯氯或甲烷磺醯氯反應而轉化成甲苯磺醯氧基或甲 -85- 200951136 烷磺醯氧基。然後’讓所得式II化合物的反應性衍生物（IIB )與式III化合物反應而得到式I化合物。此反應是在適當的溶劑（如乙醇、甲醇、丁醇、N，N-二甲基甲醯胺、二甲亞颯、四氫呋喃、乙腈或甲苯）裡，於鹼（包括有機胺，如三乙胺、N，N-二異丙基乙基胺、二甲基苯胺、及二乙基苯胺）存在下’並加熱（較佳係在介於50與140 °C之間的溫度）之下進行。加熱可以熱方式進行，或藉著在一可達到上述溫度的瓦數（wattage )之下微波輻射的方式進行〇大致而言，在進行式II與式III化合物之間或式IIB 與式III化合物之間的反應之前，先將式III化合物的胺基取代基加以保護，以避免產生副產物。此外，必要時，也可將式II與式IIB化合物的胺基（R,)加以保護。可用任何適當的胺基保護基，如第三丁氧羰基（Boc)。當式Π及/或式III及/或式IIB化合物的胺基取代基被保護時，可能需要後續去除保護基的步驟，此係於標準條件下進行。所以當所用的保護基是Boc時，可透過添加由強酸（如HC1 )在適當溶劑如1,4-二噁烷、***、或甲醇裡所形成的溶液或透過二氯甲烷中三氟乙酸的處理，而直接對粗產物進行去除保護基。式III化合物可由購買取得，或者可藉文獻中所揭示的步驟製得。視取代基R! ( NH2或H)的本質而定，式II化合物 200951136 可藉由式IV與氰胺（cyanamide )或甲醯胺反應而製得’ 如以下流程圖所示：Wherein RrRrRrIU and n5 have the definitions described above for formula I, and Rio is a leaving group such as halogen, mesylate, tosylate or trifluoromethanesulfonyloxy. (triflate ). The reaction between the compound of the formula II and the hydrazine compound can be carried out using a coupling agent such as PyBOP (benzotriazol hexafluoro-l-yloxypyrrolidinyl iron, -84- 200951136 benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate ), in a suitable solvent (such as 1,4 - dioxin, tetrahydrofuran, dichloromethane, N, N-dimethylformamide, acetonitrile or a mixture thereof, preferably a mixture of acetonitrile or acetonitrile / dioxane) In the presence of a base (such as N,N-diisopropylethylamine, dimethylaniline, diethylaniline, triethylamine or 1,8-diazabicyclo[5.4.0] eleven carbon It is carried out in the case of -7-ene (DBU), preferably triethylamine. This reaction can be carried out at a temperature between room temperature and reflux temperature (preferably heating). Alternatively, a compound of formula I can be prepared by a reaction between a compound of formula III and a reactive derivative of the compound of formula II (ΠΒ) wherein the reactive derivative (ΠΒ) converts the hydroxyl group of compound II to a leaving group. Prepared by (e.g., halogen, methanesulfonyloxy, toluenesulfonyloxy or trifluoromethanesulfonyloxy). The -OH group of the compound of the formula II can be permeated with a halogenating agent such as P oxime in the presence of a suitable solvent, optionally with a base such as tetraethylammonium chloride, diisopropylethylamine or diethylaniline. The reaction of Cl3; or it may be permeated with P〇Cl3/PCl5 or N,N-dimethylformamide/grass chloride in a suitable solvent such as 1,4-dioxane or 1,2-dichloroethane. The reaction is converted to a leaving group (e.g., halogen, preferably chlorine). This reaction is carried out by heating (preferably at a temperature between 100 ° C and 140 ° C). Further, in the presence of pyridine, the hydroxyl group of the compound of formula II can be converted to the trifluoromethanesulfonyloxy group by reaction with trifluoromethanesulfonic anhydride. In a suitable solvent such as dichloromethane, in the presence of a base such as triethylamine or pyridine, the hydroxyl group of the compound of formula π can be converted to tosyloxy or a group by reaction with p-toluenesulfonyl chloride or methanesulfonyl chloride. -85- 200951136 alkanesulfonyloxy. The resulting reactive derivative (IIB) of the compound of formula II is then reacted with a compound of formula III to provide a compound of formula I. This reaction is carried out in a suitable solvent (such as ethanol, methanol, butanol, N,N-dimethylformamide, dimethyl hydrazine, tetrahydrofuran, acetonitrile or toluene) in a base (including organic amines such as triethyl) Amine, N,N-diisopropylethylamine, dimethylaniline, and diethylaniline are present in the presence of 'heating (preferably at a temperature between 50 and 140 ° C) . Heating can be carried out thermally, or by means of microwave radiation at a wattage at which the above temperatures can be reached. Roughly, between compounds of formula II and formula III or compounds of formula IIB and formula III The amine substituent of the compound of formula III is first protected prior to the reaction to avoid the formation of by-products. Further, if necessary, the amine group (R,) of the compound of the formula II and the formula IIB can also be protected. Any suitable amine protecting group such as a third butoxycarbonyl group (Boc) can be used. When the amine substituent of the formula Π and/or the compound of the formula III and/or the formula IIB is protected, a subsequent step of removing the protecting group may be required, which is carried out under standard conditions. Therefore, when the protecting group used is Boc, it can be added by adding a solution of a strong acid (such as HCl) in a suitable solvent such as 1,4-dioxane, diethyl ether or methanol or by passing trifluoroacetic acid in dichloromethane. The crude product is directly subjected to removal of the protecting group. The compound of formula III can be obtained by purchase or can be prepared by the procedures disclosed in the literature. Depending on the nature of the substituent R! (NH2 or H), the compound of formula II 200951136 can be prepared by reacting formula IV with cyanamide or formamide as shown in the following scheme:

❹ 其中R!、R4及R5具有上述式I所述意義。與氰胺之反應係在酸（如HC1)在適當溶劑（如1,4-二噁烷或二***）中於酸（如HC1)之存在下藉由在適當溫度下加熱（通常爲介於室溫與迴流溫度之間的適當溫度，較佳爲迴流溫度）而進行。反應可藉由後續在適當溫度 (較佳爲迴流溫度）加入鹼（如氫氧化鈉）而完成。〇與甲醯胺之反應係在適當溫度（通常在100°C與200 °C之間）藉由加熱純甲醯胺中之式IV化合物而進行之。式IV化合物可藉由式V化合物與氯丙二酸二乙酯反應而製得，如以下流程圖所示： -87- 200951136❹ wherein R!, R4 and R5 have the meanings of the above formula I. The reaction with cyanamide is carried out by heating at an appropriate temperature (usually between the acid (such as HCl) in a suitable solvent (such as 1,4-dioxane or diethyl ether) in the presence of an acid (such as HCl). It is carried out at a suitable temperature between room temperature and reflux temperature, preferably at reflux temperature. The reaction can be carried out by subsequently adding a base such as sodium hydroxide at a suitable temperature, preferably at reflux temperature. The reaction of hydrazine with formamide is carried out at a suitable temperature (usually between 100 ° C and 200 ° C) by heating a compound of formula IV in pure formamide. The compound of formula IV can be prepared by reacting a compound of formula V with diethyl chloromalonate as shown in the following scheme: -87- 200951136

VBVB

其中R4及R5具有上述式I所述意義，M爲族IA中之鹼金屬，如鋰、鈉或鉀，較佳爲鋰。反應可在適當溶劑（如Ν，Ν-二甲基甲醯胺）中進行，接著加入於適當溶劑（如乙醇）中之鹼（如1,8 -二氮雜雙環[5.4.0]十一碳-7-烯（DBU)或較佳爲1，5-二氮雜雙環 [4.3.0]壬-5-烯（DBN ) 。 Ο 或者，式IV化合物可藉由式VB化合物與乙醇酸乙酯反應而製得。反應是利用三苯基膦與偶氮二羧酸二乙酯 (diethyl azodicarboxy late，DEAD )在適當溶劑（如四氫呋喃）中進行。此反應可在介於0°C與迴流溫度之間的溫度下進行’較佳爲在室溫下進行。通常必須添加鹼（如 NaH)以造成環化反應。式V及VB化合物係可購得或自可購得之化合物藉由標準流程輕易地製得。例如，烯醇酯形成可在標準條件（ -88 - 200951136 如二異丙基胺化鋰（LDA ) /四氫呋喃，氫化鈉/二***或第三丁氧化鉀/四氫呋喃）中進行（參見例如Journal of Medicinal Chemistry 2004，47，1448-1464 及 Tetrahedron Letters 1 982，23，47，4977-4980 ) ° 再者，本發明某些化合物亦可從其他式I化合物開始藉由，使用有機化學中習知反應在標準實驗條件下，在一或多個步驟將官能基適當轉化而製得。這些轉化反應包括Wherein R4 and R5 have the meanings of the above formula I, and M is an alkali metal in the group IA, such as lithium, sodium or potassium, preferably lithium. The reaction can be carried out in a suitable solvent such as hydrazine, hydrazine-dimethylformamide, followed by addition of a base in a suitable solvent such as ethanol (e.g., 1,8-diazabicyclo[5.4.0] eleven Carbon-7-ene (DBU) or preferably 1,5-diazabicyclo[4.3.0]non-5-ene (DBN). Alternatively, the compound of formula IV can be obtained from a compound of formula VB and glycolate B. The ester reaction is carried out by using triphenylphosphine and diethyl azodicarboxylate (DEAD) in a suitable solvent such as tetrahydrofuran. The reaction can be carried out at 0 ° C and reflux. Performing at a temperature between temperatures is preferably carried out at room temperature. It is usually necessary to add a base such as NaH to cause a cyclization reaction. The compounds of formula V and VB are commercially available or can be purchased from a standard by standard. The process is easily prepared. For example, the enol ester formation can be carried out under standard conditions (-88 - 200951136 such as lithium diisopropylamide (LDA) / tetrahydrofuran, sodium hydride / diethyl ether or potassium tert-butoxide / tetrahydrofuran) Carry out (see for example the Journal of Medicinal Chemistry 2004, 47, 1448-1464 and Tetrahedron Letters 1 982, 23, 47 , 4977-4980) ° Further, certain compounds of the invention may also be suitably converted from other compounds of formula I by using customary reactions in organic chemistry under standard experimental conditions, in one or more steps. Made. These conversion reactions include

式I化合物，其中R5爲H ( la )，藉由鹵化劑處理進行鹵化反應，製得式lb化合物：A compound of formula I, wherein R5 is H(la), is subjected to a halogenation reaction by treatment with a halogenating agent to produce a compound of formula lb:

其中R!、R2、R3及R4具有上述式I化合物所述意義，及 Y爲鹵素，較佳爲氯。例如，當Y爲C1時，反應可利用適當氯化劑（如磺醯氯）在適當溶劑（如三氯甲烷、甲苯或乙腈，較佳爲乙腈）在-5 0 °C與室溫間之溫度（較佳約-l〇°C )下進行；式lb化合物藉由氰化劑之處理進行氰化反應，產生式I c化合物： -89- 200951136Wherein R!, R2, R3 and R4 have the meanings as defined above for the compound of formula I, and Y is halogen, preferably chlorine. For example, when Y is C1, the reaction can be carried out using a suitable chlorinating agent (such as sulfonium chloride) in a suitable solvent (such as chloroform, toluene or acetonitrile, preferably acetonitrile) at -5 ° C and room temperature. The temperature is (preferably about -10 ° C); the compound of formula lb is cyanated by treatment with a cyanating agent to produce a compound of formula Ic: -89- 200951136

其中Ri、R2、R3及R4具有上述式I化合物所述意義，及 γ爲鹵素，較佳爲氯或溴，更佳爲氯。反應可在適當溶劑 (二甲基亞碾、Ν,Ν-二甲基甲醯胺或N-甲基吡咯啶酮，較佳二甲基亞諷）中藉由用氰化物來源（如氰化鈉、鉀、銅或鋅）處理式lb化合物，及加熱（較佳在110°C)下進行，或者在適當溶劑（如Ν,Ν-二甲基甲醯胺）中藉由用氰化銅或鋅及鈀觸媒，如四（三苯基膦）鈀（0)或乙酸鈀，處理及加熱下進行。在進行上述式I化合物之轉化反應前，建議用適當保護基，較佳第三丁氧羰基（Boc)，保護存在NR2R3中之胺基。若使用Boc，去保護可藉由將在適當溶劑（如1，4-二噁烷、二***或甲醇）中之強酸（如HC1)或者於二氯甲烷中之三氟乙酸加至粗產物而直接進行。如以上所述，本發明化合物顯現出很強的組織胺h4 受體拮抗劑活性。因此預期本發明化合物可用於治療或預防哺乳動物（包括人類）由H4受體所媒介之疾病。 -90- 200951136 可用本發明化合物治療或預防的疾病包括過敏性、免疫性、或發炎性之疾病或疼痛。可用本發明化合物治療或預防的過敏性、免疫性、或發炎性之疾病例子包括（但不限於）：呼吸系統疾病，如氣喘、過敏性鼻炎、和慢性阻塞性肺疾病（C〇pd ):眼部疾病，如過敏性鼻結膜炎、乾眼、和白內障；皮膚疾病 ’如皮膚炎（例如異位性皮膚炎）、牛皮癣、蓴麻疹、和 ❿ 搔癢症；發炎性腸疾病’如潰瘍性結腸炎和Crohn氏症 :類風濕性關節炎；多發性硬化症；皮膚狼瘡；全身性紅斑性狼瘡；以及移植排斥。可用本發明化合物治療或預防的疼痛例子包括發炎性疼痛、發炎性痛覺過敏、痛覺過敏、手術後疼痛、偏頭痛、癌症疼痛、內臟痛、骨關節炎疼痛、及神經病性疼痛。在一較佳實施態樣中’本發明化合物是用來治療或預防過敏性、免疫性、或發炎性疾病。在一更佳實施態樣中 φ ’本發明化合物是用來治療或預防選自以下的過敏性、免疫性、或發炎性疾病：呼吸系統疾病、眼部疾病、皮膚疾病、發炎性腸疾病、類風濕性關節炎、多發性硬化症、皮膚狼瘡、全身性紅斑性狼瘡、及移植排斥。在一又更佳的實施態樣中，該過敏性、免疫性、或發炎性疾病係選自氣喘、過敏性鼻炎、慢性阻塞性肺疾病（COPD )、過敏性鼻結膜炎、乾眼、白內障、皮膚炎（例如異位性皮膚炎）、牛皮癬、蓴麻疹、搔癢症、潰瘍性結腸炎、Crohn氏症、類風濕性關節炎、多發性硬化症、皮膚狼瘡、全身性紅 -91 - 200951136 斑性狼瘡、以及移植排斥。在另一較佳實施態樣中，本發明化合物是用於治療或預防疼痛，較佳爲發炎性疼痛、發炎性痛覺過敏、痛覺過敏、手術後疼痛、偏頭痛、癌症疼痛、內臟痛'骨關節炎疼痛、或神經病性疼痛。用來測定化合物與組織胺h4受體相互作用之能力的分析方法在此技術領域中是已知的，例如可利用h4受體結合分析方法，如實施例47中所詳述者。另一種有用的分析方法是對表現H4受體的膜進行GTP〔 r -35S〕結合分析。也可以利用以表現H4受體之細胞所進行的功能性分析方法，例如在用以測量任何種類之由與該H4受體有關之第二信使（如細胞內cAMP含量或Ca2 +移動）所媒介的細胞活性的系統中進行。在此方面，一種用於測定抗-H4受體活性之非常有用的功能性分析方法是於嗜酸性球 (例如人類嗜酸性球）中進行的 Gated 自體螢光 Forward Scatter assay ( GAFS)，詳述於實施例 48，此爲此技術領域中已知者（例如參考以上先前技術段落中所引述 Buckl及KF等人在2003年所揭示的方法，其以參照方式納入本文）。可用於測試本發明化合物活性的活體內分析方法亦爲此技術領域中已知者（例如參考以上先前技術段落中針對活體內動物模型所列出的各種文獻資料，尤其是與腹膜炎、胸膜炎、過敏性氣喘、發炎性腸疾病、異位性皮膚炎、搔癢症、及疼痛的活體內模型有關的文獻資料，其均以參照方式納入本文）。 -92- 200951136 本發明化合物之選擇性可藉由利用標準組織胺受體結合分析分法使用類似於實施例47所揭示之不同組織胺受體而加以測試。另外，爲了測試其他受體或離子通道之選擇性，可根據述於文獻中之標準流程（參見例如Cerep-Le Bois l’Ev6que 2008目錄及其中引述之參考資料）使用對應之放射性配位體的替代分析方法。爲了測試對於酵素之選擇性，可使用藉由從其基質之產物的形成測定及酵素活性。爲了選擇活性化合物，在實施例47所提供的測試裡，化合物在1〇μΜ下所進行的測試對於H4受體活性必須達到高於5 0 %的抑制活性。在此分析中，更佳地化合物在ΙμΜ下（又更佳地在0.1 μΜ下）應呈現高於50%的抑制程度。較佳化合物在實施例48之GAFS分析中亦呈現有效的活性；較佳地，在此分析中，化合物在ι〇μΜ (更佳地在ΙμΜ下，又更佳地在〇·1μΜ下）下應達到高於50 %的抑制活性。相對於其他受體（特別是Η3、蕈毒鹼、腎上腺素、多巴胺及血清素受體）而言，較佳化合物對於Η4受體應呈現選擇之親和性。發明亦有關含有本發明化合物（或其藥學上可接受之鹽或溶劑合物）與一或多種藥學上可接受之賦形劑的藥學組成物。賦形劑從與組成物其他成分可相容的意義上而言必須是「可接受的」’而且對於該賦形劑的接受者無害。本發明化合物可以任何藥學調合物的形式投予’這些 -93- 200951136 調合物的本質（係已知者）將視活性化合物的本質及其投予途徑而定。可使用任何途徑，例如口服、非經腸、經鼻部、經眼部、經局部、及經直腸之投予。在較佳實施態樣中’本發明化合物係口服的。在另一實施態樣中，本發明化合物係經局部投予。用於口服的固體組成物包括錠劑、顆粒、與膠囊。在任一種固體組成物的情況下，其製造方法是基於將活性化合物與賦形劑簡單混合、乾式粒化或濕式粒化。這些賦形劑可爲例如：稀釋劑，如乳糖、微晶纖維素、甘露醇、或磷酸氫銘；黏合劑（binding agents)，如澱粉、明膠、或聚乙稀基吡咯陡酮（povidone);崩解劑，如錢甲基澱粉鈉、或交聯殘甲基纖維素鈉（sodium croscarmellose) :及潤滑劑，如硬脂酸鎂、硬脂酸、或滑石。爲了延遲錠劑在胃腸道中的崩解和吸收，可利用已知技術再對錠劑塗覆適當的賦形劑，因而提供較長時間的持續作用，或僅改善其感官性質或安定性。也可以利用天然或合成的膜塗覆劑，藉塗覆於惰性粒子上的方式而將活性化合物摻入。軟性明膠膠囊也是可以的，其中活性化合物係與水或油性介質（例如椰子油、礦物油、或橄欖油）混合。用於透過加水以配製口服懸浮液的粉末和顆粒可藉混合活性化合物和分散劑或濕潤劑、懸浮劑、和保存劑的方式獲得，也可以添加其他賦形劑，例如甜味劑、風味劑（ flavouring agents)、和著色劑。口服用的液體形式包括含有一般惰性稀釋劑（如純化 -94- 200951136 的水、乙醇、山梨醇、甘油、聚乙二醇（macrogols)、和丙二醇）的乳化液、溶液、懸浮液、糖漿、和酏劑。該等組成物也可含有輔助佐劑（coadjuvants )，如濕潤劑、懸浮劑、甜味劑、風味劑、保存劑、和緩衝劑。根據Φ發明’用於非經腸投予的可注射製劑含有在水性或非水性溶劑（如丙二醇、聚乙二醇、或植物油）中所形成的無菌溶液、懸浮液、或乳化液。這些組成物也可含 φ 有輔助佐劑’如濕潤劑、乳化劑、分散劑、和保存劑。它們可藉任何已知方法滅菌或製成無菌固體組成物，此無菌固體組成物則在就要使用之前才被溶於水中或任何無菌的可注射介質裡。也可以從無菌材料開始，並在所有製造過程中均將這些材料保持在這些條件下。本發明化合物也可以經過調製，以用於局部施用來治療發生在透過例如眼睛、皮膚、和腸道等途徑可及的區域或器官的病狀。調合物包括霜劑（creams )、洗劑、凝膠 φ 、粉末、溶液、和貼片’其中該化合物係分散或溶解於適當的賦形劑裡。爲供經鼻投予或吸入’該化合物可調製成氣溶膠，利用適當的推進劑可方便地從該氣溶膠釋出該化合物。劑量與給藥頻率將視所要治療疾病的本質與嚴重程度 ’患者的年齡、一般狀況.、和體重，以及所投予的特定化合物和投予途徑等因素而定。舉例而言，合適的劑量範圍爲每日約0_01 mg/Kg至約100 mg/Kg，此劑量可以單次或分成多次來投予。 -95- 200951136 【實施方式】本發明透過以下實施例來說明。實施例實施例中使用下列縮寫：Wherein Ri, R2, R3 and R4 have the meanings as defined above for the compound of formula I, and γ is halogen, preferably chlorine or bromine, more preferably chlorine. The reaction can be carried out in a suitable solvent (dimethyl sulfite, hydrazine, hydrazine-dimethylformamide or N-methylpyrrolidone, preferably dimethyl succinyl) by using a cyanide source (eg cyanide). Sodium, potassium, copper or zinc) treatment of the compound of formula lb, and heating (preferably at 110 ° C), or in a suitable solvent (such as hydrazine, hydrazine-dimethylformamide) by using copper cyanide Or zinc and palladium catalysts, such as tetrakis(triphenylphosphine)palladium(0) or palladium acetate, are treated and heated. Prior to carrying out the conversion reaction of the above compound of formula I, it is recommended to protect the amine group present in NR2R3 with a suitable protecting group, preferably a third butoxycarbonyl group (Boc). If Boc is used, deprotection can be carried out by adding a strong acid (such as HCl) in a suitable solvent (such as 1,4-dioxane, diethyl ether or methanol) or trifluoroacetic acid in dichloromethane to the crude product. Directly. 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 may be used to treat or prevent diseases mediated by the H4 receptor in mammals, including humans. -90- 200951136 Diseases which can be treated or prevented by the compounds of the invention include allergic, immunological, or inflammatory diseases or pain. Examples of allergic, immunological, or inflammatory diseases that can be treated or prevented by the compounds of the invention include, but are not limited to, respiratory diseases such as asthma, allergic rhinitis, and chronic obstructive pulmonary disease (C〇pd): Eye diseases such as allergic rhinoconjunctivitis, dry eye, and cataract; skin diseases such as dermatitis (eg atopic dermatitis), psoriasis, urticaria, and pruritus; inflammatory bowel disease such as ulcerative colon Inflammation and Crohn's disease: rheumatoid arthritis; multiple sclerosis; cutaneous lupus; systemic lupus erythematosus; and transplant rejection. Examples of pain that can be treated or prevented with the compounds of the present invention include inflammatory pain, 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 or prevent allergic, immunological, or inflammatory diseases. In a preferred embodiment, φ 'the compound of the invention is used to treat or prevent an allergic, immunological, or inflammatory disease selected from the group consisting of respiratory diseases, eye diseases, skin diseases, inflammatory bowel diseases, Rheumatoid arthritis, multiple sclerosis, cutaneous lupus, systemic lupus erythematosus, and transplant rejection. In 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, cutaneous lupus, systemic red-91 - 200951136 Lupus, and transplant rejection. In another preferred embodiment, the compounds of the invention are useful for treating or preventing pain, preferably inflammatory pain, inflammatory hyperalgesia, hyperalgesia, post-operative pain, migraine, cancer pain, visceral pain. Arthritis pain, 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 47. Another useful analytical method is the GTP [r -35S] binding assay for 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. In this regard, a very useful functional assay for determining anti-H4 receptor activity is the Gated Forward Scatter assay (GAFS) in eosinophils (eg, human eosinophils). This is described in Example 48, which is known to those skilled in the art (see, for example, the methods disclosed in 2003 by Buckl and KF et al., 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, pruritus, and pain are incorporated herein by reference). -92- 200951136 The selectivity of the compounds of the invention can be tested by using standard histamine receptor binding assays using different histamine receptors similar to those disclosed in Example 47. In addition, in order to test the selectivity of other receptors or ion channels, the corresponding radioligand can be used according to the standard procedures described in the literature (see, for example, the Cerep-Le Bois l'Ev6que 2008 catalogue and references cited therein). Alternative analytical methods. To test for selectivity to an enzyme, enzyme activity can be determined by formation of a product from its matrix. In order to select the active compound, the test carried out at 1 〇 μΜ of the compound in the test provided in Example 47 must achieve an inhibitory activity of more than 50% for H4 receptor activity. In this analysis, a better compound should exhibit a degree of inhibition greater than 50% at ΙμΜ (and more preferably at 0.1 μΜ). The preferred compound also exhibits potent activity in the GAFS analysis of Example 48; preferably, in this assay, the compound is in ι〇μΜ (more preferably under ΙμΜ, more preferably at 〇·1μΜ) More than 50% inhibition activity should be achieved. Preferred compounds should exhibit a selective affinity for the Η4 receptor relative to other receptors (especially Η3, muscarinic, epinephrine, dopamine, and serotonin receptors). The invention also relates to a pharmaceutical composition comprising a compound of the invention (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients. The excipient must be "acceptable" in the sense of being compatible with the other ingredients of the composition and is not deleterious to the recipient of the excipient. The compounds of the present invention can be administered in the form of any pharmaceutical composition. The nature of the compounds of the above-mentioned -93-200951136 (known to those skilled in the art) 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. In a preferred embodiment, the compounds of the invention are administered orally. In another embodiment, the compounds of the invention are administered topically. 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 hydrogen phosphate; binding agents such as starch, gelatin, or povidone. a disintegrant such as sodium methyl starch, or sodium croscarmellose: 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 organoleptic properties or stability. It is also possible to incorporate the active compound by means of a natural or synthetic film coating by application to 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 formulating an oral suspension by adding water may be obtained by mixing the active compound with a dispersing or wetting agent, a suspending agent, and a preservative, and other excipients such as a sweetener or a flavoring agent may be added. ( flavouring agents), and colorants. Liquid forms for oral administration include emulsions, solutions, suspensions, syrups containing a general inert diluent such as water, ethanol, sorbitol, glycerol, macrogols, and propylene glycol from -94-200951136. And tincture. The compositions may also contain coadjuvants such as wetting agents, suspending agents, sweeteners, flavoring agents, preservatives, and buffering agents. The injectable preparation for parenteral administration according to the Φ invention 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 φ with auxiliary adjuvants such as wetting agents, emulsifiers, 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 φ, 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 compound and route of administration being administered. For example, a suitable dosage range is from about 0 mg to about 100 mg per kg per day, and that the dose can be administered in a single or divided dose. -95-200951136 [Embodiment] The present invention will be described by way of the following examples. EXAMPLES The following abbreviations are used in the examples:

AcN ··乙腈 DMF : N，N-二甲基甲醯胺 DMSO :二甲基亞颯 EtOAc:乙酸乙酯 MeOH :甲醇 Min :分鐘 MS :質譜AcN ··acetonitrile DMF : N,N-dimethylformamide DMSO : dimethyl hydrazine EtOAc: ethyl acetate MeOH : methanol Min : min MS : mass spectrum

PyBOP ：六氟磷酸（苯並***-1-基-氧基）三吡咯啶基鱗〔（benzotriazol-l - yloxy ) tripyrrolidinopho sphonium hexafluorophosphate〕 tR :停留時間 LC-MS :液相層析-質譜法 LC-MS光譜法是利用下列方法之一進行：方法 1 : X-Terra MS C 1 8 5 μιη ( 1 〇〇 mmx2 · 1 mm )，溫度：30°C，流速：0.35 mL/min，沖提液：A = AcN ’ B = 10 mM NH4HC03，梯度·· 0 min 10% A ; 10 min 90% A； 15 min 90% A。 200951136 方法 2 :管柱 Acquity UPLC BEH C18 1.7μπι ( 2.1x50 mm )，溫度：40°C，流速：0.50 mL/min，沖提液： A = AcN，B = 10 mM NH4HC03，梯度：0 min 1 〇% A ; 0.25 min 10% A ； 3.00 min 90% A ； 3.75 min 90% A。參考性實施例1 甲基[(3R)-吡咯啶-3-基]胺基甲酸第三丁酯 0 ( a) [ ( 3R) -1-苄基吡咯啶-3-基]甲基胺基甲酸第三丁酯在一由（3R) -1-苄基-N-甲基吡咯啶-3-胺（1〇 g， 52.5 5 mmol)於115 mL CH2C12中所形成並冷卻到〇°C的溶液裡，把溶於15 mL CH2C12的二碳酸二（第三丁酯） (di-tert-butyl dicarbonate ) ( 11.6 g，53.07 mmol)加入。將所得溶液於室溫下攪拌1 8小時。溶劑蒸發後，所得粗產物以矽膠進行層析，用極性漸增的己烷/ EtOAc混 φ 合物作爲沖提液，而得到14.5 g所要的化合物（產率： 95% )。 LC-MS (方法 1) : tR = 9.55 min; m/z = 291 (MH + (b )標題化合物將以上所得到的化合物（1 4 · 5 g，5 0.1 4 mmol )、 Pd/C ( 10% > 50% 於水中）（3g)、以及甲酸銨（12.7 g，200.5 mmol)在 MeOH( 390 mL)與水（45 mL)的 -97- 200951136 混合物中所形成的溶液於迴流下加熱5小時。反應混合物透過Celite®過濾後，濾液以EtOAc和MeOH洗過。把溶劑濃縮至乾，而得到10 · 6 g呈油狀的標題化合物（產率：100% )。 RMN ( 3 00 MHz，CDC13 ) δ 1.38 ( s，9Η )， 1.72 ( m > 1Η ) ，1.96(m，lH) ，2.53(s，NH) > 2.80 (s，3H) ，2.87(m，lH) > 2.93 ( m > 1H ) - 3.11 ( in ，2H ) ，4.58 ( m，1H )。參考性實施例2 氮雜環丁烷-3-基（甲基）胺基甲酸第三丁酯 (a) [1-(二苯基甲基）氮雜環丁烷-3-基]甲基胺基甲酸第三丁酯依參考性實施例1中（a )部份所述類似步驟，但使用1-(二苯基甲基）-N -甲基氮雜環丁烷-3-胺而非（3R )-1-节基-N -甲基啦略陡-3-胺，得到所要化合物（產率： 73% )。 LC-MS (方法 1) : tR = 10.14 min ; m/z = 353 ( MH + (b )標題化合物將以上所得化合物（6·18 g，17.53 mmol)於60 mL MeOH和15 mL EtOAc中所形成的溶液用氬氣沖滌。接著添加Pd/C(10%、50%於水中）（929 mg)，用氬氣 200951136 再度沖滌該溶液，並於H2氣氛下攪拌1 8小時。反應混合物透過Celite®過濾後，濾液以EtOAc和MeOH洗過，把溶劑濃縮至乾而得到5.66 g含有標題化合物與一當量二苯基甲烷的混合物，以所得型態繼續使用於下一步驟。 lH RMN ( 3 00 MHz · CD3〇D) <5 : 1 · 44 ( s，9H )， 2.88 (s，3H) . 3.56 ( m > 2H ) ，3.71(m，2H) » 4.75 (m，1 H )。 ❿ 參考性實施例3 甲基（3-甲基氮雜環丁烷-3_基）胺基甲酸第三丁酯 (a) [1-(二苯基甲基）-3-甲基氮雜環丁烷-3-基]甲基胺基甲酸第三丁酯依參考性實施例1中（a)部份所述類似步驟，但使用1-(二苯基甲基）-N,3-二甲基氮雜環丁烷-3-胺而非（ 3R ) -1-苄基-N-甲基吡咯啶-3-胺，得到全量產率（鲁 quantitative yield)之所要化合物。 'H NMR ( 300 MHz » CDC13) δ : 1.53 ( s，12Η)， 2.59 ( s，3H) ，2.89 ( m，2H) ，3.16 ( m，2H) - 4.30 (s > 1H ) ，7.17(m，lH) > 7.26 ( m > 2H ) - 7.42 ( m ，1 H )。 (b )標題化合物 (a )部份所得化合物（6.06 g，16.5 mmol )於60 mL MeOH及15 mL EtOAc中之溶液以用氬氣沖滌。接著添加 -99- 200951136PyBOP: benzotriazol-1-yl-oxyl tripyrrolidinopho sphonium hexafluorophosphate tR: residence time LC-MS: liquid chromatography-mass spectrometry LC-MS spectroscopy was performed using one of the following methods: Method 1: X-Terra MS C 1 8 5 μιη (1 〇〇mmx2 · 1 mm), temperature: 30 ° C, flow rate: 0.35 mL/min, elution Solution: A = AcN ' B = 10 mM NH4HC03, gradient · · 0 min 10% A ; 10 min 90% A; 15 min 90% A. 200951136 Method 2: Column Acquity UPLC BEH C18 1.7μπι (2.1x50 mm), Temperature: 40°C, Flow Rate: 0.50 mL/min, Eluent: A = AcN, B = 10 mM NH4HC03, Gradient: 0 min 1 〇% A ; 0.25 min 10% A ; 3.00 min 90% A ; 3.75 min 90% A. Reference Example 1 Methyl [(3R)-pyrrolidin-3-yl]carbamic acid tert-butyl ester 0 ( a) [( 3R) -1-benzylpyrrolidin-3-yl]methylamino The third butyl formate was formed in (3R)-1-benzyl-N-methylpyrrolidine-3-amine (1〇g, 52.5 5 mmol) in 115 mL of CH2C12 and cooled to 〇 °C. In the solution, di-tert-butyl dicarbonate (11. 6 g, 53.07 mmol) dissolved in 15 mL of CH2C12 was added. The resulting solution was stirred at room temperature for 18 hours. After evaporating the solvent, the obtained crude product was chromatographed eluted from EtOAc (EtOAc: EtOAc) LC-MS (method 1): tR = 9.55 min; m/z = 291 (MH + (b) % > 50% in water) (3g), and ammonium formate (12.7 g, 200.5 mmol) in a mixture of MeOH (390 mL) and water (45 mL) in -97-200951136 mixture was heated under reflux 5 After the reaction mixture was filtered through Celite®, EtOAc (EtOAc)EtOAc. CDC13) δ 1.38 ( s, 9Η ), 1.72 ( m > 1Η ) , 1.96 (m, lH) , 2.53 (s, NH) > 2.80 (s, 3H) , 2.87 (m, lH) > 2.93 ( m > 1H ) - 3.11 ( in , 2H ) , 4.58 ( m, 1H ). Reference Example 2 Azetidine-3-yl(methyl)aminocarbamic acid tert-butyl ester (a) [1 -(Diphenylmethyl)azetidin-3-yl]methylcarbamic acid tert-butyl ester according to the similar procedure described in part (a) of Reference Example 1, but using 1-(two) Phenylmethyl)-N-methylazetidin-3-amine instead of (3R)-1-pyrustyyl-N-methyl Slightly tert--3-amine gave the desired compound (yield: 73%). LC-MS (Method 1): t:::::::::::: • 18 g, 17.53 mmol) of a solution of 60 mL of MeOH and 15 mL of EtOAc was washed with argon. Then Pd/C (10%, 50% in water) (929 mg) was added and argon was used again. The solution was washed with EtOAc (3 mL) EtOAc (EtOAc)EtOAc. The mixture was used in the next step in the form obtained. lH RMN (3 00 MHz · CD3〇D) <5 : 1 · 44 ( s, 9H ), 2.88 (s, 3H) . 3.56 ( m > 2H ) , 3.71 (m, 2H) » 4.75 (m, 1 H ). ❿ Reference Example 3 Tert-butyl methyl (3-methylazetidin-3-yl)carbamate (a) [1-(Diphenylmethyl)-3-methylaza Cyclobutane-3-yl]methylcarbamic acid tert-butyl ester according to a similar procedure as described in part (a) of Reference Example 1, but using 1-(diphenylmethyl)-N,3- Dimethylazetidin-3-amine instead of (3R)-1-benzyl-N-methylpyrrolidin-3-amine gives the desired compound in full yield. 'H NMR ( 300 MHz » CDC13) δ : 1.53 ( s, 12 Η), 2.59 ( s, 3H) , 2.89 ( m, 2H) , 3.16 ( m, 2H) - 4.30 (s > 1H ) , 7.17 (m , lH) > 7.26 ( m > 2H ) - 7.42 ( m , 1 H ). (b) title compound (a) A portion of the obtained compound (6.06 g, 16.5 mmol) in 60 mL MeOH and 15 mL EtOAc. Then add -99- 200951136

Pd/C( 10%) (814 mg)，用氬氣再度沖滌該溶液，並於 H2氣氛下攪拌整夜。反應混合物透過Celite®過濾後，濾液以EtOAc和MeOH洗過，把溶劑濃縮至乾而得到4.55 g含有標題化合物與一當量二苯基甲烷的混合物，以所得型態使用。 ]Η NMR ( 300 MHz > CDC13) <5 : 1 · 4 5 ( s，12 Η )， 2.67(s，3H) ，3.28(m，lH) ，3.61(m，lH) · 3.87 (m，1H)，4.00 ( m，1H) ❹ 參考性實施例4a 2-環丙基-3-羥基丙烯腈鋰鹽在-78 °C 下，至二異丙基胺（18.3 mL，129.44 mmol )於四氫呋喃（ 220 mL)中之溶液逐滴加入正丁基鋰（ 1.6 Μ 於己垸中，81 mL，129.44 mmol)。反應混合物在-78 °C下攪拌1小時。加入環丙基乙腈（1 1.4 mL， 123.27 mmol )於四氫呋喃（20 mL )中之溶液，然後溫熱 ◎ 至-30 °C (歷時 40 min)。加入甲酸乙酯（12.3 mL， 147.93 mmol)，及反應混合物在-1 0°C下攪拌1小時，然後溫熱至室溫及攪拌整夜。沉澱之固體經由真空過濾收集，以二***清洗，及加以空氣乾燥至製得爲白色粉末之所要化合物（7.8g，55% )。 lU NMR ( 3 00 MHz > DMSO) <5 : 〇. 12 ( m，2 Η )， 0.43 ( m > 2H ) > 1.39 ( m > 1H ) ，8_16(s，lH)。 -100- 200951136 參考性實施例4b-4k 用述於參考性實施例4a之類似步驟，但使用適當起 ^ 料而非環丙基乙腈，製得下列化合物：Pd/C (10%) (814 mg), the solution was again washed with argon and stirred overnight under H2 atmosphere. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc. Η NMR ( 300 MHz > CDC13) <5 : 1 · 4 5 ( s, 12 Η ), 2.67 (s, 3H) , 3.28 (m, lH) , 3.61 (m, lH) · 3.87 (m, 1H), 4.00 (m, 1H) ❹ Reference Example 4a 2-Phenylpropyl-3-hydroxyacrylonitrile lithium salt at -78 ° C to diisopropylamine (18.3 mL, 129.44 mmol) in tetrahydrofuran The solution in (220 mL) was added dropwise n-butyllithium (1.6 Μ in hexane, 81 mL, 129.44 mmol). The reaction mixture was stirred at -78 °C for 1 hour. Add a solution of cyclopropylacetonitrile (1 1.4 mL, 123.27 mmol) in tetrahydrofuran (20 mL) and warm to -30 °C (40 min). Ethyl formate (12.3 mL, 147.93 mmol) was added, and the mixture was stirred at -1 °C for 1 hour, then warmed to room temperature and stirred overnight. The solid which precipitated was collected by vacuum filtration, washed with diethyl ether and dried in vacuo to give the desired compound (7.8 g, 55%). lU NMR (3 00 MHz > DMSO) <5 : 〇. 12 ( m, 2 Η ), 0.43 ( m > 2H ) > 1.39 ( m > 1H ) , 8_16 (s, lH). -100- 200951136 Reference Examples 4b-4k The following compounds were prepared using similar procedures as described in Reference Example 4a, but using the appropriate starting materials instead of cyclopropylacetonitrile:

4i 名稱起始物料方法(LC-MS) 2-乙基-3-羥基丙烯腈鋰鹽丁腈 (1) 3-羥基-2-丙基丙烯腈鋰鹽戊腈 (2) 3-羥基-2-異丙基丙烯腈鋰鹽異戊腈 (3) 2-苄基-3-羥基丙烯腈鋰鹽 3-苯基丙腈 ⑷ — 2-環丁基-3-羥基丙烯腈鋰鹽環丁基乙腈 (5) 2-環戊基-3-羥基丙烯腈鋰鹽環戊基乙腈 ⑹ 3-羥基-2-異丁基丙烯腈鋰鹽異己腈 ⑺ ~~-- 2-第三丁基-3-羥基丙烯腈鋰鹽 3,3-二甲基丁腈 ⑻ 3-羥基-2-(四氫-2H-耻喃-4-基) 丙烯腈鋰鹽 2-(四氫-2H-吡喃-4-基) 乙腈 (9) 3-羥基-2-(1-(甲氧基甲基)環丙基)丙烯腈鋰鹽 2-(1-(甲氧基甲基)環丙基)乙腈 (10) "”Η 7·2 ΗΖ) (2) ιΗ NMR ( 3 00 MHz > DMSO ) δ ： 0.86 ( t . 3H * J ，1.93 ( q，2H，J 7.2 Hz ) ，8.04 ( s，1H)。 7·2 η2) 8 〇6 ( s '4i designation starting material method (LC-MS) 2-ethyl-3-hydroxyacrylonitrile lithium salt nitrile (1) 3-hydroxy-2-propyl acrylonitrile lithium salt valeronitrile (2) 3-hydroxy-2 -isopropyl acrylonitrile lithium salt isovaleronitrile (3) 2-benzyl-3-hydroxy acrylonitrile lithium salt 3-phenylpropionitrile (4) - 2-cyclobutyl-3-hydroxyacrylonitrile lithium salt cyclobutyl Acetonitrile (5) 2-cyclopentyl-3-hydroxyacrylonitrile lithium salt cyclopentylacetonitrile (6) 3-hydroxy-2-isobutyl acrylonitrile lithium salt isohexyl nitrile (7) ~~-- 2- tert-butyl-3 -Hydroxyacrylonitrile lithium salt 3,3-dimethylbutyronitrile (8) 3-hydroxy-2-(tetrahydro-2H-pyran-4-yl) acrylonitrile lithium salt 2-(tetrahydro-2H-pyran- 4-yl)acetonitrile (9) 3-hydroxy-2-(1-(methoxymethyl)cyclopropyl)acrylonitrile lithium salt 2-(1-(methoxymethyl)cyclopropyl)acetonitrile ( 10) ""Η 7·2 ΗΖ) (2) ιΗ NMR (3 00 MHz > DMSO ) δ : 0.86 ( t . 3H * J , 1.93 ( q, 2H, J 7.2 Hz ) , 8.04 ( s, 1H 7·2 η2) 8 〇6 ( s '

NMR ( 3 00 MHz，DMSO) 6 ： 0.85 ( t > 3H > J ，1.27(m，2H) ，1.85(q，2H，J9.6Hz)， 1 H )。NMR (3 00 MHz, DMSO) 6 : 0.85 (t > 3H > J, 1.27 (m, 2H), 1.85 (q, 2H, J 9.6 Hz), 1 H ).

NMR ( 3 00 MHz，DMSO ) δ 0.86 ( d . 6H > J ，2.7 ( m，1H ) > 7.98 ( s - 1H )。 NMR ( 300 MHz，DMSO ) <5 : 3.2 ( s，2H) ，7- 坩，5H ) > 8.26 ( s - 1H )。 200951136 (5) lU NMR ( 3 00 MHz > DMSO) (5 : 1.5-1.9(m，6H) ，3.28 ( m，1H ) ，7.99 ( s，1H )。 (6) NMR ( 3 00 MHz > DMSO) δ ： 0.82 ( d > 6H > J 6.6 Hz) ，1.54(hept，1H，J 6.9 Hz) ，1.78(d，2H，J 6.9 Hz) ，8.12 ( s，1H)。NMR (3 00 MHz, DMSO) δ 0.86 (d. 6H > J, 2.7 (m, 1H ) > 7.98 ( s - 1H ) NMR ( 300 MHz, DMSO ) < 5 : 3.2 ( s, 2H) , 7- 坩, 5H ) > 8.26 ( s - 1H ). 200951136 (5) lU NMR (3 00 MHz > DMSO) (5: 1.5-1.9 (m, 6H), 3.28 (m, 1H), 7.99 (s, 1H). (6) NMR (3 00 MHz > DMSO) δ : 0.82 ( d > 6H > J 6.6 Hz) , 1.54 (hept, 1H, J 6.9 Hz), 1.78 (d, 2H, J 6.9 Hz), 8.12 (s, 1H).

(7) JH NMR ( 3 00 MHz > DMSO) δ ： 1 .1 -1.75 ( m > 8H )，2.8 ( m，1H ) ，8.05 ( s，1H )。 (8) NMR ( 3 00 MHz > DMSO) δ ： 1.05 ( s - 9H )， 8.00 (s1 1H)。(7) JH NMR (3 00 MHz > DMSO) δ : 1 -1 - 1.75 (m > 8H), 2.8 (m, 1H), 8.05 (s, 1H). (8) NMR (3 00 MHz > DMSO) δ : 1.05 (s - 9H), 8.00 (s1 1H).

(9) *H NMR ( 300 MHz > DMSO) (5 ： 1.25- 1.45 ( m · 4H )，2.55(m，lH) ，3.25(m，2H) ，3.79(m，2H)， 8.1 1 ( s，1 H )。 (10) lH NMR ( 3 00 MHz，DMSO) δ ： 0.3 5-0.50 ( m， 4H ) ，3.11(s，2H) ，3.32(s，3H) ，8.06(s，lH) o 參考性實施例5 a 3-胺基·4-環丙基呋喃-2-羧酸乙酯參考性實施例4a所製得化合物（5 g，43·47 mm〇l) 於DMF( 108 mL)中之溶液加入氯丙二酸二乙醋（8.4 mL，52.17 mmol)。反應混合物在室溫下攪拌整夜。用水（500 mL)稀釋後，反應混合物以乙酸乙酯萃取。混合的有機萃取液以Na2S04乾燥。過濾後，濾液濃縮至乾，提供橘色泥漿。橘色泥漿溶於乙醇（217 mL)，加入I,5- -102- 200951136 二氮雜雙環[4.3.0]壬.5-嫌（5.9 d，47.8 mm〇1)，及混合物在室溫下攪拌整夜。溶液濃縮至乾，粗殘餘物在砂膠上進行層析，用極性漸增的乙酸乙酯及己垸之混合物作爲沖提液，而得到淡棕色油之3 g標題化合物（產率·· 65 % )。 . LC-MS (方法 2) ： tR = 1.88 min ； m/z 196 ( MH + 參考性實施例5b_5l 用述於參考性實施例5a之類似步驟，但使用適當起始物料而非參考性實施例4a所製得化合物，製得下列化合物：(9) *H NMR (300 MHz > DMSO) (5: 1.25- 1.45 (m · 4H ), 2.55 (m, lH), 3.25 (m, 2H), 3.79 (m, 2H), 8.1 1 (s , 1 H ). (10) lH NMR (3 00 MHz, DMSO) δ: 0.3 5-0.50 (m, 4H), 3.11 (s, 2H), 3.32 (s, 3H), 8.06 (s, lH) o Reference Example 5 a 3-Amino-4-cyclopropylfuran-2-carboxylic acid ethyl ester Reference compound 4a obtained compound (5 g, 43·47 mm 〇l) in DMF (108 mL) The solution was added to chloromalonic acid diethyl ether (8.4 mL, 52.17 mmol). The mixture was stirred at room temperature overnight. After diluted with water (500 mL), the mixture was extracted with ethyl acetate. Drying with Na2S04. After filtration, the filtrate was concentrated to dryness to give an orange mud. The orange mud was dissolved in ethanol (217 mL), and I,5--102-200951136 diazabicyclo[4.3.0]壬.5- Iris (5.9 d, 47.8 mm 〇 1), and the mixture was stirred at room temperature overnight. The solution was concentrated to dryness and the crude residue was chromatographed on silica gel using a mixture of ethyl acetate and hexane. As a rinse, 3 g of the title compound was obtained as a light brown oil. ·· 65 % ) . LC-MS (Method 2): tR = 1.88 min; m/z 196 (MH + Reference Example 5b_5l using a similar procedure as described in Reference Example 5a, but using the appropriate starting materials Instead of the compound prepared in Reference Example 4a, the following compounds were obtained:

-103- 200951136 參考性實施例名稱起始物料方法 (LC-MS) tR(min) m/z (MH+) 5b 3-胺基-4-乙基呋喃-2-羧酸乙酯參考性實施例4b 2 2.06 198 5c 3-胺基-4-丙基呋喃-2-羧酸乙酯參考性實施例4c 2 1.80 184 5d 3-胺基-4-異丙基呋喃-2-羧酸乙酯參考性實施例4d 2 1.98 198 5e 3-胺基-4-苄基呋喃-2-羧酸乙酯參考性實施例4e 2 2.22 244 (ΜΗ*) 5f 3-胺基-4-環丁基呋喃-2-羧酸乙酯參考性實施例4f 2 2.09 210 5g 3-胺基-4-環戊基呋喃-2-羧酸乙酯參考性實施例4g 2 2.28 224 5h 3-胺基-4-異丁基呋喃-2-殘酸乙酯參考性實施例4h 2 2.22 212 5i 3-胺基-4-苯基呋喃-2-羧酸乙酯 3-羥基-2·苯基丙烯睛鈉鹽 2 2.19 232 5j 3-胺基-4-第三丁基呋喃-2-羧酸乙酯參考性實施例4i 2 2.20 212 5k 3-胺基-4-(四氫-2H-吡喃-4-基)呋喃-2-羧酸乙酯參考性實施例4j 2 1.59 240 51 3-胺基-4-(1-(甲氧基甲基) 環丙基)呋喃-2-羧酸乙酯參考性實施例4k 2 1.88 240 參考性實施例6a2 -胺基-7 -環丙基呋喃並[3，2 d ]嘴:陡-4 -醇 200951136 參考性實施例5a所製廣化合物（2., )於1，4-二噁烷（37 mL)中之溶液加 48.66 mmol)，然後緩慢地加入4 μ 1，4 液（24 mL )。所得懸浮液在室溫下攪拌迴流下攪拌整夜。將溶劑蒸發，加入2M 60 mL) ’所得混合物在迴流下加熱6 /] 以3M HC1水溶液中和。所得沉澱物經 ΗζΟ清洗，加以乾燥，製得1.6 g標題介 % )。 LC-MS (方法 2) ： tR = 1.03 min；參考性實施例 6b-61 用述於參考性實施例6a之類似步驟始物料，製得下列化合物： ❹ g » 12.17 mmol 、氰胺（2.0 g，二噁烷的HC1溶 2小時，然後在 NaOH水溶液（時。反應混合物由過濾收集，以合物（產率：69 m/z = 192 ( MH + ，但使用適當起 -105- 200951136 參考性實施例名稱起始物料方法 (LC-MS) tR(min) m/z (ΜΗ) 6b 2-胺基-7-乙基呋喃並[3,2-d] 密陡-4-醇參考性實施例5b 2 0.96 180 6c 2-胺基-7-丙基呋喃並[3,2-d] 密啶-4-醇參考性實施例5c 2 1.22 194 6d 2-胺基-7-異丙基呋喃並[3,2-d]嘧啶斗醇參考性實施例5d 2 1.17 194 6e 2-胺基-7-苄基呋喃並[3,2-d] 嘧啶_4_醇參考性實施例5e 2 1.45 242 6f 2-胺基-7-環丁基呋喃並[3,2-d]嘧啶-4-醇參考性實施例5f 2 1.28 206 6g 2-胺基-7-環戊基呋喃並[3,2-d]嘧啶-4-醇參考性實施例5g 2 1.46 220 6h 2-胺基-7-異丁基呋喃並[3,2-d]嘧啶-4-醇參考性實施例5h 2 1.38 208 6i 2-胺基-7-苯基呋喃並[3,2-d] 密啶-4-醇參考性實施例5i 2 1.43 228 6j 2-胺基-7-第三丁基呋喃並 [3,2-d]嘧啶-4-醇參考性實施例5j 2 1.46 208 6k 2-胺基-7-(四氫-2H-吡喃-4-基)呋喃並[3,2-d]嘧啶-4-醇參考性實施例5k 2 0.85 236 61 2-胺基-7-(1-(甲氧基甲基)環丙基)呋喃並[3,2-d]嘧啶-4-醇參考性實施例51 2 0.98 236 參考性實施例7 a 7-環丙基呋喃並[3,2 d]嘧啶-4-醇 -106- 200951136 參考性實施例5 a製得之化合物（1 g，5.1 mmol )及甲醯胺（20 mL)之混合物在130 °C下攪拌3小時及在170 °C下攪拌整夜。H20倒至反應混合物，及以乙酸乙酯萃取。混合的有機萃取液以Na2S04乾燥。過濾後，濾液濃縮至乾’用己烷/乙酸乙酯（1/1)之混合物清洗所得固體及加以乾燥，製得0.66 g所要化合物（產率：73% )。 LC-MS (方法 2) ： tR = 1.03 min ； m/z = 177 ( MH + 參考性實施例8a (R) -1-( 2-胺基-7-異丙基呋喃並[3,2-d]嘧啶-4-基）吡咯啶-3-基（甲基）胺基甲酸第三丁酯參考性實施例6d製得之化合物 (1.3 g > 6.7 mmol ) 於乙腈（26 mL )中之懸浮液加入三乙胺（26 mL )、 PyBOP ( 3.85 g，7·4 mm〇l)及參考性實施例1製得之化 φ 合物（2.15 g ’ 10.8 mmol )。所得懸浮液在80°c加熱整夜。將溶劑蒸發至乾，殘餘物以二氯甲烷及水稀釋。用1 N NaOH將pH調整至9-10，及將各相分離。水相以二氯再次萃取’混合的有機相以Na2S04乾燥及濃縮至乾。製得之粗產物在矽膠上進行層析，用Et0Ac作爲沖提液’而得到2.08 g所要化合物（產率：82 % ) LC-MS (方法 2) : tR = 2.39 min ； m/z 376 ( MH + -107- 200951136 參考性實施例8b 1-(2-胺基-7-環丙基呋喃並[3,2-(1]嘧啶-4_基）氮雜環丁烷-3-基（甲基）胺基甲酸第三丁酯用述於參考性實施例8 a之類似步驟，但使用參考性實施例6a及2製得之化合物爲適當起始物料，製得朽題化合物。 LC-MS (方法 2) : tR = 2.11 min; m/z 360 (MH+) 參考性實施例9a 1- ( 2 -胺基-6-氯-7-環丙基呋喃並[3,2-d]嚼陡-4 -基）氮雜環丁烷-3-基（甲基）胺基甲酸第三丁酯在-10 °C下冷卻之參考性實施例8b所製得化合物（ 1.38 g’ 3.84 mmol)於乙腈（38 mL)中之懸浮液加入磺醯氯（0.31 mL，3.84 mmol) 。45分鐘後，加入另外之磺醯氯（0.2mL)，混合物在-10°C下另攪拌30分鐘。再次加入另外之磺醯氯（0.15 mL)，反應混合物在-10°C另攪拌30分鐘。然後，在-1(TC下加入NaHC03飽和溶液，以使反應混合物驟冷，然後再以乙酸乙酯稀釋。將各相分離，水相以乙酸乙酯萃取。混合的有機相以Na2S04乾燥，及濃縮至乾。粗殘餘物在矽膠上進行層析’用極性漸增的己烷/EtO Ac混合物作爲沖提液，而得到790 mg所要化合物（產率：52% ) LC-MS (方法 2) ： tR = 2.49 min ； m/z 3 94/3 96 ( 200951136 MH+ )。參考性實施例9b (R) -1- ( 2-胺基-6-氯-7-異丙基呋喃並[3,2-d]嘧啶-4-基 )吡咯啶-3-基（甲基）胺基甲酸第三丁酯用述於參考性實施例9 a之類似步驟，但使用參考性實施例 8a製得之化合物爲適當起始物料及三氯甲烷爲反應溶劑，製得標題化合物。 LC-MS (方法 2 ) : tR = 2 · 8 3 min ; m/z 410/412 ( MH+ )。實施例 1 7-環丙基-4- (4-甲基哌嗪-1-基）呋喃並[3,2-d]嘧啶-2-胺參考性實施例6a所製得化合物（0.15 g，0.78 mmol )於1，4-二噁烷（5 mL )及乙腈（5 mL )之混合物中之懸浮液加入三乙胺（4.7 inL ) 、PyBOP ( 0.41 g，0.78 mmol)及 1 -甲基哌嗪（0· 12 mL，1.09 mmol )。所得懸浮液在80 °C下加熱20小時。反應混合物在乙酸乙酯及 NaHC03飽和水溶液間分配。有機相以Na2S04乾燥及濃縮至乾。粗產物以製備性HPLC-MS (管柱X-Terra PREP MS C18 5μιη ( 100 mmxl9 mm)，流速：20 mL/min，沖提液：A = AcN，B = NH4HC03 75 mM，梯度：0 min A 10% ; 1 min A 10% ; 8 min A 90% )純化，包含產物之部分蒸發至乾，製得67 mg標題化合物（產率：31%) -109- 200951136-103- 200951136 Reference Example Name Starting Material Method (LC-MS) tR(min) m/z (MH+) 5b 3-Amino-4-ethylfuran-2-carboxylic acid ethyl ester Reference Example 4b 2 2.06 198 5c 3-Amino-4-propylfuran-2-carboxylic acid ethyl ester Reference Example 4c 2 1.80 184 5d 3-Amino-4-isopropylfuran-2-carboxylic acid ethyl ester reference Example 4d 2 1.98 198 5e ethyl 3-amino-4-benzylfuran-2-carboxylate Reference Example 4e 2 2.22 244 (ΜΗ*) 5f 3-Amino-4-cyclobutylfuran- Ethyl 2-carboxylate Reference Example 4f 2 2.09 210 5 g Ethyl 3-amino-4-cyclopentylfuran-2-carboxylate Reference Example 4g 2 2.28 224 5h 3-Amino-4-iso Butylfuran-2-residual acid ethyl ester Reference Example 4h 2 2.22 212 5i 3-Amino-4-phenylfuran-2-carboxylic acid ethyl ester 3-hydroxy-2·phenyl acrylonitrile sodium salt 2. 2.19 232 5j 3-Amino-4-t-butylfuran-2-carboxylic acid ethyl ester Reference Example 4i 2 2.20 212 5k 3-Amino-4-(tetrahydro-2H-pyran-4-yl) Ethyl furan-2-carboxylate Reference Example 4j 2 1.59 240 51 3-Amino-4-(1-(methoxymethyl)cyclopropyl)furan-2-carboxylic acid ethyl ester Reference example 4k 2 1.88 240 Reference Example 6a2 -Amino-7-cyclopropylfuro[3,2d] Mouth: Steep-4-Alcohol 200951136 The broad compound (2., ) prepared in Reference Example 5a is 1,4- A solution of dioxane (37 mL) was added to 48.66 mmol), then 4 μl, 4 (24 mL) was slowly added. The resulting suspension was stirred at room temperature under reflux and stirred overnight. The solvent was evaporated, 2M 60 mL) was added and the mixture obtained was heated under reflux 6 /] and neutralized with a 3M aqueous HCl solution. The resulting precipitate was washed with hydrazine and dried to give 1.6 g of title. LC-MS (method 2): tR = 1.03 min; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; , dioxane HC1 dissolved for 2 hours, then in aqueous NaOH (when the reaction mixture was collected by filtration, the yield (yield: 69 m / z = 192 (MH + , but use appropriate -105- 200951136) EXAMPLES Name Starting Materials Method (LC-MS) tR(min) m/z (ΜΗ) 6b 2-Amino-7-ethylfuro[3,2-d]-dense-4-ol Reference Construction Example 5b 2 0.96 180 6c 2-Amino-7-propylfuro[3,2-d]-mididin-4-ol Reference Example 5c 2 1.22 194 6d 2-Amino-7-isopropylfuran And [3,2-d]pyrimidinol Reference Example 5d 2 1.17 194 6e 2-Amino-7-benzylfuro[3,2-d]pyrimidin-4-ol Reference Example 5e 2 1.45 242 6f 2-Amino-7-cyclobutylfuro[3,2-d]pyrimidin-4-ol Reference Example 5f 2 1.28 206 6 g 2-Amino-7-cyclopentylfuran [3, 2-d]pyrimidin-4-ol Reference Example 5g 2 1.46 220 6h 2-Amino-7-isobutylfuro[3,2-d]pyrimidin-4-ol Reference Example 5h 2 1.38 208 6i 2-Amino-7-phenylfuro[3,2-d]-mididin-4-ol Reference Example 5i 2 1.43 228 6j 2-Amino-7-Third Nifuro[,,,,,,,,,,,,, -d]pyrimidin-4-ol Reference Example 5k 2 0.85 236 61 2-Amino-7-(1-(methoxymethyl)cyclopropyl)furo[3,2-d]pyrimidine-4 -Alcohol Reference Example 51 2 0.98 236 Reference Example 7 a 7-Cyclopropylfuro[3,2 d]pyrimidin-4-ol-106- 200951136 Reference Example 5 Compound obtained by a (1) A mixture of g, 5.1 mmol) and formamide (20 mL) was stirred at 130 ° C for 3 hours and at 170 ° C overnight. H20 was poured to the reaction mixture and extracted with ethyl acetate. The liquid was dried over Na 2 SO 4 . After filtration, the filtrate was concentrated to dry <RTI ID=0.0># </ RTI> </ RTI> </ RTI> </ RTI> hexane/ethyl acetate (1/1) mixture and dried to give the desired compound (yield: 73%). LC-MS (method 2): tR = 1.03 min; m/z = 177 (MH + + + - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - d]pyrimidin-4-yl)pyrrolidin-3-yl(methyl)aminocarbamic acid tert-butyl ester The compound obtained in Reference Example 6d (1.3 g > 6.7 mmol) in acetonitrile (26 mL) The suspension was added with triethylamine (26 mL), PyBOP ( 3.85 g, 7.4 mmol) and the yt compound (2.15 g ' 10.8 mmol) obtained in Reference Example 1. The resulting suspension was at 80°. c. Heat overnight. Evaporate the solvent to dryness. The residue is diluted with dichloromethane and water. The pH is adjusted to 9-10 with 1 N NaOH and the phases are separated. The aqueous phase is re-extracted with dichloride. The phase was dried over Na 2 SO 4 and concentrated to dryness. The obtained crude product was chromatographed on silica gel, using Et0Ac as a solvent to give 2.08 g of the desired compound (yield: 82 %) LC-MS (Method 2): tR = 2.39 min ; m/z 376 (MH + -107- 200951136 Reference Example 8b 1-(2-Amino-7-cyclopropylfuro[3,2-(1]pyrimidin-4-yl)nitrogen Tributyl butyl butane-3-yl (methyl) carbamic acid is described in the reference A similar procedure to Example 8a, but using the compound prepared in Reference Examples 6a and 2 as the appropriate starting material to give the title compound. LC-MS (Method 2): tR = 2.11 min; m/z 360 ( MH+) Reference Example 9a 1-(2-Amino-6-chloro-7-cyclopropylfuro[3,2-d]-cryros-4-yl)azetidin-3-yl ( The suspension of the compound (1.38 g ' 3.84 mmol) obtained in Reference Example 8b, which was cooled at -10 ° C, was added to the sulfonyl chloride (0.31). mL, 3.84 mmol). After 45 minutes, additional sulfonium chloride (0.2 mL) was added and the mixture was stirred at -10 ° C for another 30 min. additional sulfonium chloride (0.15 mL) was added again. The mixture was stirred for another 30 minutes. Then, a saturated solution of NaHC03 was added at -1 (TC) to quench the reaction mixture and then diluted with ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over Na 2 SO 4 and concentrated to dryness. The crude residue was chromatographed on silica gel, using a mixture of hexane/EtO Ac mixture with increasing polarity as a solvent to obtain 790 mg. Was obtained (yield: 52%) LC-MS (Method 2): tR = 2.49 min; m / z 3 94/3 96 (200951136 MH +). Reference Example 9b (R)-1-(2-Amino-6-chloro-7-isopropylfuro[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl (methyl The title compound was prepared using a similar procedure as described in Reference Example 9a, but using the compound obtained in Reference Example 8a as the appropriate starting material and chloroform as the solvent. LC-MS (method 2): tR = 2 · 8 3 min; m/z 410/412 (MH+). Example 1 7-Cyclopropyl-4-(4-methylpiperazin-1-yl)furo[3,2-d]pyrimidin-2-amine The compound obtained in Reference Example 6a (0.15 g, 0.78 mmol) of a suspension of a mixture of 1,4-dioxane (5 mL) and acetonitrile (5 mL) was added triethylamine (4.7 inL), PyBOP (0.41 g, 0.78 mmol) and 1-methylpiper Azine (0·12 mL, 1.09 mmol). The resulting suspension was heated at 80 ° C for 20 hours. The reaction mixture was partitioned between ethyl acetate and aqueous NaHCO3. The organic phase was dried over Na 2 SO 4 and concentrated to dryness. Crude product to preparative HPLC-MS (column X-Terra PREP MS C18 5 μιη (100 mm×l9 mm), flow rate: 20 mL/min, extract: A = AcN, B = NH4HC03 75 mM, gradient: 0 min A 10%; 1 min A 10%; 8 min A 90%) Purified, part of the product was evaporated to dryness to give 67 mg of the title compound (yield: 31%) -109 - 200951136

LC-MS (方法 2) ： tR 1.53 mi: ,/z 274 ( MH' 實施例 2-4 用述於實施例1之類似步驟，但使用適當起始物料，製得下列化合物：實施例名稱起始物料方法 (LC-MS) tR(min) m/z (Mlt) 2 7-環丙基-4-[(3S)-3-甲基哌嗪-1-基]呋喃並[3,2-d]嘧啶-2-胺 _—-— 參考性實施例6a 及(8)-(+)-2-甲基哌嗪 2 1.33 274 3 7-乙基-4-[4-甲基哌嗪-1-基]呋喃並[3,2-d]嘧啶-2-胺參考性實施例6b 及1-甲基哌嗪 2 1.44 262 4 4-[4_甲基峨曉-1-基]-7-丙基肤喃並[3,2-d]嘧啶-2·胺參考性實施例6c 及1-甲基哌嗪 2 1.64 276 實施例 5 7-環丙基-4- ( 3-(甲基胺基）氮雜環丁烷-丨-基）呋喃並 [3,2-d]嘧啶-2-胺 (a) 1-(2 -胺基-7-環丙基呋喃並[3,2-d]嘧陡-4-基）氮雜環丁烷-3-基（甲基）胺基甲酸第三丁酯參考性實施例6 a所製得化合物（0 · 1 5 g，〇 . 7 8 mm ο 1 )於1,4-二噁烷（5 mL)及乙腈（5mL)之混合物中之懸浮液加入三乙胺（4.7 mL) 、PyBOP (0.41 g，0.78 mmol 200951136 )及參考性實施例2所製得化合物（0.38 g，1·〇9 mmol) 。所得懸浮液在8 0 °C下加熱2 0小時。反應混合物在乙酸乙酯及NaHC03飽和水溶液間分配。有機相以Na2S04乾燥及濃縮至乾。所製得粗產物在矽膠上進行層析，用極性漸增的EtOAc/MeOH混合物作爲沖提液，而得到3 3 0 mg 所要化合物。 LC-MS (方法 2) ： tR = 2.15 min ； ra/z 360 ( MH+) ❹ b)標題化合物步驟a)所製得化合物（〇.33g，0.92 mmol)及4 Μ HC1於1，4-二噁烷溶液（7 mL )中之混合物在室溫下攪拌1小時。加入Me OH，另攪拌反應混合物15分鐘，然後濃縮至乾。殘餘物溶於水及以乙酸乙酯萃取一次並丟去該乙酸乙酯’然後將IN NaOH溶液加至水相直到爲鹼性 φ PH’及以乙酸乙酯萃取三次。混合之有機相用Na2S〇4乾燥及濃縮至乾。所製得粗產物在矽膠上進行層析，用極性漸增的EtOAc/MeOH混合物作爲沖提液，而得到1〇5 mg 標題化合物（二步驟產率：52%)。 LC-MS (方法 2) : tR = 1.28 min; m/z 260 (MH+) 實施例 6-36 用述於實施例5之類似步驟，但使用適當起始物料， -111 - 200951136 製得下列化合物：實施例名稱起始物料方法 (LC-MS) tR(min) m/z (MH+) 6 7-環丙基-4-[(3R)-3-(甲基胺基) 卩比咯啶-1-基]呋喃並[3,2-d]嘧 D定-2-胺參考性實施例6a 及參考性實施例1 2 1.25 274 7 4-[(3R)-3-胺基吡咯啶-1-基]-7-環丙基呋喃並[3,2-d]嘧啶-2-胺參考性實施例6a 及[(3R)-吡咯啶-3_ 基]胺基甲酸第三丁酯 2 1.16 260 8 4-(3-胺基氮雜環丁烷-1-基)-7-環丙基呋喃並[3,2-d]嘧啶-2-胺參考性實施例6a 及氮雜環丁烷-3-基胺基甲酸第三丁酯 2 1.13 246 9 7-環丙基-4-(3-甲基-3-(甲基胺基)氮雜環丁烷-1-基)呋喃並 [3,2-d]嘧啶-2-胺參考性實施例6a 及參考性實施例3 2 1.37 274 10 7-環丙基-4-(哌嗪-1-基)呋喃並 [3,2-d]嘧啶-2-胺參考性實施例6a 及哌嗪-1-基羧酸第三丁酯 2 1.14 260 11 7-環丙基-4-(l，4-二氮雜環庚院-1-基)呋喃並[3,2-d]嘧啶-2- 胺參考性實施例6a 及1,4-二氮雜環庚烷-1-羧酸第三丁酯 2 1.21 274 12 7-乙基-4-(3-(甲基胺基)氮雜環丁烷-1-基)呋喃並[3,2-d]嘧陡-2-胺參考性實施例6b 及參考性實施例2 2 1.24 248 13 7-乙基-4-[(3R)-3-(甲基胺基)吡略啶·1-基]呋喃並[3,2-d]嘧啶-2-胺參考性實施例6b 及參考性實施例1 2 1.23 262 14 4-[(3R)-3-胺基吡咯啶-1-基]-7-乙基呋喃並[3,2-d]嘧啶-2-胺參考性實施例6b 及[(3R)-吡咯啶-3-基]胺基甲酸第三丁酯 2 1.11 248 -112- 200951136 15 7-乙基-4-(3-甲基-3-(甲基胺基) 氮雜環丁烷-1-基)呋喃並[3,2-d]嘧啶-2-胺參考性實施例6b 及參考性實施例3 2 1.34 262 16 7-乙基-4-(哌嗪-1-基)呋喃並 [3,2-d]嘧啶-2-胺參考性實施例6b 及哌嗪-1-基羧酸第三丁酯 2 1.10 248 17 4-(3-(甲基胺基)氮雜環丁烷_l-基)-7-丙基呋喃並[3,2-d]嘧陡-2-胺參考性實施例6c 及參考性實施例2 2 1.42 262 18 4-[(3R)-3-(甲基胺基)吡咯啶-1-基]-7-丙基呋喃並[3,2-d]嘧啶-2-胺參考性實施例6c 及參考性實施例1 2 1.39 276 19 4-[(3R)-3-胺基吡咯啶-1-基]-7-丙基呋喃並[3,2-d]嘧啶-2-胺參考性實施例6c 及[(3R)-吡咯啶-3-基]胺基甲酸第三丁酯 2 1.32 262 20 4-(3-甲基-3-(甲基胺基)氮雜環丁烷-1-基)-7-丙基呋喃並[3,2-d]嘧啶-2-胺參考性實施例6c 及參考性實施例3 2 1.52 276 21 4-(哌嗪-1·基)-7-丙基呋喃並 [3,2-d]嘧啶-2-胺參考性實施例6c 及哌嗪-1-基羧酸第三丁酯 2 1.32 262 22 7_異丙基_4-(3-(甲基胺基)氮雜環丁烷-1-基)呋喃並[3,2-d]嘧陡-2-胺參考性實施例6d 及參考性實施例2 2 1.42 262 23 7-異丙基-4-[(3R)-3-(甲基胺基) 啦咯啶-1-基]呋喃並[Hd]嘧陡-2-胺參考性實施例6d 及參考性實施例1 2 1.42 276 24 7-苄基-4-(3-(甲基胺基)氮雜環丁烷-1-基)呋喃並[3,2-d]嘧陡· 2-胺參考性實施例6e 及參考性實施例 2(*) 2 1.63 310 25 7-苄基-4-[(3R)-3-(甲基胺基账塔啶-1-基]呋喃並[3,2-d]嘧啶· 2-胺參考性實施例6e 及參考性實施例 ie) 2 1.63 324 200951136 26 7-環丁基-4-(3-(甲基胺基)氮雜環丁烷-1-基)呋喃並[3,2-d]嘧淀-2-胺參考性實施例6ί 及參考性實施例 2(” 2 1.50 274 7-環丁基-4-[(3R)-3-(甲基胺基) 參考性實施例6ί 27 啦略啶-1-基]呋喃並P,2-d]嘧及參考性實施例 2 1.50 288 μ-2-m 1(*) 7-環戊基-4-(3-(甲基胺基)氮雜 t考性實施例6g 28 環丁烷-1-基)呋喃並[3,2-d]嘧及參考性實施例 2 1.65 288 陡-2-胺 7-環戊基-4-[(3R)-3-(甲基胺基) 參考性實施例6g 29 丨肚咯啶-1-基]呋喃並[3,2-d]嘧及參考性實施例 2 1.62 302 陡-2-胺 7-異丁基-4-(3-(甲基胺基)氮雜參考性實施例6h 30 環丁烷-1-基)呋喃並[3,2-d]嘧及參考性實施例 2 1.59 276 陡-2-胺 7-異丁基-4-[(3R)-3-(甲基胺基) 參考性實施例6h 31 ttfc咯啶-1-基]呋喃並[3,2-d]嘧及參考性實施例 2 1.58 290 陡-2-胺 ίί!1_ 4-(3-(甲基胺基)氮雜環丁烷-1- 參考性實施例6i 32 基)-7-苯基呋喃並[3,2-d]嘧啶- 及參考性實施例 2 1.62 296 2-胺 2(ϋ_ 4-[(3R)-3-(甲基胺基)吡咯啶-1· 參考性實施例6i 33 華]-7-苯基呋喃並[3,2-d]嘧啶- 及參考性實施例 2 1.61 310 2-胺 7-第三丁基·4·(3-(甲基胺基)氮參考性實施例6j 34 雜環丁烷-1-基)呋喃並[3,2-d] 及參考性實施例 2 1.67 276 _啶-2-胺 7-第三丁基-4-[(3R)-3-(甲基胺參1考性實施例6j 35 基)吡咯啶-1-基]呋喃並[3,2-d] 及參考性實施例 2 1.67 290 嘹啶-2-胺 7-環丙基-4-(3-(甲基胺基)氮雜參考性實施例 36 環丁烷-1-基)呋喃並[3,2-d]嚼及參考性實施例 2 1.33 245 淀 (*)反應在乙腈’而非1，4 -二噁烷-乙腈混合物，中進行。 -114- 200951136 實施例 3 7 6-氯-7-環丁基- 4-(3-(甲基胺基）氮雜環丁烷-1-基）呋喃並[3,2-d]嘧啶-2-胺實施例 26所製得化合物（〇·1 g，0.36 mmol) 、4 Μ HC1於1，4-二嚼院中之溶液（0.5 mL)及甲醇（1 mL)之混合物在室溫下攪拌2小時，然後濃縮至乾。該鹽懸浮於 CHC13及加入磺醯氯（0.44 mmol，0.036 mL)。反應混合物攪拌2小時，然後加入更多之磺醯氯（0.44 mmol， 0.03 6 mL)。另攪拌1小時後，殘餘物溶於水，及以被丟棄之CHC13萃取一次，然後將1 N NaOH溶液加入水相，直到變成鹼性pH，及以CHC13萃取三次。混合之有機相以Na2S04乾燥及濃縮至乾。所製得粗產物經由製備性 HPLC (管柱 X-Terra PREP MS Cl 8 5μιη ( 100 mmxl9 mm )，流速：19 mL/min，沖提液：A = AcN，B = NH4HC03 75 mM，梯度：0 min A 20% ; 3 min A 20% ; 6 min A 80 % )純化，及將包含產物之部分蒸發至乾，製得3.45 mg 標題化合物（產率：1%)。 LC-MS (方法 2) ： tR = 1.87 min ； m/z 3 08 ( MH+) 實施例 38-42 用述於實施例37之類似步驟，但使用適當起始物料，製得下列化合物： -115- 200951136 實施例名稱起始物料方法 (LC-MS) tR(min) m/z (Μί^) 38 6_氯-7-環丙基-4-(3-(甲基胺基)氮雜環丁烷-1-基)呋喃並 [3,2-d]嘧啶-2-胺實施例5 2 1.64 294 39 6-氯-7-環丙基-4-[(3R)-3-(甲基胺基)吡咯啶-1-基]呋喃並 P，2-d]嘧啶-2-胺實施例6 2 1.61 307 40 6-氯-7-異丙基-4-(3-(甲基胺基)氮雜環丁院-1-基)呋喃並 [3,2-d]嘧啶-2-胺實施例22 2 1.77 296 41 6-氯-7-異丙基-4-[(3 R)-3-(甲 #胺基)吡咯啶-1 -基]呋喃並 [3,2-d]嘧陡-2-胺實施例23 2 1.81 310 42 6-氯-7-環戊基-4-[(3R)-3-(甲基胺基)吡咯啶-1-基]呋喃並 P,2-d]嘧啶-2-胺實施例29 2 2.06 336 實施例 4 3 4-(3-(甲基胺基）氮雜環丁烷-1_基）_7_(四氫_21^吡喃-4-基）呋喃並[3,2-d]嘧啶-2-胺用述於實施例5之類似步驟但使用參考性實施例 6k及2所製得化合物爲起始物料，製得產率52%之標題化合物。 LC-MS (方法 2 ) ： tR min ； m/z = 3 04 ( MH + -116- 200951136 實施例 44 2-胺基-7_異丙基-4- ( ( 3R) -3-(甲基胺基）吡咯啶-1-基 )呋喃並[3,2-d]嘧啶-6-甲腈 (a) ( R) -1- ( 2-胺基-6-氰基-7-異丙基呋喃並[3,2-d]嘧啶-4-基）吡咯啶-3-基（甲基）胺基甲酸第三丁酯參考性實施例 9b (80 mg，0.19 mmol)於 DMS〇( 1.5 mL)中之溶液加入氰化鈉（iio mg，2.25 mmol) > ❹ 混合物在100 °C下加熱整夜。另加入氰化鈉（50mg，0.98 mmol)，混合物在1 10°C下加熱3天。冷卻反應混合物，然後以乙酸乙酯及水稀釋。將各相分離，及水相再以乙酸乙酯萃取三次。混合之有機相以Na2S04乾燥及濃縮至乾。所製得粗產物在矽膠上進行層析，用極性漸增的己烷 /EtOAc混合物作爲冲提液，而得到19 mg所要化合物（產率：24% ) LC-MS (方法 2) ： tR = 2.54 min ； m/z 401 ( MH+) (b )標題化合物步驟a)所製得化合物（19 mg，0.05 mmol )於二氯甲烷（0.6 mL)中之溶液加入三氟乙酸（〇·3 mL)，及反應混合物在室溫攪拌2小時，然後濃縮至乾。殘餘物溶於水，及以丟棄之乙酸乙酯萃取兩次。然後將1 N NaOH溶液加至水相直到變成鹼性pH，及以乙酸乙酯萃取三次。混合之有機相以Na2S04乾燥及濃縮至乾。所製得粗產物 -117- 200951136 在氧化鋁上進行層析’用極性漸增的EtOAc/MeOH混合物作爲沖提液，而得到9.7 mg標題化合物（產率：6 8 % ) 〇 LC-MS (方法 2) ： tR = 1.60 min ； m/z 301 ( MH+) 實施例 45 2-胺基-7-環丙基-4- (3-(甲基胺基）氮雜環丁烷-1-基）呋喃並[3,2-d]嘧啶-6-甲腈用述於]實施例44之類似步驟，但使用參考性實施例 9a所製得化合物爲起始物料，製得所要化合物。 LC-MS (方法 2) : tR = 1.47 min ； m/z = 28 5 ( MH + 實施例 46LC-MS (method 2): tR 1.53 mi:, /z 274 (MH) </RTI> </ RTI> </ RTI> </ RTI> </ RTI> Starting Material Method (LC-MS) tR(min) m/z (Mlt) 2 7-Cyclopropyl-4-[(3S)-3-methylpiperazin-1-yl]furan[3,2- d] pyrimidin-2-amine _--- Reference Examples 6a and (8)-(+)-2-methylpiperazine 2 1.33 274 3 7-ethyl-4-[4-methylpiperazine- 1-yl]furo[3,2-d]pyrimidin-2-amine Reference Example 6b and 1-methylpiperazine 2 1.44 262 4 4-[4-methylindol-1-yl]-7 -propyl-pyrano[3,2-d]pyrimidin-2.amine Reference Example 6c and 1-methylpiperazine 2 1.64 276 Example 5 7-Cyclopropyl-4-(3-(methyl) Amino)azetidin-indole-yl)furo[3,2-d]pyrimidin-2-amine (a) 1-(2-amino-7-cyclopropylfuro[3,2- d]pyrimust-4-yl)azetidin-3-yl(methyl)aminocarbamic acid tert-butyl ester Reference Example 6 a compound obtained (0 · 15 g, 〇. 7 8 Mm ο 1 ) A suspension of a mixture of 1,4-dioxane (5 mL) and acetonitrile (5 mL) was added triethylamine (4.7 mL), PyBOP (0.41 g, 0.78 mmol 200951136) and the compound obtained in Reference Example 2 (0.38 g, 1·〇9 mmol). The obtained suspension was heated at 80 ° C for 20 hours. The reaction mixture was between ethyl acetate and aq. The organic phase was dried over Na.sub.2SO.sub.sub.sub.sub.sub.sub.sssssssssssssssssssssssssssssssssssssssssssss (Method 2): tR = 2.15 min; ra/z 360 (MH+) ❹ b) title compound Compound (a.33 g, 0.92 mmol) and 4 Μ HC1 in 1,4-dioxane The mixture in (7 mL) was stirred at room temperature for 1 hour. Me OH was added and the reaction mixture was stirred for additional 15 min then concentrated to dryness. The residue was dissolved in water and extracted with ethyl acetate <RTI ID=0.0>>>> The combined organic phases were dried over Na 2 S 4 and concentrated to dry. The crude product was purified by chromatography eluting elut elut elut elut elut elut elut elut LC-MS (Method 2): m / s 260 (MH+) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; : Example name Starting material method (LC-MS) tR(min) m/z (MH+) 6 7-cyclopropyl-4-[(3R)-3-(methylamino)p-pyrrolidine- 1-yl]furo[3,2-d]pyrimidine-2-amine Reference Example 6a and Reference Example 1 2 1.25 274 7 4-[(3R)-3-Aminopyrrolidin-1 -yl]-7-cyclopropylfuro[3,2-d]pyrimidin-2-amine Reference Example 6a and [(3R)-pyrrolidin-3-yl]carbamic acid tert-butyl ester 2 1.16 260 8 4-(3-Aminoazetidin-1-yl)-7-cyclopropylfuro[3,2-d]pyrimidin-2-amine Reference Example 6a and azetidine- 3-butylaminocarbamic acid tert-butyl ester 2 1.13 246 9 7-cyclopropyl-4-(3-methyl-3-(methylamino)azetidin-1-yl)furan[3 , 2-d] pyrimidin-2-amine Reference Example 6a and Reference Example 3 2 1.37 274 10 7-Cyclopropyl-4-(piperazin-1-yl)furo[3,2-d] Pyrimidine-2-amine Reference Example 6a and piperazine-1-ylcarboxylic acid tert-butyl ester 2 1.14 260 11 7-cyclopropyl-4-(l , 4-diazepine-1-yl)furo[3,2-d]pyrimidin-2-amine Reference Example 6a and 1,4-diazepane-1-carboxylic acid Tributyl ester 2 1.21 274 12 7-ethyl-4-(3-(methylamino)azetidin-1-yl)furo[3,2-d]pyrimidin-2-amine reference Example 6b and Reference Example 2 2 1.24 248 13 7-Ethyl-4-[(3R)-3-(methylamino)pyrrolidine·1-yl]furo[3,2-d] Pyrimidine-2-amine Reference Example 6b and Reference Example 1 2 1.23 262 14 4-[(3R)-3-Aminopyrrolidin-1-yl]-7-ethylfuro[3,2- d]pyrimidin-2-amine Reference Example 6b and [(3R)-pyrrolidin-3-yl]carbamic acid tert-butyl ester 2 1.11 248 -112- 200951136 15 7-ethyl-4-(3- Methyl-3-(methylamino)azetidin-1-yl)furo[3,2-d]pyrimidin-2-amine Reference Example 6b and Reference Example 3 2 1.34 262 16 7-Ethyl-4-(piperazin-1-yl)furo[3,2-d]pyrimidin-2-amine Reference Example 6b and piperazine-1-ylcarboxylic acid tert-butyl ester 2 1.10 248 17 4-(3-(Methylamino)azetidin-1-yl)-7-propylfuro[3,2-d]pyrimidin-2-amine Reference Example 6c and Reference Example 2 2 1.42 2 62 18 4-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-7-propylfuro[3,2-d]pyrimidin-2-amine Reference Example 6c and reference Example 1 2 1.39 276 19 4-[(3R)-3-Aminopyrrolidin-1-yl]-7-propylfuro[3,2-d]pyrimidin-2-amine Reference Example 6c And [(3R)-pyrrolidin-3-yl]carbamic acid tert-butyl ester 2 1.32 262 20 4-(3-methyl-3-(methylamino)azetidin-1-yl) -7-propylfuro[3,2-d]pyrimidin-2-amine Reference Example 6c and Reference Example 3 2 1.52 276 21 4-(Piperazine-1·yl)-7-propylfuran And [3,2-d]pyrimidin-2-amine Reference Example 6c and piperazine-1-ylcarboxylic acid tert-butyl ester 2 1.32 262 22 7-isopropyl- 4-(3-(methylamine) (Azetidin-1-yl)furo[3,2-d]pyrimidin-2-amine Reference Example 6d and Reference Example 2 2 1.42 262 23 7-isopropyl-4- [(3R)-3-(Methylamino)-loxaridin-1-yl]furo[Hd]pyrimidin-2-amine Reference Example 6d and Reference Example 1 2 1.42 276 24 7-Benzyl 4-(3-(methylamino)azetidin-1-yl)furo[3,2-d]pyrimidin-2-amine Reference Example 6e and Reference Example 2 ( *) 2 1.63 310 25 7-Benzyl-4-[(3R)-3-(methylaminobutyridine-1-yl)furo[3,2-d]pyrimidin-2-amine Reference Example 6e and Reference EXAMPLES i) 2 1.63 324 200951136 26 7-Cyclobutyl-4-(3-(methylamino)azetidin-1-yl)furo[3,2-d]pyrimidine-2- Amine Reference Example 6 ί and Reference Example 2 (" 2 1.50 274 7-cyclobutyl-4-[(3R)-3-(methylamino) Reference Example 6 ί 27 ralidine -1- Furan P,2-d]pyrimidine and reference example 2 1.50 288 μ-2-m 1(*) 7-cyclopentyl-4-(3-(methylamino) aza t Example 6g 28 cyclobutane-1-yl)furo[3,2-d]pyrene and reference example 2 1.65 288 steep-2-amine 7-cyclopentyl-4-[(3R)-3- (Methylamino) Reference Example 6g 29 丨咯咯 -1- -1 -yl]furo[3,2-d]pyrimidine and Reference Example 2 1.62 302 Strep-2-amine 7-isobutyl- 4-(3-(Methylamino)azepine reference example 6h 30 cyclobutane-1-yl)furo[3,2-d]pyrene and reference example 2 1.59 276 steep-2-amine 7-Isobutyl-4-[(3R)-3-(methylamino) Reference Example 6h 31 ttfc-r-hexyl-1-yl]furan And [3,2-d]pyrimidine and reference example 2 1.58 290 steep-2-amine ίί! 1_ 4-(3-(methylamino)azetidin-1-reference embodiment 6i 32 Benzyl-7-phenylfuro[3,2-d]pyrimidine- and Reference Example 2 1.62 296 2-Amine 2 (ϋ_4-[(3R)-3-(methylamino)pyrrolidine- 1. Reference Example 6i 33 Hua]-7-Phenylfuro[3,2-d]pyrimidine- and Reference Example 2 1.61 310 2-Amine 7-Third Butyl·4·(3-( Methylamino)nitrogen reference example 6j 34 heterocyclobutan-1-yl)furo[3,2-d] and reference example 2 1.67 276 pyridine-2-amine 7-t-butyl -4-[(3R)-3-(methylamine 11 test example 6j 35 yl) pyrrolidin-1-yl]furo[3,2-d] and reference example 2 1.67 290 acridine 2-Amine 7-cyclopropyl-4-(3-(methylamino)aza reference embodiment 36 cyclobutane-1-yl)furo[3,2-d] chew and reference implementation Example 2 1.33 245 The precipitation (*) reaction was carried out in a mixture of acetonitrile instead of 1,4-dioxane-acetonitrile. -114- 200951136 Example 3 7 6-Chloro-7-cyclobutyl 4-(3-(methylamino)azetidin-1-yl)furo[3,2-d]pyrimidine- 2-Amine Example 26 Preparation of a compound (〇·1 g, 0.36 mmol), a mixture of 4 Μ HC1 in 1,4-two chews (0.5 mL) and methanol (1 mL) at room temperature Stir for 2 hours and then concentrate to dryness. The salt was suspended in CHC13 and sulfonium chloride (0.44 mmol, 0.036 mL) was added. The reaction mixture was stirred for 2 hours then more sulfonium chloride (0.44 mmol, 0.03 6 mL). After stirring for an additional hour, the residue was dissolved in water and extracted once with <RTIgt;</RTI><RTIgt;</RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The combined organic phases were dried over Na 2 SO 4 and concentrated to dry. The crude product obtained was subjected to preparative HPLC (column X-Terra PREP MS Cl 8 5 μιη (100 mm×l9 mm), flow rate: 19 mL/min, extract: A = AcN, B = NH4HC03 75 mM, gradient: 0 Purification of the residue, and the fractions containing the product were evaporated to dryness to give the title compound (yield: 1%). LC-MS (Method 2): tj = 1.87 min; m/z s s s s s s s s s s s s s s s s s s s s - 200951136 Example name Starting material method (LC-MS) tR(min) m/z (Μί^) 38 6_Chloro-7-cyclopropyl-4-(3-(methylamino)aza heterocycle Butan-1-yl)furo[3,2-d]pyrimidin-2-amine Example 5 2 1.64 294 39 6-Chloro-7-cyclopropyl-4-[(3R)-3-(methyl Amino)pyrrolidin-1-yl]furan P,2-d]pyrimidin-2-amine Example 6 2 1.61 307 40 6-Chloro-7-isopropyl-4-(3-(methylamino) Azetidin-1-yl)furo[3,2-d]pyrimidin-2-amine Example 22 2 1.77 296 41 6-chloro-7-isopropyl-4-[(3 R)- 3-(A#Amino)pyrrolidin-1 -yl]furo[3,2-d]pyrimidin-2-amine Example 23 2 1.81 310 42 6-Chloro-7-cyclopentyl-4-[ (3R)-3-(Methylamino)pyrrolidin-1-yl]furo P,2-d]pyrimidin-2-amine Example 29 2 2.06 336 Example 4 3 4-(3-(methyl Amino)azetidin-1-yl)-7-(tetrahydro-21^pyran-4-yl)furo[3,2-d]pyrimidin-2-amine is similarly described in Example 5. But using reference The compound obtained in the examples 6k and 2 was obtained as a starting material to give the title compound. LC-MS (Method 2): tR min ; m/z = 3 04 (MH + -116 - 200951136 Example 44 2-amino-7-isopropyl-4-((3R)-3-(methyl) Amino)pyrrolidin-1-yl)furo[3,2-d]pyrimidine-6-carbonitrile (a) (R)-1-(2-amino-6-cyano-7-isopropyl Tributyl benzofuro[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl(methyl)carbamate Reference Example 9b (80 mg, 0.19 mmol) in DMS ( 1.5 mL The solution in the solution was added with sodium cyanide (iio mg, 2.25 mmol) > ❹ The mixture was heated at 100 ° C overnight. Additional sodium cyanide (50 mg, 0.98 mmol) was added and the mixture was heated at 10 ° C for 3 days. The reaction mixture was cooled, then diluted with ethyl acetate and water. The phases were separated and the aqueous phase was extracted three times with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated to dryness. Chromatography was carried out using a hexane/EtOAc mixture of increasing polarity as a solvent to give 19 mg of the desired compound (yield: 24%) LC-MS (Method 2): tR = 2.54 min; m/z 401 ( MH+) (b) title compound Compound (19 mg, 0.05 mmol) A solution of the alkane (0.6 mL) was added trifluoroacetic acid (3 mL), and the mixture was stirred at room temperature for 2 hr then concentrated to dryness. The residue was dissolved in water and extracted twice with ethyl acetate. The 1 N NaOH solution was then added to the aqueous phase until it became an alkaline pH and extracted three times with ethyl acetate. The combined organic phases were dried over Na 2 SO 4 and concentrated to dry. The crude product obtained - 117-200951136 was chromatographed on alumina <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Method 2): tR = 1.60 min; m/z 301 (MH+) Example 45 2-amino-7-cyclopropyl-4-(3-(methylamino)azetidin-1-yl Furano[3,2-d]pyrimidine-6-carbonitrile was used in the analogous procedure of Example 44, but using the compound obtained in Reference Example 9a as starting material to give the desired compound. LC-MS (Method 2): tR = 1.47 min; m/z = 28 5 (MH + EXAMPLE 46

7-(1-(甲氧基甲基）環丙基）-4_(3_ (甲基胺基）氮雜環丁烷-1-基）呋喃並[3,2-d]囉陡_2-胺用述於實施例5之類似步驟，但使用參考性實施例61 及2所製得化合物爲起始物料，製得產率73%之標題化合物。 304 ( ΜΗ • 22 min; m/z LC-MS (方法 2 ) ： tR = 實施例 47 -118- 200951136 〔3H〕-組織胺對人類組織胺H4受體的結合競爭分析爲進行此結合分析，使用從表現人類組織胺H4受體的穩定CHO重組細胞株所製備的膜萃取物（Euroscreen /Perkin-Elmer )。將測試用化合物以所選定的濃度（兩套）連同1 0 nM 〔3H〕·組織胺和15μ8膜萃取物在總體積爲250 /zL含有 5 0 mM Tris-HCl，pH 7.4，1.25 mM EDTA 的溶液中在 25 °C下溫育60分鐘。在有100"M未標記的組織胺之下界定出非特異性結合（non-specific binding)。在已事先在〇°C下於0.5%聚乙燦亞胺（polyethylenimine)溶液中浸泡 2 小時的 96 孔盤（Multiscreen HTS Millipore)中，利用真空收集器（Multiscreen Millipore)透過過濾中止反應。然後，將96孔盤以0°C之50mM Tris ( pH 7.4 )、 1.25 mM EDTA洗過，而過濾器則在50-60°C下於1小時期間內乾燥，然後添加閃爍液，利用/3 -盤（betaplate )閃爍計數器測定結合的放射活性。在此分析中對實施例1至44及46之化合物進行測試，結果在1 ΟμΜ濃度下測試時，所有化合物均顯現出對於組織胺結合人類組織胺Η4受體的情形有高於50%的抑制程度。另外，實施例1至14、16至35、37至44及46之化合物，在1 y Μ濃度下測試時，顯現出對於組織胺結合人類組織胺Η4受體的情形有高於50%的抑制程度° 實施例 48 -119- 200951136 人類嗜酸性球中經組織胺誘發形狀改變之分析（閘控制自體螢光前向散射分析’ GAFS ) 此分析中，人類嗜酸性球中經由組織胺所誘發之形狀改變係藉由流動式細胞測量術加以測定，所偵測到的是細胞大小之增加（前向散射，FSC)。從健康人類自願者之全血液中取得多形核白血球（ PMNL，包含嗜中性球及嗜酸性球之部分）。簡言之，藉由在1.2% Dextran(SIGMA)中之沉積分離紅血球，及藉由在Ficoll-Paque®(Biochrom)之存在下於450g離心過濾20分鐘而單離出富含白血球之部分（PMNL )。 PMNL再懸浮於PBS緩衝液，濃度爲1.1 xlO6細胞/ml/管，及在37 °C下以不同濃度之測試用化合物（溶於PBS ) 預處理30分鐘，然後以300 ιιΜ組織胺（Fluka)剌激5 分鐘。最後，加入聚甲醛（1%最終濃度於PBS中）以終止反應及維持細胞形狀。細胞形狀改變係藉由流動式細胞測量術（FACS Calibur, BD Biosystems)力卩以分析。 PMNL中之嗜酸性球經閘控制，基於相對於嗜中性球，嗜酸性球具有較高自體螢光（螢光通道FL2)。細胞形狀改變在前向散射訊號（F S C )中偵測。結果以各濃度測試用化合物對於組織胺所誘發形狀改變之抑制％表示。在此分析中對實施例1至14、16至35、37至44及 46之化合物進行測試，結果在1 // Μ濃度下測試時，所有化合物均顯現出對於組織胺所誘發人類嗜酸性球形狀改變有高於50%的抑制程度。 -120-7-(1-(Methoxymethyl)cyclopropyl)-4_(3-(methylamino)azetidin-1-yl)furo[3,2-d]啰 steep_2- The amine was used in a similar procedure as described in Example 5, but using the compound obtained in Reference Examples 61 and 2 as starting material to afford the title compound. 304 ( ΜΗ • 22 min; m/z LC-MS (method 2): tR = Example 47 -118- 200951136 [3H]-histamine binding competition analysis of human histamine H4 receptor for this binding analysis, A membrane extract (Euroscreen / Perkin-Elmer) prepared from a stable CHO recombinant cell strain expressing the human histamine H4 receptor was used. The test compound was selected at the selected concentration (two sets) together with 10 nM [3H]· Histamine and 15 μ8 membrane extract were incubated in a total volume of 250 /zL containing 50 mM Tris-HCl, pH 7.4, 1.25 mM EDTA for 60 minutes at 25 ° C. In the presence of 100 "M unlabeled tissue Under the amine, non-specific binding is defined. In a 96-well plate (Multiscreen HTS Millipore) that has been previously immersed in 0.5% polyethylenimine solution for 2 hours at 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 0 ° C, and the filter was at 50-60 ° C. Dry for 1 hour, then add scintillation fluid, using /3 - plate The combined radioactivity was determined by a betaplate scintillation counter. The compounds of Examples 1 to 44 and 46 were tested in this assay and, when tested at a concentration of 1 ΟμΜ, all compounds showed up for histamine-binding human histamine Η4 In the case of the body, there is a degree of inhibition higher than 50%. In addition, the compounds of Examples 1 to 14, 16 to 35, 37 to 44 and 46, when tested at a concentration of 1 Μ, exhibit amine-bound human histamine for histamine The case of the Η4 receptor has a degree of inhibition greater than 50%. Example 48 -119- 200951136 Analysis of histamine-induced shape change in human eosinophils (Gate control autofluorescence forward scatter analysis 'GAFS) This analysis In the human eosinophils, the shape change induced by histamine is determined by flow cytometry, and the increase in cell size (forward scatter, FSC) is detected. Polymorphonuclear leukocytes (PMNL, part of neutrophils and eosinophils) are obtained in whole blood. In short, red blood cells are separated by deposition in 1.2% Dextran (SIGMA), and borrowed In the presence of Ficoll-Paque® (Biochrom) of the centrifugal filtration at 450g for 20 minutes are isolated from the leukocyte enriched portion (PMNL). PMNL was resuspended in PBS buffer at a concentration of 1.1 x 10 6 cells/ml/tube, and pretreated with different concentrations of test compound (dissolved in PBS) for 30 minutes at 37 °C, then with 300 mM mesamine (Fluka). Speak for 5 minutes. Finally, polyoxymethylene (1% final concentration in PBS) was added to stop the reaction and maintain cell shape. Cell shape changes were analyzed by flow cytometry (FACS Calibur, BD Biosystems). The eosinophilic ball in the PMNL is controlled by a gate, based on which the eosinophil has a higher autofluorescence (fluorescent channel FL2) relative to the neutrophil. Cell shape changes are detected in the forward scatter signal (F S C ). The results are expressed as % inhibition of the shape change induced by histamine by each concentration of the test compound. The compounds of Examples 1 to 14, 16 to 35, 37 to 44 and 46 were tested in this analysis, and all of the compounds showed human eosinophils induced by histamine when tested at a concentration of 1 // hydrazine. Shape changes have a degree of inhibition greater than 50%. -120-

Claims

200951136 七、申請專利範圍：200951136 VII. Patent application scope:

其中： Ri 爲 Η 或 NH2 ; R2與Rs連同與其鍵結的N原子形成飽和雜環基，此飽和雜環基可爲4至7員單環、7至8員橋接雙環、或8至12 員稠合雙環’其中該雜環基可含有至多兩個N原子且不含任何其他雜原子’而且可選擇性被一或多個獨立選自Cl_4 Φ 院基及NRaRb之取代基所取代，惟該雜環基含有2個N原子且不被NRaRb基所取代，或者含有1個n原子且被一個 NRaRb基所取代；或者R2爲11或Cl-4烷基’且R3爲氮雜環丁烷基、吡略啶基、脈D定基或氮雜環庚烷基’其可選擇性被一或多個Ci4 烷基所取代； Ra爲Η或Cl.4烷基； Rb爲Η或Cl_4烷基；或者Ra及Rb —起與所連接之氮原子形成氮雜環丁烷基、 -121 - 200951136 吡咯啶基、哌啶基或氮雜環庚烷基，其可選擇性被〜個C 1 - 4院基所取代， R 4爲· (1 ) Cm烷基； (2 ) C3-8環烷基-C〇-6烷基； (3 )芳基-C〇-6烷基；其中，在基團（Ο至（3)中之任何烷基可選擇性輕—或多個鹵素原子取代，及以·8環烷基可選擇性經一或多個獨立地選自-4烷基、鹵素及芳基之取代基取代； (4)式（ί )之基團Wherein: Ri is Η or NH2; R2 and Rs together with the N atom to which they are bonded form a saturated heterocyclic group which may be a 4 to 7 membered single 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 the group consisting of Cl_4 Φ and NRaRb, The heterocyclic group contains 2 N atoms and is not substituted by the NRaRb group, or contains 1 n atom and is substituted by one NRaRb group; or R 2 is 11 or Cl-4 alkyl ' and R 3 is azetidinyl group a pyrrolidinyl group, a vein D-group or azacycloheptyl group' which may be optionally substituted by one or more Ci4 alkyl groups; Ra is a hydrazine or a Cl. 4 alkyl group; Rb is a hydrazine or a Cl 4 alkyl group; Or Ra and Rb together with the nitrogen atom to which they are attached form azetidinyl, -121 - 200951136 pyrrolidinyl, piperidinyl or azepanyl, which may be selectively selected from C 1 - 4 Substituted by the institute, R 4 is (1) Cm alkyl; (2) C3-8 cycloalkyl-C〇-6 alkyl; (3) aryl-C〇-6 alkyl; Group Any alkyl group in (3) may be optionally lightly substituted or substituted with a plurality of halogen atoms, and may be optionally substituted with one or more substituents selected from the group consisting of -alkyl, halogen and aryl. Substituent; (4) group of formula (ί)

(5 )式（ii )之基團(5) a group of formula (ii)

R5爲Η、鹵素、Cu烷基或CN ; Re及R7係各自獨立地選自11及Ci·4烷基’及另外地r6 或R7基團中之一者可爲芳基或C：3_8環院基- C〇·6院基’及另外地在相同C原子上之R6基團及R?基團可連接而與該C原子一起形成C3·8環烷基； R8爲選自Ci.8院基、C3-8環院基_C〇-6院基及芳基-CG.4院 200951136 基之基團，其中任何烷基可選擇性經一或多個鹵素代，且c3_8環烷基可選擇性經一或多個獨立地選自基、鹵素及芳基之取代基取代：尺9爲4-至7-員飽和單環雜環，其包含一個雜原子 0、S、SO及S02之基團，且不包含任何其他另外子，其中該環可藉由任何可用之C原子連接至該其餘部分，其中R9可選擇性經獨立地選自Ci-4烷義素之一或多個基團取代； X 爲〇、S、so 或 so2 ; η爲1、2或3 ; ρ爲〇、1或2 ;及芳基爲苯基，其選擇性經獨立地選自Cb4烷基、 Cu烷氧基、Cu鹵烷基、Cu鹵烷氧基、CN及一或多個基團取代；或其鹽。 φ 2.如申請專利範圍第1項之化合物，其中Ri 〇 3.如申請專利範圍第1或2項之化合物，其c Η、鹵素、Cu烷基或CN。 4 ·如申請專利範圍第3項之化合物，其中R5 鹵素或CN。 5. 如申請專利範圍第4項之化合物，其中Rs: 6. 如申請專利範圍第4項之化合物，其中Rs 原子取 Cl-4 烷或選自的雜原分子之基及鹵鹵素、 NH2之爲NH2 ]R5爲爲Η、薄Η 〇爲齒素 -123- 200951136 7. 如申請專利範圍第6項之化合物，其中R5爲氯。 8. 如申請專利範圍第4項之化合物，其中R5爲CN 〇 9. 如申請專利範圍第1至8項中任一項之化合物，其中R4爲烷基或C3-8環烷基-C〇_6烷基；其中該烷基可選擇性經一或多個鹵素原子取代及該C3.8環烷基可選擇性經一或多個獨立地選自Ch4烷基、鹵素及芳基之取代基取代。 10. 如申請專利範圍第9項之化合物，其中以爲 C2-8烷基或C3_8環烷基，其中該烷基可選擇性經一或多個鹵素原子取代及該C3_8環烷基可選擇性經一或多個獨立地選自C!.4烷基、鹵素及芳基之取代基取代。 11. 如申請專利範圍第10項之化合物，其中r4爲乙基、異丙基、第三丁基或環丙基。 1 2.如申請專利範圍第1至8項中任一項之化合物，其中R4爲Ch8烷基，其選擇性經一或多個鹵素原子取代〇 1 3 .如申請專利範圍第1 2項之化合物，其中R4爲乙基、異丙基或第三丁基。 14. 如申請專利範圍第1至8項中任一項之化合物，其中R4爲C3-8環烷基-C〇-6烷基’其中該烷基可選擇性經一或多個國素原子取代及該C3.8環烷基可選擇性經一或多個獨立地選自Ci-4院基、鹵素及芳基之取代基取代。 15. 如申請專利範圍第14項之化合物，其中厌4爲 -124- 200951136 C：3-8環烷基’其可選擇性經—或多個獨立地選自Ci 4烷基、鹵素及芳基之取代基取代。 16. 如申請專利範圍第15項之化合物，其中R4爲 C3-8環烷基。 17. 如申請專利範圍第16項之化合物，其中R4爲環丙基。 18·如申請專利範圍第1至8項中任一項之化合物， φ 其中R4爲式（i)之基團。 1 9.如申請專利範圍第1至8項中任一項之化合物，其中R4爲式（ii)之基團。 20.如申請專利範圍第1至ip項中任一項之化合物 ’其中R2及R3 —起與所連接之N原子形成飽和雜環基，其可爲4-至7-員單環、7-至8-員橋接雙環或8-至12-員稠合雙環’其中該雜環基可包含高至兩個N原子且不含任何其他雜原子，及可選擇性經一或多個獨立地選自-4烷基〇及NRaRb之取代基取代，惟雜環基包含兩個N原子且不經 NRaRb基團取代，或包含一個N原子且經一個NRaRb基團取代。 2 1.如申請專利範圍第20項之化合物，其中R2及R3 一起與所連接之氮原子形成選自如下之飽和雜環基： -125- 200951136R5 is fluorene, halogen, Cu alkyl or CN; Re and R7 are each independently selected from 11 and Ci.4 alkyl' and additionally one of the r6 or R7 groups may be an aryl group or a C:3_8 ring The base group - C 6 · 6 base ' and additionally the R 6 group and the R? group on the same C atom may be bonded to form a C 3 · 8 cycloalkyl group together with the C atom; R 8 is selected from Ci. 8 a group based on the base of the C3-8 ring, _C〇-6, and aryl-CG.4, 200951136, wherein any alkyl group may be selectively substituted by one or more halogens, and c3_8 cycloalkyl Optionally substituted with one or more substituents independently selected from the group consisting of a halogen group and an aryl group: Rule 9 is a 4- to 7-membered saturated monocyclic heterocycle containing a hetero atom 0, S, SO and S02 a group, and does not comprise any other additional, wherein the ring may be attached to the remainder by any available C atom, wherein R9 is optionally independently selected from one or more of Ci-4 alkylemin Substituted; X is 〇, S, so or so2; η is 1, 2 or 3; ρ is 〇, 1 or 2; and aryl is phenyl, the selectivity of which is independently selected from Cb4 alkyl, Cu Alkoxy, Cu haloalkyl, Cu haloalkoxy, C N and one or more groups are substituted; or a salt thereof. φ 2. The compound of claim 1, wherein Ri 〇 3. The compound of claim 1 or 2, wherein c Η, halogen, Cu alkyl or CN. 4. A compound as claimed in claim 3, wherein R5 is halogen or CN. 5. The compound of claim 4, wherein Rs: 6. The compound of claim 4, wherein the Rs atom is a Cl-4 alkane or a hetero atom molecule selected from the group consisting of halogen halogen, NH2 Is NH2]R5 is Η, Η 〇 is dentate-123- 200951136 7. The compound of claim 6 wherein R5 is chlorine. 8. The compound of claim 4, wherein R5 is CN 〇9. The compound of any one of claims 1 to 8, wherein R4 is alkyl or C3-8 cycloalkyl-C〇 a 1-6 alkyl group; wherein the alkyl group is optionally substituted with one or more halogen atoms and the C3.8 cycloalkyl group is optionally substituted by one or more substituents independently selected from the group consisting of a C4 alkyl group, a halogen group, and an aryl group. Substituted. 10. The compound of claim 9, wherein the compound is C2-8 alkyl or C3_8 cycloalkyl, wherein the alkyl group is optionally substituted with one or more halogen atoms and the C3_8 cycloalkyl group is selectively Substituted one or more substituents independently selected from C..4 alkyl, halo and aryl. 11. The compound of claim 10, wherein r4 is ethyl, isopropyl, tert-butyl or cyclopropyl. The compound according to any one of claims 1 to 8, wherein R4 is a Ch8 alkyl group, the selectivity of which is substituted by one or more halogen atoms to 〇1 3 as described in claim 12 A compound wherein R4 is ethyl, isopropyl or tert-butyl. 14. The compound of any one of clauses 1 to 8 wherein R4 is C3-8 cycloalkyl-C〇-6 alkyl' wherein the alkyl group is selectively capable of passing through one or more national atoms The substitution and the C3.8 cycloalkyl group may be optionally substituted with one or more substituents independently selected from the group consisting of Ci-4, halogen and aryl. 15. A compound according to claim 14 wherein anaphylide 4 is -124-200951136 C: 3-8 cycloalkyl' which may be optionally selected from - or independently selected from Ci 4 alkyl, halogen and aromatic Substituent substitution. 16. The compound of claim 15 wherein R4 is C3-8 cycloalkyl. 17. The compound of claim 16, wherein R4 is cyclopropyl. 18. The compound of any one of claims 1 to 8 wherein φ is a group of formula (i). The compound of any one of claims 1 to 8, wherein R4 is a group of formula (ii). 20. The compound of any one of claims 1 to 5 wherein R2 and R3 together form a saturated heterocyclic group with the attached N atom, which may be a 4- to 7-membered monocyclic ring, 7- To 8-membered bicyclic or 8- to 12-membered fused bicyclic rings wherein the heterocyclic group may contain up to two N atoms and no other heteroatoms, and may be independently selected by one or more Substituted from a substituent of a-4 alkyl anthracene and NRaRb, except that the heterocyclic group contains two N atoms and is not substituted by the NRaRb group, or contains one N atom and is substituted with one NRaRb group. 2 1. A compound according to claim 20, wherein R2 and R3 together with the nitrogen atom to which they are attached form a saturated heterocyclic group selected from the group consisting of: -125- 200951136

其中R。及Rd獨立地爲11或Cw烷基。 22.如申請專利範圍第2 1項之化合物，其中R。爲Η 2 3.如申請專利範圍第21或22項之化合物，其中R2 及R3 —起與所連接之N原子形成選自（a) 、（b) 、（e )及（f)之飽和雜環基。 24. 如申請專利範圍第21或22項之化合物，其中R2 及R3 —起與所連接之N原子形成選自（a)及（b)之飽和雜環基。 25. 如申請專利範圍第21或22項之化合物，其中R2 及R3 —起與所連接之N原子形成式（a)之飽和雜環基。 26. 如申請專利範圍第21或22項之化合物，其中R2 及R3 —起與所連接之N原子形成式（b)之飽和雜環基。 -126- 200951136 2 7 ·如申請專利範圍第1至2 6項中任一項之化合物 ’其中1及Rb獨立地爲Η或Cl_4烷基。 28.如申請專利範圍第27項之化合物，其中Ra及Rb 獨立地爲Η或甲基。 29·如申請專利範圍第28項之化合物，其中Ra爲η 及Rb爲甲基。 3 0 .如申請專利範圍第1至1 9項中任一項之化合物〇 ’其中112爲C1·4烷基，及r3爲氮雜環丁烷基、吡咯陡基、峨啶基或氮雜環庚烷基，其可選擇性經一或多個 Ci-4烷基取代。 3 1· —種藥學組成物’其包含如申請專利範圍第丨至 3〇項中任一項之式〗化合物或其藥學上可接受之鹽以及一或多種藥學上可接受的賦形劑。 3 2.如申請專利範圍第1至3 0項中任一項之式I化合物或其藥學上可接受之鹽，係用於醫療。〇 33·如申請專利範圍第1至30項中任一項之化合物或其藥學上可接受之鹽’係用於治療或預防由組織胺H4 受體所媒介之疾病。 34_如申請專利範圍第1至30項中任一項之化合物或其藥學上可接受之鹽，係用於治療或預防過敏性、免疫性、或發炎性疾病，或疼痛。 3 5 . —種如申請專利範圍第1至3 0項中任一項之化合物或其藥學上可接受之鹽的用途，係用於製造用於治療或預防由組織胺H4受體所媒介之疾病的藥劑。 -127- 200951136 36.如申請專利範圍第35項之用途，其中該由組織胺H4受體所媒介之疾病爲過敏性、免疫性、或發炎性疾病，或疼痛。 3 7. —種製備如申請專利範圍第1項之式I化合物的方法，其包括： (a )式II化合物與式III化合物（或其經胺基保護形式）反應， RiWhere R. And Rd is independently 11 or Cw alkyl. 22. A compound as claimed in claim 21, wherein R. Is a compound according to claim 21 or 22, wherein R2 and R3 together with the N atom to be bonded form a saturated impurity selected from (a), (b), (e) and (f) Ring base. 24. The compound of claim 21, wherein R2 and R3 together with the N atom to which they are attached form a saturated heterocyclic group selected from (a) and (b). 25. The compound of claim 21, wherein R2 and R3 together with the N atom to be bonded form a saturated heterocyclic group of formula (a). 26. The compound of claim 21, wherein R2 and R3 together with the N atom to be bonded form a saturated heterocyclic group of formula (b). -126-200951136 2 7 - The compound of any one of claims 1 to 26 wherein '1' and Rb are independently hydrazine or Cl_4 alkyl. 28. The compound of claim 27, wherein Ra and Rb are independently hydrazine or methyl. 29. The compound of claim 28, wherein Ra is η and Rb is methyl. The compound of any one of claims 1 to 19, wherein 112 is C1·4 alkyl, and r3 is azetidinyl, pyrrole, acridinyl or aza Cycloheptyl, which may be optionally substituted with one or more Ci-4 alkyl groups. A pharmaceutical composition comprising a compound of any one of the formulas of any one of claims 3 to 3, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 3. A compound of the formula I according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, for use in medical treatment. The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, is for use in the treatment or prevention of a disease mediated by histamine H4 receptor. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of an allergic, immune, or inflammatory disease, or pain. Use of a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, for the manufacture or prevention of a substance mediated by histamine H4 receptor The agent of the disease. The use of the subject of the histamine H4 receptor is an allergic, immunological, or inflammatory disease, or pain, as claimed in claim 35. 3. A method of preparing a compound of formula I as claimed in claim 1 which comprises: (a) reacting a compound of formula II with a compound of formula III (or an amine protected form thereof), Ri

HNR2R3 III 其中Ri、R2、R3、R4及R5具有如申請專利範圍第1項所述之意義，若需要，接著移除任何可能存在之保護基；或 (b)式IIB化合物與式III化合物（或其經胺基保護形式 )反應，HNR2R3 III wherein Ri, R2, R3, R4 and R5 have the meanings as set forth in claim 1 of the patent application, if necessary, subsequently removing any protecting groups which may be present; or (b) a compound of formula IIB and a compound of formula III ( Or its reaction in the form of an amine-protected form,

hnr2r3 III 200951136 其中Rio爲離去基，及Ri、R2、R3、r4$ 專利範圍第1項所述之意義，若需要，接存在之保護基；或 (C )當式I化合物中R5爲鹵素時，則R5 物（或其經胺基保護形式）與鹵化劑反應移除任何可能存在之保護基；或 (d )當式I化合物中R5爲CN時，貝IJ R5 合物（或其經胺基保護形式）與氰化劑反著移除任何可能存在之保護基；或 (e)在一或數個步驟中將式I化合物轉變物。〇 L R·5具有如申請著移除任何可能爲Η之式I化合，若需要，接著爲鹵素之式I化應，若需要，接成另一式I化合 -129- 200951136 四、指定代表圖： (一）、本案指定代表圖為：無 (二）、本代表圖之元件符號簡單說明：無Hnr2r3 III 200951136 wherein Rio is a leaving group, and the meaning of the Ri, R2, R3, r4$ patent range, item 1, if necessary, a protecting group present; or (C) when the compound of formula I is a halogen When R5 (or its protected form of the amine) is reacted with a halogenating agent to remove any protecting groups that may be present; or (d) when R5 is CN in the compound of formula I, the shell IJ R5 compound (or its The amine-protected form), in combination with the cyanating agent, removes any protecting groups that may be present; or (e) converts the compound of formula I in one or several steps. 〇LR·5 has the formula I to remove any possible formula I, if necessary, followed by the formula I of the halogen, if necessary, to form another formula I-129- 200951136 IV, the designated representative figure: (1) The representative representative of the case is: No (2), the symbol of the representative figure is simple: No

200951136 五、本案若有化學式時，請揭示最能顯示發明特徵的化學式：式（I)200951136 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: (I)

-4--4-