CN103373996A - Bicyclic derivatives serving as CRTH2 receptor antagonist - Google Patents

Bicyclic derivatives serving as CRTH2 receptor antagonist Download PDF

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CN103373996A
CN103373996A CN 201310136418 CN201310136418A CN103373996A CN 103373996 A CN103373996 A CN 103373996A CN 201310136418 CN201310136418 CN 201310136418 CN 201310136418 A CN201310136418 A CN 201310136418A CN 103373996 A CN103373996 A CN 103373996A
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cu
burn
cycloalkyl
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吴永谦
张艳
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山东亨利医药科技有限责任公司
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Abstract

The invention belongs to the technical field of medicine, and particularly relates to bicyclic derivatives (shown in a general formula (I)) serving as CRTH2 receptor antagonist and pharmaceutically acceptable salt and stereoisomeride thereof, wherein in the general formula (I), X1, X2, X3, X4, X5, X6, X7, X8, Y, Z, R1 and R2 are as defined in the specification. The invention also relates to a preparation method of these compounds, a pharmaceutical preparation and pharmaceutical composition containing these compounds, and application of these compounds in preparation of medicaments for treating and/or preventing diseases related to CRTH2 activity.

Description

作为CRTH2受体拮抗剂的二并环衍生物 As CRTH2 receptor antagonists and two ring derivative

技术领域 FIELD

[0001] 本发明属于医药技术领域,具体涉及作为CRTH2受体拮抗剂的二并环衍生物,其药学上可接受的盐及其立体异构体,这些化合物的制备方法,含有这些化合物的药物制剂和药物组合物,以及这些化合物、其药学上可接受的盐或其立体异构体在制备治疗和/或预防与CRTH2活性相关的疾病的药物中的应用。 [0001] The drug of the present invention belongs to the technical field of medicine, particularly as relates to CRTH2 receptor antagonists and two ring derivatives, their pharmaceutically acceptable salts and stereoisomers thereof, the preparation of these compounds, these compounds containing formulations and pharmaceutical compositions of these compounds, their use pharmaceutically acceptable salt or a stereoisomer thereof in the manufacture of the treatment and / or prophylaxis of diseases associated with CRTH2 activity in the.

背景技术 Background technique

[0002] CRTH2是G 蛋白偶联的化学引诱剂受体,在Th2细胞、嗜酸性粒细胞上表达。 [0002] CRTH2 is a G protein-coupled chemoattractant receptor, expressed on Th2 cells, eosinophils. 在过敏性疾病,如哮喘、过敏性鼻炎、遗传性过敏皮炎和过敏性结膜炎中已观察到Th2-极化。 Th2- polarization has been observed in allergic diseases such as asthma, allergic rhinitis, atopic dermatitis and allergic conjunctivitis. Th2细胞通过产生Th2细胞因子,如IL-4、IL-5和IL-3来调节过敏性疾病。 Th2 cells by producing Th2 cytokines, such as IL-4, IL-5 and IL-3 to regulate allergic diseases. 在过敏性疾病中,这些Th2细胞因子直接或间接诱导了效应细胞,如嗜酸性粒细胞和嗜碱性粒细胞的迁移、激活、触发和延长的存活。 In allergic diseases, the Th2 cytokines directly or indirectly induce effector cells, such as the migration of eosinophils and basophils, activated, triggering and prolonging survival.

[0003] PGD2 (前列腺素D2),CRTH2的配基,在过敏性疾病中,是由肥大细胞和其它重要的效应细胞产生的。 [0003] PGD2 (prostaglandin D2), CRTH2 ligand, allergic diseases, are produced by mast cells and other important effector cells. 在人细胞中,PGD2通过CRTH2诱导了Th2细胞、嗜酸性粒细胞和嗜碱性的迁移和激活。 In human cells, CRTH2 of PGD2 induced by Th2 cells, eosinophils and basophils migration and activation. 因而,抑制CRTH2和PGD2结合的拮抗剂对治疗过敏性疾病,如哮喘、过敏性鼻炎、遗传性过敏皮炎和过敏性结膜炎应该有用。 Thus, inhibition of binding of CRTH2 and PGD2 antagonist for the treatment of allergic diseases, such as asthma, allergic rhinitis, atopic dermatitis and allergic conjunctivitis should be useful.

[0004] 此外,几个系列的实验证据证明了嗜酸性粒细胞在鼻窦炎和Churg-Strauss综合症中的作用。 [0004] In addition, several series of experimental evidence to prove the role of eosinophils in sinusitis and Churg-Strauss syndrome in. 在这些病人的组织里,能够观察到肥大细胞与嗜酸性粒细胞共同定位。 In the organization of these patients, mast cells can be observed with the co-located eosinophils. 这表明肥大细胞产生的PGD2诱导了嗜酸性粒细胞的募集。 This shows that PGD2 mast cells induces the recruitment of eosinophils. 因而,CRTH2受体拮抗剂对治疗其他的嗜酸性粒细胞相关的疾病,如Churg-Strauss综合症和鼻窦炎也是有用的。 Thus, for the CRTH2 receptor antagonists treat other diseases associated eosinophils, such as Churg-Strauss syndrome and sinusitis are also useful. 由于CRTH2在嗜碱性粒细胞上的高水平表达,CRTH2受体拮抗剂对治疗某些嗜碱性粒细胞相关的疾病,如嗜碱性白血病、慢性风疹和嗜碱性白细胞增多也是有用的。 Since high level expression of CRTH2 on basophils, CRTH2 receptor antagonists for the treatment of some basophil-related diseases, such as basophilic leukemia, chronic urticaria and basophilic leukocytosis are also useful.

[0005] 雷马曲班(Ramatroban)作为血栓烷A2受体拮抗剂上市,具有极强的血小板活化作用,对CRTH2受体的拮抗作用弱,其选择性差,主要不良反应为紫斑、凝血酶原时间/活化部分凝血活酶时间延长、皮下出血。 [0005] ramatroban (ramatroban) as the thromboxane A2 receptor antagonists listed, with a strong platelet activation, antagonistic action of CRTH2 receptor weak, poor selectivity, main side effects purpura, prothrombin time / activated partial thromboplastin time prolonged, subcutaneous bleeding.

[0006] [0006]

'OH (雷马曲班) 'OH (ramatroban)

[0007] 因此目前市场上缺乏有效的CRTH2拮抗活性的药物,需要开发高选择性、高活性、结构新颖的化合物,优化理化性质,提高成药性。 [0007] Thus on the market today lack effective activity CRTH2 antagonist drugs, development of high selectivity, high activity, a compound of novel structure, physical and chemical properties optimized to improve sexual medicine. 发明内容 SUMMARY

[0008] 本发明要解决的技术问题是,提供一种二并环衍生物的CRTH2受体拮抗剂。 [0008] The present invention is to solve the technical problem and to provide a two-ring derivative of CRTH2 receptor antagonists.

[0009] 本发明的技术方案如下: [0009] aspect of the present invention is as follows:

[0010] 通式(I)所示的化合物,其药学上可接受的盐,及其立体异构体: [0010] The compounds of general formula (I), and pharmaceutically acceptable salts, and stereoisomers thereof:

[0011] [0011]

Figure CN103373996AD00071

[0012] 其中,X1、X2、X3、X4和X7分别独立地为N或C(R3); [0012] wherein, X1, X2, X3, X4, and X7 are each independently N or C (R3);

[0013] X5、X6和X8分别独立地为N或C,且X5和X6至少有一个为N ; [0013] X5, X6, and X8 are each independently N or C, and at least one of X5 and X6 is N;

[0014] O代表环上的键为单键或双键; [0014] O represents a bond on the ring is a single bond or a double bond;

[0015] YS-(C(RaRb))p-; [0015] YS- (C (RaRb)) p-;

[0016] Z 为-(C(RaRb))p-或-S-; [0016] Z is - (C (RaRb)) p-, or -S-;

[0017] R1 为R4OC (O) _、(R4) 2NC (O) -、R4C (O) NHC (O)-或四氮唑基; [0017] R1 is R4OC (O) _, (R4) 2NC (O) -, R4C (O) NHC (O) -, or tetrazol-yl;

[0018] R2为芳基、苯并C3_8环烷基或杂芳基,所述的芳基、苯并C3_8环烷基和杂芳基可任选被1-3个独立地选自以下的取代基取代:卤素原子、羟基、氨基、氰基、CV6烷基、C1^6烷氧基、齒代Cu烧基、齒代Cu烧氧基或C3_8环烧基; [0018] R2 is aryl, benzo C3_8 cycloalkyl or heteroaryl, said aryl, heteroaryl and benzo C3_8 cycloalkyl, aryl groups may be optionally substituted with 1-3 substituents independently selected from substituents: halogen atoms, hydroxy, amino, cyano, CV6 alkyl, C1 ^ 6 alkoxy, substituting Cu burning yl teeth, the teeth on behalf C3_8 cycloalkyl group or a Cu burn burn-yl;

[0019] R3为氢原子、氰基、硝基、羟基、氧代、羧基、氨基、卤素原子、CV6烷基、羟基CV6烷基、C3_8环烧基、Cu烧氧基、轻基C3_8环烧基、齒代C3_8环烧基、C3_8环烧基Cp6烧基、齒代C3_8环烧基Cu烧基、代Cu烧基、C2_6稀基、代C2_6稀基、轻基C2_6稀基、Cp6烧氧基、齒代CV6烷氧基、C1^6烷硫基、C3_8环烷基硫基、CV6烷基胺基、二(Cu烷基)胺基、C1^6烷基胺基甲酰基、C1^6烷基酰胺基、CV6烷基磺酰基、CV6烷基胺基磺酰基、CV6烷基磺酰胺基、二((V6烷基)胺基甲酰基或二(Cp6烷基)胺基磺酰基; [0019] R3 is a hydrogen atom, cyano, nitro, hydroxy, oxo, carboxy, amino, a halogen atom, an alkyl group CV6, CV6 hydroxyl group, C3_8 cycloalkyl group burning, Cu burned group, C3_8 cycloalkyl group light burned group, the teeth on behalf C3_8 cycloalkyl burning group, C3_8 cycloalkyl burn group Cp6 burn group, the teeth on behalf C3_8 cycloalkyl burning group Cu burn group, substituting Cu burning yl, C2_6 dilute group, substituting C2_6 dilute group light group C2_6 dilute group, Cp6 burning oxygen group, on behalf of the teeth CV6 alkoxy, C1 ^ 6 alkylthio, C3_8 cycloalkylthio, CV6 alkylamino, di (Cu alkyl) amino, C1 ^ 6 alkyl carbamoyl, C1 ^ 6 alkyl amide group, an alkylsulfonyl group CV6, CV6 alkyl aminosulfonyl group, an alkylsulfonyl group CV6, di ((V6 alkyl) carbamoyl or di (Cp6 is alkyl) aminosulfonyl;

[0020] R4为氢、CV6烷基、Cp6杂烷基、C3_8环烷基、C3_8杂环烷基或芳基,所述CV6烷基、CV6杂烷基、c3_8环烷基、C3_8杂环烷基或芳基可任选被1-3个独立地选自以下的取代基取代:卤素原子、氧代、氛基、轻基、竣基、氣基、C1^烧氧基或Cu烧基; [0020] R4 is hydrogen, CV6 alkyl, Cp6 is heteroalkyl, C3_8 cycloalkyl, C3_8 heterocycloalkyl or aryl group, the alkyl group CV6, CV6 heteroalkyl, c3_8 cycloalkyl, C3_8 heterocycloalkyl group or aryl group may be optionally substituted with 1-3 substituents independently selected from the group: halogen atom, oxo, group atmosphere, light group, Jun group, gas-based, C1 ^ alkoxy or Cu burn burn-yl;

[0021] Ra和Rb分别独立地为氢、CV6烷基或卤素原子,其中Ra和Rb可以与它们所连接的碳形成c3_8环烷基,所述C3_8环烷基可任选被1-3个独立地选自以下的取代基取代:卤素原子、氧代、氰1基、轻基、羧基、M基、c3_8环烧基、(V6烧氧基或(V6烧基; [0021] Ra and Rb are each independently hydrogen, a halogen atom or a CV6 alkyl group, wherein Ra and Rb may form c3_8 cycloalkyl with the carbon they are attached, a C3_8 cycloalkyl group may be optionally substituted with 1-3 is independently selected from the following substituents: halogen atom, oxo, cyano group 1, light group, a carboxyl group, M group, c3_8 burning ring group, (V6 group or burning (V6 burn-yl;

[0022] P 为0,1,2,3 或4。 [0022] P is 0, 1 or 4.

[0023] 通式(I )所示的化合物,其药学上可接受的盐,及其立体异构体的优选技术方案为: [0023] The compounds of general formula (I), preferable aspect pharmaceutically acceptable salts thereof, stereoisomers thereof as follows:

[0024] 其中,X1、X2、X3、X4和X7分别独立地为N或C (R3); [0024] wherein, X1, X2, X3, X4, and X7 are each independently N or C (R3);

[0025] X5、X6和X8分别独立地为N或C,且X5和X6至少有一个为N ; [0025] X5, X6, and X8 are each independently N or C, and at least one of X5 and X6 is N;

[0026] Γ '代表环上的键为单键或双键; [0026] Γ 'represents a bond is single or double bond on the ring;

Ri (I)[0027] YS-(C(RaRb))p-; Ri (I) [0027] YS- (C (RaRb)) p-;

[0028] Z 为-(C (RaRb)) p-或-S-; [0028] Z is - (C (RaRb)) p-, or -S-;

[0029] R1 为R4OC (O) _、(R4) 2NC (O)-或四氮唑基; [0029] R1 is R4OC (O) _, (R4) 2NC (O) -, or tetrazol-yl;

[0030] R2为芳基或苯并C3_8环烷基,所述的芳基和苯并C3_8环烷基可任选被1-3个独立地选自以下的取代基取代:齒素原子、轻基、氣基、氰1基、Cu烧基、Cu烧氧基、齒代Cu烧基或齒代Cu烧氧基; [0030] R2 is an aryl group or a benzo C3_8 cycloalkyl group, aryl group and the benzo C3_8 cycloalkyl can be optionally substituted with 1-3 substituents independently selected from substituents: teeth atom, light group, gas group, a cyano group, a group burning Cu, Cu burned group, on behalf of the tooth or teeth on behalf of the group Cu Cu burning burning group;

[0031] R3为氧原子、氛基、轻基、氧代、氣基、齒素原子、C1^烧基、轻基CV6烧基、C3_8环烧基、CV6烧氧基、轻基C3_8环烧基、齒代C3_8环烧基、C3_8环烧基Cu烧基、齒代C3_8环烧基Cp6烷基、卤代Cu烷基、卤代CV6烷氧基、CV6烷硫基、CV6烷基胺基、二(Cu烷基)胺基、Cu烷基胺基甲酰基、C1^6烷基酰胺基、CV6烷基胺基磺酰基或CV6烷基磺酰胺基; [0031] R3 is an oxygen atom, a group atmosphere, light, oxo, gas-based, tooth element atom, C1 ^ group burning, light burned group CV6 group, C3_8 cycloalkyl group burn, burn CV6 alkoxy, C3_8 cycloalkyl group light burned group, C3_8 cycloalkyl burning toothed substituting group, C3_8 cycloalkyl group burn burn Cu group, C3_8 cycloalkyl toothed substituting burning Cp6 alkyl group, haloalkyl group Cu, CV6 alkoxy, haloalkoxy, alkylthio CV6, CV6 alkyl group , di (Cu alkyl) amino, Cu alkyl carbamoyl, C1 ^ 6 alkyl amide group, a sulfonyl group or alkylamino CV6 CV6 alkyl sulfonamido;

[0032] R4为氣、C^6烧基、C3_8环烧基、C3_8杂环烧基或苯基,所述CV6烧基、C3_8环烧基、C3_8杂环烷基或苯基可任选被1-3个独立地选自以下的取代基取代:卤素原子、氧代、氰基、羟基、羧基、氨基或Cu烷基; [0032] R4 is a gas, C ^ 6 burning group, C3_8 cycloalkyl group burning, C3_8 heterocyclyl group, or a phenyl burning, the burning CV6 group, C3_8 cycloalkyl group burning, C3_8 heterocycloalkyl, or optionally substituted phenyl may be 1-3 substituents independently selected from the following substituents: halogen atom, oxo, cyano, hydroxy, carboxy, amino, or Cu alkyl;

[0033] Ra和Rb分别独立地为氢、CV6烷基或卤素原子,其中Ra和Rb可以与它们所连接的碳形成c3_8环烷基,所述C3_8环烷基可任选被1-3个独立地选自以下的取代基取代:卤素原子、氧代、氰1基、轻基、羧基、M基、C1^烧氧基或Cu烧基; [0033] Ra and Rb are each independently hydrogen, a halogen atom or a CV6 alkyl group, wherein Ra and Rb may form c3_8 cycloalkyl with the carbon they are attached, a C3_8 cycloalkyl group may be optionally substituted with 1-3 is independently selected from the following substituents: halogen atom, oxo, cyano group 1, light group, a carboxyl group, M group, C1 ^ alkoxy or Cu burn burn-yl;

[0034] P 为0,1,2 或3。 [0034] P is 0, 1 or 3.

[0035] 通式(I )所示的化合物,其药学上可接受的盐,及其立体异构体的优选技术方案为: [0035] The compounds of general formula (I), preferable aspect pharmaceutically acceptable salts thereof, stereoisomers thereof as follows:

[0036] 其中,X1、X2、X3、X4和X7分别独立地为N或C (R3); [0036] wherein, X1, X2, X3, X4, and X7 are each independently N or C (R3);

[0037] X5、X6和X8分别独立地为N或C,且X5和X6至少有一个为N ; [0037] X5, X6, and X8 are each independently N or C, and at least one of X5 and X6 is N;

[0038] O代表环上的键为单键或双键; [0038] O represents a bond on the ring is a single bond or a double bond;

[0039] YS-(C(RaRb))p-; [0039] YS- (C (RaRb)) p-;

[0040] Z 为-(C (RaRb)) p-或-S-; [0040] Z is - (C (RaRb)) p-, or -S-;

[0041] R1为R4OC(O)-或四氮唑基; [0041] R1 is R4OC (O) -, or tetrazol-yl;

[0042] R2为芳基,所述的芳基可任选被1-3个独立地选自以下的取代基取代:卤素原子、 [0042] R2 is aryl, the aryl group may be optionally substituted with 1-3 substituents independently selected from substituents: a halogen atom,

轻基、氣基、氛基、C1^烧基、Cp6烧氧基、1¾代Cu烧基或1¾代Cu烧氧基; Light group, gas-based, group atmosphere, C1 ^ yl burn, burn Cp6 is group, group or burning 1¾ 1¾ substituting Cu Cu burning substituting group;

[0043] R3为氢!原子、氛基、轻基、氧代、氣基、1¾素原子、CV6烧基、C3_8环烧基、Cu烧氧基、c3_8环烷基CV6烷基、C1^6烷硫基、CV6烷基胺基、二(Cu烷基)胺基、C1^6烷基胺基甲酰基、(V6烷基酰胺基或CV6烷基磺酰胺基; [0043] R3 is a hydrogen! Atom, group atmosphere, light, oxo, gas-based, 1¾ prime atoms, burning CV6 group, C3_8 cycloalkyl group burning, Cu burned group, c3_8 CV6 cycloalkyl group, C1 ^ 6 alkylthio, CV6 alkylamino, di (Cu alkyl) amino, C1 ^ 6 alkyl carbamoyl, (V6 CV6 alkyl amido or sulfonamido group;

[0044] R4为氢、Cu烷基或C3_8环烷基,所述Cu烷基或C3_8环烷基可任选被1-3个独立地选自以下的取代基取代:卤素原子、氧代、氰基、羟基、羧基、氨基或CV6烷基; [0044] R4 is hydrogen, alkyl or C3_8 cycloalkyl group Cu, the Cu alkyl or C3_8 cycloalkyl group may be optionally substituted with 1 to 3 substituents independently selected from the group: halogen atom, oxo, cyano, hydroxy, carboxy, amino or CV6 alkyl;

[0045] Ra和Rb分别独立地为氢、CV6烷基或卤素原子,其中Ra和Rb可以与它们所连接的碳形成c3_6环烷基,所述C3_6环烷基任选被1-3个独立地选自以下的取代基取代:卤素原子、氧代、氛基、轻基、竣基、M基、C1^烧氧基或Cu烧基; [0045] Ra and Rb are each independently hydrogen, a halogen atom or a CV6 alkyl group, wherein Ra and Rb may form c3_6 cycloalkyl with the carbon they are attached, a C3_6 cycloalkyl group optionally substituted with 1-3 independent selected from the following substituents: halogen atom, oxo, group atmosphere, light group, Jun group, M group, C1 ^ alkoxy or Cu burn burn-yl;

[0046] P 为0,I 或2。 [0046] P is 0, I or 2.

[0047] 通式(I )所示的化合物,其药学上可接受的盐,及其立体异构体的优选技术方案为: [0047] The compounds of general formula (I), preferable aspect pharmaceutically acceptable salts thereof, stereoisomers thereof as follows:

[0048] 其中,X1、X2、X3、X4和X7分别独立地为N或C (R3);[0049] X5、X6和X8分别独立地为N或C,且X5和X6至少有一个为N ; [0048] wherein, X1, X2, X3, X4, and X7 are each independently N or C (R3); [0049] X5, X6, and X8 are each independently N or C, and X5 and X6 have at least one of N ;

[0050] O代表环上的键为单键或双键; [0050] O represents a bond on the ring is a single bond or a double bond;

[0051] Y 为-CH2-; [0051] Y is -CH2-;

[0052] Z 为-S-; [0052] Z is -S-;

[0053] R1为-C (O) OH或四氮唑基; [0053] R1 is -C (O) OH or tetrazol-yl;

[0054] R2为苯基,所述的苯基可任选被1-3个独立地选自以下的取代基取代:卤素原子、 [0054] R2 is phenyl, said phenyl is optionally substituted with 1-3 substituents independently selected from substituents: a halogen atom,

轻基、氣基、氰1基、二氣甲基、C1^烧基或Cu烧氧基; Light-yl, gas group, a cyano group 1, two gas-methyl, C1 ^ Cu burning or burnt-yl group;

[0055] R3为氢!原子、氛基、轻基、氧代、氣基、1¾素原子、CV6烧基、C3_8环烧基、Cu烧氧基、(V6烷基酰胺基或c3_8环烷基Cu烷基。 [0055] R3 is a hydrogen! Atom, group atmosphere, light, oxo, gas-based, 1¾ prime atoms, burning CV6 group, C3_8 cycloalkyl group burning, Cu burned group, (V6 alkylamide group or cycloalkyl group c3_8 Cu alkyl.

[0056] 通式(I )所示的化合物,其药学上可接受的盐,及其立体异构体的优选技术方案为: [0056] The compounds of general formula (I), preferable aspect pharmaceutically acceptable salts thereof, stereoisomers thereof as follows:

[0057] 其中,X1、X2、X3、X4和X7分别独立地为N或C (R3); [0057] wherein, X1, X2, X3, X4, and X7 are each independently N or C (R3);

[0058] X5、X6和X8分别独立地为N或C,且X5和X6至少有一个为N ; [0058] X5, X6, and X8 are each independently N or C, and at least one of X5 and X6 is N;

[0059] O代表环上的键为单键或双键; [0059] O represents a bond on the ring is a single bond or a double bond;

[0060] Y 为_CH2_ ; [0060] Y is _CH2_;

[0061 ] Z 为_S-; [0061] Z is _S-;

[0062] R1 为-C (O) OH ; [0062] R1 is -C (O) OH;

[0063] R2为苯基,所述的苯基可任选被1-3个独立地选自以下的取代基取代:卤素原子、 [0063] R2 is phenyl, said phenyl is optionally substituted with 1-3 substituents independently selected from substituents: a halogen atom,

轻基、氣基、氰1基、C1 _4烧基或二氣甲基; Light-yl, gas group, a cyano group, C1 _4 burning gas or di-methyl;

[0064] R3为氢原子、轻基、氧代、卤素原子或CV4烧基。 [0064] R3 is a hydrogen atom, light, oxo, a halogen atom or a group CV4 burning.

[0065] 本发明的技术方案,还包括通式(II)所示的化合物,其药学上可接受的盐,及其立 [0065] aspect of the present invention further comprises a compound of formula (II) represented by the pharmaceutically acceptable salts thereof, and established

体异构体: Isomer of:

[0066] [0066]

Figure CN103373996AD00091

[0067]其中,Y 为-CH2-; [0067] wherein, Y is -CH2-;

[0068] R1 为-C (O) OH ; [0068] R1 is -C (O) OH;

[0069] Z 为-S-; [0069] Z is -S-;

[0070] R2为苯基,所述苯基可被1-3个独立地选自以下的取代基取代:卤素原子、羟基、 [0070] R2 is phenyl, said phenyl group may be independently selected from 1-3 substituents: a halogen atom, a hydroxyl group,

氣基、氰1基、Cj_4烧基或二氣甲基。 Gas group, a cyano group, Cj_4 burning gas or di methyl.

[0071] 通式(II)所示的化合物,其药学上可接受的盐,及其立体异构体的优选技术方案为: [0071] The compounds of formula (II) shown preferred aspect of its pharmaceutically acceptable salts, and stereoisomers thereof is:

[0072]其中,Y 为-CH2-; [0072] wherein, Y is -CH2-;

[0073] R1 为-C (O) OH ;[0074] Z 为-S-; [0073] R1 is -C (O) OH; [0074] Z is -S-;

[0075] R2为苯基,所述苯基可被I个选自以下的取代基取代滷素原子、羟基、氨基、CV4 [0075] R2 is phenyl, said phenyl may be substituted with I substituent selected from a halogen atom, a hydroxyl group, an amino group, CV4

烧基或二氣甲基。 Group or two methyl burning gas.

[0076] 利用以下定义对本发明进行描述,具体定义方式包括但不限于以下描述。 [0076] The present invention will be described using the following definitions and specific definitions including but not limited to the following description.

[0077] 本发明所述的“卤素原子”包括氟原子、氯原子、溴原子、碘原子。 [0077] according to the present invention, "halogen atom" includes fluorine atom, chlorine atom, bromine atom, iodine atom.

[0078] 本发明所述的“Cu烷基”指含有1-6个碳原子的烷烃去除一个氢原子衍生的直链或支链的烷基,具体实例包括但不限于:甲基、乙基、正丙基、异丙基、正丁基、2-甲基丙基、1-甲基丙基、1,1-二甲基乙基、正戊基、3-甲基丁基、2-甲基丁基、1-甲基丁基、1-乙基丙基、正己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1- 二甲基丁基、1,2- 二甲基丁基、1,3- 二甲基丁基、2,3- 二甲基丁基、2-乙基丁基、1-甲基-2-甲基丙基等。 [0078] The present invention is "a Cu alkyl" refers to a removal of one hydrogen atom of the alkyl group derived from an alkane having 1 to 6 carbon atoms, a straight-chain or branched, and specific examples include, but are not limited to: methyl, ethyl, , n-propyl, isopropyl, n-butyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl, n-pentyl, 3-methylbutyl, 2- methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl group, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1-methyl-2-methylpropyl and the like. 本发明所述的“(V4烷基”指上述实例中的含有1-4个碳原子的具体实例。 According to the present invention, "(V4 alkyl" refers to a specific example containing 1-4 carbon atoms in the above examples.

[0079] 本发明所述的“Cm烷氧基”指“Cm烷基”通过氧原子与其他结构相连接的基团,如 [0079] The present invention is "Cm is alkoxy" refers to "alkyl Cm is" group via an oxygen atom is connected with other structures, such as

甲氧基、乙氧基、丙基氧基、异丙基氧基、丁基氧基、异丁基氧基、叔丁基氧基、仲丁基氧基、戍基氧基、新戍基氧基、己基氧基等。 Methoxy, ethoxy, propyl group, isopropyl group, butyl group, isobutyl group, a tert-butyl group, sec-butyl group, pentyl group, pentyl new group, hexyl group and the like.

[0080] 本发明所述的“C 3_8环烷基”为含有3-8个碳原子的环状烷基,具体实例包括但不限于:环丙基、环丁基、环戊基、环己基、环庚基、环辛基、1-甲基环丙基、1-戊基环丙基、1,2-二乙基环丁基、1-甲基环丁基、1-丁基环丁基、1,3-二甲基环丁基、1-甲基环戊基、1- 丁基环戊基、1-甲基环己基、1-乙基环戊基等。 [0080] The present invention is "C 3_8 cycloalkyl" is a cyclic alkyl group containing 3-8 carbon atoms and specific examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 1-pentyl-cyclopropyl, 1,2-diethyl-cyclobutyl, 1-methylcyclobutyl, 1-butyl, cyclobutyl, 1,3-dimethyl-cyclobutyl, 1-methylcyclopentyl, 1-butyl-cyclopentyl group, 1-methylcyclohexyl group, 1-ethyl-cyclopentyl group and the like.

[0081 ] 本发明所述的“卤代C^6烷基”指一至多个“卤素原子”取代“Cu烷基”所衍生的基团,所述“卤素原子”和“Cu烷基”如前文所定义。 [0081] "halo C ^ 6 alkyl group" of the invention refers to a plurality of "halogen atom" substituent group, "a Cu alkyl group" derived, the "halogen atom" and "a Cu alkyl" previously defined.

[0082] 本发明所述的“C2_6烯基”是指含有双键的碳原子数为2-6的直链或支链或环状的烯基,具体实例包括但不限于:乙烯基、1-丙烯基、2-丙烯基、3-丙烯基、1-甲基乙烯基、 [0082] The present invention "C2_6 alkenyl" refers to the number of carbon atoms containing a double bond of 2 to 6 straight or branched chain or cyclic alkenyl group, specific examples include, but are not limited to: ethenyl, 1 - propenyl, 2-propenyl, 3-propenyl, 1-methylvinyl,

1- 丁稀基、2_ 丁稀基、3_ 丁稀基、1-甲基_1-丙稀基、2_甲基_1-丙稀基、1_甲基-2-丙稀基、2_甲基-2-丙稀基、1_戍稀基、2_戍稀基、3_戍稀基、4_戍稀基、1-甲基-1-丁稀基、2_甲基-1- 丁稀基、3_甲基-1- 丁稀基、1-甲基-2- 丁稀基、2_甲基_2_ 丁稀基、3_甲基_2_ 丁稀基、1-甲基_3_ 丁稀基、2_甲基_3_ 丁稀基、3_甲基_3_ 丁稀基、1,1- 二甲基_2_丙稀基、1,2_ 二甲基-1-丙稀基、1,2_ 二甲基_2_丙稀基、1-乙基_1-丙稀基、1-乙基_2_丙稀基、1-己稀基、2_己稀基、3_己稀基、4_己稀基、5_己稀基、1-甲基_1_戍稀基、2_甲基-1-戍稀基、3_甲基-1-戍稀基、4_甲基-1-戍稀基、1-甲基_2_戍稀基、2_甲基_2_戍稀基、3_甲基_2_戍稀基、4_甲基_2_戍稀基、1-甲基_3_戍稀基、2_甲基_3_戍稀基、3_甲基-3-戍稀基、4_甲基-3-戍稀基、1-甲基-4-戍稀基、2_甲基-4-戍稀基、3_甲基-4-戍稀基、4_甲基-4-戍稀基、1,1-二甲基 1-yl dilute, dilute 2_ butyl group, dilute 3_ butyl group, 1-methyl-_1- acryl group, acryl group _1- methyl 2_, 1_-2-propenyl, 2 _ methyl-2-propenyl, Shu dilute group 1_, 2_ Shu group dilute, dilute Shu-yl 3_, 4 _ Shu dilute, 1-methyl-1-yl dilute, methyl 2_ - 1-yl dilute, dilute 3_ methyl-1-yl, 1-methyl-2-yl dilute, dilute 2_ methyl _2_ butyl group, 3_ butyl methyl _2_ dilute group, 1- _3_ dilute butyl methyl group, 2_ _3_ butyl methyl group dilute, dilute 3_ butyl methyl _3_ yl, 1,1-dimethyl propylene group _2_, 1,2_-dimethyl-1 - propylene group, 1,2_ _2_ dimethyl acryl group, 1-ethyl _1- propenyl, 1-ethyl _2_ propylene, 1-hexene group, hexene 2_ group, a hexene group 3_, 4 _ hexene group, 5_ hexene, 1-methyl group _1_ Shu dilute, dilute 2_ Shu-methyl-1-yl, methyl-1-shu 3_ dilute base, dilute 4_ Shu-methyl-1-yl, 1-methyl group _2_ Shu dilute, dilute Shu 2_ _2_ methyl group, methyl _2_ Shu dilute yl 3_, 4 _ A Shu dilute _2_ group, 1-methyl group _3_ Shu dilute, dilute Shu _3_ 2_ methyl group, dilute Shu-methyl-3-yl 3_, 4 _ dilute Shu-methyl-3- group, l-methyl-4- yl Shu dilute, dilute 2_ Shu-methyl-4-yl, methyl-4-Shu dilute yl 3_, 4 _ dilute Shu-methyl-4-yl, 1,1- dimethyl _2_ 丁稀基、1,1-二甲基-3-丁稀基、1,2-二甲基_1_ 丁稀基、1,2_ 二甲基_2_ 丁稀基、1,2_ 二甲基_3_ 丁稀基、1,3_ 二甲基-1- 丁稀基、1,3_ 二甲基_3_ 丁稀基、I,4_ 二甲基_2_ 丁稀基、2,2_ 二甲基-3- 丁稀基、2,3- 二甲基_1_ 丁稀基、2,3_ 二甲基_2_ 丁稀基、2,3_ 二甲基_3_ 丁稀基、3,3- 二甲基-1- 丁稀基、3,3- 二甲基_2_ 丁稀基、1-乙基-1- 丁稀基、1-乙基_2_ 丁稀基、1-乙基-3- 丁稀基、2-乙基_1_ 丁稀基、2-乙基_2_ 丁稀基、2-乙基-3- 丁稀基、I,1,2-二甲基_2_丙稀基、1_乙基-1-甲基_2_丙稀基、1-乙基_2_甲基-1-丙稀基、1-乙基_2_甲基_2_丙稀基、I, 3- 丁二烯基、I, 4-戊二烯基、I, 4-己二烯基、环戊烯基、I, 3-环戊二烯基、环己烯基、I, 4-环己二烯基、1,3, 5-己三烯基等。 _2_ dilute butyl group, a 1,1-dimethyl-3-butenoic lean-yl, 1,2-dimethyl-butyl _1_ group dilute, dilute 1,2_ dimethyl _2_ butyl group, dimethyl 1,2_ _3_ dilute butyl group, 1,3_-dimethyl-1-yl dilute, dilute 1,3_ dimethyl butyl group _3_, I, 4_ dilute dimethyl _2_ butyl group, 2,2_ dimethyl - dilute 3-butoxy group, a 2,3-dimethyl butyl _1_ group dilute, dilute 2,3_ dimethyl _2_ butyl group, 2,3_-dimethyl-butyl _3_ dilute yl, 3,3-dimethyl dilute-1-yl, 3,3-dimethyl-butyl dilute _2_ group, 1-ethyl-1-lean-yl, 1-ethyl _2_ dilute butyl group, 1-ethyl-butoxy dilute group, ethyl group dilute _1_ butyl, 2-butyl dilute _2_ group, 2-ethyl -3-yl dilute, I, 1,2- dimethyl _2_ propenyl, 1 _-ethyl-1-methyl _2_ propenyl, 1-ethyl _2_ methyl-1-propenyl, 1-ethyl _2_ _2_ methyl acryl group, I, 3 - butadienyl, I, 4- pentadienyl, I, 4- hexadiene group, cyclopentenyl group, I, 3- cyclopentadienyl, cyclohexenyl, I, 4- cyclohexyl pentadienyl, 1,3,5-hexatrienyl and the like.

[0083] 本发明所述的“卤代Cu烷氧基”指一至多个“卤素原子”取代“Cu烷氧基”所衍生的基团,所述“卤素原子”和“Cu烷氧基”如前文所定义。 [0083] The present invention 'haloalkyl Cu alkoxy "refers to a plurality of" halogen atom "substituted" Cu alkoxy "group derived from the" halogen atom "and" Cu alkoxy " are as defined hereinbefore.

[0084] 本发明所述的“Cu烷硫基”是指CV6烷基通过硫原子(-S-)与其它部分相连接所衍生的基团,即Cu烷基-S-,所述“Cu烷基”如前文所述。 [0084] "Cu alkylthio" in the present invention means connected CV6 alkyl group derived from the other portions through a sulfur atom (-S-), i.e., Cu alkyl group -S-, a "Cu alkyl "is as previously described.

[0085] 本发明所述的“芳基”是指环原子全部为碳原子的环状芳香基团,包括6-8元单环芳基和8-14元稠环芳基。 [0085] The present invention "aryl" refers to a ring atom of a cyclic aromatic group of all carbon atoms, including 6-8 membered monocyclic aryl and 8-14 membered fused ring aromatic group.

[0086] 6-8元单环芳基是指全部不饱和的芳基,具体实例包括但不限于:苯基、环辛四烯基等。 [0086] 6-8 membered monocyclic aromatic group refers to fully unsaturated aryl group, specific examples include, but are not limited to: phenyl, cyclooctatetraene group.

[0087] 8-14元稠环芳基是指由两个或两个以上环状结构彼此共用两个相邻的碳原子所形成的,至少有一个环为芳香环的稠环基团,包括8-14元全部不饱和稠环芳基,具体实例包括但不限于:萘、菲等。 [0087] 8-14 membered fused ring aryl refers shared by two or more cyclic structures to one another two adjacent carbon atoms form at least one ring is an aromatic ring fused ring group, comprising 8-14 membered fully unsaturated condensed ring aryl group, specific examples include, but are not limited to: naphthalene, phenanthrene and the like.

[0088] 本发明所述的“C3_8杂环烷基”指C3_8环烷基中的一至多个碳原子被S、0、N或C(O)原子取代所衍生的基团,所述“C3_8环烷基”如前文所述。 [0088] "C3_8 heterocycloalkyl" according to the present invention refers to a plurality of carbon atoms in the cycloalkyl is C3_8 S, 0, N, or C (O) atom substituent groups are derived, the "C3_8 cycloalkyl "as previously described. 本发明所述的“c3_6杂环烷基”指上述实例中的含有3-6个环原子的具体实例。 According to the present invention "c3_6 heterocycloalkyl" refers to a specific example containing 3-6 ring atoms in the above examples.

[0089] 本发明所述的“杂芳基”,是指含有5-14个环原子(其中至少含有一个杂原子)的不饱和的具有芳香性的环状基团,包括5-8元单杂芳基、6-14元稠杂芳基,所述的杂原子有氮、氧和硫等,同时包括碳原子和硫原子可以被氧代。 [0089] The present invention "heteroaryl" refers to an unsaturated cyclic group having an aromatic ring containing 5-14 atoms (containing at least one hetero atom) include 5-8 membered monocyclic heteroaryl, 6-14 membered fused heteroaryl, said heteroatoms nitrogen, oxygen and sulfur, including both carbon and sulfur atoms may be oxo.

[0090] 5-8元单杂芳基是指·芳香性的含有杂原子的环状基团,具体实例包括但不仅限于呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、吡啶基、嘧啶基、1,4- 二氧杂环己二烯基、2H-1,2-噁嗪基、4H-1, 2-噁嗪基、6H-1,2-噁嗪基、4H-1,3-噁嗪基、6H-1,3-噁嗪基、4H-1,4-噁嗪基、哒嗪基、吡嗪基、I, 2,3-三嗪基、I, 2,4-三嗪基、I, 3,5-三嗪基、I, 3,4-三嗪基、I, 2,4,5-四嗪基、氧杂环庚三烯基、硫杂环庚三烯基、氮杂环庚三烯基、1,3-二氮杂环庚三烯基、氮杂环辛四稀基等。 [0090] 5-8 membered monocyclic heteroaryl group refers to a-aromatic-containing cyclic group including a hetero atom, and specific examples include, but are not limited to furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3- oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrimidinyl, 1,4- hexadiene heterocyclyl group, 2H-1,2- oxazinyl, 4H-1, 2- oxazin-yl, 6H-1,2- oxazinyl, 4H-1,3- oxazinyl, 6H-1 3-oxazinyl, 4H-1,4- oxazinyl, pyridazinyl, pyrazinyl, I, 2,3- triazinyl, I, 2,4- triazinyl, I, 3,5 - triazinyl, I, 3,4- triazinyl, I, 2,4,5- tetrazine, oxepin-yl, thietan clohepten- group, azepine group , 1,3-azepine group, azocine lean group.

[0091] 6-14元稠杂芳基,是指含有6-14个环原子(其中至少含有一个杂原子)由两个或两个以上环状结构彼此共用两个相邻的环原子连接起来形成的不饱和的具有芳香性的稠环结构,具体实例包括但不限于:苯并呋喃基、苯并异呋喃基、苯并噻吩基、吲哚基、苯并噁唑基、苯并咪唑基、吲唑基、苯并三唑基、喹啉基、异喹啉基、吖啶基、菲啶基、苯并哒嗪基、酞嗪基、喹唑啉基、喹喔啉基、酚嗪基、喋啶基、嘌呤基、萘啶基等。 [0091] 6-14 membered fused heteroaryl, refers to a 6 to 14 ring atoms (containing at least one hetero atom) are shared by two or more cyclic structures adjacent to each other two ring atoms connected unsaturated condensed with aromatic ring structure, examples include, but are not limited to specific form: benzofuranyl, iso-benzo furanyl, benzothienyl, indolyl, benzoxazolyl, benzimidazolyl , indazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, acridinyl, phenanthridinyl, benzo pyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenol triazine group, pteridinyl, purinyl, naphthyridinyl and the like.

[0092] 本发明所述的“Cu杂烷基”指Cu烷基中的一至多个碳原子被S、O、N或C(O)原子替换所衍生的基团,所述“Cu烷基”如前文所述。 [0092] "heteroalkyl Cu 'according to the present invention means a Cu more carbon atoms in the alkyl group is S, O, N, or C (O) atom replacing a group derived, the" alkyl group Cu "as described above.

[0093] 本发明所述立体异构体包括所有旋光异构体、非对映异构体、几何异构体和互变异构体,式(I)的化合物包含一种或多种不对称中心,并由此能够作为消旋体和外消旋混合物、单对映体、非对映异构体混合物和单非对映异构体混合物存在。 [0093] The present invention includes all stereoisomers of optical isomers, diastereomers, geometric isomers and tautomers, the compounds of formula (I) comprises one or more asymmetrical center, and thus can be used as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single diastereomeric mixture of isomers exist. 一些本发明描述的化合物包含烯烃双健,并且除非特别指明,意在包括E几何异构体和Z几何异构体。 Some of the compounds described in the present invention contain olefinic double bonds, and unless otherwise specified, is intended to include geometrical isomers E and Z geometric isomers. 一些本发明描述的化合物可以存在不同的氢连接点,被称为互变异构体。 Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. 此实例可以为酮及其烯醇形式,称为酮-烯醇互变异构体。 This example may be a ketone and its enol form, known as keto - enol tautomers. 式(I)的化合物包括单个互变异构体及其混合物。 The compounds of formula (I) includes a single tautomers and mixtures thereof. 本发明意在包含式(I)的化合物所有此类异构形式。 The present invention is intended to comprehend all such isomeric forms of the compound of formula (I) are. 所述异构体可以通过标准分离技术和立体化学控制合成获得充分纯度异构体。 The isomers can be separated and stereochemically controlled synthesis techniques to obtain a sufficient purity of the isomers by standard.

[0094] 本发明上述任一化合物药学上可接受的盐包括碱金属盐,如钠盐、钾盐、锂盐等;碱土金属盐,如钙盐、镁盐等;其他金属盐,如铝盐、铁盐、锌盐、铜盐、镍盐、钴盐等;无机碱盐,如铵盐;有机碱盐,如叔辛基胺盐、二苄基胺盐、吗啉盐、葡糖胺盐、苯基甘氨酸烷基酯盐、乙二胺盐、N-甲基葡糖胺盐、胍盐、二乙胺盐、三乙胺盐、二环己基胺盐、N,N' - 二苄基乙二胺盐、氯普鲁卡因盐、普鲁卡因盐、二乙醇胺盐、N-苄基-苯乙基胺盐、哌嗪盐、四甲基胺盐、三(羟甲基)胺基甲烷盐;当本发明的化合物为碱性时,可以由包括无机酸和有机酸在内的药学上可接受的无毒酸制备盐,此类酸包括:氢齒酸盐,如氢氟酸盐、盐酸盐、氢溴酸盐、氢碘酸盐等;无机酸盐,如硝酸盐、高氯酸盐、硫酸盐、磷酸盐等;低级烷磺酸盐,如甲磺酸盐、三氟甲磺酸盐 [0094] Pharmaceutically acceptable salts of the invention any of the above compounds include alkali metal salts such as sodium, potassium, and lithium salts; alkaline earth metal salts, such as calcium, magnesium and the like; other metal salts, such as aluminum salts , iron, zinc, copper, nickel salt, cobalt salt and the like; an inorganic base salts, such as ammonium salts; organic base salts, such as t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts , phenylglycine alkyl ester salts, ethylenediamine salts, N- methylglucamine salts, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N '- dibenzyl ethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N- benzyl - phenethylamine salts, piperazine salts, tetramethylammonium salts, tris (hydroxymethyl) amine methane salt; when the compound of the present invention is basic, may be acceptable by the inorganic and organic acids, including the preparation of pharmaceutically acceptable salts of non-toxic acids, such acids include: hydrogen tooth acid salts such as hydrofluoric acid , hydrochloride, hydrobromide, hydroiodide and the like; inorganic acid salts such as nitrate, perchlorate, sulfate, phosphate and the like; a lower alkyl sulfonates such as methanesulfonate, three triflate 乙磺酸盐等;芳基磺酸盐,如苯磺酸盐、对苯磺酸盐等;有机酸盐,如醋酸盐、苹果酸盐、富马酸盐、琥珀酸盐、柠檬酸盐、酒石酸盐、草酸盐、马来酸盐等;氨基酸盐,如甘氨酸盐、三甲基甘氨酸盐、精氨酸盐、鸟氨酸盐、谷氨酸盐、天冬氨酸盐等。 Ethanesulfonate and the like; aryl sulfonates such as benzenesulfonate, p-toluenesulfonate and the like; organic acid salts such as acetate, malate, fumarate, succinate, citrate , tartrate, oxalate, maleate and the like; amino acid salts such as glycine salts, salts of trimethyl glycine, arginine salt, ornithine salt, glutamate, aspartate and the like. 为了避免疑问,可能有一个、两个或三个成盐阳离子,但这取决于羧基官能团的数量以及所述阳离子的价数。 For the avoidance of doubt there may be one, two or three salt-forming cation, but this depends on the number of carboxyl functions and valency of said cations. 对于本领域专业人员来说显而易见的是,本发明化合物的药学上可接受的盐可以在该化合物的游离羧基处等形成,可以通过常规方法制得。 It will be apparent to the skilled in the art that the pharmaceutically acceptable salts of the compounds of the present invention may be formed at a free carboxy group of the compound, and the like, can be prepared by conventional methods.

[0095] 可以与载体物质组合从而产生单剂量形式的活性成分的量,将根据治疗个体和具体的给药模式而变化。 The amount of active ingredient [0095] can be combined with the carrier materials to produce a single dosage form will vary depending upon the treating and the particular mode of administration. 例如,要经口施用给人患者的制剂可以包含约0.05mg至约5g活性试剂并结合以适当量和常规量的载体物质,其中载体物质的量可以为整个组合物的约5%指约99.95%。 For example, may comprise from about 0.05mg to about 5g of active agent to oral formulations administered to a human patient in combination with appropriate amounts of carrier material and conventional amounts, wherein the amount of the support material may be from about 5% to about refers to the entire composition 99.95 %. 剂量单位形式通常包含约0.1mg至约0.4g式(I)的化合物作为活性成分,通常为0.5mg、lmg、2mg、5mg、10mg、25mg、50mg、100mg、200mg 或400mg.[0096] 本发明所述的“药物组合物”,是指通式(I )所示的化合物和药学上可接受的载体的药物组合物。 Dosage unit forms will generally contain from about 0.1mg to about 0.4g compound of formula (I) as an active ingredient, typically 0.5mg, lmg, 2mg, 5mg, 10mg, 25mg, 50mg, 100mg, 200mg or 400mg. [0096] The present invention the "pharmaceutical composition", refers to a formula (I) and a pharmaceutically acceptable compound represented by the pharmaceutical composition carrier. 其药学上可接受的盐及其立体异构体与一种或多种药用载体制成药学上可接受的药物制剂,以口服、肠胃外等方式施用于需要这种治疗的患者。 Its pharmaceutically acceptable salts and stereoisomers thereof with one or more pharmaceutically acceptable carriers for the pharmaceutical preparations made pharmaceutically acceptable, orally, parenterally administered to a patient, etc. need of such treatment. 口服给药时,可以与常规的填充剂、粘合剂、崩解剂、`润滑剂、稀释剂等制成常规的固体制剂,如片剂、胶囊剂、丸剂、颗粒剂等;用于肠胃外给药时,可制成注射剂,包括注射液、注射用无菌粉末与注射用浓溶液。 For oral administration, a conventional solid formulation with conventional fillers, binders, disintegrants, lubricants `, diluents or the like, such as tablets, capsules, pills, granules and the like; for parenteral when administration, may be formulated as injections, including injections, sterile powder for injection with a concentrated solution for injection. 制成注射剂时,可采用现有制药领域中的常规方法生产,配制注射剂时,可以不加入附加剂,也可根据药物的性质加入适宜的附加剂。 When prepared as injectables, using conventional methods conventional in the pharmaceutical art production, formulating injections, additives may not be added, may be added suitable additives according to the nature of the drug.

[0097] 本发明还提供了通式(I )所示的化合物、其药学上可接受的盐及其立体异构体在制备治疗和/或预防与CRTH2活性相关的疾病的药物中的应用,与CRTH2活性相关的疾病选自哮喘、过敏性鼻炎、过敏性皮炎、过敏性结膜炎、Churg-Strauss综合症、鼻窦炎、嗜碱性白血病、慢性风疹、嗜碱性白细胞增多、牛皮癣、湿疹、炎症性的肠疾病、溃疡性结肠炎、克罗恩氏病、关节炎或慢性阻塞性肺病。 [0097] The present invention also provides compounds (I) shown in the application pharmaceutically acceptable salts and stereoisomers thereof in the preparation of the treatment and / or prophylaxis of diseases associated with CRTH2 activity in the formula, diseases associated with CRTH2 activity is selected from asthma, allergic rhinitis, allergic dermatitis, allergic conjunctivitis, Churg-Strauss syndrome, sinusitis, basophilic leukemia, chronic urticaria, basophilic leukocytosis, psoriasis, eczema, inflammatory bowel disease, ulcerative colitis, Crohn's disease, arthritis or chronic obstructive pulmonary disease.

[0098] 本发明还提供了包含通式(I )所示的化合物、其药学上可接受的盐及其立体异构体和一种或多种治疗活性物质的药物组合物,所述治疗活性物质选自TNF-α抑制剂、C0X-1/C0X-2抑制剂、C0X-2抑制剂、糖皮质激素、白介素的灭活抗体、趋化因子受体调节剂、组胺Hl受体拮抗剂/抗组胺剂、白三烯D4受体拮抗剂、白三烯拮抗剂、LTD4拮抗剂、VLA-4拮抗剂、皮质类固醇、皮质类固醇类似物、β 2-激动剂、茶碱、白三烯生物合成抑制剂、环氧酶-2抑制剂、磷酸二酯酶IV型抑制剂、阿片类镇痛药、抗凝血剂、β -阻断剂、β -肾上腺素能激动剂、血管紧张素转化酶抑制剂或HMG-CoA还原酶抑制剂。 [0098] The present invention further provides a compound comprising formula (I) shown, pharmaceutically acceptable salts thereof and stereoisomers thereof and one or more therapeutically active substances of the pharmaceutical composition, said therapeutically active TNF-α inhibitor is selected from materials, C0X-1 / C0X-2 inhibitors, C0X-2 inhibitors, glucocorticoids, interleukin-inactivated antibody, chemokine receptor modulators, histamine Hl receptor antagonists / antihistamine, leukotriene D4 receptor antagonists, leukotriene antagonists, LTD4-antagonists, VLA-4 antagonists, corticosteroids, corticosteroid analogs, β 2- agonists, theophylline, and white ene biosynthesis inhibitors, cyclooxygenase-2 inhibitors, phosphodiesterase type IV inhibitor, an opioid analgesics, anticoagulants, β - blockers, β - adrenergic agonists, angiotensin converting enzyme inhibitors or HMG-CoA reductase inhibitors.

[0099] 本发明所述的“治疗”,是指减轻、改善、消除或减少与疾病或病症相关的征兆和症状。 [0099] according to the present invention, "treatment" refers to alleviating, ameliorating, eliminating or reducing the signs and symptoms associated with a disease or disorder.

[0100] 本发明所述的“预防”,是指防止或延迟疾病或病症的发生或发展、或者防止或延迟与此疾病或病症相关的征兆或症状。 [0100] according to the present invention, "prevention" refers to preventing or delaying the development or progression of a disease or condition, or delaying or preventing the signs or symptoms associated with the disease or condition.

[0101] 本发明所述的“组合物”,是指在药物组合物中,旨在包括含有活性成分和构成载体的惰性络合或聚合,或者从一种或多种成分的分解,或者从一种或多种成分的其它类型的反应或相互作用产生的任何产品,因此,本发明的药物组合物包括通过将式(I)的化合物与一种或多种药学上可接受的赋形剂混合而制备的任何组合物。 [0101] "composition" of the present invention, refers to a pharmaceutical composition, is intended to include the active ingredient comprising an inert carrier and constituting complexation or aggregation of, or one or more ingredients from decomposition, or from One or more of the ingredients of other types of reactions or interactions of any product, and therefore, the pharmaceutical composition of the invention comprises a compound with one by the formula (I) one or more pharmaceutically acceptable excipients any composition prepared by mixing.

[0102] 本发明的部分化合物:[0103] [0102] Some compounds of the invention: [0103]

Figure CN103373996AD00141

[0104] 以下通过体外药理活性实验进一步阐述本发明化合物的有益效果,但不应将此理解为本发明化合物仅具有下列有益效果。 [0104] The following compounds further illustrate the advantageous effects of the present invention by in vitro pharmacological activity test, but this should not be understood that the present invention is a compound having only the following advantageous effects.

[0105] 实验例本发明化合物对CRTH2受体的体外药理活性 [0105] In vitro experiments Example pharmacologically active compounds of the invention CRTH2 receptor

[0106] 供试品: [0106] Test products:

[0107] 本发明化合物I,由实施例1方法自制; [0107] Compounds of the invention I, made by the method of Example 1;

[0108] 实验方法:准确称取供试品,加入DMSO溶解,充分混匀,配成10mM。 [0108] Experimental method: the test sample was accurately weighed, dissolved in DMSO was added, thoroughly mixed, dubbed 10mM. 然后用pH7.4的20mM的HEPES (羟乙基哌嗪乙硫磺酸)缓冲液稀释到50 μ M,再5倍稀释为10000,2000,400,80,16,3.2,0.64,0.128,0.0256nM 备用。 Then (B hydroxyethylpiperazine-sulfuric acid) was diluted with buffer of 20mM HEPES pH7.4 to 50 μ M, then diluted to 5-fold 10000,2000,400,80,16,3.2,0.64,0.128,0.0256nM spare.

[0109] FLIPR检测(实时荧光成像分析) [0109] FLIPR assay (real-time fluorescence imaging analysis)

[0110] 在384黑色微孔板中加入20μ I含20000个CH0_K1/CRTH2/Ga 15细胞溶液,37°C,5%C02孵育18h后加入20 μ I FLlPR ® Calcium4assay kit (试剂盒)中的染色剂,再加入 [0110] 15 cells was added a solution containing 20μ I 20000 CH0_K1 / CRTH2 / Ga black microplate at 384, 37 ° C, 5% C02 after 18h incubation were added staining (kit) in 20 μ I FLlPR ® Calcium4assay kit agent, then add

10 μ I化合物溶液,然后37°C孵育60min,室温孵育15min。 10 μ I compound solution, and then 37 ° C for 60min, incubated for 15min at room temperature. 在20秒内加入激动剂I3DG2 (环前列腺素)EC80浓度下的ToG2HEPES缓冲液,检测21-120秒的荧光值。 Addition of agonist I3DG2 (prostacyclin) ToG2HEPES buffer at EC80 concentration within 20 seconds, 21-120 seconds fluorescence detection.

[0111] 数据处理 [0111] Data processing

[0112] ARFU (相对荧光强度)=21-120秒的最大的荧光值减去1_20秒的荧光值的平均值。 Average of the maximum fluorescence value [0112] ARFU (relative fluorescence intensity) = 21-120 seconds minus 1_20 second fluorescence values.

[0113] 抑制率={卜(Λ RFU化合物-Δ RFU背景)/ ( Δ RFU激动麵照-Δ RFU背景)} XlOO [0113] Bu inhibition rate = (Λ RFU compound -Δ RFU background) / (Δ RFU excited surface illuminated background -Δ RFU)} XlOO

[0114] 根据抑制率计算每个化合物的IC5tl值(即阻断PGD2在EC8tl浓度下所诱导CRTH2受体活化50%所需要的待测化合物的浓度)。 [0114] IC5tl calculated value of each compound according to the inhibition rate (i.e., blocking the PGD2 activation of the CRTH2 receptor concentration required for 50% of the test compound induced at EC8tl concentration).

[0115] 实验结果和结论: [0115] The results and conclusions:

[0116] 表I本发明化合物对CRTH2受体的拮抗作用 [0116] TABLE I compounds of the present invention at the CRTH2 receptor antagonism

[0117] [0117]

Figure CN103373996AD00151

[0118] +++表示IC5tl为0_300ηΜ,说明化合物具有很好的拮抗作用;++表示IC5tl为 [0118] +++ means IC5tl as 0_300ηΜ, described compound has good antagonistic action; ++ means as IC5tl

0.3-3 μ Μ,说明化合物具有较好的拮抗作用;+表示IC5tl为>3 μ Μ,说明化合物的拮抗作用一般; 0.3-3 μ Μ, better described compound having antagonism; + IC5tl expressed as> 3 μ Μ, antagonism of the compound described in general;

[0119] 由上表可知,本申请化合物I对CRTH2受体具有较好的拮抗作用。 [0119] From the above table can be seen, Compound I of the present application have good CRTH2 receptor antagonism.

具体实施方式 detailed description

[0120] 以下通过实施例形式的具体实施方式,对本发明的上述内容作进一步的详细说明。 [0120] DETAILED DESCRIPTION The following embodiments by the form of the above-described present invention will be described in further detail. 但不应将此理解为本发明上述主题的范围仅限于以下实施例。 However, this should not be understood that the present invention relating to the above-described range is limited to the following embodiments. 凡基于本发明上述内容所实现的技术均属于本发明的范围。 Where the above-described technique based on the present invention are achieved within the scope of the present invention.

[0121] 实施例1 2-[1-(4-氯苯硫基)咪唑并[1,5-a]吡啶_3_基]乙酸(化合物I)的 [0121] Example 1 2- [1- (4-chlorophenylthio) imidazo [1,5-a] pyridin-_3_ yl] acetic acid (Compound I) is

制备 preparation

[0122] [0122]

Figure CN103373996AD00161

[0123] (I)丙二酸乙酯单酰氯 [0123] (I) chloride ethyl malonate

[0124] 将丙二酸乙酯(13.2g, 100.0mmol)和N,N-二甲基甲酰胺(0.05mL)搅拌溶于二氯甲烷(200mL)中,冰水浴冷却至0°C,滴加草酰氯(25.4g, 200mmol),混合物室温下搅拌2h,浓缩得到丙二酸乙酯单酰氯(14.5g, 97%),为白色油状物。 [0124] The ethyl malonate (13.2g, 100.0mmol) and N, N- dimethylformamide (0.05mL) was stirred in dichloromethane (200mL) in a ice-water bath was cooled to 0 ° C, dropwise was added oxalyl chloride (25.4g, 200mmol), the mixture was stirred at room temperature for 2h, and concentrated to give ethyl malonate chloride (14.5g, 97%), as a white oil.

[0125] (2) 3-氧代-3-(吡啶-2-基亚甲基胺基)丙酸乙酯 [0125] (2) 3-oxo-3- (pyridin-2-ylmethylene amino) propanoate

[0126] [0126]

Figure CN103373996AD00162

[0127] 将丙二酸乙酯单酰氯(14.5g, 96.7mmol)溶于二氯甲烷(150mL)中,冰7K浴冷却至O °C,滴加溶于50mL 二氯甲烷的三乙胺(19.5g, 193mmol)和2-胺甲基批P定(13.6g,125.7mmol),室温搅拌3小时。 [0127] The ethyl malonate chloride (14.5g, 96.7mmol) was dissolved in dichloromethane (150 mL), cooled to ice bath 7K O ° C, was dissolved in 50mL of dichloromethane was added dropwise triethylamine ( 19.5g, 193mmol) and 2-aminomethyl P given batch (13.6g, 125.7mmol), stirred at room temperature for 3 hours. 然后旋蒸除去溶剂,残余物经硅胶柱层析(V(EtOAc)/V(PE) =1/5〜2/1)分离得3-氧代_3_(吡啶-2-基亚甲基胺基)丙酸乙酯(16.0g, 75%),为黄色油状物。 The solvent was then removed by rotary evaporation, and the residue was purified by silica gel column chromatography (V (EtOAc) / V (PE) = 1 / 5~2 / 1) to give 3-oxo _3_ separation (pyridin-2-ylmethylene-amine yl) propanoate (16.0g, 75%), as a yellow oil.

[0128] (3)2-(咪唑并[15-a]吡啶_3_基)乙酸乙酯 [0128] (3) 2- (imidazo [15-a] pyridin-_3_ yl) acetate

Figure CN103373996AD00163

[0130] 将3-氧代-3-(吡啶-2-基亚甲基胺基)丙酸乙酯(16.0g,72.1mmoI)溶于1,2_二氯乙烷(150mL)中,冰水浴冷却至0°C,滴加三氯氧磷(20mL,216.2mmol),然后回流4小时。 [0130] The 3-oxo-3- (pyridin-2-ylmethylene amino) propanoate (16.0g, 72.1mmoI) 1,2_ was dissolved in dichloroethane (150 mL) in an ice water bath was cooled to 0 ° C, was added dropwise phosphorus oxychloride (20mL, 216.2mmol), and then refluxed for 4 hours. 完毕后冷却至室温,混合物倾至冰水混合物中,碳酸钠调PH至8,二氯甲烷提取。 After completion of cooling to room temperature, the mixture was poured into ice-water mixture, sodium carbonate adjusted to PH 8 and extracted with dichloromethane. 合并的有机相依次用水、饱和氯化钠溶液洗,无水硫酸钠干燥,浓缩。 The combined organic phases were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. 所得残余物经柱层析(V (EtOAc)/V (PE)=O 〜1/2)分离得2-(咪唑并[I, 5-a]吡啶_3_基)乙酸乙酯(8.0g, 54%),为淡黄色固体。 The resulting residue was purified by column chromatography (V (EtOAc) / V (PE) = O ~1 / 2) separated to give 2- (imidazo [I, 5-a] pyridin-_3_ yl) acetate (8.0g , 54%) as a pale yellow solid.

[0131] (4) 2-(1-溴咪唑并[l,5_a]吡啶_3_基)乙酸乙酯 [0131] (4) 2- (1-bromo-imidazo [l, 5_a] pyridin _3_ yl) acetate

[0132] [0132]

Figure CN103373996AD00164

[0133] 将2-(咪唑并[I, 5-a]吡啶_3_基)乙酸乙酯(8.0g, 39.2mmol)溶于冰乙酸(IOOmL)中,然后滴加液溴(6.2g,38.8mmol)的60mL冰乙酸溶液,完毕后室温搅拌2小时,然后浓缩。 [0133] 2- (imidazo [I, 5-a] pyridin-_3_ yl) acetate (8.0g, 39.2mmol) was dissolved in glacial acetic acid (IOOmL), followed by dropwise addition of bromine solution (6.2 g of, 38.8 mmol) in 60mL glacial acetic acid solution, after the completion of stirring at room temperature for 2 hours and then concentrated. 残余物溶于400mL乙酸乙酯,依次用饱和碳酸钠,盐溶液洗,无水碳酸钠干燥,浓缩。 The residue was dissolved in 400mL ethyl acetate, washed with saturated sodium carbonate, saline solution, dried over anhydrous sodium sulfate, and concentrated. 所得粗品经硅胶柱(V(EtOAc)/V(PE)=O〜1/4)纯化得2-(1-溴咪唑并[I, 5-a]吡啶-3-基)乙酸乙酯(4.0g, 36%),为棕色油状物。 The resulting crude product was purified by silica gel column (V (EtOAc) / V (PE) = O~1 / 4) was purified to give 2- (1-bromo-imidazo [I, 5-a] pyridin-3-yl) acetate (4.0 g, 36%), as a brown oil.

[0134] (5) 2-[1-(4-氯苯硫基)咪唑并[l,5_a]吡啶_3_基]乙酸乙酯 [0134] (5) 2- [1- (4-chlorophenylthio) imidazo [l, 5_a] pyridin _3_ yl] acetate

[0135] [0135]

Figure CN103373996AD00171

[0136] 将2-(1-溴咪唑并[I, 5-a]卩比唳_3_基)乙酸乙酯〈ouumg, 1.75mmol)和4_氯苯硫酹(500mg, 3.5mmol)置于50mL 二甲苯中加热至140°C保持16小时,然后冷却至室温,旋蒸除去溶剂,硅胶柱(V (EtOAc)/V (PE)=O〜1/3)层析得2-[1-(4-氯苯硫基)咪唑并[I, 5-a]吡啶-3-基]乙酸乙酯(200mg,33%),为淡黄色固体。 [0136] 2- (1-bromo-imidazo [I, 5-a] Jie Li ratio _3_ yl) acetate <ouumg, 1.75mmol) and sprinkle 4_ chlorothiophenol (500mg, 3.5mmol) set in 50mL of xylene was heated to 140 ° C for 16 hours, then cooled to room temperature, the solvent was removed by rotary evaporation, silica gel column (V (EtOAc) / V (PE) = O~1 / 3) chromatography to give 2- [1 - (4-chlorophenylthio) imidazo [I, 5-a] pyridin-3-yl] acetate (200mg, 33%), as a pale yellow solid.

[0137] (6) 2-[1-(4-氯苯硫基)咪唑并[l,5_a]吡啶_3_基]乙酸 [0137] (6) 2- [1- (4-chlorophenylthio) imidazo [l, 5_a] pyridin _3_ yl] acetic acid

[0138] [0138]

Figure CN103373996AD00172

[0139] 将2-[1-(4-氯苯硫基)咪唑并[1,5-a]吡啶_3_基]乙酸乙酯(200mg,0.57mmol)溶于15mL的四氢呋喃和甲醇(体积比1/1)混合液中,加入氢氧化锂(48mg,2mmol)的水(7.5mL)溶液。 [0139] 2- [1- (4-chlorophenylthio) imidazo [1,5-a] pyridin-_3_ yl] acetate (200mg, 0.57mmol) was dissolved in 15mL of tetrahydrofuran and methanol (by volume ratio 1/1) mixture was added lithium hydroxide (48mg, 2mmol) in water (7.5 mL) was added. 反应液室温搅拌4小时。 The reaction solution was stirred at room temperature for 4 hours. 旋蒸除去溶剂,加20mL水稀释,用IN的盐酸调pH至3,有沉淀析出,抽滤并干燥得产物2-[1-(4-氯苯硫基)咪唑并[l,5-a]吡啶-3-基]乙酸(170mg,92%),为白色固体。 The solvent was removed by rotary evaporation, adding 20mL water, diluted hydrochloric acid, adjusted with pH IN to 3, there is precipitated, filtered off with suction and dried to give the product 2- [1- (4-chlorophenylthio) imidazo [l, 5-a ] pyridin-3-yl] acetic acid (170mg, 92%), as a white solid. 质谱(m/e):320.0 (M+1) Mass spectrum (m / e): 320.0 (M + 1)

[0140] 1H-NMR (DMS0-d6, 400ΜΗζ) δ:8.30 (m, 1Η),7.53 (m, 1Η),7.27 (m, 2Η),7.00 (m, 3Η),6.84 (m, 1Η), 4.19 (m, 2Η).[0141] 参照上述方法,还可以制备本发明其他化合物: [0140] 1H-NMR (DMS0-d6, 400ΜΗζ) δ: 8.30 (m, 1Η), 7.53 (m, 1Η), 7.27 (m, 2Η), 7.00 (m, 3Η), 6.84 (m, 1Η), . 4.19 (m, 2Η) [0141] Referring to the method described above, other compounds of the invention can also be prepared:

[0142] [0142]

Figure CN103373996AD00181

Claims (11)

  1. 1.通式(I)所示的化合物,其药学上可接受的盐,及其立体异构体, 1. A compound of formula (I) shown, pharmaceutically acceptable salts, and stereoisomers thereof,
    Figure CN103373996AC00021
    环烷基硫基及其立体异构体其中,X1、X2、X3、X4和X7分别独立地为N或C (R3); X5、X6和X8分别独立地为N或C,且X5和X6至少有一个为N ; G代表环上的键为单键或欢键; Y 为-(C(RaRb))p-; Z 为-(C (RaRb)) p-或-S-; R1 为R4OC (0) -、(R4) 2NC (0) -、R4C (0) NHC (0)-或四氮唑基; R2为芳基、苯并C3_8环烷基或杂芳基,所述的芳基、苯并C3_8环烷基和杂芳基可任选被1-3个独立地选自以下的取代基取代:卤素原子、羟基、氨基、氰基、CV6烷基、C^6烷氧基、卤代Cu烧基、1¾代Cu烧氧基或C3_8环烧基; R3为氢!原子、氰1基、硝基、轻基、氧代、竣基、氣基、齒素原子、Ci_6烧基、轻基CV6烧基、C3_8环烧基、Cu烧氧基、轻基C3_8环烧基、齒代C3_8环烧基、C3_8环烧基Cu烧基、齒代C3_8环烧基Cu烷基、齒代Cu烷基、C2_6烯基、齒代C2_6烯基、羟基C2_6烯基、Cu烷氧基、齒代Cu烷氧基、CV6烧硫基、C3_8环烧基硫基、Cp6 Cycloalkyl group and stereoisomers thereof wherein, X1, X2, X3, X4, and X7 are each independently N or C (R3); X5, X6, and X8 are each independently N or C, and X5 and X6 At least one is N; G represents a bond in the ring is a single bond or joy bond; Y is - (C (RaRb)) p-; Z is - (C (RaRb)) p-, or -S-; R1 is R4OC (0) -, (R4) 2NC (0) -, R4C (0) NHC (0) - group or tetrazol; R2 is an aryl group, benzo C3_8 cycloalkyl or heteroaryl, said aryl benzo C3_8 cycloalkyl, aryl and heteroaryl groups may be optionally substituted with 1-3 substituents independently selected from the following group: halogen atom, hydroxy, amino, cyano, CV6 alkyl, C ^ 6 alkoxy, haloalkyl group burning Cu, Cu burning 1¾ substituting group or a C3_8 cycloalkyl group burn;! R3 is a hydrogen atom, a cyano group, a nitro group, light, oxo, Jun group, gas-based, tooth element atom, Ci_6 burn-yl light burned CV6 yl group, C3_8 cycloalkyl group burn, burn Cu group, C3_8 cycloalkyl group light group burn, burn toothed ring group substituting C3_8, C3_8 cycloalkyl group burn burn Cu group, C3_8 cycloalkyl burning toothed substituting Cu alkyl group, the teeth Generation Cu alkyl, C2_6 alkenyl, C2_6 alkenyl substituting teeth, hydroxy C2_6 alkenyl group, an alkoxy group Cu, Cu-generation teeth alkoxy, alkylthio CV6 burning, C3_8 cycloalkyl burn-ylthio, Cp6 is 基胺基、_.((V6烧基)胺基、CV6烧基胺基甲酸基、CV6烷基酰胺基、Cu烷基磺酰基、CV6烷基胺基磺酰基、Cu烷基磺酰胺基、二(Cu烷基)胺基甲酰基或二(Cu烷基)胺基磺酰基; R4为氢、C^6烷基、Cu杂烷基、C3_8环烷基、C3_8杂环烷基或芳基,所述CV6烷基、C1^杂烷基、c3_8环烷基、C3_8杂环烷基或芳基可任选被1-3个独立地选自以下的取代基取代:卤素原子、氧代、氰1基、轻基、竣基、氣基、C1^烧氧基或Cu烧基; Ra和Rb分别独立地为氢、CV6烷基或卤素原子,其中Ra和Rb可以与它们所连接的碳形成C3_8环烷基,所述C3_8环烷基可任选被1-3个独立地选自以下的取代基取代:卤素原子、氧代、氰!基、轻基、竣基、氣基、c3_8环烧基、(V6烧氧基或(V6烧基; P 为0,1,2,3 或4。 Ylamino, _. ((V6 burn-yl) amino, formyl amine group burning CV6, CV6 alkyl amido, Cu alkylsulfonyl, aminosulfonyl CV6 alkyl, Cu alkylsulfonyl group, two (Cu alkyl) carbamoyl or di (Cu alkyl) aminosulfonyl; R4 is hydrogen, C ^ 6 alkyl, Cu heteroalkyl, C3_8 cycloalkyl, C3_8 heterocycloalkyl, or aryl group the CV6 alkyl, C1 ^ heteroalkyl, c3_8 cycloalkyl, C3_8 heterocycloalkyl or aryl group may be optionally substituted with 1-3 substituents independently selected from the group: halogen atom, oxo, a cyano group, a group of light, Jun group, gas-based, C1 ^ alkoxy or burn burn Cu group; Ra and Rb are each independently hydrogen, a halogen atom or a CV6 alkyl group, wherein Ra and Rb may be the carbon to which they are attached form a c3_8 cycloalkyl group, a c3_8 cycloalkyl group may be optionally substituted with 1-3 substituents independently selected from substituents:! a halogen atom, oxo, cyano, light group, Jun group, gas-based, c3_8 burning ring group, (V6 group or burning (V6 burning group; P is 0, 1 or 4.
  2. 2.如权利要求1所述的化合物,其药学上可接受的盐,及其立体异构体, 其中,X1、X2、X3、X4和X7分别独立地为N或C (R3); X5、X6和X8分别独立地为N或C,且X5和X6至少有一个为N ; O代表环上的键为单键或双键; Y 为-(C(RaRb))p-; Z 为-(C (RaRb)) p-或-S-; R1 为R4OC(O)' (R4)2NC(O)-或四氮唑基; R2为芳基或苯并C3_8环烷基,所述的芳基和苯并C3_8环烷基可任选被1-3个独立地选自以下的取代基取代:齒素原子、轻基、氣基、氰1基、Cu烧基、Cu烧氧基、齒代Cu烧基或齒代Cu烧氧基; R3为氢!原子、氰1基、轻基、氧代、氣基、1¾素原子、Ci_6烧基、轻基Cu烧基、C3_8环烧基、CV6烧氧基、轻基C3_8环烧基、齒代C3_8环烧基、C3_8环烧基Cu烧基、齒代C3_8环烧基Cu烧基、卤代Cu烷基、卤代Cu烷氧基、C1^6烷硫基、CV6烷基胺基、二((V6烷基)胺基、C1^6烷基胺基甲酰基、C1^6烷基酰胺基、CV6烷基胺基磺酰基或 2. The compound according to claim 1, its pharmaceutically acceptable salts, and stereoisomers thereof, wherein, X1, X2, X3, X4, and X7 are each independently N or C (R3); X5, X6 and X8 are each independently N or C, and at least one of X5 and X6 is N; key on the ring O represents a single bond or a double bond; Y is - (C (RaRb)) p-; Z is - ( C (RaRb)) p-, or -S-; R1 is R4OC (O) '(R4) 2NC (O) -, or tetrazol-yl; R2 is an aryl group or a benzo C3_8 cycloalkyl, said aryl and benzo C3_8 cycloalkyl can be optionally substituted with 1-3 substituents independently selected from substituents: teeth atom, group of light, gas group, a cyano group 1, Cu-yl burning, Cu burned group, on behalf of the teeth Cu Cu burn burn substituting group or teeth group;! R3 is a hydrogen atom, a cyano group, light, oxo, gas-based, 1¾ prime atom, Ci_6 group burning, light burned Cu-yl group, C3_8 cycloalkyl group burning, CV6 burn group, C3_8 cycloalkyl group light group burn, burn toothed ring group substituting C3_8, C3_8 cycloalkyl group burn burn Cu group, C3_8 cycloalkyl toothed substituting group burn burn group Cu, Cu haloalkyl group, haloalkoxy Cu alkoxy, C1 ^ 6 alkylthio, CV6 alkylamino, di ((V6 alkyl) group, a C1 ^ 6 carbamoyl alkyl group, a C1 ^ 6 alkylamide group, a sulfonyl group or a CV6 alkyl group Cu烷基磺酰胺基; R4为氢*、C1^烧基、C3_8环烧基、C3_8杂环烧基或苯基,所述CV6烧基、C3_8环烧基、C3_8杂环烷基或苯基可任选被1-3个独立地选自以下的取代基取代:卤素原子、氧代、氰基、羟基、羧基、氨基或Ch6烷基; Ra和Rb分别独立地为氢、CV6烷基或卤素原子,其中Ra和Rb可以与它们所连接的碳形成C3_8环烷基,所述C3_8环烷基可任选被1-3个独立地选自以下的取代基取代:卤素原子、氧代、氛基、轻基、竣基、M基、C1^烧氧基或Cu烧基; P 为0,1,2 或3。 Cu alkylsulfonyl group; R4 is hydrogen *, C1 ^ burned group, C3_8 cycloalkyl group burning, C3_8 heterocyclyl group, or a phenyl burning, the burning CV6 group, C3_8 cycloalkyl group burning, C3_8 heterocycloalkyl, or phenyl It may be optionally substituted with 1-3 substituents independently selected from the group: halogen atom, oxo, cyano, hydroxy, carboxy, amino or Ch6 alkyl; and Ra of the Rb each independently hydrogen, alkyl, or CV6 a halogen atom, wherein Ra and Rb may form a C3_8 cycloalkyl group and the carbon to which they are attached, a C3_8 cycloalkyl group may be optionally substituted with 1-3 substituents independently selected from the group: halogen atom, oxo, group atmosphere, light group, Jun group, M group, C1 ^ alkoxy or burn burn Cu group; P is 0, 1 or 3.
  3. 3.如权利要求2所述的化合物,其药学上可接受的盐,及其立体异构体, 其中,X1、X2、X3、X4和X7分别独立地为N或C (R3); X5、X6和X8分别独立地为N或C,且X5和X6至少有一个为N ; G代表环上的键为单键或欢键; Y 为-(C(RaRb))p-; Z 为-(C (RaRb)) p-或-S-; R1为R4OC(O)-或四氮唑基; R2为芳基,所述的芳基可任选被1-3个独立地选自以下的取代基取代:卤素原子、羟基、氣基、氰1基、C1^烧基、C^6烧氧基、齒代Cu烧基或齒代Cu烧氧基; R3为氢!原子、氰1基、轻基、氧代、氣基、齒素原子、C1^烧基、C3_8环烧基、C^6烧氧基、C3_8环烷基Cu烷基、CV6烷硫基、C1^6烷基胺基、二(Cu烷基)胺基、CV6烷基胺基甲酰基、CV6烷基酰胺基或Cu烷基磺酰胺基; R4为氢、C1^6烷基或C3_8环烷基,所述Cu烷基或C3_8环烷基可任选被1-3个独立地选自以下的取代基取代:齒素原子、氧代、氰1基、轻基、竣基、氣基或C 3. The compound according to claim 2, pharmaceutically acceptable salts, and stereoisomers thereof, wherein, X1, X2, X3, X4, and X7 are each independently N or C (R3); X5, X6 and X8 are each independently N or C, and at least one of X5 and X6 is N; G represents a bond in the ring is a single bond or joy bond; Y is - (C (RaRb)) p-; Z is - ( C (RaRb)) p-, or -S-; R1 is R4OC (O) -, or tetrazol-yl; R2 is an aryl group, the aryl group may be optionally substituted with 1-3 substituents independently selected from substituents: halogen atoms, hydroxy, gas group, a cyano group, C1 ^ burn-yl, C ^ 6 alkoxy burning, generation of the tooth or teeth on behalf of the group Cu Cu burning burning group; R3 is a hydrogen atom, a cyano group,! light, oxo, gas-based, tooth element atom, C1 ^ burned group, C3_8 cycloalkyl group burning, C ^ 6 burning group, C3_8 cycloalkyl group Cu, CV6 alkylthio, C1 ^ 6 alkyl group , di (Cu alkyl) amino, carbamoyl group CV6, CV6 alkyl amide or Cu alkylsulfonamido group; R4 is hydrogen, C1 ^ 6 alkyl or C3_8 cycloalkyl group, the alkoxy Cu or C3_8 cycloalkyl group may be optionally substituted with 1-3 substituents independently selected from substituents: teeth atom, oxo, cyano group 1, light group, Jun group, or gas group C V6烧基; Ra和Rb分别独立地为氢、CV6烷基或卤素原子,其中Ra和Rb可以与它们所连接的碳形成C3_6环烷基,所述C3_6环烷基任选被1-3个独立地选自以下的取代基取代:卤素原子、氧代、氰1基、轻基、竣基、M基、Cu烧氧基或Cu烧基; P为0,1或2。 V6 burning group; Ra and Rb are each independently hydrogen, a halogen atom or a CV6 alkyl group, wherein Ra and Rb may form a C3_6 cycloalkyl group and the carbon to which they are attached, a C3_6 cycloalkyl group optionally substituted with 1-3 is independently selected from the following substituents: halogen atom, oxo, cyano group 1, light group, Jun group, M group, or a Cu Cu burn burn-yl group; P is 0, 1 or 2.
  4. 4.如权利要求3所述的化合物,其药学上可接受的盐,及其立体异构体, 其中,X1、X2、X3、X4和X7分别独立地为N或C (R3); X5、X6和X8分别独立地为N或C,且X5和X6至少有一个为N ; O代表环上的键为单键或欢键; Y 为-CH2-; Z 为-S-; R1为-C (O)OH或四氮唑基;R2为苯基,所述的苯基可任选被1-3个独立地选自以下的取代基取代:卤素原子、羟基、氣基、氰1基、二氣甲基、C1^烧基或Cu烧氧基; R3为氢!原子、氰1基、轻基、氧代、氣基、齒素原子、C1^烧基、C3_8环烧基、C^6烧氧基、C^6烷基酰胺基或c3_8环烷基Cu烷基。 4. The compound according to claim 3, a pharmaceutically acceptable salt thereof, and stereoisomers thereof, wherein, X1, X2, X3, X4, and X7 are each independently N or C (R3); X5, X6 and X8 are each independently N or C, and at least one of X5 and X6 is N; key on the ring O represents a single bond or joy bond; Y is -CH2-; Z is -S-; R1 is -C (O) OH or tetrazol-yl; R2 is phenyl, said phenyl optionally substituted with 1-3 substituents independently selected from substituents: a halogen atom, a hydroxyl group gas, a cyano group, two gas methyl, C1 ^ Cu burn or burn-yl group;! R3 is a hydrogen atom, a cyano group, light, oxo, gas-based, tooth element atom, C1 ^ burned group, C3_8 cycloalkyl group burning, C ^ burning 6 alkoxy, C ^ 6 alkyl group or an amide group c3_8 cycloalkyl Cu.
  5. 5.如权利要求4所述的化合物,其药学上可接受的盐,及其立体异构体, 其中,X1、X2、X3、X4和X7分别独立地为N或C (R3); X5、X6和X8分别独立地为N或C,且X5和X6至少有一个为N ; 5. The compound according to claim 4, a pharmaceutically acceptable salt thereof, and stereoisomers thereof, wherein, X1, X2, X3, X4, and X7 are each independently N or C (R3); X5, X6 and X8 are each independently N or C, and at least one of X5 and X6 is N;
    Figure CN103373996AC00041
    代表环上的键为单键或欢键; Y 为-CH2-; Z 为-S-; R1 为-C (O) OH ; R2为苯基,所述的苯基可任选被1-3个独立地选自以下的取代基取代:卤素原子、羟基、氣基、氰1基、Cu烧基或二氣甲基; R3为氢原子、羟基、氧代、卤素原子或Cy烷基。 Key represents a single bond or the ring is Huan bond; Y is -CH2-; Z is -S-; R1 is -C (O) OH; R2 is phenyl, said phenyl optionally substituted with 1-3 independently selected from the following substituents: a halogen atom, a hydroxyl group gas, a cyano group 1, Cu burning gas or di-methyl; R3 is a hydrogen atom, hydroxyl, oxo, halogen atom or alkyl group Cy.
  6. 6.通式(II)所示的化合物,其药学上可接受的盐及其立体异构体, 6. A compound represented by the general formula (II), pharmaceutically acceptable salts and stereoisomers thereof,
    Figure CN103373996AC00042
    其中,Y为-CH2-; R1 为-C (0) OH ; Z 为-S-; R2为苯基,所述苯基可被1-3个独立地选自以下的取代基取代:卤素原子、羟基、氨基、氰基、Ch烷基或三氟甲基。 Wherein, Y is -CH2-; R1 is -C (0) OH; Z is -S-; R2 is phenyl, said phenyl group may be independently selected from 1-3 substituents: a halogen atom , hydroxy, amino, cyano, alkyl or trifluoromethyl Ch.
  7. 7.如权利要求6所述的化合物,其药学上可接受的盐及其立体异构体, 其中,R2为苯基,所述苯基可被I个选自以下的取代基取代:卤素原子、羟基、氨基、CV4烷基或三氟甲基。 7. The compound according to claim 6, its pharmaceutically acceptable salts and stereoisomers thereof, wherein, R2 is phenyl, said phenyl may be substituted with I substituent selected from the following group: a halogen atom , hydroxy, amino, CV4 alkyl or trifluoromethyl.
  8. 8.如权利要求1所述的化合物,其药学上可接受的盐及其立体异构体, 8. A compound of claim 1 pharmaceutically acceptable salts and stereoisomers claim,
    Figure CN103373996AC00051
  9. 9.含有权利要求1〜8任一项所述的化合物、其药学上可接受的盐或其立体异构体的药物制剂,其特征在于包括一种或多种药用载体。 9. The compound of claim containing any one of claims 1~8, its pharmaceutically acceptable salt or stereoisomer thereof a pharmaceutical formulation, comprising one or more pharmaceutically acceptable carriers.
  10. 10.权利要求1〜8任一项所述的化合物、其药学上可接受的盐或其立体异构体在制备治疗和/或预防与CRTH2活性相关的疾病的药物中的应用,与CRTH2活性相关的疾病选自哮喘、过敏性鼻炎、过敏性皮炎、过敏性结膜炎、Churg-Strauss综合症、鼻窦炎、嗜碱性白血病、慢性风疹、嗜碱性白细胞增多、牛皮癣、湿疹、炎症性的肠疾病、溃疡性结肠炎、克罗恩氏病、关节炎或慢性阻塞性肺病。 Compound of any one of claims 1~8 applications pharmaceutically acceptable salt or a stereoisomer thereof in the manufacture of the treatment and / or prophylaxis of diseases associated with CRTH2 activity in, and claimed in claim 10. CRTH2 activity, related disease is selected from asthma, allergic rhinitis, allergic dermatitis, allergic conjunctivitis, Churg-Strauss syndrome, sinusitis, basophilic leukemia, chronic urticaria, basophilic leukocytosis, psoriasis, eczema, inflammatory bowel disease, ulcerative colitis, Crohn's disease, arthritis or chronic obstructive pulmonary disease.
  11. 11.药物组合物,其特征在于包含权利要求1〜8任一项所述的化合物、其药学上可接受的盐或其立体异构体和一种或多种治疗活性物质,所述治疗活性物质选自TNF-α抑制剂、C0X-1/C0X-2抑制剂、C0X-2抑制剂、糖皮质激素、白介素的灭活抗体、趋化因子受体调节剂、组胺Hl受体拮抗剂/抗组胺剂、白三烯D4受体拮抗剂、白三烯拮抗剂、LTD4拮抗剂、VLA-4拮抗剂、皮质类固醇、皮质类固醇类似物、β 2-激动剂、茶碱、白三烯生物合成抑制剂、环氧酶-2抑制剂、磷酸二酯酶IV型抑制剂、阿片类镇痛药、抗凝血剂、β -阻断剂、β -肾上腺素能激动剂、血管紧张素转化酶抑制剂或HMG-CoA还原酶抑制剂。 11. A pharmaceutical composition, characterized by comprising a compound according to any one of claims 1~8, pharmaceutically acceptable salt or a stereoisomer thereof and one or more therapeutically active substances, the therapeutically active TNF-α inhibitor is selected from materials, C0X-1 / C0X-2 inhibitors, C0X-2 inhibitors, glucocorticoids, interleukin-inactivated antibody, chemokine receptor modulators, histamine Hl receptor antagonists / antihistamine, leukotriene D4 receptor antagonists, leukotriene antagonists, LTD4-antagonists, VLA-4 antagonists, corticosteroids, corticosteroid analogs, β 2- agonists, theophylline, and white ene biosynthesis inhibitors, cyclooxygenase-2 inhibitors, phosphodiesterase type IV inhibitor, an opioid analgesics, anticoagulants, β - blockers, β - adrenergic agonists, angiotensin converting enzyme inhibitors or HMG-CoA reductase inhibitors.
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US9334244B2 (en) 2010-05-12 2016-05-10 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
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US9365557B2 (en) 2008-12-19 2016-06-14 Vertex Pharmaceuticals Incorporated Substituted pyrazin-2-amines as inhibitors of ATR kinase
US9701674B2 (en) 2008-12-19 2017-07-11 Vertex Pharmaceuticals Incorporated Substituted pyrazines as ATR kinase inhibitors
US9630956B2 (en) 2010-05-12 2017-04-25 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9334244B2 (en) 2010-05-12 2016-05-10 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9309250B2 (en) 2011-06-22 2016-04-12 Vertex Pharmaceuticals Incorporated Substituted pyrrolo[2,3-b]pyrazines as ATR kinase inhibitors
US9862709B2 (en) 2011-09-30 2018-01-09 Vertex Pharmaceuticals Incorporated Processes for making compounds useful as inhibitors of ATR kinase
US9791456B2 (en) 2012-10-04 2017-10-17 Vertex Pharmaceuticals Incorporated Method for measuring ATR inhibition mediated increases in DNA damage
US8912198B2 (en) 2012-10-16 2014-12-16 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9340546B2 (en) 2012-12-07 2016-05-17 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9650381B2 (en) 2012-12-07 2017-05-16 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9718827B2 (en) 2012-12-07 2017-08-01 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9458164B2 (en) 2013-03-11 2016-10-04 Bristol-Myers Squibb Company Pyrrolopyridazines as potassium ion channel inhibitors
US9050345B2 (en) 2013-03-11 2015-06-09 Bristol-Myers Squibb Company Pyrrolotriazines as potassium ion channel inhibitors
US8957078B2 (en) 2013-03-15 2015-02-17 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US8969360B2 (en) 2013-03-15 2015-03-03 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9663519B2 (en) 2013-03-15 2017-05-30 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9670210B2 (en) 2014-02-13 2017-06-06 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9493450B2 (en) 2014-02-13 2016-11-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9493442B2 (en) 2014-02-13 2016-11-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9527835B2 (en) 2014-02-13 2016-12-27 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9994546B2 (en) 2014-02-13 2018-06-12 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9670215B2 (en) 2014-06-05 2017-06-06 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9695180B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors
US9758523B2 (en) 2014-07-10 2017-09-12 Incyte Corporation Triazolopyridines and triazolopyrazines as LSD1 inhibitors
US9695167B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted triazolo[1,5-a]pyridines and triazolo[1,5-a]pyrazines as LSD1 inhibitors
US9695168B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,5-α]pyridines and imidazo[1,5-α]pyrazines as LSD1 inhibitors
US9944647B2 (en) 2015-04-03 2018-04-17 Incyte Corporation Heterocyclic compounds as LSD1 inhibitors
US9981975B2 (en) 2016-03-28 2018-05-29 Incyte Corporation Pyrrolotriazine compounds as tam inhibitors

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