TW201925186A - Novel heterocyclic derivatives useful as SHP2 inhibitors - Google Patents

Novel heterocyclic derivatives useful as SHP2 inhibitors Download PDF

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TW201925186A
TW201925186A TW106142823A TW106142823A TW201925186A TW 201925186 A TW201925186 A TW 201925186A TW 106142823 A TW106142823 A TW 106142823A TW 106142823 A TW106142823 A TW 106142823A TW 201925186 A TW201925186 A TW 201925186A
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TWI697490B (en
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馬存波
高攀亮
褚杰
吳新平
溫春偉
康迪
白金龍
裴曉言
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大陸商北京加科思新藥研發有限公司
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Abstract

This invention relates to certain novel pyrazine derivatives (Formula I) as SHP2 inhibitors which is shown as formula I, their synthesis and their use for treating a SHP2 mediated disorder. More particularly, this invention is directed to fused heterocyclic derivatives useful as inhibitors of SHP2, methods for producing such compounds and methods for treating a SHP2-mediated disorder.

Description

用於作為SHP2抑制劑之新穎雜環衍生物Novel heterocyclic derivatives for use as SHP2 inhibitors

本發明涉及可作為SHP2抑制劑的某些新型吡嗪衍生物（如結構式I所示），以及它們的合成及其用於治療SHP2介導的病症的用途。更具體地說，本發明涉及可用作SHP2抑制劑的稠合雜環衍生物，製備此類化合物的方法以及治療SHP2介導的疾病的方法。The present invention relates to certain novel pyrazine derivatives (as shown in Structural Formula I) which are useful as SHP2 inhibitors, as well as their synthesis and their use for the treatment of SHP2-mediated disorders. More particularly, the present invention relates to fused heterocyclic derivatives useful as SHP2 inhibitors, methods of preparing such compounds, and methods of treating SHP2-mediated diseases.

SHP2（Src同源結構域，The Src homology-2 domain）是一個由PTPN11基因編碼的非受體酪氨酸磷酸酶，包含一個保守的酪氨酸磷酸酶結構域、兩個N-端SH2結構域、一個C-端尾巴。兩個SH2結構域決定了SHP2的亞細胞定位及功能調節。在非活化狀態下，N-端SH2結構域會與PTP結構域結合，並使之失去活性。當SH2結構域與受體或者與接頭蛋白上的特定酪氨酸殘基結合時，PTP結構域會被釋放出來。例如，通過細胞因子和生長因子的刺激導致催化位點的暴露，導致SHP2的活化。SHP2 (Src homology-2 domain) is a non-receptor tyrosine phosphatase encoded by the PTPN11 gene, comprising a conserved tyrosine phosphatase domain and two N-terminal SH2 structures. Domain, a C-terminal tail. The two SH2 domains determine the subcellular localization and functional regulation of SHP2. In the non-activated state, the N-terminal SH2 domain binds to the PTP domain and renders it inactive. When the SH2 domain binds to a receptor or to a specific tyrosine residue on a linker protein, the PTP domain is released. For example, stimulation by cytokines and growth factors results in exposure of the catalytic site, resulting in activation of SHP2.

SHP2表達廣泛，且參與到多條細胞信號過程中，比如Ras-Erk、PI3K-Akt、Jak-Stat、Met、FGFR、EGFR，以及胰島素受體和NF-kB通路，在細胞增殖、分化、細胞週期和遷移中起重要作用。SHP2 is widely expressed and involved in multiple cellular signaling processes such as Ras-Erk, PI3K-Akt, Jak-Stat, Met, FGFR, EGFR, and insulin receptor and NF-kB pathways in cell proliferation, differentiation, and cell It plays an important role in the cycle and migration.

由種系或體細胞突變引起的SHP2的超活化已經在努南氏症候群（Noonan Syndrome）、豹皮症候群（Leopard Syndrome）、青少年骨髓單核細胞白血病（Juvenile myelomonocytic leukemia）、骨髓增生異常症候群（myelodysplastic syndrome）、B細胞急性淋巴細胞白血病（B cell acute lymphoblastic leukemia）和急性骨髓性白血病中發現。另外，PTPN11的活化突變也在實體瘤中發現，如肺癌、結腸癌、黑色素瘤、神經母細胞瘤和肝癌。因此，人類腫瘤中或其它疾病中活化的SHP2或者上調的SHP2蛋白成為新的治療靶點。本發明中的化合物滿足了對SHP2小分子抑制劑的需求。Superactivation of SHP2 caused by germline or somatic mutations has been observed in Noonan Syndrome, Leopard Syndrome, Juvenile myelomonocytic leukemia, myelodysplastic syndrome (myelodysplastic) Syndrome), B cell acute lymphoblastic leukemia and acute myeloid leukemia. In addition, activating mutations in PTPN11 are also found in solid tumors such as lung cancer, colon cancer, melanoma, neuroblastoma, and liver cancer. Therefore, SHP2 or up-regulated SHP2 protein activated in human tumors or other diseases becomes a new therapeutic target. The compounds of the present invention satisfy the need for SHP2 small molecule inhibitors.

本發明涉及雜環吡嗪化合物，其可作為SHP2抑制劑及用於治療由SHP2介導的疾病，本發明提供了如結構式I所示的通式化合物及其藥學上可接受的鹽：結構式 I 其中， X為不存在或選自O、S、SO、S(O)2 、C(O)、 C(O)R11 、CR11 R12 或-NR11 ；其中每個R11 和R12 分別獨立地選自-H、鹵素、-NH2 、-CN、-OH、 -NO2 、羰基、=O、氧代基、羧基、取代或未取代的C1-6 烷氧基或取代或未取代的C1-6 烷基； Y1 選自N或CR1 ； 當與R3 連接的C原子與Y2 上的原子之間形成雙鍵時，Y2 選自N或CR2 ； 當與R3 連接的C原子與Y2 上的N原子之間形成單鍵時，Y2 是-NR2 ； 每個R1 和R2 分別獨立地選自-H、鹵素、-CN、-OH、-NH2 、-N3 、-NO2 、取代或未取代的C1-6 烷氧基，或者取代或未取代的C1-6 烷基；或 R1 與R3 共同形成、或R2 與R3 共同形成，5-10元雜芳環、5-10元碳環或5-10元雜環，且每個環系獨立地任意地被一個或多個取代基取代或不取代，所述取代基選自鹵素、-CN、-OH、-NR8 R9 、-N3 、-NO2 、羰基、=O、氧代基、取代或未取代的C1-6 烷基、取代或未取代的C1-6 烷氧基、或C(O)R8 ；或 R3 選自-H、鹵素、-CN、-OH、-N3 、-NO2 、-NR8 R9 、-N(R8 )(CH2 )p NR8 R9 、-N(R8 )(CH2 )p R8 、-N(R8 )Gp R8 、-N(R8 )Gp NR8 R9 、-N(R8 )(C=O)q R8 、-N(R8 )(C=O)q NR8 R9 、-N(R8 )(C=O)q Gp R8 、-N(R8 )(C=O)q Gp NR8 R9 、-N(R8 )(C=O)q Gp (C=O)q R8 、-N(R8 )(C=O)q Gp (C=O)q NR8 R9 、-N(R8 )(C=O)q N(R8 )(C=O)q R8 、-N(R8 )(C=O)q N(R8 ) (C=O)q NR8 R9 、-N(R8 )(C=O)q N(R8 )Gq (C=O)p R8 、-N(R8 )(C=O)q N(R8 )Gp (C=O)q NR8 R9 、-C(=O)q R8 、-C(=O)q OR8 、-C(=O)q NH2 、-C(=O)q NR8 R9 、C1-6 烷基、C6-10 芳基、芳基烷基、烷氧基、雜芳基、雜環基或碳環基，且所述每個基團獨立地任意地被取代或不取代；且每個p和q分別獨立地選自0、1、2或3； 每個G分別獨立地選自C6-10 芳基、C3-8 碳環基或C5-10 雜芳基，且所述每個環系獨立地任意地取代或不取代； R4 選自-H、鹵素、-CN、-OH、-NR8 R9 、-N3 、-NO2 、取代或未取代的C1-6 烷氧基、取代或未取代的C1-6 烷基、C5-18 雜環基或C5-18 碳環基，且每個環系獨立地任意地不取代或被鹵素、-CN、-OH、-NO2 、羰基、=O、氧代基、取代或未取代的C1-6 烷基、取代或未取代的C1-6 烷氧基、-NR8 R9 或-CH2 NR8 R9 取代； R5 選自-H、鹵素、-CN、-OH、-NR8 R9 、-N3 、-NO2 、C1-6 烷基、C1-6 烷氧基、 C6-10 芳基、 C6-10 芳基烷基、 C6-10 雜芳基、 C5-18 雜環基或C5-18 碳環基，且每個環系包括單環、螺環、橋環、稠環和/或其組合，且所述每個基團獨立地任意地取代或不取代； 每個R8 和R9 分別獨立地選自-H、鹵素、-CN、-OH、-N3 、-NO2 、C1-6 烷基、C1-6 烷氧基、C2-6 烯基、NH(C1-6 烷基)、N(C1-6 烷基)2 、C5-10 螺雜環基或C5-10 碳環基，且所述每個基團獨立地任意地取代或不取代。The present invention relates to heterocyclic pyrazine compounds which are useful as SHP2 inhibitors and for the treatment of diseases mediated by SHP2. The present invention provides compounds of the formula of formula I and pharmaceutically acceptable salts thereof: Wherein X is absent or selected from O, S, SO, S(O) 2 , C(O), C(O)R 11 , CR 11 R 12 or -NR 11 ; wherein each R 11 And R 12 are each independently selected from -H, halogen, -NH 2 , -CN, -OH, -NO 2 , carbonyl, =0, oxo, carboxy, substituted or unsubstituted C 1-6 alkoxy or a substituted or unsubstituted C 1-6 alkyl group; Y 1 is selected from N or CR. 1; when a double bond is formed between C atom attached to the R 3 and the atoms of Y 2, Y 2 is selected from N or CR 2; when a single bond is formed between C atom attached to R 3 and the N atom on Y 2, Y 2 is -NR 2; each R 1 and R 2 are each independently selected from -H, halogen, -CN , -OH, -NH 2 , -N 3 , -NO 2 , a substituted or unsubstituted C 1-6 alkoxy group, or a substituted or unsubstituted C 1-6 alkyl group; or R 1 and R 3 together form Or R 2 and R 3 together form a 5-10 membered heteroaryl ring, a 5-10 membered carbocyclic ring or a 5-10 membered heterocyclic ring, and each ring system is independently optionally substituted with one or more substituents or Without substitution, the substituent is selected from the group consisting of halogen, -CN, -OH, -NR 8 R 9 , -N 3 , -NO 2 , carbonyl, =0, oxo, substituted or unsubstituted C 1-6 alkane Base, substitution or not Substituted C 1-6 alkoxy, or C(O)R 8 ; or R 3 is selected from -H, halogen, -CN, -OH, -N 3 , -NO 2 , -NR 8 R 9 , -N (R 8 )(CH 2 ) p NR 8 R 9 , -N(R 8 )(CH 2 ) p R 8 , -N(R 8 )G p R 8 , -N(R 8 )G p NR 8 R 9 , -N(R 8 )(C=O) q R 8 , -N(R 8 )(C=O) q NR 8 R 9 , -N(R 8 )(C=O) q G p R 8 , -N(R 8 )(C=O) q G p NR 8 R 9 , -N(R 8 )(C=O) q G p (C=O) q R 8 , -N(R 8 )( C=O) q G p (C=O) q NR 8 R 9 , -N(R 8 )(C=O) q N(R 8 )(C=O) q R 8 , -N(R 8 ) (C=O) q N(R 8 ) (C=O) q NR 8 R 9 , -N(R 8 )(C=O) q N(R 8 )G q (C=O) p R 8 , -N(R 8 )(C=O) q N(R 8 )G p (C=O) q NR 8 R 9 , -C(=O) q R 8 , -C(=O) q OR 8 , -C(=O) q NH 2 , -C(=O) q NR 8 R 9 , C 1-6 alkyl, C 6-10 aryl, arylalkyl, alkoxy, heteroaryl, hetero a cyclic group or a carbocyclic group, and each of the groups is independently arbitrarily substituted or unsubstituted; and each of p and q are independently selected from 0, 1, 2 or 3; each G is independently selected from C 6-10 aryl, C 3-8 carbocyclic aryl group or a C 5-10 heteroaryl group, and each of said ring system is optionally independently substituted or unsubstituted; R 4 is selected from -H, halogen -CN, -OH, -NR 8 R 9 , -N 3, -NO 2, a substituted or unsubstituted C 1-6 alkoxy group, a substituted or unsubstituted C 1-6 alkyl, C 5-18 heteroaryl a cyclic group or a C 5-18 carbocyclic group, and each ring system is independently unsubstituted or halogenated, -CN, -OH, -NO 2 , carbonyl, =0, oxo, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, -NR 8 R 9 or -CH 2 NR 8 R 9 substituted; R 5 is selected from -H, halogen, -CN, -OH, -NR 8 R 9 , -N 3 , -NO 2 , C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl, C 6-10 arylalkyl, C 6-10 An aryl group, a C 5-18 heterocyclic group or a C 5-18 carbocyclic group, and each ring system includes a monocyclic ring, a spiro ring, a bridged ring, a condensed ring, and/or combinations thereof, and each of the groups is independent Optionally substituted or unsubstituted; each R 8 and R 9 are independently selected from -H, halogen, -CN, -OH, -N 3 , -NO 2 , C 1-6 alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , C 5-10 spiroheterocyclyl or C 5-10 carbocyclyl, Each of the groups is independently substituted or unsubstituted.

本發明進一步提供了結構式（I）所示的通式化合物的一些優選技術方案。The invention further provides some preferred embodiments of the compounds of the formula of formula (I).

在一些優選技術方案中，結構式（I）所示的通式化合物中，R1 選自-H、-F、-Cl、-Br、-I、-CN、-OH、-NH2 、取代或未取代的C1-3 烷氧基或取代或未取代的C1-3 烷基。In some preferred embodiments, in the compound of the formula of the formula (I), R 1 is selected from the group consisting of -H, -F, -Cl, -Br, -I, -CN, -OH, -NH 2 , and substituted Or an unsubstituted C 1-3 alkoxy group or a substituted or unsubstituted C 1-3 alkyl group.

在一些優選技術方案中，結構式（I）所示的通式化合物中，R2 選自-H、-F、-Cl、 -Br、-I、-CN、-OH、-NH2 、取代或未取代的C1-3 烷氧基或取代或未取代的C1-3 烷基。In some preferred embodiments, in the compound of the formula of the formula (I), R 2 is selected from the group consisting of -H, -F, -Cl, -Br, -I, -CN, -OH, -NH 2 , and substituted Or an unsubstituted C 1-3 alkoxy group or a substituted or unsubstituted C 1-3 alkyl group.

在一些優選技術方案中，結構式（I）所示的通式化合物中，R3 選自-H、-F、-Cl、 -Br、-CN、-OH、-NO2 、-NR8 R9 、-N(R8 )(CH2 )p NR8 R9 、-N(R8 )(CH2 )p R8 、-N(R8 )Gp R8 、-N(R8 )Gp NR8 R9 、-N(R8 )(C=O)q R8 、-N(R8 )(C=O)q NR8 R9 、-N(R8 )(C=O)q Gp R8 、-N(R8 )(C=O)q Gp NR8 R9 、-N(R8 )(C=O)q Gp (C=O)q R8 、-N(R8 )(C=O)q Gp (C=O)q NR8 R9 、-N(R8 )(C=O)q N(R8 )(C=O)q R8 、-N(R8 )(C=O)q N(R8 ) (C=O)q NR8 R9 、-N(R8 )(C=O)q N(R8 )Gq (C=O)p R8 、-N(R8 )(C=O)q N(R8 )Gp (C=O)q NR8 R9 、-(C=O)q R8 、-(C=O)q OR8 、-(C=O)q NH2 、-(C=O)q NR8 R9 、C1-6 烷基或C6-10 芳基，且每個基團獨立地任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自鹵素、-CN、-OH、-NH2 、-N3 、-NO2 、取代或未取代的C1-6 烷基或者取代或未取代的C1-6 烷氧基。In some preferred embodiments, in the compound of the formula of the formula (I), R 3 is selected from the group consisting of -H, -F, -Cl, -Br, -CN, -OH, -NO 2 , -NR 8 R 9 , -N(R 8 )(CH 2 ) p NR 8 R 9 , -N(R 8 )(CH 2 ) p R 8 , -N(R 8 )G p R 8 , -N(R 8 )G p NR 8 R 9 , -N(R 8 )(C=O) q R 8 , -N(R 8 )(C=O) q NR 8 R 9 , -N(R 8 )(C=O) q G p R 8 , -N(R 8 )(C=O) q G p NR 8 R 9 , -N(R 8 )(C=O) q G p (C=O) q R 8 , -N( R 8 )(C=O) q G p (C=O) q NR 8 R 9 , -N(R 8 )(C=O) q N(R 8 )(C=O) q R 8 ,-N (R 8 )(C=O) q N(R 8 ) (C=O) q NR 8 R 9 , -N(R 8 )(C=O) q N(R 8 )G q (C=O) p R 8 , -N(R 8 )(C=O) q N(R 8 )G p (C=O) q NR 8 R 9 , -(C=O) q R 8 , -(C=O) q OR 8 , —(C=O) q NH 2 , —(C=O) q NR 8 R 9 , C 1-6 alkyl or C 6-10 aryl, and each group is independently and optionally one or more substituents or unsubstituted, the substituents are each independently selected from halogen, -CN, -OH, -NH 2, -N 3, -NO 2, a substituted or unsubstituted C 1-6 alkoxy A substituted or unsubstituted C 1-6 alkoxy group.

在一些優選技術方案中，結構式（I）所示的通式化合物中，p選自0或1。In some preferred embodiments, in the compound of the formula of the formula (I), p is selected from 0 or 1.

在一些優選技術方案中，結構式（I）所示的通式化合物中，q選自0、1或2。In some preferred embodiments, in the compound of the formula of the formula (I), q is selected from 0, 1, or 2.

在一些優選技術方案中，結構式（I）所示的通式化合物中， R3 選自-NH2 、、、、、、、或。In some preferred embodiments, in the compound of the formula of the formula (I), R 3 is selected from -NH 2 , , , , , , , or .

在一些優選技術方案中，結構式（I）所示的通式化合物中，R1 與R3 共同形成，或者R2 與R3 共同形成，5元雜芳環、6元雜芳環、7元雜芳環、8元雜芳環、5元雜環、6元雜環、7元雜環或8元雜環，且每個環系含有1、2、3或4個雜原子，所述雜原子選自N、O或S，且每個環系獨立地任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自-F、-Cl、-Br、-I、-CN、-OH、-NH2 、羰基、=O、氧代基、取代或未取代的C1-3 烷基、取代或未取代的C1-3 烷氧基、或-(C=O)R8 。In some preferred embodiments, in the compound of the formula of the formula (I), R 1 and R 3 are formed together, or R 2 and R 3 are co-formed, a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, and 7 a heteroaromatic ring, an 8-membered heteroaryl ring, a 5-membered heterocyclic ring, a 6-membered heterocyclic ring, a 7-membered heterocyclic ring or an 8-membered heterocyclic ring, and each ring system contains 1, 2, 3 or 4 hetero atoms, The hetero atom is selected from N, O or S, and each ring system is independently or optionally substituted or unsubstituted with one or more substituents, each independently selected from -F, -Cl, -Br, - I, -CN, -OH, -NH 2 , carbonyl, =0, oxo, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1-3 alkoxy, or -(C =O)R 8 .

在一些優選技術方案中，結構式（I）所示的通式化合物中，R1 與R3 共同形成5元雜芳環、6元雜芳環、5元雜環或6元雜環，每個環系含有1或2個雜原子，所述雜原子選自N或O，且每個環系獨立地任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自-F、-Cl、-Br、-OH、-NH2 、-NH-甲基、-NH-乙基、-NH-丙基、-NH-異丙基、-NHOCH3 、羰基、=O、氧代基、甲基、乙基、丙基、異丙基、甲氧基、CHF2 、CH2 F、CF3 或-(C=O)R8 ；且每個甲基、乙基、丙基、異丙基、甲氧基、CHF2 、CH2 F或-(C=O)R8 獨立地任意地被一個或多個取代基取代或不取代，所述取代基選自-F、-Cl、-Br或-I。In some preferred embodiments, in the compound of the formula of the formula (I), R 1 and R 3 together form a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, a 5-membered heterocyclic ring or a 6-membered heterocyclic ring. The ring system contains 1 or 2 heteroatoms selected from N or O, and each ring system is independently or optionally substituted or unsubstituted with one or more substituents, which are independently selected From -F, -Cl, -Br, -OH, -NH 2 , -NH-methyl, -NH-ethyl, -NH-propyl, -NH-isopropyl, -NHOCH 3 , carbonyl, =O , oxo, methyl, ethyl, propyl, isopropyl, methoxy, CHF 2 , CH 2 F, CF 3 or -(C=O)R 8 ; and each methyl, ethyl, Propyl, isopropyl, methoxy, CHF 2 , CH 2 F or -(C=O)R 8 are independently optionally substituted or unsubstituted with one or more substituents selected from -F , -Cl, -Br or -I.

在一些優選技術方案中，結構式（I）所示的通式化合物中，R2 與R3 共同形成5元雜芳環、6元雜芳環、7元雜芳環、8元雜芳環、5元雜環、6元雜環、7元雜環、8元雜環、5元碳環、6元碳環、7元碳環或8元碳環，每個雜環系含有1或2個雜原子，所述雜原子選自N或O，且每個環系獨立地任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自-F、-Cl、-Br、-OH、-NH2 、-NH-甲基、-NH-乙基、-NH-丙基、-NH-異丙基、-NHOCH3 、羰基、=O、氧代基、甲基、乙基、丙基、異丙基、甲氧基、CHF2 、CH2 F、CF3 或-(C=O)R8 ；且每個甲基、乙基、丙基、異丙基、甲氧基、CHF2 、CH2 F或-(C=O)R8 獨立地任意地被一個或多個取代基取代或不取代，所述取代基選自-F、-Cl、-Br或-I。In some preferred embodiments, in the compound of the formula of the formula (I), R 2 and R 3 together form a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, a 7-membered heteroaryl ring, and an 8-membered heteroaryl ring. , 5-membered heterocyclic ring, 6-membered heterocyclic ring, 7-membered heterocyclic ring, 8-membered heterocyclic ring, 5-membered carbocyclic ring, 6-membered carbocyclic ring, 7-membered carbocyclic ring or 8-membered carbocyclic ring, each heterocyclic ring containing 1 or 2 a hetero atom, the hetero atom being selected from N or O, and each ring system is independently or optionally substituted or unsubstituted with one or more substituents, each independently selected from -F, -Cl, -Br, -OH, -NH 2 , -NH-methyl, -NH-ethyl, -NH-propyl, -NH-isopropyl, -NHOCH 3 , carbonyl, =O, oxo, methyl , ethyl, propyl, isopropyl, methoxy, CHF 2 , CH 2 F, CF 3 or -(C=O)R 8 ; and each methyl, ethyl, propyl, isopropyl, Methoxy, CHF 2 , CH 2 F or -(C=O)R 8 are independently and optionally substituted or unsubstituted with one or more substituents selected from -F, -Cl, -Br or -I.

在一些優選技術方案中，結構式（I）所示的通式化合物中，R4 選自-H、-F、-Cl、-CN、-OH、-NH2 、取代或未取代的C1-3 烷基、取代或未取代的C1-3 烷氧基、含有1、2或3個選自N或O雜原子的5元雜環、含有1、2或3個選自N或O雜原子的6元雜環、5元碳環或6元碳環；且每個環系獨立地任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自-F、-Cl、-Br、-CN、-OH、羰基、=O、氧代基、取代或未取代的C1-3 烷基、取代或未取代的C1-3 烷氧基、-NH2 、-NH-C1-3 烷基、-NH-C1-3 烷氧基、-C1-3 亞烷基-NH2 或-C1-3 亞烷基-NH-C1-3 烷基。In some preferred embodiments, in the compound of the formula of the formula (I), R 4 is selected from -H, -F, -Cl, -CN, -OH, -NH 2 , substituted or unsubstituted C 1 a -3 alkyl, substituted or unsubstituted C 1-3 alkoxy group, containing 1, 2 or 3 5-membered heterocyclic rings selected from N or O heteroatoms, containing 1, 2 or 3 selected from N or O a 6-membered heterocyclic ring, a 5-membered carbocyclic ring or a 6-membered carbocyclic ring of a hetero atom; and each ring system is independently or optionally substituted or unsubstituted with one or more substituents, each independently selected from -F , -Cl, -Br, -CN, -OH, carbonyl, =0, oxo, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1-3 alkoxy, -NH 2 , -NH-C 1-3 alkyl, -NH-C 1-3 alkoxy, -C 1-3 alkylene-NH 2 or -C 1-3 alkylene-NH-C 1-3 alkane base.

在一些優選技術方案中，結構式（I）所示的通式化合物中，R4 選自-Cl、-NH2 、甲基或哌啶基（piperidinyl），所述環系獨立地任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自甲基、-NH2 或-CH2 NH2 。In some preferred embodiments, in the compound of the formula of the formula (I), R 4 is selected from -Cl, -NH 2 , methyl or piperidinyl, and the ring system is independently and optionally One or more substituents are substituted or unsubstituted, and the substituents are each independently selected from methyl, -NH 2 or -CH 2 NH 2 .

在一些優選技術方案中，結構式（I）所示的通式化合物中，R5 選自-F、-Cl、-Br、-NR8 R9 、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、丙氧基、異丙氧基、6元雜芳基、7元雜芳基、8元雜芳基、9元雜芳基、6元雜環基、7元雜環基、8元雜環基、9元雜環基、10元雜環基、11元雜環基、12元雜環基、13元雜環基、14元雜環基、6元碳環基、7元碳環基、8元碳環基、9元碳環基、10元碳環基、11元碳環基、12元碳環基、13元碳環基或14元碳環基；且所述的每個含有雜原子的環系含有1、2或3個選自N、O或S的雜原子，每個環系包括單環、螺環、橋環、稠環及它們的組合；且上述每個基團獨立地任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自-F、-Cl、-Br、-I、-CN、-OH、-NO2 、-NH2 、羰基、=O、氧代基、取代或未取代的C1-3 烷基、取代或未取代的C1-3 烷氧基、取代或未取代的-(CH2 )k NR8 R9 、取代或未取代的-(CH2 )k NHCOOR8 、或取代或未取代的-(C=O)R8 ；k選自0、1或2。In some preferred embodiments, in the compound of the formula of the formula (I), R 5 is selected from the group consisting of -F, -Cl, -Br, -NR 8 R 9 , methyl, ethyl, propyl, isopropyl Base, methoxy, ethoxy, propoxy, isopropoxy, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 6-membered heterocyclic, 7 A heterocyclic group, an 8-membered heterocyclic group, a 9-membered heterocyclic group, a 10-membered heterocyclic group, an 11-membered heterocyclic group, a 12-membered heterocyclic group, a 13-membered heterocyclic group, a 14-membered heterocyclic group, and a 6-membered carbon. a cyclic group, a 7-membered carbocyclic group, an 8-membered carbocyclic group, a 9-membered carbocyclic group, a 10-membered carbocyclic group, an 11-membered carbocyclic group, a 12-membered carbocyclic group, a 13-membered carbocyclic group or a 14-membered carbocyclic group. And each of the hetero atom-containing ring systems contains 1, 2 or 3 heteroatoms selected from N, O or S, each ring system comprising a monocyclic ring, a spiro ring, a bridged ring, a fused ring, and Combination; and each of the above groups is independently or optionally substituted or unsubstituted with one or more substituents, each independently selected from -F, -Cl, -Br, -I, -CN, -OH , -NO 2 , -NH 2 , carbonyl, =0, oxo, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1-3 alkoxy a substituted or unsubstituted -(CH 2 ) k NR 8 R 9 , a substituted or unsubstituted -(CH 2 ) k NHCOOR 8 , or a substituted or unsubstituted -(C=O)R 8 ;k is selected from 0, 1 or 2.

在一些優選技術方案中，結構式（I）所示的通式化合物中，所述C1-3 烷基是甲基，所述-(CH2 )k NHCOOR8 是-CH2 NHCOOBoc或–NHCOOBoc，所述-(CH2 )k NR8 R9 是-CH2 NH2 或-CH2 NH2 。In some preferred embodiments, in the compound of the formula of the formula (I), the C 1-3 alkyl group is a methyl group, and the -(CH 2 ) k NHCOOR 8 is -CH 2 NHCOOBoc or -NHCOOBoc The -(CH 2 ) k NR 8 R 9 is -CH 2 NH 2 or -CH 2 NH 2 .

在一些優選技術方案中，結構式（I）所示的通式化合物中，所述單環包括或; 所述螺環包括或; 所述它們的組合包括、、、或。In some preferred embodiments, in the compound of the formula of the formula (I), the single ring includes or The spiral ring includes or ; the combination of them includes , , , or .

在一些優選技術方案中，結構式（I）所示的通式化合物中，R5 選自；每個R21 和R22 分別獨立地選自鹵素、 C1-3 烷基、-NH2 、-C1-3 亞烷基-NH2 、-C1-3 亞烷基-NH-C1-3 烷基、-C1-3 亞烷基-N(C1-3 烷基)2 、-NHBoc或-CH2 NHBoc；或者R21 和R22 與它們共同連接的C原子一起形成5-10元的雜芳環、5-10元的碳環、5-10元的雜環、5-10元的螺雜環或5-10元稠合的雜環，且每個環系獨立地任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自鹵素、-CN、-OH、羰基、=O、氧代基、NH2 、C1-3 烷氧基、-C1-3 亞烷基-NH2 、-C1-3 亞烷基-NH-C1-3 烷基、-C1-3 亞烷基-N(C1-3 烷基)2 、-NHBoc、-CH2 NHBoc或C1-3 烷基。In some preferred embodiments, in the compound of the formula of the formula (I), R 5 is selected from the group consisting of Each of R 21 and R 22 is independently selected from the group consisting of halogen, C 1-3 alkyl, -NH 2 , -C 1-3 alkylene-NH 2 , -C 1-3 alkylene-NH-C 1-3 alkyl, -C 1-3 alkylene-N(C 1-3 alkyl) 2 , -NHBoc or -CH 2 NHBoc; or R 21 and R 22 together with the C atom to which they are attached form 5 a 10-membered heteroaryl ring, a 5-10 membered carbocyclic ring, a 5-10 membered heterocyclic ring, a 5-10 membered spiro heterocyclic ring or a 5-10 membered fused heterocyclic ring, and each ring system is independently Optionally substituted or unsubstituted with one or more substituents, each independently selected from the group consisting of halogen, -CN, -OH, carbonyl, =0, oxo, NH 2 , C 1-3 alkoxy , -C 1-3 alkylene-NH 2 , -C 1-3 alkylene-NH-C 1-3 alkyl, -C 1-3 alkylene-N(C 1-3 alkyl) 2 , -NHBoc, -CH 2 NHBoc or C 1-3 alkyl.

在一些優選技術方案中，結構式（I）所示的通式化合物中，R21 和R22 與它們共同連接的C原子一起形成5元雜芳環、6元雜芳環、7元雜芳環、8元雜芳環、9元雜芳環、10元雜芳環、5元雜環、6元雜環、7元雜環、8元雜環、9元雜環、5元螺雜環、6元螺雜環、7元螺雜環、8元螺雜環、9元螺雜環、5元稠合雜環、6元稠合雜環、7元稠合雜環、8元稠合雜環、9元稠合雜環、或10元稠合雜環，且每個環系含有1、2或3個雜原子，所述雜原子選自N、O或S，且每個環系獨立地任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自鹵素、-CN、-OH、羰基、=O、氧代基、-NH2 、C1-3 烷氧基或C1-3 烷基。In some preferred embodiments, in the compound of the formula of the formula (I), R 21 and R 22 together with the C atom to which they are attached form a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, and a 7-membered heteroaryl group. Ring, 8-membered heteroaryl ring, 9-membered heteroaryl ring, 10-membered heteroaryl ring, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 7-membered heterocyclic ring, 8-membered heterocyclic ring, 9-membered heterocyclic ring, 5-membered heterocyclic ring , 6-membered spiro heterocycle, 7-membered spiro heterocycle, 8-membered spiro heterocycle, 9-membered spiro heterocycle, 5-membered fused heterocycle, 6-membered fused heterocycle, 7-membered fused heterocycle, 8-membered fused a heterocyclic ring, a 9-membered fused heterocyclic ring, or a 10-membered fused heterocyclic ring, and each ring system contains 1, 2 or 3 heteroatoms selected from N, O or S, and each ring system Independently arbitrarily substituted or unsubstituted with one or more substituents, each independently selected from the group consisting of halogen, -CN, -OH, carbonyl, =0, oxo, -NH 2 , C 1-3 Alkoxy or C 1-3 alkyl.

在一些優選技術方案中，結構式（I）所示的通式化合物中，R5 選自-NH2 、、、、、、、、、、、、、、、、或者。In some preferred embodiments, in the compound of the formula of the formula (I), R 5 is selected from -NH 2 , , , , , , , , , , , , , , , , or .

在一些優選技術方案中，結構式（I）所示的通式化合物中，每個R8 和R9 分別獨立地選自-H、甲基、叔丁基、-CH=CH2 、-N(CH3 )2 、或。In some preferred embodiments, in the compound of the formula of the formula (I), each of R 8 and R 9 is independently selected from -H, methyl, t-butyl, -CH=CH 2 , -N. (CH 3 ) 2 , or .

在一些優選技術方案中，結構式（I）所示的通式化合物中，X是O、S或者不存在。In some preferred embodiments, in the compound of the formula of the formula (I), X is O, S or absent.

在一些優選技術方案中，結構式（I）所示的通式化合物中，Y1 是N，Y2 是CR2 ，所述R2 是H、鹵素或C1-6 烷基；或者R2 與R3 共同形成5元雜芳環、6元雜芳環、7元雜芳環、8元雜芳環、5元雜環、6元雜環、7元雜環、8元雜環、5元碳環、6元碳環、7元碳環或8元碳環，每個含有雜原子的環系含有1個或2個選自N或O的雜原子，上述基團獨立地任意地被1個或多個基團取代或不取代，所述取代基選自-F、-Cl、-Br、-OH、-NH2 、-NH甲基、-NH乙基、-NH丙基、-NH異丙基、-NHOCH3 、羰基、=O、氧代基、甲基、乙基、丙基、異丙基、甲氧基、CHF2 、CH2 F、CF3 或-(C=O)R8 ；上述每個甲基、乙基、丙基、異丙基、甲氧基、CHF2 、CH2 F、CF3 或-(C=O)R8 獨立地任意地被一個或多個取代基取代或不取代，所述取代基選自-F、-Cl、-Br或-I。In some preferred embodiments, in the compound of the formula of the formula (I), Y 1 is N, Y 2 is CR 2 , and the R 2 is H, halogen or C 1-6 alkyl; or R 2 Together with R 3 , a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, a 7-membered heteroaryl ring, an 8-membered heteroaryl ring, a 5-membered heterocyclic ring, a 6-membered heterocyclic ring, a 7-membered heterocyclic ring, and an 8-membered heterocyclic ring are formed. a carbon ring, a 6-membered carbocyclic ring, a 7-membered carbocyclic ring or an 8-membered carbocyclic ring, and each ring system containing a hetero atom contains 1 or 2 hetero atoms selected from N or O, and the above groups are independently and optionally One or more groups substituted or unsubstituted, the substituent being selected from -F, -Cl, -Br, -OH, -NH 2 , -NH methyl, -NHethyl, -NHpropyl, - NH isopropyl, -NHOCH 3 , carbonyl, =O, oxo, methyl, ethyl, propyl, isopropyl, methoxy, CHF 2 , CH 2 F, CF 3 or -(C=O R 8 ; each of the above methyl, ethyl, propyl, isopropyl, methoxy, CHF 2 , CH 2 F, CF 3 or -(C=O)R 8 is independently arbitrarily one or more Substituents are substituted or unsubstituted, and the substituents are selected from -F, -Cl, -Br or -I.

在一些優選技術方案中，結構式（I）所示的通式化合物中，Y2 是N，Y1 是CR1 ，所述R1 選自-H、鹵素或 C1-6 烷基，或者R1 與R3 共同形成5元雜芳環、6元雜芳環、5元雜環或6元雜環，每個環系含有1個或2個選自N或O的雜原子，上述基團獨立地任意地被1個或多個基團取代或不取代，所述取代基選自-F、-Cl、-Br、-OH、-NH2 、-NH甲基、-NH乙基、-NH丙基、-NH異丙基、-NHOCH3 、羰基、=O、氧代基、甲基、乙基、丙基、異丙基、甲氧基、CHF2 、CH2 F、CF3 或-(C=O)R8 ；上述每個甲基、乙基、丙基、異丙基、甲氧基、 CHF2 、CH2 F、CF3 或-(C=O)R8 獨立地任意地被一個或多個取代基取代或不取代，所述取代基選自-F、-Cl、-Br或者-I。In some preferred embodiments, in the compound of the formula of the formula (I), Y 2 is N, Y 1 is CR 1 , and R 1 is selected from -H, halogen or C 1-6 alkyl, or R 1 and R 3 together form a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, a 5-membered heterocyclic ring or a 6-membered heterocyclic ring, each ring system containing 1 or 2 hetero atoms selected from N or O, the above groups groups are independently optionally substituted with one or more groups unsubstituted or substituted with a substituent group selected from -F, -Cl, -Br, -OH, -NH 2, -NH -methyl, -NH-ethyl, -NH propyl, -NH isopropyl, -NHOCH 3 , carbonyl, =O, oxo, methyl, ethyl, propyl, isopropyl, methoxy, CHF 2 , CH 2 F, CF 3 Or -(C=O)R 8 ; each of the above methyl, ethyl, propyl, isopropyl, methoxy, CHF 2 , CH 2 F, CF 3 or -(C=O)R 8 independently Optionally substituted or unsubstituted with one or more substituents selected from -F, -Cl, -Br or -I.

在一些優選技術方案中，結構式（I）所示的通式化合物中，一些化合物的通式如結構式（II）所示：結構式II 其中： Y1 選自N或CR25 ； Y2 選自N或C； R25 選自H、鹵素、C1-3 烷基、C1-3 烷氧基、C2-3 烯基或C2-3 炔基；環選自5-8元含有1、2、3或4個選自N、O或S雜原子的雜芳環、5-8元碳環、或5-8元含有1、2、3或4個選自N、O或S雜原子的雜環；每個環系獨立地任意地被一個或多個取代基取代或不取代，所述取代基選自鹵素、-CN、-OH、-NR8 R9 、-N3 、-NO2 、羰基、 =O、氧代基、C1-3 烷基、一個或多個鹵素取代的C1-3 烷基、C1-6 烷氧基、一個或多個鹵素取代的C1-6 烷氧基或-(C=O)R8 ； R31 選自-H、鹵素、-OH、-NH2 、-(C=O)C1-3 烷基、-CN、-NO2 、羰基、=O、氧代基、羧基、C1-3 烷基、一個或多個鹵素取代的C1-3 烷基、C1-3 烷氧基或一個或多個鹵素取代的C1-3 烷氧基； m選自0、1、2、3或4； R4 選自-H、鹵素、-NH2 、取代或未取代的C1-3 烷氧基或者取代或未取代的 C1-3 烷基； 每個R32 和R33 分別獨立地選自-H、鹵素、-OH、-NH2 、-CN、-NO2 、 -C1-3 亞烷基-NH2 、-C1-3 亞烷基-NH-C1-3 烷基、-C1-3 亞烷基-N(C1-3 烷基)2 、 -NHBoc、 -CH2 NHBoc、-NH-C1-3 烷基、-N(C1-3 烷基)2 、-NH-C1-3 烷氧基、-N(C1-3 烷氧基)2 、C1-3 烷基、一個或多個鹵素取代的C1-3 烷基、C1-3 烷氧基或一個或多個鹵素取代的C1-3 烷氧基；或者， R32 和R33 與它們共同連接的C原子一起形成5-8元含有1、2或3個選自N、O或S雜原子的雜芳環或5-8元含有1、2或3個選自N、O或S雜原子的雜環，且每個環系獨立地任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自鹵素、-CN、-OH、-NH2 、羰基、=O、氧代基、-CH2 NH2 、-C1-3 亞烷基-NH2 、-C1-3 亞烷基-NH-C1-3 烷基、-C1-3 亞烷基-N(C1-3 烷基)2 、-NHBoc、-CH2 NHBoc、-NH-C1-3 烷基、-N(C1-3 烷基)2 、-NH-C1-3 烷氧基、-N(C1-3 烷氧基)2 、取代或未取代的C1-3 烷基或者取代或未取代的C1-3 烷氧基。In some preferred embodiments, among the compounds of the formula represented by the formula (I), some of the compounds have the formula shown in the formula (II): Wherein Y 1 is selected from N or CR 25 ; Y 2 is selected from N or C; R 25 is selected from H, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 2-3 alkene Or a C 2-3 alkynyl group; The ring is selected from 5-8 members containing 1, 2, 3 or 4 heteroaryl rings selected from N, O or S heteroatoms, 5-8 membered carbocyclic rings, or 5-8 members containing 1, 2, 3 or 4 a heterocyclic ring selected from N, O or S heteroatoms; each ring system is independently or optionally substituted or unsubstituted with one or more substituents selected from the group consisting of halogen, -CN, -OH, -NR 8 R 9 , -N 3 , -NO 2 , carbonyl, =O, oxo, C 1-3 alkyl, one or more halogen-substituted C 1-3 alkyl, C 1-6 alkoxy, One or more halogen-substituted C 1-6 alkoxy groups or -(C=O)R 8 ; R 31 is selected from -H, halogen, -OH, -NH 2 , -(C=O)C 1-3 Alkyl, -CN, -NO 2 , carbonyl, =0, oxo, carboxy, C 1-3 alkyl, one or more halogen substituted C 1-3 alkyl, C 1-3 alkoxy or One or more halogen-substituted C 1-3 alkoxy groups; m is selected from 0, 1, 2 , 3 or 4; R 4 is selected from -H, halogen, -NH 2 , substituted or unsubstituted C 1-3 Alkoxy or substituted or unsubstituted C 1-3 alkyl; each R 32 and R 33 are independently selected from -H, halogen, -OH, -NH 2 , -CN, -NO 2 , -C 1 -3 alkylene-NH 2 , -C 1-3 alkylene-NH-C 1-3 alkyl, -C 1-3 alkylene-N (C 1-3 alkyl) 2 , -NHBoc, -CH 2 NHBoc, -NH-C 1-3 alkyl, -N(C 1-3 alkyl) 2 , -NH-C 1-3 alkoxy, - N (C 1-3 alkoxy) 2 , C 1-3 alkyl, one or more halogen-substituted C 1-3 alkyl, C 1-3 alkoxy or one or more halogen substituted C 1 -3 alkoxy; or, R 32 and R 33 together with the C atom to which they are attached form a 5-8 membered heteroaryl ring containing 1, 2 or 3 heteroatoms selected from N, O or S or 5-8 The element contains 1, 2 or 3 heterocyclic rings selected from N, O or S heteroatoms, and each ring system is independently or optionally substituted or unsubstituted with one or more substituents, which are independently selected From halogen, -CN, -OH, -NH 2 , carbonyl, =0, oxo, -CH 2 NH 2 , -C 1-3 alkylene-NH 2 , -C 1-3 alkylene-NH -C 1-3 alkyl, -C 1-3 alkylene-N(C 1-3 alkyl) 2 , -NHBoc, -CH 2 NHBoc, -NH-C 1-3 alkyl, -N(C 1-3 alkyl) 2 , -NH-C 1-3 alkoxy, -N(C 1-3 alkoxy) 2 , substituted or unsubstituted C 1-3 alkyl or substituted or unsubstituted C 1-3 alkoxy group.

本發明進一步提供了結構式（II）所示的通式化合物的優選技術方案。The present invention further provides a preferred embodiment of the compound of the formula of the formula (II).

在一些優選技術方案中，結構式（II）所示的通式化合物中，環選自5元雜芳環、6元雜芳環、7元雜芳環、5元雜環、6元雜環、7元雜環、5元碳環、6元碳環、7元碳環或8元碳環，且每個含有雜原子的環系含有1、2或3個雜原子，所述雜原子選自N、O或S。In some preferred embodiments, among the compounds of the formula of the formula (II), The ring is selected from the group consisting of a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, a 7-membered heteroaryl ring, a 5-membered heterocyclic ring, a 6-membered heterocyclic ring, a 7-membered heterocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, and a 7-membered carbocyclic ring. Or an 8-membered carbocyclic ring, and each ring system containing a hetero atom contains 1, 2 or 3 heteroatoms selected from N, O or S.

在一些優選技術方案中，結構式（II）所示的通式化合物中，環選自5元含有1或2個選自N或O雜原子的雜芳環、5元含有1或2個選自N或O雜原子的雜環、6元含有1或2個選自N或O雜原子的雜環或5元碳環。In some preferred embodiments, among the compounds of the formula of the formula (II), The ring is selected from 5-membered heteroaryl rings containing 1 or 2 heteroatoms selected from N or O heteroatoms, 5-membered heterocyclic rings containing 1 or 2 heteroatoms selected from N or O, 6-membered containing 1 or 2 selected from N Or a heterocyclic or 5-membered carbon ring of an O hetero atom.

在一些優選技術方案中，結構式（II）所示的通式化合物中，R31 選自-H、-F、-Cl、-Br、-I、-OH、-NH2 、羰基、=O、氧代基、甲基、-(C=O)CH3 或者被-F、-Cl、-Br 或者-I取代的甲基。In some preferred embodiments, in the compound of the formula of the formula (II), R 31 is selected from the group consisting of -H, -F, -Cl, -Br, -I, -OH, -NH 2 , carbonyl, =O An oxo group, a methyl group, -(C=O)CH 3 or a methyl group substituted by -F, -Cl, -Br or -I.

在一些優選技術方案中，結構式（II）所示的通式化合物中，每個R32 和R33 獨立地選自-H、-F、-Cl、-OH、-NH2 、CN、-NO2 、-CH2 -NH2 、甲基或者被一個或多個-F、-Cl、-Br或者-I取代的甲基；或R32 和R33 與它們共同連接的C原子一起形成5元雜環、6元雜環或7元雜環，所述環系含有1或2個雜原子，所述雜原子選自N或O，且每個環系獨立地任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自-F、-Cl、-Br、-I、-CN、-OH、-NH2 、羰基、=O、氧代基、羧基、-N3 或者-NO2 。In some preferred embodiments, in the compound of the formula of the formula (II), each of R 32 and R 33 is independently selected from -H, -F, -Cl, -OH, -NH 2 , CN, - NO 2 , -CH 2 -NH 2 , methyl or a methyl group substituted by one or more -F, -Cl, -Br or -I; or R 32 and R 33 together with the C atom to which they are attached form 5 a heterocyclic ring, a 6-membered heterocyclic ring or a 7-membered heterocyclic ring, the ring system containing 1 or 2 heteroatoms selected from N or O, and each ring system is independently arbitrarily one or more Substituents substituted or unsubstituted, each independently selected from -F, -Cl, -Br, -I, -CN, -OH, -NH 2 , carbonyl, =0, oxo, carboxy, - N 3 or -NO 2 .

在一些優選技術方案中，結構式（II）所示的通式化合物中，每個R32 和R33 獨立地選自 -CH2 NH2 或-CH3 ；或者R32 與R33 與他們連接的碳原子一起形成。In some preferred embodiments, in the compound of the formula of the formula (II), each R 32 and R 33 are independently selected from -CH 2 NH 2 or -CH 3 ; or R 32 and R 33 are attached thereto. Carbon atoms form together .

在一些優選技術方案中，結構式（II）所示的通式化合物中，Y1 是N。In some preferred embodiments, in the compound of the formula of the formula (II), Y 1 is N.

在一些優選技術方案中，結構式（II）所示的通式化合物中，Y2 是C。In some preferred embodiments, in the compound of the formula of the formula (II), Y 2 is C.

在一些優選技術方案中，結構式（II）所示的通式化合物中，R25 是-H或-Cl。In some preferred embodiments, in the compound of the formula of the formula (II), R 25 is -H or -Cl.

在一些優選技術方案中，結構式（II）所示的通式化合物中，R4 是-NH2 。In some preferred embodiments, in the compound of the formula of the formula (II), R 4 is -NH 2 .

在一些優選技術方案中，結構式（I）所示的通式化合物中，一些化合物的通式如結構式（III）所示：結構式III 其中， X選自不存在或S； R26 選自-H、鹵素、取代或未取代的 C1-3 烷基或者取代或未取代的C1-3 烷氧基；環選自5-8元雜環，且每個環系獨立地含有1或2個雜原子，所述的雜原子選自N、O或S； R34 選自-H、鹵素、-OH、-NR35 R36 、-CN、-NO2 、羰基、=O、氧代基、取代或未取代的C1-3 烷基或者取代或未取代的C1-3 烷氧基； n選自0、1、2或3； R4 選自-H、鹵素、-NH2 、C1-6 烷基；或者R4 是5、6、7元雜環，每個環系獨立地含有1或2個N原子，且每個環系獨立地任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自鹵素、-C1-3 烷基或者-C1-3 亞烷基-NH2 ； 每個R35 和R36 分別獨立地選自-H、鹵素、-OH、-NH2 、-CN、-C1-3 亞烷基-NH2 、-NO2 、-CH2 NH2 、取代或未取代的C1-3 烷基或者取代或未取代的C1-3 烷氧基；或者， R35 和R36 與它們共同連接的C原子一起形成5-8元雜環，且每個環系獨立地含有1、2或3個雜原子，所述雜原子選自N、O或S，且每個環系獨立地任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自鹵素、-CN、-OH、-NH2 、取代或未取代的C1-3 烷基或者取代或未取代的C1-3 烷氧基。In some preferred embodiments, among the compounds of the formula represented by the formula (I), some of the compounds have the formula shown in the formula (III): Wherein X is selected from the absence or S; R 26 is selected from -H, halogen, substituted or unsubstituted C 1-3 alkyl or substituted or unsubstituted C 1-3 alkoxy; The ring is selected from a 5-8 membered heterocyclic ring, and each ring system independently contains 1 or 2 heteroatoms, said hetero atom being selected from N, O or S; R 34 is selected from -H, halogen, -OH, -NR 35 R 36 , -CN, -NO 2 , carbonyl, =0, oxo, substituted or unsubstituted C 1-3 alkyl or substituted or unsubstituted C 1-3 alkoxy; n selected from 0, 1, 2 or 3; R 4 is selected from -H, halogen, -NH 2 , C 1-6 alkyl; or R 4 is a 5, 6, 7-membered heterocyclic ring, each ring system independently containing 1 or 2 N atoms, and each ring system is independently or optionally substituted or unsubstituted with one or more substituents, each independently selected from halogen, -C 1-3 alkyl or -C 1-3 Alkylene-NH 2 ; each R 35 and R 36 are independently selected from -H, halogen, -OH, -NH 2 , -CN, -C 1-3 alkylene-NH 2 , -NO 2 , -CH 2 NH 2 , a substituted or unsubstituted C 1-3 alkyl group or a substituted or unsubstituted C 1-3 alkoxy group; or, R 35 and R 36 together with the C atom to which they are attached form 5-8 a heterocyclic ring, and each ring system independently contains 1, 2 or 3 heteroatoms selected from N, O or S, and each ring system is independently arbitrarily one or Substituents or substituted, the substituents are each independently selected from halogen, -CN, -OH, -NH 2, substituted or unsubstituted C 1-3 alkyl or C 1-3 substituted or unsubstituted Alkoxy.

本發明進一步提供了結構式（III）所示的通式化合物的優選技術方案。The present invention further provides a preferred embodiment of the compound of the formula of the formula (III).

在一些優選技術方案中，結構式（III）所示的通式化合物中，環選自5元雜環、6元雜環或7元雜環，且每個環系獨立地含有1個N原子。In some preferred embodiments, among the compounds of the formula of formula (III), The ring is selected from a 5-membered heterocyclic ring, a 6-membered heterocyclic ring or a 7-membered heterocyclic ring, and each ring system independently contains 1 N atom.

在一些優選技術方案中，結構式（III）所示的通式化合物中，每個R32 和R33 獨立地選自-H、-F、-Cl、-OH、-NH2 、-CN、-NO2 、-CH2 -NH2 、甲基、由1個或多個-F、-Cl、 -Br或-I取代的甲基，或者R35 和R36 與它們共同連接的C原子一起形成5元雜環、6元雜環或7元雜環，每個環系獨立地含有1個N原子，且每個環系獨立地任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自鹵素、-CN、-OH、-NH2 、羰基、=O、氧代基、或者-CH2 NH2 。In some preferred embodiments, in the compound of the formula of the formula (III), each of R 32 and R 33 is independently selected from -H, -F, -Cl, -OH, -NH 2 , -CN, -NO 2 , -CH 2 -NH 2 , methyl, methyl substituted by 1 or more -F, -Cl, -Br or -I, or R 35 and R 36 together with the C atom to which they are attached Forming a 5-membered heterocyclic ring, a 6-membered heterocyclic ring or a 7-membered heterocyclic ring, each ring system independently containing 1 N atom, and each ring system is independently substituted or unsubstituted by one or more substituents, The substituents are each independently selected from the group consisting of halogen, -CN, -OH, -NH 2 , carbonyl, =0, oxo, or -CH 2 NH 2 .

在一些優選技術方案中，結構式（III）所示的通式化合物中，R26 選自-H或-Cl。In some preferred embodiments, in the compound of the formula of the formula (III), R 26 is selected from -H or -Cl.

在一些優選技術方案中，結構式（III）所示的通式化合物中，R4 是-NH2 ，或者是含有1個N原子的6元雜環，環系任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自鹵素、-NH2 、甲基、乙基、或者-CH2 NH2 。In some preferred embodiments, in the compound of the formula of the formula (III), R 4 is -NH 2 or a 6-membered heterocyclic ring containing 1 N atom, and the ring system is optionally substituted by one or more The substituents are substituted or unsubstituted, and the substituents are each independently selected from halogen, -NH 2 , methyl, ethyl, or -CH 2 NH 2 .

在一些優選技術方案中，結構式（III）所示的通式化合物中R34 選自-F、-COCH3 、羰基、=O、氧代基、-CH3 或-CF3 。In some preferred embodiments, R 34 of the formula of formula (III) wherein R 34 is selected from the group consisting of -F, -COCH 3 , carbonyl, =0, oxo, -CH 3 or -CF 3 .

本發明進一步提供了結構式（I）或結構式（II）所示的通式化合物中的一些具體化合物，具體如下： 1)(S) -N1 -(3-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-2-氯苯基)-N2 ,N2 -二甲基草醯胺鹽酸鹽； 2)N1 -(4-((3-胺基-5-(4-胺基-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-3-氯吡啶-2-基)-N2 ,N2 -二甲基草醯胺； 3) N-(3-((3-胺基-5-(4-胺基-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-2-氯苯基)-4-(2-(二甲基胺基)-2-氧代乙醯基)苯甲醯胺； 4) 6-((3-胺基-5-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-2H-苯並[b][1,4]惡嗪-3(4H)-酮； 5) 6-(3-胺基-5-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)-2H-苯並[b][1,4]惡嗪-3(4H)-酮； 6) 5-((2-胺基-3-氯吡啶-4-基)硫代)-N2 -(2-氮雜螺[4.5]癸烷-8-基)吡嗪-2,6-二胺； 7) (S)-1-(4-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-3,3-二氟吲哚啉-1-基)乙酮； 8) (S)-4-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-3,3-二氟吲哚啉-2-酮； 9) 4-((3-胺基-5-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫代)吲哚啉-2-酮； 10) (S)-4-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-3,3-二氟-1H-吡咯並[2,3-b]吡啶-2(3H)-酮； 11) (S)-4-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-3,3-二氟-1-甲基吲哚-2-酮； 12) (S)-4-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)吲哚啉-2,3-二酮鹽酸鹽； 13) 1-(4-((3-胺基-5-(4-(氨甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-3,3-二氟吲哚啉-1-基)乙酮； 14) 4-((3-胺基-5-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫代)吲哚啉-2,3-二酮； 15) 5-((2-胺基-3-氯吡啶-4-基)硫代)-6-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-胺； 16)N1 -(4-((3-胺基-5-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-3-氯吡啶-2-基)-N2 ,N2 -二甲基草醯胺； 17) ((1-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡嗪-2-基)-4-甲基哌啶-4-基)甲基)胺基甲酸叔丁酯； 18)(S) -N1 -(4-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-3-氯吡啶-2-基)-N2 ,N2 -二甲基草醯胺； 19)(S) -N1 -(3-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-2-氯苯基)-N2 ,N2 -二甲基草醯胺； 20)N1 -(3-((3-胺基-5-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-2-氯苯基)-N2 ,N2 -二甲基草醯胺； 21) N-(3-((3-胺基-5-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-2-氯苯基)-3-(2-(二甲基胺基)-2-氧代乙醯基)苯甲醯胺； 22) 2-(3-(3-(3-((3-胺基-5-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-2-氯苯基)脲基)苯基)-N,N-二甲基-2-氧代乙醯胺； 23) 2-(4-(3-(3-((3-胺基-5-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-2-氯苯基)脲基)苯基)-N,N-二甲基-2-氧代乙醯胺； 24) 6-(4-(胺基甲基)-4-甲基哌啶-1-基)-3-((3,4-二氫-2H-苯並[b][1,4]惡嗪-6-基)硫代)吡嗪-2-胺； 25) (1-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡嗪-2-基)-4-甲基哌啶-4-基)胺基甲酸叔丁酯； 26) (1-(5-((2-丙烯醯胺-3-氯吡啶-4-基)硫代)-6-胺基吡嗪-2-基)-4-甲基哌啶-4-基)胺基甲酸叔丁酯； 27) (1-(6-胺基-5-((3-氯-2-(2-(二甲基胺基)-2-氧代乙醯胺基)吡啶-4-基)硫代)吡嗪-2-基)-4-甲基哌啶-4-基)胺基甲酸叔丁酯； 28) (1-(6-胺基-5-((2-氯-3-(2-(二甲基胺基)-2-氧代乙醯胺基)苯基)硫代)吡嗪-2-基)-4-甲基哌啶-4-基)胺基甲酸叔丁酯； 29)N1 -(3-((3-胺基-5-(4-胺基-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-2-氯苯基)-N2 ,N2 -二甲基草醯胺； 30) (1-(6-胺基-5-((3-胺基-2-氯苯基)硫代)吡嗪-2-基)-4-甲基哌啶-4-基)胺基甲酸叔丁酯； 31) N-(3-((3-胺基-5-(4-胺基-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-2-氯苯基)-2-氧代-2-(4-甲苯基)乙醯胺； 32) (1-(5-((3-丙烯醯基-2-氯苯基)硫代)-6-胺基吡嗪-2-基)-4-甲基哌啶-4-基)胺基甲酸叔丁酯； 33) 6-(3-胺基-5-(4-胺基-4-甲基哌啶-1-基)吡嗪-2-基)-2H-苯並[b][1,4]惡嗪-3(4H)-酮； 34) N-(4-((3-胺基-5-(4-胺基-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-3-氯吡啶-2-基)-4-(2-(二甲基胺基)-2-氧代乙醯基)苯甲醯胺； 35) N-(4-((3-胺基-5-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-3-氯吡啶-2-基)-4-(2-(二甲基胺基)-2-氧代乙醯基)苯甲醯胺； 36) N-(3-((3-胺基-5-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-2-氯苯基)-4-(2-(二甲基胺基)-2-氧代乙醯基)苯甲醯胺； 37) 5-((2-胺基-3-氯吡啶-4-基)硫代)-N2 -環己基吡嗪-2,6-二胺； 38) (S)-8-(5-((1H-吡咯並[2,3-b]吡啶-4-基)硫代)-6-胺基吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 39) (S)-8-(6-胺基-5-((3,3-二甲基吲哚啉-4-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 40) (S)-8-(6-胺基-5-((3-氟-1H-吲哚-4-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 41) 5-((2-胺基-3-氯吡啶-4-基)硫代)-N2 -(4-(胺基甲基)-4-甲基環己基)吡嗪-2,6-二胺； 42) (S)-8-(5-((1H-吲哚-4-基)硫代)-6-胺基吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 43) (S)-1-(4-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-1H-吲哚-1-基)乙酮； 44) 5-((2-胺基-3-氯吡啶-4-基)硫代)-N2 -(4-胺基-4-甲基環己基)吡嗪-2,6-二胺； 45) (S)-6-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-2H-苯並[b][1,4]惡嗪-3(4H)-酮； 46) (S)-4-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-1,3,3-三甲基吲哚啉-2-酮； 47) (4S)-8-(6-胺基-5-((3-氟代吲哚啉-4-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 48) 1-(4-((3-胺基-5-((S)-4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-3-氟-3-甲基吲哚啉-1-基)乙酮； 49) (S)-8-(6-胺基-5-((3,3-二氟吲哚啉-4-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 50) 1-(4-((3-胺基-5-((S)-4-胺基-2-氧雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-3-甲基吲哚啉-1-基)乙酮； 51) (S)-8-(6-胺基-5-((8-氯-4,4-二氟-1,2,3,4-四氫喹啉-5-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 52) (4S)-8-(6-胺基-5-((8-氯-4-氟-1,2,3,4-四氫喹啉-5-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 53) (S)-8-(6-胺基-5-((3,3-二氟-1-甲基吲哚啉-4-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 54) (S)-6-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-3,3-二氟吲哚啉-2-酮； 55) 4-((3-胺基-5-((S)-4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-3-氟吲哚啉-2-酮； 56) (S)-8-(6-胺基-5-((3,3-二氟-2,3-二氫苯並呋喃-4-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 57) (S)-8-(6-胺基-5-((4,4-二氟苯並二氫吡喃-5-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 58) 4-((3-胺基-5-((S)-4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-3-氟-1-甲基-3-(三氟甲基)吲哚啉-2-酮； 59) (S)-6-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-7-氯吲哚啉-2-酮； 60) (S)-8-(6-胺基-5-((5-氯-3,4-二氫-2H-苯並[b][1,4]惡嗪-6-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 61) (S)-7-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-8-氯-3,4-二氫喹啉-2(1H)-酮； 62) (S)-6-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-5-氯-2H-苯並[b][1,4]惡嗪-3(4H)-酮； 63) (S)-2-(3-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-2-氯苯基)-N,N-二甲基-2-氧代乙醯胺； 64) 4-((3-胺基-5-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-3,3-二氟-1H-吡咯並[2,3-b]吡啶-2(3H)-酮； 65) (S)-4-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-1H-苯並[d]咪唑-2(3H)-酮； 66) (S)-4-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-1,3-二甲基-1H-苯並[d]咪唑-2(3H)-酮； 67) (S)-8-(6-胺基-5-((2,2-二氟-2,3-二氫-1H-苯並[d]咪唑-4-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 68) (S)-8-(6-胺基-5-((2,2-二氟-1,3-二甲基-2,3-二氫-1H-苯並[d]咪唑-4-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 69) (4S)-8-(6-胺基-5-((1-胺基-3,3-二氟-2,3-二氫-1H-茚-4-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 70) (S)-5-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-2-甲基-[1,2,4]三氮唑並[4,3-a]吡啶-3(2H)-酮； 71) (S)-8-(6-胺基-5-((3,3-二氟-2-甲基-2,3-二氫-[1,2,4]三氮唑[4,3-a]吡啶-5-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 72) (S)-1-(4-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)吲哚-1-基)乙酮； 73) 1'-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡嗪-2-基)六氫螺[環戊烷[b]呋喃-5,4'-哌啶]-4-胺； 74) 1'-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡嗪-2-基)螺[二環[3.1.0]己烷-3,4'-哌啶]-2-胺； 75) 1'-胺基-1-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡嗪-2-基)四氫螺[哌啶-4,2'-吡咯]-3'(1'H)-酮； 76) 1'-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡嗪-2-基)螺[二環[3.1.0]己烷-2,4'-哌啶]-3-胺。The present invention further provides some specific compounds of the formula (I) or the formula (II), as follows: 1) (S) - N 1 -(3-((3-amino)- 5-(4-Amino-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl) -N 2 ,N 2- dimethyl oxalyl hydrochloride; 2) N 1 -(4-((3-amino-5-(4-amino-4-methylpiperidin-1-yl)pyrazine-2 -yl)thio)-3-chloropyridin-2-yl) -N 2 ,N 2 -dimethylformamide; 3) N-(3-((3-amino-5-(4-amine)) 4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-4-(2-(dimethylamino)-2-oxoethylhydrazine Benzobenzamide; 4) 6-((3-amino-5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio -2H-benzo[b][1,4]oxazin-3(4H)-one; 5) 6-(3-amino-5-(4-(aminomethyl)-4-methyl) Piperidin-1-yl)pyrazin-2-yl)-2H-benzo[b][1,4]oxazine-3(4H)-one; 6) 5-((2-amino-3- Chloropyridin-4-yl)thio) -N 2 -(2-azaspiro[4.5]decane-8-yl)pyrazine-2,6-diamine; 7) (S)-1-(4 -((3-Amino-5-(4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl)thio)-3,3 -difluoroporphyrin-1-yl) Ketone; 8) (S)-4-((3-Amino-5-(4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2- ()thio)-3,3-difluoroporphyrin-2-one; 9) 4-((3-amino-5-(4-(aminomethyl)-4-methylpiperidine-) 1-yl)pyrazin-2-yl)thio)porphyrin-2-one; 10) (S)-4-((3-amino-5-(4-amino-2-oxo-) 8-Azaspiro[4.5]decane-8-yl)pyrazin-2-yl)thio)-3,3-difluoro-1H-pyrrolo[2,3-b]pyridine-2(3H) -ketone; 11) (S)-4-((3-Amino-5-(4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2 -yl)thio)-3,3-difluoro-1-methylindol-2-one; 12) (S)-4-((3-amino-5-(4-amino-2-) Oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl)thio)porphyrin-2,3-dione hydrochloride; 13) 1-(4-( (3-Amino-5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3,3-difluoroporphyrin-1 -yl)ethanone; 14) 4-((3-amino-5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio) Porphyrin-2,3-dione; 15) 5-((2-Amino-3-chloropyridin-4-yl)thio)-6-(4-(aminomethyl)-4-methyl Nipiperidin-1-yl)pyrazine-2-amine; 16) N 1 -(4-((3-amino-5-(4-(aminomethyl)-4-methylpiperidine-1) -base) Triazin-2-yl) thio) -3-chloro-pyridin-2-yl) - N 2, N 2 - dimethyl grass Amides; 17) ((l- (6-amino-5 - ((2 -Amino-3-chloropyridin-4-yl)thio)pyrazine-2-yl)-4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester; 18) (S) - N 1 -(4-((3-Amino-5-(4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl)sulfide ))-3-chloropyridin-2-yl) -N 2 ,N 2 -dimethyl oxazinamide; 19) (S) - N 1 -(3-((3-amino-5-(4-) Amino-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl) -N 2 ,N 2 -dimethyl Glutamine; 20) N 1 -(3-((3-amino-5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)sulfide ))- 2 -chlorophenyl) -N 2 ,N 2 -dimethylformamide; 21) N-(3-((3-amino-5-(4-(aminomethyl))-4) -methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-3-(2-(dimethylamino)-2-oxoethyl)benzene Methionine; 22) 2-(3-(3-(3-((3-amino)-5-(4-(amino)methyl)-4-methylpiperidin-1-yl)pyrazine- 2-yl)thio)-2-chlorophenyl)ureido)phenyl)-N,N-dimethyl-2-oxoethylamine; 23) 2-(4-(3-(3- ((3-Amino-5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazine- 2-yl)thio)-2-chlorophenyl)ureido)phenyl)-N,N-dimethyl-2-oxoethylamine; 24) 6-(4-(aminomethyl) 4-methylpiperidin-1-yl)-3-((3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)thio)pyrazine-2 -amine; 25) (1-(6-Amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidine- Tert-butyl 4-amino)carbamate; 26) (1-(5-((2-propenylamine-3-chloropyridin-4-yl)thio)-6-aminopyrazin-2-yl) Tert-butyl 4-methylpiperidin-4-yl)carbamate; 27) (1-(6-Amino-5-((3-chloro-2-(2-(dimethylamino)) ,-2-oxoethylamino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamic acid tert-butyl ester; 28) (1) -(6-Amino-5-((2-chloro-3-(2-(dimethylamino)-2-oxoethylamino)phenyl)thio)pyrazin-2-yl) Tert-butyl 4-methylpiperidin-4-yl)carbamate; 29) N 1 -(3-((3-amino-5-(4-amino-4-methylpiperidin-1) -yl)pyrazin-2-yl)thio)-2-chlorophenyl) -N 2 ,N 2 -dimethylformamide; 30) (1-(6-amino-5-((3) -Amino-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamic acid tert-butyl ester; 31) N-(3-((3- Amino-5-(4-amino-4-methylpiperidine -1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-oxo-2-(4-methylphenyl)acetamide; 32) (1-(5-(( 3-propenyl-2-chlorophenyl)thio)-6-aminopyrazin-2-yl)-4-methylpiperidin-4-yl)carbamic acid tert-butyl ester; 33) 6- (3-Amino-5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)-2H-benzo[b][1,4]oxazine-3 ( 4H)-keto; 34) N-(4-((3-amino-5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3 -chloropyridin-2-yl)-4-(2-(dimethylamino)-2-oxoethyl)benzamide; 35) N-(4-((3-amino-5) -(4-(Aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-(2-(two Methylamino)-2-oxoethyl)benzamide; 36) N-(3-((3-amino-5-(4-(aminomethyl)-4-methyl)) Pyridin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-4-(2-(dimethylamino)-2-oxoethyl)benzamide; 37) 5-((2-Amino-3-chloropyridin-4-yl)thio) -N 2 -cyclohexylpyrazine-2,6-diamine; 38) (S)-8-(5- ((1H-pyrrolo[2,3-b]pyridin-4-yl)thio)-6-aminopyrazin-2-yl)-2-oxa-8-azaspiro[4.5]decane -4-amine; 39) (S)-8-(6-Amino-5-((3,3-dimethylporphyrin-4-) Thio)pyrazin-2-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine; 40) (S)-8-(6-amino-5-(( 3-fluoro-1H-indol-4-yl)thio)pyrazin-2-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine; 41) 5-(( 2-amino-3-chloropyridin-4-yl)thio) -N 2 -(4-(aminomethyl)-4-methylcyclohexyl)pyrazine-2,6-diamine; 42) (S)-8-(5-((1H-indol-4-yl)thio)-6-aminopyrazin-2-yl)-2-oxa-8-azaspiro[4.5]癸Alk-4-amine; 43) (S)-1-(4-((3-amino-5-(4-amino-2-oxa-8-azaspiro[4.5]decane-8-) Pyrazin-2-yl)thio)-1H-indol-1-yl)ethanone; 44) 5-((2-amino-3-chloropyridin-4-yl)thio) -N 2- (4-Amino-4-methylcyclohexyl)pyrazine-2,6-diamine; 45) (S)-6-((3-Amino-5-(4-amino-2-) Oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl)thio)-2H-benzo[b][1,4]oxazin-3(4H)-one 46) (S)-4-((3-Amino-5-(4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl )thio)-1,3,3-trimethylindol-2-one; 47) (4S)-8-(6-amino-5-((3-fluoroporphyrin-4-) Thio)pyrazin-2-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine; 48) 1-(4-((3-amino-5-) (S)-4-amine -2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl)thio)-3-fluoro-3-methylindol-1-yl)ethanone 49) (S)-8-(6-Amino-5-((3,3-difluoroporphyrin-4-yl)thio)pyrazine-2-yl)-2-oxa-8 -azaspiro[4.5]decane-4-amine; 50) 1-(4-((3-amino-5-((S)-4-amino-2-oxaspiro[4.5]decane) -8-yl)pyrazin-2-yl)thio)-3-methylindol-1-yl)ethanone; 51) (S)-8-(6-amino-5-((8) -chloro-4,4-difluoro-1,2,3,4-tetrahydroquinolin-5-yl)thio)pyrazin-2-yl)-2-oxa-8-azaspiro[4.5 ] decane-4-amine; 52) (4S)-8-(6-Amino-5-((8-chloro-4-fluoro-1,2,3,4-tetrahydroquinolin-5-yl) Thio)pyrazin-2-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine; 53) (S)-8-(6-amino-5-(( 3,3-difluoro-1-methylindol-4-yl)thio)pyrazine-2-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine; 54) (S)-6-((3-Amino-5-(4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl) Thio)-3,3-difluoroporphyrin-2-one; 55) 4-((3-amino-5-((S)-4-amino-2-oxa-8-aza) Spiro[4.5]decane-8-yl)pyrazin-2-yl)thio)-3-fluoroporphyrin-2-one; 56) (S)-8-(6-amino-5-( (3,3-difluoro-2,3-dihydrobenzo喃-4-yl)thio)pyrazine-2-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine; 57) (S)-8-(6-amino group -5-((4,4-difluorochroman-5-yl)thio)pyrazine-2-yl)-2-oxa-8-azaspiro[4.5]decane-4 -amine; 58) 4-((3-Amino-5-((S)-4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2 -yl)thio)-3-fluoro-1-methyl-3-(trifluoromethyl)porphyrin-2-one; 59) (S)-6-((3-amino-5-( 4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl)thio)-7-chloroindol-2-one; 60) ( S)-8-(6-Amino-5-((5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)thio)pyrazine -2-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine; 61) (S)-7-((3-amino-5-(4-amino-2) -oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl)thio)-8-chloro-3,4-dihydroquinolin-2(1H)-one; 62) (S)-6-((3-Amino-5-(4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl) Thio)-5-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one; 63) (S)-2-(3-((3-amino-5-) (4-Amino-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-N,N-dimethyl Base-2-oxoethylamine; 64) 4-((3 -amino-5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3,3-difluoro-1H-pyrrolo[ 2,3-b]pyridine-2(3H)-one; 65) (S)-4-((3-amino-5-(4-amino-2-oxa-8-azaspiro[4.5 ] decane-8-yl)pyrazin-2-yl)thio)-1H-benzo[d]imidazole-2(3H)-one; 66) (S)-4-((3-amino-) 5-(4-Amino-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl)thio)-1,3-dimethyl-1H-benzene And [d]imidazole-2(3H)-one; 67) (S)-8-(6-amino-5-((2,2-difluoro-2,3-dihydro-1H-benzo[ d] imidazol-4-yl)thio)pyrazine-2-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine; 68) (S)-8-(6- Amino-5-((2,2-difluoro-1,3-dimethyl-2,3-dihydro-1H-benzo[d]imidazol-4-yl)thio)pyrazine-2- (4-)oxa-8-azaspiro[4.5]decane-4-amine; 69) (4S)-8-(6-amino-5-((1-amino-3,3-) Difluoro-2,3-dihydro-1H-indol-4-yl)thio)pyrazine-2-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine; 70 (S)-5-((3-Amino-5-(4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl)sulfide ))-2-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one; 71) (S)-8-(6-Amino-5 -((3,3-difluoro-2-methyl-2,3-dihydro-[1,2, 4] Triazol [4,3-a]pyridin-5-yl)thio)pyrazine-2-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine; 72 (S)-1-(4-((3-Amino-5-(4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine-2-) ()thio)indol-1-yl)ethanone; 73) 1'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazine- 2-yl)hexahydrospiro[cyclopentane[b]furan-5,4'-piperidine]-4-amine; 74) 1'-(6-amino-5-((2-amino-3) -Chloropyridin-4-yl)thio)pyrazine-2-yl)spiro[bicyclo[3.1.0]hexane-3,4'-piperidine]-2-amine; 75) 1'-amino group 1-(6-Amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazine-2-yl)tetrahydrospiro[piperidine-4,2'-pyrrole ]-3'(1'H)-one; 76) 1'-(6-Amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl Spirulina [bicyclo[3.1.0]hexane-2,4'-piperidinyl]-3-amine.

本發明還提供了上述的至少一種化合物用於製備藥物的用途。The invention also provides the use of at least one of the compounds described above for the preparation of a medicament.

在一些優選技術方案中，由此製備的藥物可以用作治療由SHP2的活性介導的病症。In some preferred embodiments, the medicament thus prepared can be used to treat a condition mediated by the activity of SHP2.

在一些優選技術方案中，由SHP2的活性介導的所述病症是癌症、癌症轉移、心血管疾病、免疫學病症或眼部病症的治療或預防。In some preferred embodiments, the condition mediated by the activity of SHP2 is the treatment or prevention of cancer, cancer metastasis, cardiovascular disease, immunological condition or ocular condition.

在一些優選技術方案中，所述由SHP2活性介導的病症是努南氏症候群（Noonan Syndrome）、豹皮症候群（Leopard Syndrome）、青少年骨髓單核細胞白血病、神經母細胞瘤、黑色素瘤、頭頸部鱗狀細胞癌、急性骨髓性白血病、乳癌、食道癌、肺癌、結腸癌、頭癌、胃癌、間變性大細胞淋巴瘤或成膠質細胞瘤。In some preferred embodiments, the condition mediated by SHP2 activity is Noonan Syndrome, Leopard Syndrome, adolescent bone marrow monocytogene leukemia, neuroblastoma, melanoma, head and neck Squamous cell carcinoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric cancer, anaplastic large cell lymphoma or glioblastoma.

本發明還提供了包含至少一種如上所述的化合物和至少一種藥學上可接受的輔藥料的藥物組合物。在藥物組合物中，所述化合物與所述輔藥料的重量比約在0.0001至10的範圍內。The invention also provides a pharmaceutical composition comprising at least one compound as described above and at least one pharmaceutically acceptable adjuvant. In the pharmaceutical composition, the weight ratio of the compound to the auxiliary material is in the range of about 0.0001 to 10.

本發明另外提供了所述組合物用於製備藥物的應用。The invention further provides for the use of the composition for the preparation of a medicament.

在一些優選技術方案中，所述藥物用於治療由SHP2的活性介導的病症。In some preferred embodiments, the medicament is for treating a condition mediated by the activity of SHP2.

在一些優選技術方案中，由SHP2的活性介導的所述病症是癌症、癌症轉移、心血管疾病、免疫學病症或眼部病症的治療或預防。In some preferred embodiments, the condition mediated by the activity of SHP2 is the treatment or prevention of cancer, cancer metastasis, cardiovascular disease, immunological condition or ocular condition.

在一些優選技術方案中，所述由SHP2活性介導的病症是努南氏症候群、豹皮症候群、青少年骨髓單核細胞白血病、神經母細胞瘤、黑色素瘤、頭頸部鱗狀細胞癌、急性骨髓性白血病、乳癌、食道癌、肺癌、結腸癌、頭癌、胃癌、間變性大細胞淋巴瘤或成膠質細胞瘤。In some preferred embodiments, the condition mediated by SHP2 activity is Nunan's syndrome, leopard skin syndrome, adolescent bone marrow monocytogene leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, acute bone marrow Leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric cancer, anaplastic large cell lymphoma or glioblastoma.

除非另有說明，術語「鹵素」本發明中是指氟、氯、溴或者碘。優選的，鹵素包括F、Cl和Br。術語「鹵代C1-6 烷基」、「鹵代C2-6 烯基」、「鹵代C2-6 炔基」和「鹵代C1-6 烷氧基」是指其中一個或多個（尤其是1至3個）氫原子被鹵素原子取代，特別是氟或氯原子。在一些實施方案中，優選氟代C1-6 烷基、氟代C2-6 烯基、氟代C2-6 炔基和氟代C1-6 烷氧基，特別是氟代C1-3 烷基，例如CF3 、CHF2 、CH2 F、CH2 CH2 F、CH2 CHF2 、CH2 CF3 ；氟代C1-3 烷氧基，例如OCF3 、OCHF2 、OCH2 F、OCH2 CH2 F、OCH2 CHF2 或者OCH2 CF3 ；特別是指CF3 、OCF3 和OCHF2 。Unless otherwise indicated, the term "halogen" as used in the present invention means fluoro, chloro, bromo or iodo. Preferably, the halogen comprises F, Cl and Br. The terms "halogenated C 1-6 alkyl", "halo C 2-6 alkenyl", "halo C 2-6 alkynyl" and "halo C 1-6 alkoxy" mean one or A plurality of (especially 1 to 3) hydrogen atoms are replaced by halogen atoms, in particular fluorine or chlorine atoms. In some embodiments, preferred are fluoro C 1-6 alkyl, fluoro C 2-6 alkenyl, fluoro C 2-6 alkynyl, and fluoro C 1-6 alkoxy, especially fluoro C 1 -3 alkyl, such as CF 3 , CHF 2 , CH 2 F, CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 ; fluoro C 1-3 alkoxy, such as OCF 3 , OCHF 2 , OCH 2 F, OCH 2 CH 2 F, OCH 2 CHF 2 or OCH 2 CF 3 ; in particular CF 3 , OCF 3 and OCHF 2 .

除非另有說明，本發明中的烷基包括具有直鏈、支鏈或環狀部分的飽和一價烴基。例如，烷基包括甲基、乙基、丙基、異丙基、環丙基、正丁基、異丁基、仲丁基、叔丁基、環丁基、正戊基、3-（2-甲基）丁基、2-戊基、2-甲基丁基、新戊基、環戊基、正己基、2-己基，2-甲基戊基和環己基。類似地，本發明中C1-8 烷基的定義為以直鏈或支鏈排列的具有1、2、3、4、5、6、7或8個碳原子的基團。Unless otherwise stated, the alkyl group in the present invention includes a saturated monovalent hydrocarbon group having a linear, branched or cyclic moiety. For example, alkyl includes methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3-(2 -Methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl. Similarly, the C 1-8 alkyl group in the present invention is defined as a group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms arranged in a straight chain or a branched chain.

亞烷基是指通過從上述定義的烷基中除去氫原子而獲得的雙官能基團。例如，亞甲基(即-CH2 -)，亞乙基(即-CH2 -CH2 -或-CH(CH3 )-)和亞丙基(即-CH2 -CH2 -CH2 -，-CH(-CH2 -CH3 )-或-CH2 -CH(CH3 )-)。The alkylene group means a difunctional group obtained by removing a hydrogen atom from the alkyl group defined above. For example, methylene (ie, -CH 2 -), ethylene (ie, -CH 2 -CH 2 - or -CH(CH 3 )-), and propylene (ie, -CH 2 -CH 2 -CH 2 - , -CH(-CH 2 -CH 3 )- or -CH 2 -CH(CH 3 )-).

烯基和炔基包括直鏈、支鏈或環狀烯烴和炔烴。同樣地，「C2-8 烯基」和「C2-8 炔基」是指具有2、3、4、5、6、7或8個碳原子的線性或支鏈排列的烯基或炔基。Alkenyl and alkynyl groups include straight chain, branched or cyclic olefins and alkynes. Similarly, "C 2-8 alkenyl" and "C 2-8 alkynyl" mean a linear or branched alkenyl or alkyne having 2, 3, 4, 5, 6, 7 or 8 carbon atoms. base.

烷氧基自由基是由上述描述的直鏈、支鏈或環狀烷基形成的氧醚。The alkoxy radical is an oxygen ether formed from a linear, branched or cyclic alkyl group as described above.

除非另有說明，本發明所用的術語「芳基」是指含有碳環原子的未取代或取代的單環或多環環系。優選的芳基是單環或雙環6-10元芳環體系。苯基和萘基是優選的芳基。最優選的芳基是苯基。The term "aryl" as used herein, unless otherwise indicated, refers to an unsubstituted or substituted monocyclic or polycyclic ring system containing a carbon ring atom. Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups. The most preferred aryl group is phenyl.

除非另有說明，本發明使用的術語「雜環」是指含有一個或多個雜原子的未取代和取代的單環或多環非芳族環系。優選的雜原子包括N，O和S，包括N-氧化物，硫氧化物和二氧化物。優選完全飽和的或有一個或多個不飽和的3~8元。本定義中包括多個取代基，優選一個、兩個或三個取代基。The term "heterocycle" as used herein, unless otherwise indicated, refers to both unsubstituted and substituted monocyclic or polycyclic non-aromatic ring systems containing one or more heteroatoms. Preferred heteroatoms include N, O and S, including N-oxides, sulfur oxides and dioxides. Preferably, it is fully saturated or has one or more unsaturated 3-8 yuan. A plurality of substituents are preferred in this definition, preferably one, two or three substituents.

這樣的雜環基的實例包括但不限於環丁胺基、吡咯烷基、哌啶基、呱嗪基、氧代呱嗪基、氧代哌啶基、氧代氮雜基、氮雜卓基、四氫呋喃基、二氧戊環基、四氫咪唑基、四氫噻唑基、四氫唑基、四氫吡喃基、嗎啉基、硫代嗎啉基或惡二唑。Examples of such heterocyclic groups include, but are not limited to, cyclobutylamino, pyrrolidinyl, piperidinyl, pyridazinyl, oxoperazinyl, oxopiperidinyl, oxoaza, azatrol , tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrozolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl or oxadiazole.

除非另有說明，本發明所用的術語「雜芳基」表示含有碳和至少一個雜原子的芳族環系。雜芳基可以是單環或多環的、取代或未取代的。單環雜芳基可以在環中具有1~4個雜原子，而多環雜芳基可以含有1~10個雜原子。多環雜芳基環可以含有稠合環、螺環或橋環的連接方式，例如，環雜芳基是多環雜芳基。雙環雜芳基環可含有8至12個成員原子。單環雜芳基環可含有5至8個成員原子（碳數和雜原子）。雜芳基的實例包括但不限於噻吩基、呋喃基、咪唑基、異惡唑基、惡唑基、吡唑基、吡咯基、噻唑基、噻二唑基、***基、吡啶基、噠嗪基、吲哚基、氮雜吲哚基、吲唑基、苯並咪唑基、苯並呋喃基、苯並咪唑基、苯並呋喃基、苯並噻吩基、苯並異惡唑基、苯並惡唑基、苯並吡唑基、苯並噻唑基、苯並噻二唑基、苯並***基腺嘌呤基、喹啉基或異喹啉基。The term "heteroaryl" as used herein, unless otherwise indicated, denotes an aromatic ring system containing carbon and at least one hetero atom. Heteroaryl groups can be monocyclic or polycyclic, substituted or unsubstituted. The monocyclic heteroaryl group may have 1 to 4 hetero atoms in the ring, and the polycyclic heteroaryl group may have 1 to 10 hetero atoms. The polycyclic heteroaryl ring may contain a fused ring, a spiro ring or a bridged ring, for example, the cycloheteroaryl group is a polycyclic heteroaryl group. The bicyclic heteroaryl ring may contain from 8 to 12 member atoms. The monocyclic heteroaryl ring may contain from 5 to 8 member atoms (carbon number and hetero atom). Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, fluorene Azinyl, fluorenyl, azaindole, carbazolyl, benzimidazolyl, benzofuranyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzene And oxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adenyl, quinolinyl or isoquinolyl.

術語「環烷基」是指取代或未取代的單環、雙環或多環非芳族的飽和環，任選地包括或者不包括連接環烷基的亞烷基連接子。例如「環烷基」基團包括但不限於環丙基、環丁基、環戊基、環己基等。The term "cycloalkyl" refers to a substituted or unsubstituted monocyclic, bicyclic or polycyclic non-aromatic saturated ring, optionally including or not including an alkylene linker to which a cycloalkyl group is attached. For example, "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

術語「羰基、=O或氧代」是指基團。The term "carbonyl, =O or oxo" refers to a group .

術語「烷基」、「芳基」或者作為前綴詞根出現在取代基的名稱中（例如芳烷基或二烷基胺基），均應被解釋為包括上面對「烷基」和「芳基」給出的那些限制。碳原子數（例如，Cl-6 ）應獨立地指烷基的碳原子數，烷基作為較大取代基詞前綴詞根時，碳原子數是指烷基部分的碳原子數。The terms "alkyl", "aryl" or as a prefix root in the name of a substituent (eg aralkyl or dialkylamino) are to be construed as including the above "alkyl" and "aryl" Those given by the base. The number of carbon atoms (for example, C l-6 ) should independently refer to the number of carbon atoms of the alkyl group, and when the alkyl group is the prefix of the larger substituent, the number of carbon atoms means the number of carbon atoms of the alkyl moiety.

本發明所用的術語「組合物」旨在涵蓋包含特定量的特定成分的產品，以及直接或間接由特定量的特定成分的組合產生的任何產品。因此，含有本發明化合物作為活性成分的藥物組合物以及製備本發明化合物的方法也是本發明的一部分。此外，化合物的一些結晶形式可以以多晶型形式存在，並且因此意圖包括在本發明中。此外，一些化合物可以與水（即水合物）或普通有機溶劑形成溶劑化物，且這樣的溶劑合物也意圖包括在本發明的範圍內。The term "composition" as used in the present invention is intended to encompass a product comprising a particular amount of a particular ingredient, as well as any product that is produced, directly or indirectly, from a particular amount of a particular combination of ingredients. Accordingly, pharmaceutical compositions containing the compounds of the invention as active ingredients and methods of preparing the compounds of the invention are also part of the invention. Furthermore, some crystalline forms of the compounds may exist in polymorphic form and are therefore intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be included within the scope of the invention.

本發明的化合物也可以以藥學上可接受的鹽的形式存在。為了用於藥物，本發明化合物的鹽指無毒的「藥學上可接受的鹽」。藥學上可接受的鹽的形式包括藥學上可接受的酸性/陰離子或鹼性/陽離子鹽。藥學上可接受的酸性/陰離子鹽通常採取鹼性氮被無機酸或有機酸質子化的形式。代表性的有機酸或無機酸包括鹽酸、氫溴酸、氫碘酸、過氯酸、硫酸、硝酸、磷酸、乙酸、丙酸、乙醇酸、乳酸、琥珀酸、馬來酸、富馬酸、蘋果酸、酒石酸、檸檬酸、苯甲酸、杏仁酸、甲磺酸、羥基乙磺酸、苯磺酸、草酸、撲酸、2-萘磺酸、對甲苯磺酸、環己烷胺磺酸、水楊酸、醣酸或三氟乙酸。 藥學上可接受的鹼性/陽離子鹽包括但不限於鋁、鈣、氯普魯卡因（Chloroprocaine）、膽鹼、二乙醇胺、乙二胺、鋰、鎂、鉀、鈉和鋅。The compounds of the invention may also exist in the form of a pharmaceutically acceptable salt. For use in medicine, the salts of the compounds of the invention refer to non-toxic "pharmaceutically acceptable salts." The form of the pharmaceutically acceptable salt includes a pharmaceutically acceptable acidic/anionic or basic/cationic salt. Pharmaceutically acceptable acidic/anionic salts typically take the form of a basic nitrogen protonated by an inorganic or organic acid. Representative organic or inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid, Malic acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, oxalic acid, pamoic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfonic acid, Salicylic acid, sugar acid or trifluoroacetic acid. Pharmaceutically acceptable basic/cationic salts include, but are not limited to, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium, and zinc.

本發明在其範圍內包括本發明化合物的前驅藥。一般而言，這樣的前驅藥是本發明化合物的功能性衍生物，其容易在體內轉化成所需的化合物。因此，在本發明的治療方法中，術語「給藥」應包括用具體揭露的化合物或者可能沒有具體揭露的化合物，但可以於體內施用後將其轉化為特定化合物並治療所描述的各種病症。用於選擇和製備合適的前驅藥衍生物的常規方法描述於例如「Design of Prodrugs」，ed. H. Bundgaard，Elsevier，1985。The invention includes within its scope prodrugs of the compounds of the invention. In general, such prodrugs are functional derivatives of the compounds of the invention which are readily converted in vivo to the desired compound. Thus, in the methods of treatment of the present invention, the term "administering" shall include the use of a specifically disclosed compound or a compound that may not be specifically disclosed, but may be converted to a particular compound after administration in vivo and to treat the various conditions described. Conventional methods for the selection and preparation of suitable precursor derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

本發明中，分子中特定位置的任何取代基或變量的定義與該分子中其他地方的定義無關。應該理解的是，本發明所闡述的化合物上的取代基和取代形式可以由本領域技術人員選擇，以提供化學穩定的並且可以透過本領域習知的技術以及本發明提供的那些方法方便地合成該化合物。In the present invention, the definition of any substituent or variable at a particular position in a molecule is independent of the definition elsewhere in the molecule. It will be understood that the substituents and substituted forms on the compounds set forth herein can be selected by those skilled in the art to provide chemical stability and can be conveniently synthesized by techniques well known in the art and those provided by the present invention. Compound.

本發明包括所述的化合物可以含有一個或多個不對稱中心，並因此可以產生非鏡像異構物和旋光異構體。本發明包括所有這些可能的非鏡像異構物以及它們的外消旋混合物，它們的基本上純的經解析的鏡像異構物，所有可能的幾何異構體及其藥學上可接受的鹽。The present invention encompasses that the compounds described may contain one or more asymmetric centers and may therefore produce non-image isomers and optical isomers. The present invention includes all such possible non-image areomers as well as their racemic mixtures, their substantially pure resolved mirror image isomers, all possible geometric isomers and their pharmaceutically acceptable salts.

上面的式I是以在某些位置沒有明確的立體化學來顯示。本發明包括式I的所有立體異構物及其藥學上可接受的鹽。此外，還包括立體異構物的混合物以及分離的特定立體異構物。在用於製備這些化合物的合成方法過程中，或在使用本領域技術人員已知的外消旋化或差向異構化方法的過程中，此類方法的產物可以是立體異構物的混合物。Formula I above is shown without explicit stereochemistry at certain locations. The present invention includes all stereoisomers of formula I and pharmaceutically acceptable salts thereof. In addition, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. The product of such a process may be a mixture of stereoisomers during the synthetic process used to prepare these compounds, or during the use of racemization or epimerization processes known to those skilled in the art. .

當式（I）化合物的互變異構物存在時，除非另有特別說明，本發明包括任何可能的互變異構物和其藥學上可接受的鹽，以及其混合物。When tautomers of the compounds of formula (I) are present, the invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, unless specifically stated otherwise.

當式（I）化合物及其藥學上可接受的鹽以溶劑化物或多晶型形式存在時，本發明包括任何可能的溶劑合物和多晶型形式。形成溶劑化物的溶劑的種類沒有特別限制，只要溶劑在藥理學上可接受即可。例如，可以使用水，乙醇，丙醇，丙酮等。When the compound of formula (I) and its pharmaceutically acceptable salts exist in solvated or polymorphic form, the invention includes any possible solvate and polymorphic forms. The kind of the solvent forming the solvate is not particularly limited as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone, or the like can be used.

術語「藥學上可接受的鹽」是指由藥學上可接受的無毒鹼或酸製備的鹽。 當本發明化合物為酸性時，其相應的鹽可以方便地由藥學上可接受的無毒鹼（包括無機鹼和有機鹼）製備。當本發明化合物為鹼性時，其相應的鹽可以方便地由 藥學上可接受的無毒酸（包括無機酸和有機酸）製備。由於式（I）化合物用意在於藥物用途，因此它們優選以基本上純的形式提供，例如純度為至少60％，更適合地純度為至少75％，特別地純度為至少98％（％為基於重量）。The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids. Since the compounds of the formula (I) are intended for pharmaceutical use, they are preferably provided in substantially pure form, for example having a purity of at least 60%, more suitably a purity of at least 75%, in particular a purity of at least 98% (% by weight) ).

本發明的藥物組合物包含由式I表示的化合物（或其藥學上可接受的鹽）作為活性成分，藥學上可接受的載體和任選的其它治療成分或佐劑。儘管在任何給定情況下最合適的途徑將取決於具體的主體（host）及活性成份被用於治療的疾病的性質和嚴重程度，但該組合物包括適合於口服、直腸、局部及腸胃外（包括皮下、肌內及靜脈內）給藥的組合物。藥物組合物可以方便地以固定劑量的劑型存在並且通過藥學領域中習知的任何方法製備。The pharmaceutical composition of the present invention comprises, as an active ingredient, a compound represented by Formula I (or a pharmaceutically acceptable salt thereof), a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants. Although the most appropriate route in any given case will depend on the nature and severity of the particular host and the active ingredient being treated, the composition includes those suitable for oral, rectal, topical and parenteral administration. Compositions (including subcutaneous, intramuscular, and intravenous) administration. The pharmaceutical compositions may conveniently be presented in a fixed dosage form and may be prepared by any methods known in the art of pharmacy.

實踐中，根據常規的藥物製備工藝，本發明的由式I表示的化合物或其前驅藥或代謝物或其藥學上可接受的鹽可以作為活性成分與藥物載體結合。載體可以採取多種形式，其取決於給藥所需的製劑形式，例如口服或腸胃外（包括靜脈內）。因此，本發明的藥物組合物可以作為適合於口服給藥的固定劑量的製劑存在，例如膠囊、扁囊劑或片劑，各自含有固定量的活性成分。此外，組合物可以作為粉末形式，顆粒形式，溶液形式，水性液體中的混懸液，非水性液體，水包油乳液或油包水液體乳劑。除了上面列出的常見劑型之外，由式I表示的化合物或其藥學上可接受的鹽還可以通過控釋裝置和/或遞送裝置給藥。該組合物可以通過任何藥學方法製備。一般而言，這些方法包括使活性成分與構成一種或多種必需成分的載體結合的步驟。一般而言，組合物通過將活性成分與液體載體或細碎的固體載體或同時與兩種載體均勻且緊密地混合來製備。然後可以將產品方便地塑形成所需的形式。In practice, a compound represented by Formula I of the present invention or a prodrug or metabolite thereof, or a pharmaceutically acceptable salt thereof, of the present invention may be combined as an active ingredient with a pharmaceutical carrier according to a conventional pharmaceutical preparation process. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, such as oral or parenteral (including intravenous). Accordingly, the pharmaceutical compositions of the present invention may be presented as a fixed dose preparation suitable for oral administration, such as capsules, cachets or tablets, each containing a fixed amount of active ingredient. Further, the composition may be in the form of a powder, a granule, a solution, a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. In addition to the common dosage forms listed above, the compound represented by Formula I, or a pharmaceutically acceptable salt thereof, can also be administered by a controlled release device and/or delivery device. The composition can be prepared by any of the methods of pharmacy. In general, these methods comprise the step of bringing into association the active ingredient with carriers which comprise one or more essential ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both carriers. The product can then be conveniently molded into the desired form.

因此，本發明的藥物組合物可以包括藥學上可接受的載體和式I的化合物或藥學上可接受的鹽。式I化合物或其藥學上可接受的鹽還可以與一種或多種其他治療活性化合物組合包含在藥物組合物中。Accordingly, the pharmaceutical compositions of the present invention may comprise a pharmaceutically acceptable carrier and a compound of formula I or a pharmaceutically acceptable salt. The compound of formula I, or a pharmaceutically acceptable salt thereof, may also be included in the pharmaceutical composition in combination with one or more other therapeutically active compounds.

所用的藥物載體例如可以是固體、液體或氣體。固體載體的實例包括乳糖、白土、蔗糖、滑石粉、明膠、瓊脂、果膠、***膠、硬脂酸鎂及硬脂酸。液體載體的實例是糖漿、花生油、橄欖油及水。氣體載體的例子包括二氧化碳及氮氣。在製備用於口服劑型的組合物時，可以使用任何便利的藥物介質。例如，可以使用水、乙二醇、油、乙醇、調味劑、防腐劑、著色劑等來形成口服液體製劑，例如混懸液、酏劑及溶液；而載體如澱粉、糖、微晶纖維素、稀釋劑、成粒劑、潤滑劑、黏合劑、崩解劑等可用於形成口服固體製劑如粉末、膠囊及片劑。由於其易於給藥的性質，片劑和膠囊在使用固體藥物載體時是優選的口服劑量單位。任選地，片劑可以通過標準水性或非水性技術進行包衣。The pharmaceutical carrier used can be, for example, a solid, a liquid or a gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water. Examples of gaseous carriers include carbon dioxide and nitrogen. When preparing a composition for oral dosage forms, any convenient pharmaceutical medium can be used. For example, water, glycol, oil, ethanol, flavoring agents, preservatives, coloring agents, and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; and carriers such as starch, sugar, microcrystalline cellulose , diluents, granulating agents, lubricants, binders, disintegrating agents and the like can be used to form oral solid preparations such as powders, capsules and tablets. Tablets and capsules are preferred oral dosage units when using solid pharmaceutical carriers due to their ease of administration. Optionally, the tablets can be coated by standard aqueous or non-aqueous techniques.

含有本發明組合物的片劑可以通過壓製或模製來製備，任選地與一種或多種輔助成分或助劑一起製備。壓製片劑可以通過在合適的機器中壓製自由流動形式如粉末或顆粒的活性成分來製備，且任選地與黏合劑、潤滑劑、惰性稀釋劑、表面活性劑或分散劑混合來製備。模製片劑可以通過在合適的機器中模製以惰性液體稀釋劑潤濕的粉狀化合物的混合物來製備。每片優選含有約0.05mg至約5g的活性成分，每個扁囊劑或膠囊優選含有約0.05mg至約5g的活性成分。例如，用以人類口服給藥的製劑可含有約0.5mg至約5g的活性劑，與合適和方便量的載體材料混合，所述載體材料可在總組合物的約5％至約95％之間變化。固定劑量的劑型通常含有約1mg至約2g的活性成分，通常為25mg、50mg、100mg、200mg、300mg、400mg、500mg、600mg、800mg或1000mg。Tablets containing the compositions of the invention may be prepared by compression or molding, optionally together with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing the active ingredient in a suitable liquid such as a powder or granules in a suitable machine, and optionally mixed with a binder, a lubricant, an inert diluent, a surfactant or a dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05 mg to about 5 g of active ingredient, and each cachet or capsule preferably contains from about 0.05 mg to about 5 g of active ingredient. For example, a formulation for oral administration to humans may contain from about 0.5 mg to about 5 g of the active agent, in admixture with a suitable and convenient amount of carrier material, which may be from about 5% to about 95% of the total composition. Change between. A fixed dose dosage form will generally contain from about 1 mg to about 2 g of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

適用於腸胃外給藥的本發明藥物組合物可以製備成活性化合物在水中的溶液或混懸液。可以包含合適的表面活性劑，例如羥丙基纖維素。分散液也可以在甘油、液體聚乙二醇及其在油中的混合物中製備。此外，可以包含防腐劑以防止微生物的有害生長。Pharmaceutical compositions of the invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compound in water. A suitable surfactant such as hydroxypropylcellulose can be included. The dispersion can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. In addition, preservatives may be included to prevent the harmful growth of microorganisms.

適於注射使用的本發明藥物組合物包括無菌水溶液或分散液。此外，組合物可以是用於臨時製備這種無菌可注射溶液或分散液的無菌粉末形式。在所有情況下，最終的注射形式必須是無菌的，並且必須是有效的液體，以便於注射。藥物組合物在製造和儲存條件下必須穩定；因此保存時優選應該防止微生物如細菌和真菌的污染作用。載體可以是含有例如水、乙醇、多元醇（例如甘油、丙二醇和液體聚乙二醇）、植物油及其合適的混合物的溶劑或分散介質。Pharmaceutical compositions of the invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the composition may be in the form of a sterile powder for the temporary preparation of such sterile injectable solutions or dispersions. In all cases, the final form of injection must be sterile and must be an effective liquid to facilitate injection. The pharmaceutical composition must be stable under the conditions of manufacture and storage; therefore, it should preferably be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.

本發明的藥物組合物可以呈適合於局部使用的形式，例如氣霧劑，乳膏，軟膏，洗劑，散布劑等。這些製劑可以通過常規加工方法利用本發明式I代表的化合物或其藥學上可接受的鹽來製備。舉例而言，藉由混合親水性材料和水以及約5重量％至約10重量％的化合物來製備乳膏或軟膏，以產生具有所需稠度的乳膏或軟膏。The pharmaceutical composition of the present invention may be in a form suitable for topical use, such as an aerosol, cream, ointment, lotion, dispersion, and the like. These preparations can be produced by a conventional processing method using the compound represented by the formula I of the present invention or a pharmaceutically acceptable salt thereof. For example, a cream or ointment is prepared by mixing a hydrophilic material and water and from about 5% to about 10% by weight of the compound to produce a cream or ointment having the desired consistency.

本發明的藥物組合物可以是適於直腸給藥的形式，其中載體是固體。優選混合物形成固定劑量的栓劑。合適的載體包括可可脂和本領域常用的其它材料。栓劑可以藉由先將組合物與軟化或熔化的載體混合然後在模具中冷卻和成型而方便地形成。The pharmaceutical composition of the invention may be in a form suitable for rectal administration wherein the carrier is a solid. Preferably the mixture forms a fixed dose of suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently formed by first mixing the composition with a softened or melted carrier and then cooling and shaping in a mold.

除了上述載體成分之外，上述藥物製劑可以視情況而定地包括一種或多種額外的載體成分，例如稀釋劑、緩沖劑、調味劑、黏合劑、表面活性劑、增稠劑、潤滑劑、防腐劑（包括抗氧化劑）等等。此外，可以包含其他佐劑以使製劑與預期接受者的血液等張。含有由式I描述的化合物或其藥學上可接受的鹽的組合物也可以以粉末或液體濃縮物形式製備。In addition to the above carrier components, the above pharmaceutical preparations may optionally include one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, and preservatives. Agents (including antioxidants) and so on. In addition, other adjuvants may be included to make the formulation isotonic with the blood of the intended recipient. Compositions containing a compound described by Formula I, or a pharmaceutically acceptable salt thereof, may also be prepared in the form of a powder or liquid concentrate.

一般而言，每天約0.01mg / kg至約150mg / kg體重的劑量水平可用於治療上述病症，或者可選地每天每名患者約0.5mg至約7g。例如，發炎、癌症、牛皮癬、過敏反應/哮喘、免疫系統的疾病和病症、中樞神經系統（CNS）的疾病和病症可以通過施用約0.01至50mg的化合物（每千克體重/每天）來治療，或者可選地每天每名患者約0.5mg至約3.5g。In general, a dosage level of from about 0.01 mg / kg to about 150 mg / kg body weight per day can be used to treat the above conditions, or alternatively from about 0.5 mg to about 7 g per patient per day. For example, inflammation, cancer, psoriasis, allergic reactions/asthma, diseases and conditions of the immune system, diseases and conditions of the central nervous system (CNS) can be treated by administering about 0.01 to 50 mg of the compound (per kilogram body weight per day), or Optionally, from about 0.5 mg to about 3.5 g per patient per day.

然而，應理解的是，對於任何特定患者的具體劑量水平將取決於多種因素，包括年齡、體重、一般健康狀況、性別、飲食、給藥時間、給藥途徑、***速率、藥物組合以及正在進行治療的特定疾病的嚴重程度。However, it should be understood that the specific dosage level for any particular patient will depend on a variety of factors including age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, combination of drugs, and ongoing The severity of the particular disease being treated.

從以下對本發明的書面描述中，上述部分和其他方面將變得更清楚。The above and other aspects will become more apparent from the written description of the invention.

下列實施例可以對此專利做進一步的闡釋，除非有明確說明，否則本說明書中提及的百分比都是指質量百分比，溫度都是指攝氏。實施例中使用的試劑縮寫如下： DAST：二乙胺基三氟化硫 DCM：二氯甲烷 DIEA：二異丙基乙胺 DMF：N,N-二甲基甲醯胺 DMSO：二甲基亞碸 EA：乙酸乙酯 EtOH：乙醇 NMP：N-甲基吡咯烷酮 TEA：三乙胺 THF：四氫呋喃 TFA：三氟乙酸 Pd2 (dba)3 ：三(二亞苄基丙酮)二鈀 Xantphos：4,5-雙(二苯基膦)-9,9-二甲基氧蒽 min：分鐘 rt or RT：室溫 TLC：薄層色譜法 Pre-TLC：薄層色譜法製備The following examples are further illustrative of this patent, and unless otherwise stated, the percentages referred to in this specification are by mass and the temperatures are in degrees Celsius. The reagents used in the examples are abbreviated as follows: DAST: diethylaminosulfur trifluoride DCM: dichloromethane DIEA: diisopropylethylamine DMF: N,N-dimethylformamide DMSO: dimethyl碸EA: ethyl acetate EtOH: ethanol NMP: N-methylpyrrolidone TEA: triethylamine THF: tetrahydrofuran TFA: trifluoroacetic acid Pd 2 (dba) 3 : tris(dibenzylideneacetone) dipalladium Xantphos: 4, 5-bis(diphenylphosphino)-9,9-dimethyloxanium min: minute rt or RT: room temperature TLC: thin layer chromatography Pre-TLC: preparation by thin layer chromatography

實例1 化合物1的合成 Example 1 Synthesis of Compound 1

4-羥基-2-氧雜-8-氮雜螺[4.5]癸烷-8-羧酸叔丁酯（WO 2004078750）（173.46 g，0.67 mol）溶於DCM（1L），10℃加入Dess-Martin氧化劑（573.34 g， 1.35 mol）。攪拌3 h。反應液用飽和Na2 CO3 :Na2 S2 O3 =1:1（1000 mL）淬滅。混合物矽藻土過濾。濾液分液。有機相鹽水洗（300 mL），無水硫酸鈉乾燥，過濾減壓濃縮得到化合物1a （112.61 g, 65.43%）。4-Hydroxy-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (WO 2004078750) (173.46 g, 0.67 mol) dissolved in DCM (1 L), 10 ° C added to Dess- Martin oxidizing agent (573.34 g, 1.35 mol). Stir for 3 h. The reaction was washed with saturated Na 2 CO 3: Na 2 S 2 O 3 = 1: 1 (1000 mL) and quenched. The mixture was filtered through Celite. The filtrate was separated. The organic phase was washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 1a (112.61 g, 65.43%) .

化合物1a （570 g，2.23 mol）溶於THF（3 L），25 ℃加入 (R)-叔丁基亞磺醯胺（540 g，4.46 mol），鈦酸四乙酯（2.54 Kg，11.13 mol）。混合物加熱至60 ℃攪拌10 h。-50℃分批加入硼氫化鈉（220 g，5.82 mol）。混合物升溫至25 ℃攪拌10 h。混合物過濾，用飽和氯化銨溶液（1 L）淬滅。收集有機相，鹽水洗（500 mL），無水硫酸鈉乾燥，過濾濃縮，殘餘物柱層析純化得到化合物1b （285 g，35.40%）。Compound 1a (570 g, 2.23 mol) was dissolved in THF (3 L), and (R)-tert-butylsulfinamide (540 g, 4.46 mol), tetraethyl titanate (2.54 Kg, 11.13 mol) was added at 25 °C. ). The mixture was heated to 60 ° C and stirred for 10 h. Sodium borohydride (220 g, 5.82 mol) was added portionwise at -50 °C. The mixture was warmed to 25 ° C and stirred for 10 h. The mixture was filtered and quenched with saturated aqueous ammonium chloride (1 L). The organic phase was collected, washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography to give compound 1b (285 g, 35.40%) .

1-溴-2-氯-3硝基苯（36.61 g，154.83 mmol），鐵粉（43.35 g，774.16 mmol），氯化銨（8.28 g，154.83 mmol），乙醇（100 mL）和水（50 mL）混合，加熱到60℃反應4小時，然後體系冷卻至10℃。反應液矽藻土過濾，濾液減壓濃縮除去乙醇。剩餘水溶液EA萃取（100 mL×2）。合併有機相，鹽水洗（100 mL），無水硫酸鈉乾燥，減壓濃縮得化合物1c （30.01 g，93.88%）。MS: 206 (M+H)+ 。1-Bromo-2-chloro-3-nitrobenzene (36.61 g, 154.83 mmol), iron powder (43.35 g, 774.16 mmol), ammonium chloride (8.28 g, 154.83 mmol), ethanol (100 mL) and water (50 Mix in mL), heat to 60 ° C for 4 hours, then cool the system to 10 ° C. The reaction liquid was filtered through Celite, and the filtrate was concentrated under reduced pressure to remove ethanol. The remaining aqueous solution was extracted with EA (100 mL x 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 1c (30.01 g, 93.88%) . MS: 206 (M+H) + .

化合物1c （30.00 g，0.15 mol），3-巰基丙酸甲酯（27.60 g，0.23 mol），Pd2 (dba)3 （1.37 g, 1.5 mmol）, Xantphos（1.73 g, 3.00 mmol）, DIEA （38.75 g, 0.30 mol）加入1,4-二氧六環（200 mL）中，氮氣保護，95℃攪拌18小時。反應完全後，反應液減壓濃縮，殘餘物柱層析純化得到化合物1d （10.00 g，27.13%）。MS: 246 (M+H)+ 。Compound 1c (30.00 g, 0.15 mol), methyl 3-mercaptopropionate (27.60 g, 0.23 mol), Pd 2 (dba) 3 (1.37 g, 1.5 mmol), Xantphos (1.73 g, 3.00 mmol), DIEA ( 38.75 g, 0.30 mol) was added to 1,4-dioxane (200 mL). After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the residue was purified by column chromatography to give compound 1d (10.00 g, 27.13%) . MS: 246 (M+H) + .

金屬鈉（1.22 g，52.90 mmol）加入乙醇（25 mL）中，控溫20℃以下攪拌至鈉塊完全溶解。體系降溫至-30℃~-20℃，滴入化合物1d （10.00g，40.70 mmol）的THF（30 mL）溶液。反應液20℃攪拌3.5小時，減壓濃縮。殘留物加水（50 mL），EA萃取（50 mL×2）。水相1mol/L鹽酸溶液調節pH=2~3，EA萃取（50 mL×2）。合併有機相，鹽水洗（50 mL），無水硫酸鈉乾燥，過濾減壓濃縮得化合物1e （6.02 g，92.66%）。MS: 160 (M+H)+ 。Sodium metal (1.22 g, 52.90 mmol) was added to ethanol (25 mL), and the temperature was kept below 20 ° C until the sodium block was completely dissolved. The system was cooled to -30 ° C to -20 ° C, and a solution of compound 1d (10.00 g, 40.70 mmol) in THF (30 mL) was added dropwise. The reaction solution was stirred at 20 ° C for 3.5 hours and concentrated under reduced pressure. The residue was taken up in water (50 mL) and EtOAc (50 mL×2). The aqueous phase 1mol/L hydrochloric acid solution was adjusted to pH=2~3, and EA was extracted (50 mL×2). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 1e (6.02 g, 92.66%) . MS: 160 (M+H) + .

化合物1e （6.02 g，37.71 mol），2-胺基-3-溴-6-氯吡嗪（7.86 g，37.71 mol），Pd2 (dba)3 （0.35 g，0.38 mmol），Xantphos（0.43g,0.75 mmol），DIEA （9.74 g，75.42 mmol）加入1,4-二氧六環（70 mL）中，氮氣保護，95℃攪拌17小時。反應完全後，反應液過濾，濾液減壓濃縮，殘留物加EA（50 mL）攪拌0.5小時，過濾得化合物1f （8.45 g，78.03%）。MS: 287 (M+H)+ 。Compound 1e (6.02 g, 37.71 mol), 2-amino-3-bromo-6-chloropyrazine (7.86 g, 37.71 mol), Pd 2 (dba) 3 (0.35 g, 0.38 mmol), Xantphos (0.43 g) , 0.75 mmol), DIEA (9.74 g, 75.42 mmol) was added to 1,4-dioxane (70 mL). After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was added EA (50 mL) was stirred for 0.5 hours, filtered to give compound 1f (8.45 g, 78.03%) . MS: 287 (M+H) + .

化合物1f （0.81 g，2.82 mmol），(R)-2-甲基-N-((S)-2-氧雜-8-氮雜螺[4.5]癸烷-4-基)丙烷-2-亞磺醯胺（TFA鹽，1.26 g，3.38 mmol），碳酸鉀（1.17 g，8.46 mmol）和NMP（10 mL）的混合物130℃攪拌14小時。冷卻至室溫，加入EA（100 mL），水洗（30 mL），有機相無水硫酸鈉乾燥，過濾，濾液濃縮，殘餘物柱層析純化得到化合物1g （0.55 g，38%）。MS:511(M+H)+ 。Compound 1f (0.81 g, 2.82 mmol), (R)-2-methyl-N-((S)-2-oxa-8-azaspiro[4.5]decane-4-yl)propane-2- A mixture of sulfinamide (TFA salt, 1.26 g, 3.38 mmol), potassium carbonate (1.17 g, 8.46 mmol) and NMP (10 mL) was stirred at <RTIgt; Cooled to room temperature, EA (100 mL), washed with water (30 mL), the organic phase dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, the residue was purified by column chromatography to give compound 1g (0.55 g, 38%) . MS: 511 (M+H) + .

草醯氯滴加到N,N-二甲基草氨酸（0.26 g，2.15 mmol）的DCM（10 mL）溶液中，室溫攪拌2小時。反應液減壓濃縮，殘留物溶於DCM（10 mL），滴加到化合物1g （0.55 g，1.08 mmol）的DCM（10 mL）的溶液中，反應完全後，反應液加冰水（20 mL）淬滅，鹽水洗，無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘餘物柱層析純化得到化合物1h （0.42 g，64%）。MS:610(M+H)+ 。To the solution of N,N-dimethyloxaline (0.26 g, 2.15 mmol) in DCM (10 mL) A solution of DCM (10 mL) the reaction mixture was concentrated under reduced pressure, the residue was dissolved in DCM (10 mL), was added dropwise Compound 1g (0.55 g, 1.08 mmol), the reaction was completed, the reaction solution was ice water (20 mL ) quenched, brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography to give compound 1h (0.42 g, 64%) . MS: 610 (M+H) + .

化合物1h （0.41 g，0.67 mmol）溶於10 mL DCM，加入HCl/1,4-二氧六環(5 mL，4M)溶液，40℃攪拌20min。反應液冷卻至室溫，加入1M鹽酸水溶液，水相DCM萃取。氨水（28%）調節水相pH至12，DCM萃取（20 mL×3）。合併有機相，鹽水洗，無水硫酸鈉乾燥，過濾，減壓濃縮，殘餘物柱層析純化得到化合物1 （100 mg，32%）。MS:506(M+H)+ 。1 HNMR(DMSO-d6,400MHz):δ7.63(s,1H),7.43-7.45(d,1H),7.21-7.23(d,1H),6.50-6.52(d,1H),6.11(s,1H),4.00-4.05(m,4H),3.93-3.96(dd,2H),2.93-3.29(m,4H),1.54-1.98(m,4H)。Compound 1h (0.41 g, 0.67 mmol) was dissolved in 10 mL DCM, EtOAc EtOAc EtOAc EtOAc The reaction solution was cooled to room temperature, then aq. Ammonia (28%) adjusted the pH of the aqueous phase to 12 and DCM (20 mL x 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, the residue was purified by column chromatography to give compound 1 (100 mg, 32%) . MS: 506 (M+H) + . 1 H NMR (DMSO-d6, 400 MHz): δ 7.63 (s, 1H), 7.43-7.45 (d, 1H), 7.21-7.23 (d, 1H), 6.50-6.52 (d, 1H), 6.11 (s, 1H), 4.00-4.05 (m, 4H), 3.93-3.96 (dd, 2H), 2.93-3.29 (m, 4H), 1.54-1.98 (m, 4H).

實例2 化合物2的合成 Example 2 Synthesis of Compound 2

2-胺基-3-溴-6-氯吡嗪（20.02 g，96.05 mmol），3-巰基丙酸甲酯（11.53 g，96.05 mmol），DIEA（24.83 g，192.10 mmol），Pd(OAc)2 （0.30 g，1.34 mmol），Xantphos（2.78 g, 4.8 mmol）加入1,4-二氧六環（200 mL）中，氮氣保護，95℃攪拌18小時。反應完全後，反應液過濾，濾液減壓濃縮，殘餘物柱層析純化得到化合物2a （18.83 g，79%）。MS: 246 (M+H)+ 。2-Amino-3-bromo-6-chloropyrazine (20.02 g, 96.05 mmol), methyl 3-mercaptopropionate (11.53 g, 96.05 mmol), DIEA (24.83 g, 192.10 mmol), Pd (OAc) 2 (0.30 g, 1.34 mmol), Xantphos (2.78 g, 4.8 mmol) was added to 1,4-dioxane (200 mL). After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography to give compound 2a (18.83 g, 79%) . MS: 246 (M+H) + .

化合物2a （18.33 g，76.02 mmol）溶於150 mL THF，降溫至-30℃，滴加乙醇鈉（6.72 g，98.82 mmol）的乙醇（100 mL）溶液，反應液-30℃攪拌1小時，然後升溫至25℃，攪拌2小時。反應液減壓濃縮，殘留物分散於DCM（100 mL）中，過濾得棕色固體化合物2b （13.82 g，99%）。MS: 162(M+H)+ 。Compound 2a (18.33 g, 76.02 mmol) was dissolved in 150 mL of THF, cooled to -30 ° C, and a solution of sodium ethoxide (6.72 g, 98.82 mmol) in ethanol (100 mL) was added dropwise, and the mixture was stirred at -30 ° C for 1 hour, then The temperature was raised to 25 ° C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was dispersed in DCM (100 mL) and filtered to give a brown solid Compound 2b (13.82 g, 99%) . MS: 162 (M+H) + .

化合物2b （9.98 g，54.36 mmol），2-胺基-3-氯-4-碘吡啶（13.83 g，54.36 mmol），DIEA（14.04 g，108.72 mmol），Pd2 (dba)3 （1.00 g，1.09 mmol）, Xantphos（1.00 g，1.73 mmol）加入 1,4-二氧六環（200 mL）中，氮氣保護，95℃攪拌18小時。反應完全後，反應液過濾，濾液減壓濃縮，殘留物分散於DCM（100 mL）中，過濾得棕色固體化合物2c （14.62 g，93.72%）。MS: 288(M+H)+ 。Compound 2b (9.98 g, 54.36 mmol), 2-amino-3-chloro-4-iodopyridine (13.83 g, 54.36 mmol), DIEA (14.04 g, 108.72 mmol), Pd 2 (dba) 3 (1.00 g, 1.09 mmol), Xantphos (1.00 g, 1.73 mmol) was added to 1,4-dioxane (200 mL). After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was dispersed in DCM (100 mL) and filtered to give a brown solid Compound 2c (14.62 g, 93.72%) . MS: 288 (M+H) + .

化合物2c （2.31 g，8.05 mmol），(4-甲基哌啶-4-基)胺基甲酸叔丁酯（3.45 g，16.10 mmol），DIEA（3.12 g，24.15 mmol）的DMSO（50 mL）溶液100℃攪拌3小時。反應液中加入水（100 mL），過濾得棕色固體化合物2d （2.19 g，58%）。MS: 466(M+H)+ 。Compound 2c (2.31 g, 8.05 mmol), (4-methylpiperidin-4-yl)carbamic acid tert-butyl ester (3.45 g, 16.10 mmol), DIEA (3.12 g, 24.15 mmol) in DMSO (50 mL) The solution was stirred at 100 ° C for 3 hours. Water (100 mL) was added to the reaction mixture, and then filtered to give a white solid compound 2d (21.9 g, 58%). MS: 466 (M+H) + .

N,N-二甲基草氨酸（350 mg，3 mmol），DMF（2滴）溶於DCM（10 mL），滴加草醯氯（760 mg，6 mmol）。混合物20℃攪拌1小時。反應液減壓濃縮，殘留物溶於DCM（10 mL），滴加到化合物2d （460 mg，1 mmol）與三乙胺（1 mL）的DCM（10 mL）溶液中。反應完全後，反應液減壓濃縮，殘留物Pre-TLC純化得黃色固體化合物2e （142 mg，25%）。MS: 565(M+H)+ 。N,N-Dimethyloxaine (350 mg, 3 mmol), DMF (2 drops) was dissolved in DCM (10 mL) and EtOAc ( EtOAc (EtOAc) The mixture was stirred at 20 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in DCM (10 mL), was added dropwise the compound 2d (460 mg, 1 mmol) and triethylamine (1 mL) in DCM (10 mL) solution. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the residue was purified by Pre-TLC to give a yellow solid compound 2e (142 mg, 25%) . MS: 565 (M+H) + .

化合物2e （142 mg，0.25 mmol）加到HCl/1,4-二氧六環溶液中（10 mL，4M），攪拌1小時，過濾得棕色固體化合物2 （70 mg，60%）。MS: 465(M+H)+ 。1 HNMR(DMSO-d6,400MHz): δ 8.45-8.35 (m,2H), 8.06 (s, 1H), 7.71 (s, 1H), 6.45 (s, 1H), 4.06 (s, 6H), 3.38 (t, 2H), 2.93 (t, 2H), 2.86 (s, 2H), 1.84-1.71 (m, 4H), 1.39 (s, 3H)。Compound 2e (142 mg, 0.25 mmol) was added HCl / 1,4- dioxane solution (10 mL, 4M), stirred for 1 hour, the brown solid was filtered to give compound 2 (70 mg, 60%) . MS: 465 (M+H) + . 1 H NMR (DMSO-d6, 400 MHz): δ 8.45-8.35 (m, 2H), 8.06 (s, 1H), 7.71 (s, 1H), 6.45 (s, 1H), 4.06 (s, 6H), 3.38 ( t, 2H), 2.93 (t, 2H), 2.86 (s, 2H), 1.84-1.71 (m, 4H), 1.39 (s, 3H).

實例3 化合物3的合成 Example 3 Synthesis of Compound 3

對乙醯基苯甲酸甲酯（7.01 g，40.00 mmol），二氧化硒（8.95 g，80.00 mmol）吡啶（50 mL）混合，100℃反應4小時。鹽酸（70 mL，1M）調節反應液pH=3，水相EA（70 mL）萃取。有機相無水硫酸鈉乾燥，減壓濃縮得棕色固體化合物3a （6.12 g，74%）。MS: m/z 207(M-H)- 。Methyl acetoxybenzoate (7.01 g, 40.00 mmol), selenium dioxide (8.95 g, 80.00 mmol) in pyridine (50 mL) was mixed and reacted at 100 ° C for 4 hours. Hydrochloric acid (70 mL, 1 M) was adjusted to pH = 3 and aqueous phase EA (70 mL) was extracted. The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a brown solid Compound 3a (6.12 g, 74%) . MS: m/z 207 (MH) - .

化合物3a （2.51 g，12.07 mmol）、DMF（2滴）溶於DCM（30 mL），滴加草醯氯（15 mL）。反應液20℃攪拌1小時。反應液減壓濃縮，殘餘物溶於DCM（10 mL），滴加到二甲胺/THF（10 mL，2M）溶液中。反應完全後，反應液減壓濃縮得棕色固體化合物3b （2.35 g，83%）。MS: 236(M+H)+ 。Compound 3a (2.51 g, 12.07 mmol), DMF (2 mL) was dissolved in DCM (30 mL). The reaction solution was stirred at 20 ° C for 1 hour. The reaction mixture was concentrated under reduced EtOAc. After completion of the reaction, the reaction solution was concentrated under reduced pressure to give a brown solid compound 3b (2.35 g, 83%) . MS: 236 (M+H) + .

化合物3b （0.91 g，4.11 mmol），氫氧化鋰一水合物（0.85 g，20.55 mmol），水（10 mL）加入到甲醇（50 mL）中，混合物25℃攪拌1小時。反應液減壓濃縮，殘餘物加鹽酸水溶液（25 mL，1M），EA萃取（20 mL×2）。合併有機相，鹽水洗（50 mL），無水硫酸鈉乾燥，過濾，濾液減壓濃縮得棕色固體化合物3c （0.85 g，93%）。MS: 222(M+H)+ 。Compound 3b (0.91 g, 4.11 mmol), lithium hydroxide monohydrate (0.85 g, 20.55 mmol), water (10 mL) was added to methanol (50 mL), and the mixture was stirred at 25 ° C for 1 hour. The reaction mixture was concentrated under reduced vacuo. The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a brown solid compound 3c (0.85 g, 93%) . MS: 222 (M+H) + .

化合物3c （0.85 g，3.85 mmol）、DMF（2滴）溶於DCM（10 mL），滴加草醯氯（8 mL）。反應液20℃攪拌1小時。反應液減壓濃縮，殘餘物溶於DCM（10 mL）中，然後加入到 (1-(6-胺基-5-((3-胺基-2-氯苯基)硫代)吡嗪-2-基)-4-甲基哌啶-4-基)胺基甲酸叔丁酯（200 mg，0.43 mmol）與DIEA（5 mL）的DCM（10 mL）溶液中。反應完後，反應液減壓濃縮，殘留物Pre-TLC純化得黃色固體化合物3d （170 mg，57%）。MS: 668(M+H)+ 。Compound 3c (0.85 g, 3.85 mmol), DMF (2 mL) was dissolved in DCM (10 mL). The reaction solution was stirred at 20 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAc m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m A solution of tert-butyl 2-methyl)-4-methylpiperidin-4-yl)carbamate (200 mg, 0.43 mmol) eluted elute After the reaction, the reaction mixture was concentrated under reduced pressure, the residue was purified by Pre-TLC to give a yellow solid compound 3d (170 mg, 57%) . MS: 668 (M+H) + .

化合物3d （170 mg，0.24 mmol）加到HCl/1,4-二氧六環溶液中（1 mL，4M），反應液25℃，攪拌1小時，過濾得粗品（107 mg）。粗品Pre-TLC純化得棕色固體化合物3 （35 mg, 24%）。MS: 568(M+H)+ 。1 HNMR(DMSO-d6, 400MHz): δ 10.44 (s, 1H), 8.39 (s, 1H), 8.18 (d, 2H), 8.02 (d, 2H), 7.68 (s, 1H), 7.36 (d, 1H), 7.26 (t, 1H), 6.58 (d, 1H), 6.18 (s, 1H), 4.03 (d, 2H), 3.37 (d, 2H), 3.04 (s, 3H), 2.90 (s, 3H), 1.83-1.71 (m, 4H), 1.39 (s, 3H)。Compound 3d (170 mg, 0.24 mmol) was added HCl / 1,4- dioxane solution (1 mL, 4M), the reaction solution 25 ℃, stirred for 1 hour and filtered to give crude product (107 mg). The crude Pre-TLC was purified to give a brown solid compound 3 (35 mg, 24%). MS: 568 (M+H) + . 1 H NMR (DMSO-d6, 400 MHz): δ 10.44 (s, 1H), 8.39 (s, 1H), 8.18 (d, 2H), 8.02 (d, 2H), 7.68 (s, 1H), 7.36 (d, 1H), 7.26 (t, 1H), 6.58 (d, 1H), 6.18 (s, 1H), 4.03 (d, 2H), 3.37 (d, 2H), 3.04 (s, 3H), 2.90 (s, 3H) ), 1.83-1.71 (m, 4H), 1.39 (s, 3H).

實例4 化合物4的合成 Example 4 Synthesis of Compound 4

2-胺基-4-溴苯酚（10.15 g，54.29 mmol），氯乙醯氯（7.35 g，65.15 mmol）溶於150 mL DCM中，冷卻至0℃，滴入DIEA（35.06 g，271.45 mmol）。反應液20℃攪拌5小時。減壓濃縮，殘留物加水（70 mL），析出固體，過濾得紅色固體化合物4a （7.61 g，62%）。MS: 228(M+H)+ 。2-Amino-4-bromophenol (10.15 g, 54.29 mmol), chloroethyl hydrazine chloride (7.35 g, 65.15 mmol) dissolved in 150 mL DCM, cooled to 0 ° C, dropwise, DIEA (35.06 g, 271.45 mmol) . The reaction solution was stirred at 20 ° C for 5 hours. The organic layer was concentrated under reduced pressure. EtOAc (EtOAc) MS: 228 (M+H) + .

化合物4a （7.51 g，33.09 mmol），3-巰基丙酸甲酯（5.16 g，43.02 mmol），DIEA （8.55 g，62.18 mmol）， Pd2 (dba)3 （0.40 g, 0.44 mmol）， Xantphos （0.40 g，0.69 mmol）加入 1,4-二氧六環（100 mL）中，氮氣保護，反應液100℃攪拌8小時。反應液過濾，濾液減壓濃縮，殘餘物柱層析純化得到化合物4b （5.12 g，58%）。MS: 268(M+H)+ 。Compound 4a (7.51 g, 33.09 mmol), methyl 3-mercaptopropionate (5.16 g, 43.02 mmol), DIEA (8.55 g, 62.18 mmol), Pd 2 (dba) 3 (0.40 g, 0.44 mmol), Xantphos ( 0.40 g, 0.69 mmol) was added to 1,4-dioxane (100 mL), and the mixture was stirred under nitrogen, and the mixture was stirred at 100 ° C for 8 hours. The reaction was filtered, the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography to give compound 4b (5.12 g, 58%) . MS: 268 (M+H) + .

化合物4b （3.75 g，14.04 mmol）溶於THF（50 mL），冷卻至-70℃，滴加叔丁醇鉀/THF溶液（28 mL，28.00 mmol），反應液-70℃攪拌0.5小時。加入鹽酸水溶液（15 mL，1mol/L），EA萃取（20 mL×2），合併有機相，鹽水洗（50 mL），無水硫酸鈉乾燥，過濾，濾液減壓濃縮得紅色固體化合物4c （1.57g，62%）。MS: 182(M+H)+ 。Compound 4b (3.75 g, 14.04 mmol) was dissolved in THF (50 mL), cooled to -70 ° C, and a solution of potassium t-butoxide/THF (28 mL, 28.00 mmol) was added dropwise and the mixture was stirred at -70 ° C for 0.5 hour. Was added aqueous hydrochloric acid (15 mL, 1mol / L) , EA extraction (20 mL × 2), the combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a red solid Compound 4c (1.57 g, 62%). MS: 182 (M+H) + .

化合物4c （3.22 g，17.79 mmol），2-胺基-3-溴-6-氯吡嗪（3.68 g，17.79 mmol），DIEA（4.60 g，35.58 mmol），Pd2 (dba)3 （0.15 g，0.16 mmol），Xantphos（0.15 g，0.26 mmol）加到1,4-二氧六環（30 mL）中，氮氣保護，100℃攪拌18小時。反應液過濾，濾液減壓濃縮，殘留物分散到正己烷（10 mL）和乙酸乙酯（10 mL）中，過濾得棕色固體化合物4d （2.88 g，52%）。MS: 309(M+H)+ 。Compound 4c (3.22 g, 17.79 mmol), 2-amino-3-bromo-6-chloropyrazine (3.68 g, 17.79 mmol), DIEA (4.60 g, 35.58 mmol), Pd 2 (dba) 3 (0.15 g , 0.16 mmol), Xantphos (0.15 g, 0.26 mmol) was added to 1,4-dioxane (30 mL). The reaction was filtered, the filtrate was concentrated under reduced pressure, the residue was dispersed in n-hexane (10 mL) and ethyl acetate (10 mL) and filtered to give a brown solid Compound 4d (2.88 g, 52%) . MS: 309 (M+H) + .

化合物4d （0.35 g，1.13 mmol）， ((4-甲基哌啶-4-基)甲基)胺基甲酸叔丁酯（0.39 g，1.70 mmol），DIEA（0.36 g，2.83 mmol）加到DMSO（10 mL）中， 100℃攪拌2小時。反應液加入水（10 mL），EA萃取（10 mL×2），合併有機相，鹽水洗（50 mL），無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘餘物柱層析純化得到化合物4e （0.15 g，27%）。MS: 501(M+H)+ 。Compound 4d (0.35 g, 1.13 mmol), tert-butyl ((4-methylpiperidin-4-yl)methyl)carbamate (0.39 g, 1.70 mmol), DIEA (0.36 g, 2. The mixture was stirred at 100 ° C for 2 hours in DMSO (10 mL). The reaction solution was added water (10 mL), EA extraction (10 mL × 2), the combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography to give compound 4e (0.15 g, 27%). MS: 501 (M+H) + .

化合物4e （150 mg，0.30 mmol）加到HCl/1,4-二氧六環溶液（1 mL，4 M）中，反應液25℃攪拌1h，過濾得白色固體化合物4 （60 mg，50%）。MS: 401 (M+H)+ 。1 HNMR(DMSO-d6, 400MHz): δ7.5 (s, 1H), 6.87 (d, 1H), 6.75 (d, 1H), 6.73 (s, 1H), 6.00 (s, 1H),4.52 (s, 2H), 3.78-3.74 (m, 2H), 3.30-3.27 (m, 2H), 2.39 (s, 2H), 1.43-1.39 (m, 2H), 1.27-1.25 (m,2H), 0.91 (s, 3H)。Compound 4e (150 mg, 0.30 mmol) was added HCl / 1,4- dioxane (1 mL, 4 M), and the reaction was stirred for 25 IH deg.] C, and filtered to give a white solid compound 4 (60 mg, 50% ). MS: 401 (M+H) + . 1 H NMR (DMSO-d6, 400 MHz): δ 7.5 (s, 1H), 6.87 (d, 1H), 6.75 (d, 1H), 6.73 (s, 1H), 6.00 (s, 1H), 4.52 (s , 2H), 3.78-3.74 (m, 2H), 3.30-3.27 (m, 2H), 2.39 (s, 2H), 1.43-1.39 (m, 2H), 1.27-1.25 (m, 2H), 0.91 (s , 3H).

實例5 化合物5的合成 Example 5 Synthesis of Compound 5

化合物4a （3.33 g，14.67 mmol），聯硼酸頻那醇酯（4.48 g，17.61 mmol），醋酸鉀（2.88 g，29.34 mmol），Pd(dppf)Cl2 （0.15 g，0.20 mmol）加到1,4-二氧六環（40 mL）中，氮氣保護，100℃攪拌24小時。反應液過濾，濾液減壓濃縮，殘餘物柱層析純化得到化合物5a （2.25 g，56%）。MS: 276(M+H)+ 。Compound 4a (3.33 g, 14.67 mmol), pinacol borate (4.48 g, 17.61 mmol), potassium acetate (2.88 g, 29.34 mmol), Pd(dppf)Cl 2 (0.15 g, 0.20 mmol) In a 4-dioxane (40 mL), nitrogen was applied and stirred at 100 ° C for 24 hours. The reaction was filtered, the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography to give compound 5a (2.25 g, 56%) . MS: 276 (M+H) + .

化合物5a （2.20 g，8.00 mmol），2-胺基-3-溴-6-氯吡嗪（1.54 g，7.27 mmol），醋酸鉀（2.00 g，14.54 mmol），Pd(dppf)Cl2 （0.15 g，0.20 mmol），水（2 mL）加到1,4-二氧六環（40 mL）中，氮氣保護，75℃攪拌4小時。反應液冷卻至室溫，加入正己烷（50 mL），過濾得棕色固體化合物5b （0.79 g，36%）。MS: 277(M+H)+ 。Compound 5a (2.20 g, 8.00 mmol), 2-amino-3-bromo-6-chloropyrazine (1.54 g, 7.27 mmol), potassium acetate (2.00 g, 14.54 mmol), Pd (dppf) Cl 2 (0.15 g, 0.20 mmol), water (2 mL) was added to 1,4-dioxane (40 mL). The reaction was cooled to room temperature, hexane (50 mL), filtered to give a brown solid compound 5b (0.79 g, 36%) . MS: 277 (M+H) + .

化合物5b （230 mg，0.83 mmol），((4-甲基哌啶-4-基)甲基)胺基甲酸叔丁酯（0.29 g，1.25 mmol），DIEA（0.43 g，3.33 mmol）加到DMSO（10 mL）中， 100℃攪拌18小時。反應液加入水（20 mL），EA萃取（20 mL×2），合併有機相，鹽水洗（20 mL），無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘餘物柱層析純化得到化合物5c （157 mg，40%）。MS: 469(M+H)+ 。Compound 5b (230 mg, 0.83 mmol), ((4-methylpiperidin-4-yl)methyl)carbamic acid tert-butyl ester (0.29 g, 1.25 mmol), DIEA (0.43 g, 3.33 mmol) The mixture was stirred at 100 ° C for 18 hours in DMSO (10 mL). The reaction solution was added water (20 mL), EA extraction (20 mL × 2), the combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography to give Compound 5c (157 mg, 40%). MS: 469 (M+H) + .

化合物5c （150 mg，0.34 mmol）加到HCl/1,4-二氧六環溶液（1 mL，4mol/L）中，反應液25℃攪拌1小時，過濾得棕色固體化合物5 （72 mg，56%）。MS: 369 (M+H)+ 。1 HNMR(DMSO-d6, 400MHz): δ 7.55 (s, 1H), 7.21 (d, 1H), 7.17 (d, 1H), 7.15 (d, 1H), 4.57 (s, 2H), 3.77 (t, 2H), 3.30 (t, 2H), 2.73 (s, 2H), 1.53-1.38 (m, 4H), 1.07 (s, 3H)。Compound 5c (150 mg, 0.34 mmol) was added to HCl / 1,4-dioxane solution (1 mL, 4 mol/L), and the mixture was stirred at 25 ° C for 1 hour, and filtered to give a brown solid compound 5 (72 mg, 56%). MS: 369 (M+H) + . 1 H NMR (DMSO-d6, 400 MHz): δ 7.55 (s, 1H), 7.21 (d, 1H), 7.17 (d, 1H), 7.15 (d, 1H), 4.57 (s, 2H), 3.77 (t, 2H), 3.30 (t, 2H), 2.73 (s, 2H), 1.53-1.38 (m, 4H), 1.07 (s, 3H).

實例6 化合物6的合成 Example 6 Synthesis of Compound 6

化合物2c （80 mg，0.28 mmol）溶於NMP（5 mL），加熱到160℃，加入8-胺基-2-氮雜螺[4.5]癸烷-2-甲酸叔丁酯（190 mg，0.75 mmol），反應液160℃攪拌1.5小時。反應液冷卻，加入水（40 mL），EA萃取（20 mL×2），合併有機相，鹽水洗（30 mL），無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘餘物Pre-TLC得化合物6a （15 mg，10.59%）。MS:506 (M+H)+ 。Compound 2c (80 mg, 0.28 mmol) was dissolved in NMP (5 mL), then taken to &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&& (mmol), the reaction solution was stirred at 160 ° C for 1.5 hours. The reaction mixture was cooled, water (40 mL), EtOAc (EtOAc (EtOAc) 6a (15 mg, 10.59%). MS: 506 (M+H) + .

化合物6a （39 mg，0.08 mmol）溶於1,4-二氧六環（2 mL），然後加入HCl/1,4-二氧六環溶液（1 mL，4mol/L），反應液20℃攪拌1小時。反應液減壓濃縮，殘餘物加EA（5 mL）攪拌5分鐘，過濾得化合物6 （30 mg，84.76%，鹽酸鹽）。MS: 203.7 (M+2H)2+ 。Compound 6a (39 mg, 0.08 mmol) was dissolved in 1,4-dioxane (2 mL), then HCl/1,4-dioxane solution (1 mL, 4 mol/L) was added. Stir for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was added EA (5 mL) was stirred for 5 minutes and filtered to give compound 6 (30 mg, 84.76%, HCl salt). MS: 203.7 (M+2H) 2+ .

實例7 化合物7的合成 Example 7 Synthesis of Compound 7

化合物8a （24.00 g，81.34 mmol）溶於THF（100 mL），冰浴下，滴加BH3 /THF (290 mL，1M)，滴畢，自然恢復至室溫，攪拌1小時，TLC顯示反應完全。0℃反應液用10%的檸檬酸水溶液（50 mL）淬滅，加水（200 mL），EA萃取（200 mL×2），有機相鹽水洗（200 mL×2），無水硫酸鈉乾燥，過濾，濾液減壓濃縮至約300 mL，化合物7b 不經純化直接用於下一步。MS: 282(M+H)+ 。Compound 8a (24.00 g, 81.34 mmol) was dissolved in THF (100 mL), under ice-bath was added dropwise BH 3 / THF (290 mL, 1M), dropwise, naturally returned to room temperature, stirred for 1 h, TLC showed the reaction complete. The reaction mixture was quenched with 10% aqueous citric acid (50 mL), water (200 mL), EA (200 mL×2), washed with brine (200 mL×2), dried over anhydrous sodium sulfate The filtrate was concentrated under reduced pressure to ca. 300 mL. Compound 7b was used in the next step without purification. MS: 282 (M+H) + .

化合物7b 的EA溶液降溫至0℃，加入DIEA（19 mL，161.71 mmol），滴入乙醯氯（12 mL，169.68 mmol）。反應完全後，反應液加水（100 mL），分液，水相EA萃取（50 mL），合併有機相，鹽水洗（200 mL×2），無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘餘物加入80 mL（EA:Hex=1:10）溶液打漿得化合物7c （21.30 g，81.0%）。MS: 324(M+H)+ 。The EA solution of Compound 7b was cooled to 0.degree. C., DIEA (19 mL, 161.71 mmol) was added, and ethyl acetate (12 mL, 169.68 mmol) was added dropwise. After the reaction was completed, the reaction solution was added with water (100 mL), and the mixture was evaporated. EtOAc (EtOAc) The compound was slurried by adding 80 mL (EA: Hex = 1:10) solution to give compound 7c (21.30 g, 81.0%). MS: 324 (M+H) + .

化合物7c （10.00 g，30.95 mmol），3-胺基-5-氯吡嗪-2-硫鈉鹽（6.28 g，34.21 mmol），Pd2 (dba)3 （1.40 g，1.55 mmol）， Xantphos（1.80 g, 3.11 mmol），DIEA（8.00 g，62.13 mmol）加到1,4-二氧六環（120 mL）中，氮氣保護，70℃攪拌5小時。反應液冷卻至室溫，過濾，濾液減壓濃縮，殘留物加入EA（50 mL）打漿，過濾得化合物7d （9.92 g，89.8%）。MS: 357 (M+H)+ 。Compound 7c (10.00 g, 30.95 mmol), 3-amino-5-chloropyrazine-2-thiosodium salt (6.28 g, 34.21 mmol), Pd 2 (dba) 3 (1.40 g, 1.55 mmol), Xantphos ( 1.80 g, 3.11 mmol), DIEA (8.00 g, 62.13 mmol) was added to 1,4-dioxane (120 mL). The reaction was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, the residue was added EA (50 mL) was filtered to obtain compound 7d (9.92 g, 89.8%) . MS: 357 (M+H) + .

化合物1b （508 mg，1.41 mmol）溶於DCM（5 mL），加入TFA（1 mL），室溫攪拌1小時，反應液減壓濃縮，殘餘物加NMP（5 mL），K2 CO3 （0.81 g, 5.86 mmol），攪拌5 min，加入化合物7d （250 mg，0.70 mmol）。75℃加熱2小時，冷卻，減壓濃縮，殘餘物柱層析純化得到化合物7e （84 mg，20.7%）。MS:581(M+H)+ 。Compound 1b (508 mg, 1.41 mmol) was dissolved in DCM (5 mL), was added TFA (1 mL), stirred for 1 hour at room temperature, the reaction solution was concentrated under reduced pressure, the residue was added NMP (5 mL), K 2 CO 3 ( 0.81 g, 5.86 mmol), stirred for 5 min, compound 7d (250 mg, 0.70 mmol). 75 deg.] C for 2 hours, cooled, concentrated under reduced pressure, the residue was purified by column chromatography to give Compound 7e (84 mg, 20.7%) . MS: 581 (M+H) + .

化合物7e （185 mg，0.32 mmol）溶於1,4-二氧六環（3 mL）中，加入HCl/1,4-二氧六環溶液（1.2 mL，4M）。反應液室溫攪拌，反應完全後，減壓濃縮，殘留物EA（5 mL）打漿得化合物7 （136 mg，82.8%，鹽酸鹽）。MS: 477 (M+H)+ 。Compound 7e (185 mg, 0.32 mmol) was dissolved in 1,4-dioxane (3 mL). The reaction was stirred at room temperature. After completion of the reaction, concentrated under reduced pressure, the residue EA (5 mL) to give a compound of beating 7 (136 mg, 82.8%, HCl salt). MS: 477 (M+H) + .

實施例8 化合物8的合成 Example 8 Synthesis of Compound 8

4-碘靛紅（Journal of Medicinal Chemistry, 47(4), 935-946; 2004）（2.31 g，8.46 mmol），DAST（4.10 g，25.43 mmol）和DCM（100 mL）的混合，室溫攪拌24h，加入碳酸氫鈉溶液淬滅，過濾得到粗品，正己烷淋洗得到化合物8a （2.14 g，86%）。 MS: 294(M-H)+ 。Mixture of 4-iodopurine (Journal of Medicinal Chemistry, 47(4), 935-946; 2004) (2.31 g, 8.46 mmol), DAST (4.10 g, 25.43 mmol) and DCM (100 mL), stirring at room temperature 24h, quenched with sodium bicarbonate solution and filtered to give the crude product, n-hexane elution to give compound 8a (2.14 g, 86%) . MS: 294 (MH) + .

化合物8a （1.01 g， 3.42 mmol），Pd2 (dba)3 （100 mg， 0.34 mmol），Xantphos （100 mg，0.34 mmol），DIEA（883 mg，6.84 mmol），1,4-二氧六環（30 mL）混合，氮氣保護，反應液80℃攪拌30分鐘。加入3-胺基-5-氯吡嗪-2-硫鈉鹽（628mg， 3.42 mmol），氮氣保護，80℃攪拌3h。反應液冷卻，減壓濃縮，殘餘物柱層析純化得到化合物8b （545 mg，48%）。 MS: 329(M+H)+ 。Compound 8a (1.01 g, 3.42 mmol), Pd 2 (dba) 3 (100 mg, 0.34 mmol), Xantphos (100 mg, 0.34 mmol), DIEA (883 mg, 6.84 mmol), 1,4-dioxane (30 mL) was mixed, nitrogen-protected, and the reaction mixture was stirred at 80 ° C for 30 minutes. 3-Amino-5-chloropyrazine-2-sulfuric sodium salt (628 mg, 3.42 mmol) was added, and then evaporated. The reaction solution was cooled, concentrated under reduced pressure, the residue was purified by column chromatography to give Compound 8b (545 mg, 48%) . MS: 329 (M+H) + .

化合物1b （1.18 g，3.27 mmol），TFA（5 mL），DCM（20 mL）混合，室溫攪拌2h。減壓濃縮。殘餘物加化合物8b （542 mg，1.65 mmol），碳酸鉀（1.82g，13.20 mmol）和 NMP (12 mL)，80℃攪拌10h。加水（40 mL）淬滅，EA萃取（5×30 mL），合併有機相，飽和食鹽水洗（100 mL），無水硫酸鈉乾燥，過濾，減壓濃縮。殘餘物柱層析純化得到化合物8c （138 mg，15%）。 MS: 553(M+H)+ 。Compound 1b (1.18 g, 3.27 mmol), EtOAc (EtOAc) Concentrate under reduced pressure. The residue was added Compound 8b (542 mg, 1.65 mmol) , potassium carbonate (1.82g, 13.20 mmol) and NMP (12 mL), stirred for 10h 80 ℃. The mixture was stirred with EtOAc (EtOAc)EtOAc. The residue was purified by column chromatography to afford compound 8c (138 mg, 15%). MS: 553 (M+H) + .

化合物8c （138 mg，0.25 mmol）溶於1,4-二氧六環（3 mL），加入HCl/1,4-二氧六環溶液（0.5 mL，4M），室溫下攪拌0.5h，反應液減壓濃縮。殘餘物分散於EA（10 mL）中，過濾得到黃色固體化合物8 （6 mg，5.4%，鹽酸鹽）。MS: 449(M+H)+ 。Compound 8c (138 mg, 0.25 mmol) was dissolved in 1,4-dioxane (3 mL). The reaction solution was concentrated under reduced pressure. The residue was dispersed in EA (10 mL) and filtered to give a yellow solid Compound 8 (6 mg, 5.4%, HCl salt). MS: 449 (M+H) + .

實施例9 化合物9的合成 Example 9 Synthesis of Compound 9

鋅粉（8.64 g，132.13 mmol），四氯化鈦（12.60 g，66.42 mmol）加到THF（100 mL）中，80℃攪拌2h，冷卻到室溫，氮氣保護下滴入4-溴靛紅（5.01 g，22.16 mmol）的THF（100 mL）溶液。反應完全後，加入鹽酸（100 mL，3M），混合物DCM萃取（50 mL×3），合併有機相，飽和食鹽水洗（50 mL×2），無水硫酸鈉乾燥，過濾，減壓濃縮。殘餘物柱層析純化得到化合物9a （2.63 g，56.0%）。MS: 212(M+H)+ 。Zinc powder (8.64 g, 132.13 mmol), titanium tetrachloride (12.60 g, 66.42 mmol) was added to THF (100 mL), stirred at 80 ° C for 2 h, cooled to room temperature, and added with 4-bromo ruthenium under nitrogen. (5.01 g, 22.16 mmol) in THF (100 mL). After the reaction was completed, hydrochloric acid (100 mL, 3M) was evaporated. The residue was purified by column chromatography to afford compound 9a (2.63 g, 56.0%). MS: 212 (M+H) + .

化合物9a （1.00 g，4.72 mmol），3-巰基丙酸甲脂（1.13 g，9.40 mmol），Pd2 (dba)3 （0.15 g，0.16 mmol），Xantphos （0.20 g，0.35 mmol），DIEA（1.23 g， 9.52 mmol）加到1,4-二氧六環（25 mL）中，氮氣保護，100℃攪拌過夜。減壓濃縮，殘餘物柱層析純化得到化合物9b （0.73 g，61.5%）。MS: 252(M+H)+ 。Compound 9a (1.00 g, 4.72 mmol), 3-mercaptopropionic acid methyl ester (1.13 g, 9.40 mmol), Pd 2 (dba) 3 (0.15 g, 0.16 mmol), Xantphos (0.20 g, 0.35 mmol), DIEA ( 1.23 g, 9.52 mmol) was added to 1,4-dioxane (25 mL). Concentrated under reduced pressure, the residue was purified by column chromatography to give Compound 9b (0.73 g, 61.5%) . MS: 252 (M+H) + .

化合物9b （1.65 g，6.56 mmol）的THF（50 mL）溶液冷卻至-70℃，滴加叔丁醇鉀/THF（15 mL，1M）。反應完全後，加鹽酸（20 mL，1M）淬滅，EA萃取（50 mL×3），有機相合併，飽和食鹽水（100 mL×2）洗，無水硫酸鈉乾燥，過濾，減壓濃縮得到化合物9c （1.08 g，100%）不經純化直投下一步。MS: 166 (M+H)+ 。A solution of compound 9b (1.65 g, 6.56 mmol) in THF (50 mL) EtOAc. After the reaction was completed, the mixture was diluted with EtOAc (EtOAc EtOAc (EtOAc) Compound 9c (1.08 g, 100%) was taken directly to the next step without purification. MS: 166 (M+H) + .

化合物9c （1.0 g，6.54 mmol），2-胺基-3-溴-4-氯吡嗪（1.37 g，6.57 mmol）， Pd2 (dba)3 （0.31 g，0.34 mmol），Xantphos（0.40 g，0.69 mmol）和 DIEA（1.70 g， 13.16 mmol）加到 1,4-二氧六環（80 mL）中，氮氣保護，100℃攪拌5h。反應液冷卻至室溫，過濾，減壓濃縮，殘餘物柱層析純化得到化合物9d （0.53 g， 27.7%）。MS: 293 (M+H)+ 。Compound 9c (1.0 g, 6.54 mmol), 2-amino-3-bromo-4-chloropyrazine (1.37 g, 6.57 mmol), Pd 2 (dba) 3 (0.31 g, 0.34 mmol), Xantphos (0.40 g) , 0.69 mmol) and DIEA (1.70 g, 13.16 mmol) were added to 1,4-dioxane (80 mL). The reaction was cooled to room temperature, filtered, and concentrated under reduced pressure, the residue was purified by column chromatography to give Compound 9d (0.53 g, 27.7%) . MS: 293 (M+H) + .

化合物9d （146 mg，0.50 mmol），(4-甲基哌啶-4-基)甲基胺基甲酸叔丁酯（240 mg，1.05 mmol）和DIEA（203 mg，1.57 mmol）的DMSO（5 mL）溶液80℃攪拌。反應完全後，冷卻至室溫，加水（20 mL），EA萃取（20 mL×2），有機相合併，飽和食鹽水洗（50 mL×2），無水硫酸鈉乾燥，過濾。濾液減壓濃縮，殘餘物柱層析純化得到化合物9e （99 mg，40.8 %）。MS: 485(M+H)+ 。Compound 9d (146 mg, 0.50 mmol), (4-methylpiperidin-4-yl)methylcarbamic acid tert-butyl ester (240 mg, 1.05 mmol) and DIEA (203 mg, 1.57 mmol) in DMSO (5) The mL) solution was stirred at 80 °C. After the reaction was completed, it was cooled to room temperature, water (20 mL), EtOAc (20 mL×2), EtOAc. The filtrate was concentrated under reduced pressure, the residue was purified by column chromatography to give compound 9e (99 mg, 40.8%) . MS: 485 (M+H) + .

室溫下向化合物9e （24 mg, 0.049 mmol）的DCM（5 mL）溶液中通入鹽酸氣。反應完全後，加水（20 mL），EA洗（20 mL×2）。水相調節pH=11， DCM萃取（20 mL×2），無水硫酸鈉乾燥，過濾，減壓濃縮得到化合物9 （16 mg，84.9%）。MS: 385(M+H)+ 。Hydrochloric acid gas was introduced into a solution of compound 9e (24 mg, 0.049 mmol) in DCM (5 mL). After the reaction was completed, water (20 mL) was added and EA was washed (20 mL×2). The aqueous phase was adjusted pH = 11, DCM extraction (20 mL × 2), dried over anhydrous sodium sulfate, filtered, to give Compound 9 (16 mg, 84.9%) and concentrated under reduced pressure. MS: 385 (M+H) + .

實施例10化合物10的合成 Synthesis of Compound 10 of Example 10

2-氟-4-碘吡啶（10.00 g，43.50 mmol）和氨水（10 mL）的DMSO（20 mL）溶液100℃攪拌40h。反應液中加入水（100 mL），析出固體，過濾得到棕色固體化合物10a （8.62 g，90%）。MS: 221 (M+H)+ 。A solution of 2-fluoro-4-iodopyridine (10.00 g, 43.50 mmol) and aqueous ammonia (10 mL) in EtOAc (20 mL). The reaction mixture was added water (100 mL), the precipitated solid was filtered to give a brown solid Compound 10a (8.62 g, 90%) . MS: 221 (M+H) + .

-5°C下向化合物10a （8.00 g， 36.36 mmol），二氟溴乙酸乙酯（18.46 g，90.91 mmol）和二茂鐵（0.68 g，3.64 mmol）的DMSO（70 mL）混合液中滴入H2 O2 （8 mL）。25℃攪拌24h。反應液加入H2 O（100 mL），EA萃取（100 mL×2）。合併有機相，飽和食鹽水洗（50 mL），無水硫酸鈉乾燥，過濾，減壓濃縮。殘餘物柱層析純化得到黃色固體化合物10b （3.41 g，32%）。MS: 297(M+H)+ 。To a mixture of compound 10a (8.00 g, 36.36 mmol), ethyl difluorobromoacetate (18.46 g, 90.91 mmol) and ferrocene (0.68 g, 3.64 mmol) in DMSO (70 mL) at -5 °C Into H 2 O 2 (8 mL). Stir at 25 ° C for 24 h. The reaction solution was added with H 2 O (100 mL) and extracted with EA (100 mL×2). The combined organic layers were washed with EtOAcq. The residue was purified by column chromatography to give a yellow solid Compound 10b (3.41 g, 32%) . MS: 297 (M+H) + .

化合物10b （1.48 g，5.00 mmol），3-胺基-5-氯吡嗪-2-硫鈉鹽（0.92 g, 5.00 mmol），DIEA（1.29 g，10.00 mmol），Pd2 (dba)3 （0.15 g，0.16 mmol），Xantphos（0.15 g，0.26 mmol）加到1,4-二氧六環（20 mL）中，氮氣保護，反應液 95℃攪拌18h。反應液過濾，濾液減壓濃縮，殘餘物柱層析純化得到化合物10c （0.59 g，36%）。MS: 330(M+H)+ 。Compound 10b (1.48 g, 5.00 mmol), 3-amino-5-chloropyrazine-2-thiosodium salt (0.92 g, 5.00 mmol), DIEA (1.29 g, 10.00 mmol), Pd 2 (dba) 3 ( 0.15 g, 0.16 mmol), Xantphos (0.15 g, 0.26 mmol) was added to 1,4-dioxane (20 mL). The reaction was filtered, the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography to give compound 10c (0.59 g, 36%) . MS: 330 (M+H) + .

化合物1b （361 mg，1.00 mmol），TFA（1 mL）的 DCM（5 mL）混合液25℃攪拌1h。反應液減壓濃縮，殘餘物溶於NMP（8 mL），加入化合物10c （330 mg，1.00 mmol）, 碳酸鉀（1.10 g， 8.00 mmol），80℃攪拌1h。反應液過濾，濾液濃縮，殘餘物Pre-TLC得到化合物10d （80 mg，14%）。 MS: 554(M+H)+ 。A mixture of compound 1b (361 mg, 1.00 mmol), EtOAc (1 mL) The reaction solution was concentrated under reduced pressure, the residue was dissolved in NMP (8 mL), was added Compound 10c (330 mg, 1.00 mmol) , potassium carbonate (1.10 g, 8.00 mmol), 80 ℃ stirred for 1h. The reaction was filtered, the filtrate was concentrated, the residue was Pre-TLC to give compound 10d (80 mg, 14%) . MS: 554 (M+H) + .

化合物10d （80 mg，0.14 mmol）的DCM（10 mL）溶液中滴入HCl/1,4-二氧六環（1 mL，4M）。25℃攪拌1h。過濾得到棕色固體化合物10 （10 mg，16%）。MS: 450 (M+H)+ 。A solution of compound 10d (80 mg, 0.14 mmol) in EtOAc (EtOAc) Stir at 25 ° C for 1 h. Filtration gave compound 10 as a brown solid (10 mg, 16%). MS: 450 (M+H) + .

實施例11 化合物11的合成 Example 11 Synthesis of Compound 11

化合物8a （2.30 g，7.80 mmol），NaH（0.94 g，23.39 mmol，60%）加到DMF（30 mL）中，25℃攪拌0.5 h。加入碘甲烷（3.32 g，23.39 mmol），25℃攪拌1h。加入水（100 mL）淬滅，EA萃取（100 mL×2），合併有機相，飽和食鹽水洗（50 mL），無水硫酸鈉乾燥，過濾，減壓濃縮。殘餘物柱層析純化得到黃色固體化合物11a （1.10 g，46%）。 MS: 310(M+H)+ 。 化合物11a （1.10 g, 3.56 mmol），3-胺基-5-氯吡嗪-2-硫鈉鹽（0.65 g, 3.56 mmol），DIEA（0.92 g，7.12 mmol），Pd2 (dba)3 （0.10 g，0.11 mmol），Xantphos （0.10 g，0.18 mmol）加到1,4-二氧六環（30 mL）中，氮氣保護， 95℃攪拌18h。反應液減壓濃縮，殘餘物柱層析純化得到化合物11b （1.06 g，87%）。MS: 343(M+H)+ 。Compound 8a (2.30 g, 7.80 mmol), NaH (0.94 g, 23.39 mmol, 60%). Methyl iodide (3.32 g, 23.39 mmol) was added and stirred at 25 ° C for 1 h. After adding water (100 mL), EtOAc (EtOAc m. The residue was purified by column chromatography toield yellow solid compound 11a (1.10 g, 46%). MS: 310 (M+H) + . Compound 11a (1.10 g, 3.56 mmol), 3-amino-5-chloropyrazine-2-thiosodium salt (0.65 g, 3.56 mmol), DIEA (0.92 g, 7.12 mmol), Pd 2 (dba) 3 ( 0.10 g, 0.11 mmol), Xantphos (0.10 g, 0.18 mmol) was added to 1,4-dioxane (30 mL). The reaction mixture was concentrated under reduced pressure, the residue was purified by column chromatography to give Compound 11b (1.06 g, 87%) . MS: 343 (M+H) + .

化合物1b （200 mg，0.55 mmol），TFA（2 mL）的 DCM（10 mL）溶液25℃攪拌1h。反應液減壓濃縮。殘餘物溶於NMP（8 mL)，加入化合物11b （190 mg，0.55 mmol），碳酸鉀（613 mg，4.44 mmol），90℃攪拌24h。反應加水（50 mL），EA萃取（50 mL×3），合併有機相，飽和食鹽水洗（50 mL），無水硫酸鈉乾燥，過濾，減壓濃縮。殘餘物Pre-TLC純化得到黃色固體化合物11c （50 mg，16%）。 MS: 567(M+H)+ 。Compound 1b (200 mg, 0.55 mmol), EtOAc (EtOAc) The reaction solution was concentrated under reduced pressure. The residue was dissolved in NMP (8 mL), was added compound 11b (190 mg, 0.55 mmol) , potassium carbonate (613 mg, 4.44 mmol), 90 ℃ stirred for 24h. The reaction was combined with water (50 mL), EtOAc (EtOAc) The residue was purified by Pre-TLC toield of Compound 41c (50 mg, 16%). MS: 567 (M+H) + .

化合物11c （50 mg，0.14 mmol）的DCM（5 mL）溶液中滴加HCl/1,4-二氧六環（1 mL，4M）。25℃攪拌1h，反應液減壓濃縮。殘餘物Pre-TLC純化得到化合物11 （3 mg，7%）。MS: 463 (M+H)+ 。HCl/1,4-dioxane (1 mL, 4 M) was added dropwise to a solution of compound 11c (50 mg, 0.14 mmol). After stirring at 25 ° C for 1 h, the reaction solution was concentrated under reduced pressure. The residue was purified by Pre-TLC to give compound 11 (3 mg, 7%). MS: 463 (M+H) + .

實施例12 化合物12的合成 Example 12 Synthesis of Compound 12

4-碘靛紅（200 mg，0.73 mmol），3-胺基-5-氯吡嗪-2-硫鈉鹽（0.13 g，0.73mmol），Pd2 (dba)3 （20 mg，0.02 mmol），Xantphos（20 mg，0.035 mmol），DIEA（0.19 g，1.46 mmol）的 1,4-二氧六環（10 mL）溶液，氮氣保護，95℃攪拌2 h。反應完全後，減壓濃縮，殘餘物柱層析純化得到化合物12a （0.19g， 84.86%）。MS: 307 (M+H)+ 。4-iodopurine (200 mg, 0.73 mmol), 3-amino-5-chloropyrazine-2-thiosodium salt (0.13 g, 0.73 mmol), Pd 2 (dba) 3 (20 mg, 0.02 mmol) , Xantphos (20 mg, 0.035 mmol), DIEA (0.19 g, 1.46 mmol) in 1,4-dioxane (10 mL). After completion of the reaction, concentrated under reduced pressure, the residue was purified by column chromatography to give compound 12a (0.19g, 84.86%). MS: 307 (M+H) + .

化合物1b （0.28 g, 0.74 mmol），TFA（1 mL）的DCM（5 mL）溶液 20℃攪拌1h。減壓濃縮，殘餘物溶於DCM（10 mL），再次減壓濃縮。殘餘物加入碳酸鉀（0.68 g，4.96 mmol），化合物12a （0.19 g，0.62 mmol）和NMP（5 mL），80℃攪拌18 h。反應液冷卻至室溫，加水（40 mL），EA萃取（20 mL×2）。合併有機相，飽和食鹽水（30 mL）洗，無水硫酸鈉乾燥，過濾，減壓濃縮。殘餘物Pre-TLC純化得到化合物12b （18 mg, 5.47 %）。MS: 531 (M+H)+ 。Compound 1b (0.28 g, 0.74 mmol), EtOAc (1 mL) The mixture was concentrated under reduced vacuo. The residue was added potassium carbonate (0.68 g, 4.96 mmol), compound 12a (0.19 g, 0.62 mmol) and NMP (5 mL), stirred for 80 ℃ 18 h. The reaction solution was cooled to room temperature, added with water (40 mL) and EtOAc (20 mL×2). The combined organic layers were washed with EtOAc EtOAc. The residue was purified by Pre-TLC to give compound 12b (18 mg, 5.47 %). MS: 531 (M+H) + .

化合物12b （39 mg，0.08 mmol），HCl/ 1,4-二氧六環（1 mL，4M）的1,4-二氧六環溶液（2 mL）20℃攪拌2h。減壓濃縮。殘餘物分散在EA（10 mL）中，攪拌5min。過濾得到化合物12 （4 mg，25.47 %，鹽酸鹽）。MS: 427 (M+H)+ 。Compound 12b (39 mg, 0.08 mmol), EtOAc / EtOAc EtOAc (EtOAc) Concentrate under reduced pressure. The residue was taken up in EA (10 mL) and stirred for 5 min. Filtration gave compound 12 (4 mg, 25.47%, hydrochloride). MS: 427 (M+H) + .

實施例13 化合物13的合成 Example 13 Synthesis of Compound 13

化合物7d （80 mg，0.22mol），DIEA（101 mg，0.78 mmol）和(4-甲基哌啶-4-基)甲基胺基甲酸叔丁酯（200 mg，0.88 mmol）溶於DMSO（5 mL），80℃攪拌，反應完全後冷卻至室溫，加水（20 mL）, EA萃取（20 mL×2）。合併有機相，飽和食鹽水洗（50 mL×2），無水硫酸鈉乾燥，過濾，減壓濃縮。殘餘物柱層析純化得到化合物13a （120 mg, 100%）。MS: 549(M+H)+ 。Compound 7d (80 mg, 0.22 mol), DIEA (101 mg, 0.78 mmol) and (4-methylpiperidin-4-yl)methylcarbamic acid tert-butyl ester (200 mg, 0.88 mmol) dissolved in DMSO ( 5 mL), stir at 80 ° C, complete the reaction, cool to room temperature, add water (20 mL), and extract with EA (20 mL×2). The combined organic layers were washed with EtOAc EtOAc m. The residue was purified by column chromatography to afford compound 13a (120 mg, 100%). MS: 549 (M+H) + .

向化合物13a （120 mg，0.22 mmol）的1,4-二氧六環溶液（4 mL）中加入HCl/ 1,4-二氧六環（5 mL，4 M）。室溫下超聲5min。反應完全後，減壓濃縮，殘餘物EA（5 mL）洗，得到化合物13 （85 mg，79.7%，鹽酸鹽）。MS: 449(M+H)+ 。To a solution of compound 13a (120 mg, 0.22 mmol) in 1,4-dioxane (4 mL), EtOAc / EtOAc (EtOAc) Sonicate for 5 min at room temperature. After the completion of the reaction, the residue was concentrated EA (5 mL) washed (hydrochloric acid salt 85 mg, 79.7%,) under reduced pressure to give compound 13. MS: 449 (M+H) + .

實施例14 化合物14的合成 Example 14 Synthesis of Compound 14

化合物12a （0.11 g，0.36 mmol），(4-甲基哌啶-4-基)甲基胺基甲酸叔丁酯（0.25 g，1.08 mmol），DIEA（93 mg，0.72 mmol）溶於DMSO（10 mL）中，加熱到80℃攪拌17h。反應液冷卻，加入水（50 mL）, EA（30 mL×2）萃取。合併有機相，飽和食鹽水（60 mL）洗，無水硫酸鈉乾燥，過濾，減壓濃縮。殘餘物Pre-TLC純化得到化合物14b （0.13 g，72.43%）。MS: 499 (M+H)+ 。Compound 12a (0.11 g, 0.36 mmol), (4-methylpiperidin-4-yl)methylcarbamic acid tert-butyl ester (0.25 g, 1.08 mmol), DIEA (93 mg, 0.72 mmol) In 10 mL), heat to 80 ° C and stir for 17 h. The reaction solution was cooled, extracted with water (50 mL) and EA (30 mL×2). The combined organic layers were washed with EtOAc EtOAc. The residue was purified by Pre-TLC to give compound 14b (0.13 g, 72.43%). MS: 499 (M+H) + .

化合物14 b （0.13 g，0.26 mmol），TFA（1 mL）的DCM溶液（5 mL）20℃攪拌2h。減壓濃縮，殘餘物加EA（10 mL），攪拌5分鐘，過濾得到化合物14 （25 mg，18.76%，TFA鹽）。MS: 399 (M+H)+ 。 Compound 14b (0.13 g, 0.26 mmol), EtOAc (EtOAc) Concentrated under reduced pressure, the residue was added EA (10 mL), stirred for 5 minutes and filtered to give Compound 14 (25 mg, 18.76%, TFA salt). MS: 399 (M+H) + .

藥理檢測Pharmacological testing

實施例A. 磷酸酶活性檢測（單劑量抑制）Example A. Detection of phosphatase activity (single dose inhibition)

檢測方案：Detection plan:

單劑量抑制活性檢測，採用6,8-二氟-4-甲基傘形酮磷酸鹽（DiFMUP）作為反應底物，SHP2酶溶液（在反應液稀釋到0.5nM）與dPEG8肽在反應液（60 mM 4-羥乙基呱嗪乙磺酸（HEPES），pH7.2，75mM NaCl，75mM KCl，1mM EDTA，0.05% Tween 20，2mM 二硫蘇糖醇（DTT））中共同孵育30分鐘來活化SHP2酶。DMSO(0.5%（V/V）或化合物（100nM）加入混合液中，繼續在室溫下孵育30min。加入DiFMUP (12 μM，反應液總體積為100 μL)，開始反應，室溫下避光孵育30min後用2104-0020 EnVision Xcite Multilabel Reader （PerkinElmer）檢測反應液的螢光強度（激發光 340 nm，發射光450 nm）。每個劑量設三個複孔。DMSO孔的螢光值設為100%，化合物處理孔用相對於對照孔的百分比來表示。本說明書中化合物對SHP2的抑制活性見表1。 表1 Single-dose inhibition activity assay using 6,8-difluoro-4-methylumbelliferone phosphate (DiFMUP) as the reaction substrate, SHP2 enzyme solution (diluted to 0.5 nM in the reaction solution) and dPEG8 peptide in the reaction solution ( Incubate for 30 minutes with 60 mM 4-hydroxyethylpyridazine ethanesulfonic acid (HEPES), pH 7.2, 75 mM NaCl, 75 mM KCl, 1 mM EDTA, 0.05% Tween 20, 2 mM dithiothreitol (DTT) Activate the SHP2 enzyme. Add DMSO (0.5% (V/V) or compound (100 nM) to the mixture and continue to incubate for 30 min at room temperature. Add DiFMUP (12 μM, total volume of the reaction solution is 100 μL), start the reaction, and avoid the light at room temperature. After incubation for 30 min, the fluorescence intensity of the reaction solution (excitation light 340 nm, emission light 450 nm) was measured with a 2104-0020 EnVision Xcite Multilabel Reader (PerkinElmer). Three replicate wells were set for each dose. The fluorescence value of the DMSO well was set to 100%, compound treated wells are expressed as a percentage relative to control wells. The inhibitory activity of the compounds in this specification on SHP2 is shown in Table 1. Table 1

實施例B. 磷酸酶活性檢測（IC50測定）Example B. Detection of phosphatase activity (IC50 determination)

IC50值檢測，採用6,8-二氟-4-甲基傘形酮磷酸鹽（DiFMUP）作為反應底物，SHP2酶溶液（在反應液稀釋到0.5nM）與dPEG8肽在反應液（60 mM 4-羥乙基呱嗪乙磺酸（HEPES），pH7.2，75mM NaCl，75mM KCl， 1mM EDTA，0.05% Tween 20，2mM 二硫蘇糖醇（DTT））中共同孵育30分鐘來活化SHP2酶。DMSO(0.5%（V/V）或化合物（濃度：0.3nM~1 μM）加入混合液中，繼續在室溫下孵育30min。加入DiFMUP (12 μM，反應液總體積為100 μL)，開始反應，室溫下避光孵育30min後用2104-0020 EnVision Xcite Multilabel Reader (PerkinElmer)檢測反應液的螢光強度（激發光 340 nm，發射光450 nm）。每個劑量設三個複孔。本說明書中化合物抑制SHP2酶活性的IC50見表2。 表2 IC50 value detection using 6,8-difluoro-4-methylumbelliferone phosphate (DiFMUP) as the reaction substrate, SHP2 enzyme solution (diluted to 0.5 nM in the reaction solution) and dPEG8 peptide in the reaction solution (60 mM) 4-hydroxyethylpyridazine ethanesulfonic acid (HEPES), pH 7.2, 75 mM NaCl, 75 mM KCl, 1 mM EDTA, 0.05% Tween 20, 2 mM dithiothreitol (DTT) was incubated for 30 minutes to activate SHP2. Enzyme. DMSO (0.5% (V/V) or compound (concentration: 0.3nM~1 μM) was added to the mixture and incubation was continued for 30 min at room temperature. DiFMUP (12 μM, total volume of the reaction solution was 100 μL) was added to start the reaction. Incubate for 30 min at room temperature in the dark, and measure the fluorescence intensity of the reaction solution (excitation light 340 nm, emission light 450 nm) using a 2104-0020 EnVision Xcite Multilabel Reader (PerkinElmer). Three replicate wells per dose. The IC50 of the compound inhibiting SHP2 enzyme activity is shown in Table 2. Table 2

實施例C. 細胞增殖檢測Example C. Cell proliferation assay

收集對數生長期的KYSE-520細胞，用含3%胎牛血清(fetal bovine serum，FBS)的RPMI-1640培養液調整濃度（1.5×104/ml），接種於96孔培養板內，100 μL/孔。培養24小時後，加入含3%FBS的1640培養液配置的不同濃度的化合物，每個劑量設三個平行孔。第8天，每孔加入50μL MTS、PMS（吩嗪硫酸甲酯）（分別購自Promega、Sigma）的混合液（20:1），按照試劑說明書（Promega）檢測吸光值。本說明書中化合物的IC50值見表3。 表3 The KYSE-520 cells in the logarithmic growth phase were collected and adjusted to a concentration of 1.5×104/ml with RPMI-1640 medium containing 3% fetal bovine serum (FBS), and seeded in a 96-well culture plate, 100 μL. /hole. After 24 hours of incubation, different concentrations of compound were placed in a 1640 medium containing 3% FBS, with three parallel wells per dose. On the 8th day, a mixture (50:1) of 50 μL of MTS, PMS (phenazine sulfate methyl ester) (purchased from Promega, Sigma, respectively) was added to each well, and the absorbance was measured according to the reagent specification (Promega). The IC50 values of the compounds in this specification are shown in Table 3. table 3

本發明提供的化合物優選配製成通過各種途徑給藥的藥物組合物。最優選地，該藥物組合物用於口服給藥。這種藥物組合物及其製備方法在本技術領域中是公知的，可參見如雷明頓：藥學科學與實踐（阿.詹納羅等人編，第19版，麥克出版公司，1995）[REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al, eds., 19th ed., Mack Publishing Co., 1995)]，結構式I所示化合物通常在很寬的劑量範圍內有效。The compounds provided by the present invention are preferably formulated into pharmaceutical compositions for administration by various routes. Most preferably, the pharmaceutical composition is for oral administration. Such pharmaceutical compositions and methods for their preparation are well known in the art and can be found, for example, in Remington: Pharmaceutical Sciences and Practice (A. Jenaro et al., eds., 19th edition, Mike Publishing, 1995) [REMINGTON] : THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al, eds., 19th ed., Mack Publishing Co., 1995)], the compounds of formula I are generally effective over a wide dosage range.

例如，每日劑量通常約為1mg至約200mg的總每日劑量，優選1mg至150mg總每日劑量，更優選1mg至50mg總每日劑量。在一些情況下，低於上述範圍下限的劑量水平可能是足夠的，而在其他情況下，可以採用更大的劑量。上述劑量範圍並不是以任何方式限制本發明的範圍。應該理解的是，實際給藥的化合物的量將由醫生根據相關情況確定，包括待治療的病症、選擇的給藥途徑、給藥的實際化合物或化合物組合、年齡、體重和患者的個體反應以及患者病症的嚴重程度。For example, the daily dose will generally be from about 1 mg to about 200 mg total daily dose, preferably from 1 mg to 150 mg total daily dose, more preferably from 1 mg to 50 mg total daily dose. In some cases, a dose level below the lower end of the above range may be sufficient, while in other cases, a larger dose may be employed. The above dosage ranges are not intended to limit the scope of the invention in any way. It will be understood that the amount of the compound actually administered will be determined by the physician according to the circumstances, including the condition to be treated, the route of administration chosen, the actual compound or combination of compounds administered, age, weight and individual response of the patient and the patient The severity of the condition.

Claims (49)

一種式I所示的化合物或其藥學上可接受的鹽，I 其中， X為不存在或選自O、S、SO、 S(O)2 、 C(O)、 C(O)R11 、 CR11 R12 或-NR11 ；其中，每個R11 和R12 分別獨立地選自-H、鹵素、-NH2 、-CN、-OH、-NO2 、羰基、 =O、氧代基、羧基、取代或未取代的C1-6 烷氧基或取代或未取代的C1-6 烷基； Y1 選自N或CR1 ； 當與R3 連接的C原子與Y2 上的原子之間形成雙鍵時，Y2 選自N或CR2 ； 當與R3 連接的C原子與Y2 上的N原子之間形成單鍵時，Y2 是-NR2 ; 每個R1 和R2 分別獨立地選自-H、鹵素、-CN、-OH、-NH2 、-N3 、-NO2 、取代或未取代的C1-6 烷氧基，或者取代或未取代的C1-6 烷基；或 R1 與R3 共同形成、或R2 與R3 共同形成，5-10元雜芳環、5-10元碳環或5-10元雜環，且每個環系獨立地任意地被一個或多個取代基取代或不取代，所述取代基選自鹵素、-CN、-OH、-NR8 R9 、-N3 、-NO2 、羰基、=O、氧代基、取代或未取代的C1-6 烷基、取代或未取代的C1-6 烷氧基、或C(O)R8 ；或 R3 選自-H、鹵素、-CN、-OH、-N3 、-NO2 、-NR8 R9 、-N(R8 )(CH2 )p NR8 R9 、-N(R8 )(CH2 )p R8 、-N(R8 )Gp R8 、-N(R8 )Gp NR8 R9 、-N(R8 )(C=O)q R8 、-N(R8 )(C=O)q NR8 R9 、-N(R8 )(C=O)q Gp R8 、-N(R8 )(C=O)q Gp NR8 R9 、-N(R8 )(C=O)q Gp (C=O)q R8 、-N(R8 )(C=O)q Gp (C=O)q NR8 R9 、-N(R8 )(C=O)q N(R8 )(C=O)q R8 、-N(R8 )(C=O)q N(R8 )(C=O)q NR8 R9 、-N(R8 )(C=O)q N(R8 )Gq (C=O)p R8 、-N(R8 )(C=O)q N(R8 )Gp (C=O)q NR8 R9 、-C(=O)q R8 、-C(=O)q OR8 、-C(=O)q NH2 、-C(=O)NR8 R9 、C1-6 烷基、C6-10 芳基、芳基烷基、烷氧基、雜芳基、雜環基或碳環基，且所述每個基團獨立地任意地被取代或不取代；且每個p和q分別獨立地選自0、1、2或3； 每個G分別獨立地選自C6-10 芳基、C3-8 碳環基或C5-10 雜芳基，且所述每個環系獨立地任意地取代或不取代； R4 選自-H、鹵素、-CN、-OH、-NR8 R9 、-N3 、-NO2 、取代或未取代的C1-6 烷氧基、取代或未取代的C1-6 烷基、C5-18 雜環基或C5-18 碳環基，且每個環系獨立地任意地不取代或被鹵素、-CN、-OH、-NO2 、羰基、=O、氧代基、取代或未取代的C1-6 烷基、取代或未取代的C1-6 烷氧基、-NR8 R9 或-CH2 NR8 R9 取代； R5 選自-H、鹵素、-CN、-OH、-NR8 R9 、-N3 、-NO2 、C1-6 烷基、C1-6 烷氧基、 C6-10 芳基、 C6-10 芳基烷基、 C6-10 雜芳基、 C5-18 雜環基或C5-18 碳環基，且每個環系統包括單環、螺環、橋環、稠環和/或其組合，且所述每個基團獨立地任意地取代或不取代； 每個R8 和R9 分別獨立地選自-H、鹵素、-CN、-OH、-N3 、-NO2 、C1-6 烷基、C1-6 烷氧基、C2-6 烯基、NH(C1-6 烷基)、N(C1-6 烷基)2 、C5-10 螺雜環基或C5-10 碳環基，且所述每個基團獨立地任意地取代或不取代。a compound of formula I or a pharmaceutically acceptable salt thereof, Wherein X is absent or selected from O, S, SO, S(O) 2 , C(O), C(O)R 11 , CR 11 R 12 or -NR 11 ; wherein each R 11 and R 12 is each independently selected from -H, halogen, -NH 2 , -CN, -OH, -NO 2 , carbonyl, =0, oxo, carboxy, substituted or unsubstituted C 1-6 alkoxy or a substituted or unsubstituted C 1-6 alkyl group; Y 1 is selected from N or CR 1; when a double bond is formed between C atom attached to the R 3 and the atoms of Y 2, Y 2 is selected from N or CR 2 ; when a single bond is formed between the N atom and Y 2 C atoms attached to R 3, Y 2 is -NR 2; each R 1 and R 2 are each independently selected from -H, halogen, -CN, -OH, -NH 2 , -N 3 , -NO 2 , a substituted or unsubstituted C 1-6 alkoxy group, or a substituted or unsubstituted C 1-6 alkyl group; or R 1 and R 3 are formed together, Or R 2 and R 3 are co-formed, a 5-10 membered heteroaryl ring, a 5-10 membered carbocyclic ring or a 5-10 membered heterocyclic ring, and each ring system is independently optionally substituted with one or more substituents or Substituted, the substituent is selected from the group consisting of halogen, -CN, -OH, -NR 8 R 9 , -N 3 , -NO 2 , carbonyl, =0, oxo, substituted or unsubstituted C 1-6 alkyl Replace or not take A C 1-6 alkoxy, or C (O) R 8; or R 3 is selected from -H, halogen, -CN, -OH, -N 3, -NO 2, -NR 8 R 9, -N ( R 8 )(CH 2 ) p NR 8 R 9 , -N(R 8 )(CH 2 ) p R 8 , -N(R 8 )G p R 8 , -N(R 8 )G p NR 8 R 9 , -N(R 8 )(C=O) q R 8 , -N(R 8 )(C=O) q NR 8 R 9 , -N(R 8 )(C=O) q G p R 8 , -N(R 8 )(C=O) q G p NR 8 R 9 , -N(R 8 )(C=O) q G p (C=O) q R 8 , -N(R 8 )(C =O) q G p (C=O) q NR 8 R 9 , -N(R 8 )(C=O) q N(R 8 )(C=O) q R 8 , -N(R 8 )( C=O) q N(R 8 )(C=O) q NR 8 R 9 , -N(R 8 )(C=O) q N(R 8 )G q (C=O) p R 8 ,- N(R 8 )(C=O) q N(R 8 )G p (C=O) q NR 8 R 9 , -C(=O) q R 8 , -C(=O) q OR 8 ,- C(=O) q NH 2 , -C(=O)NR 8 R 9 , C 1-6 alkyl, C 6-10 aryl, arylalkyl, alkoxy, heteroaryl, heterocyclic Or a carbocyclic group, and each of said groups is independently arbitrarily substituted or unsubstituted; and each p and q are independently selected from 0, 1, 2 or 3; each G is independently selected from C 6-10 aryl, C 3-8 carbocyclic or C 5-10 heteroaryl, and each ring is independently substituted or unsubstituted; R 4 is selected from -H, halogen, -CN, - OH, -NR 8 R 9 , -N 3 , -NO 2 , substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkyl, C 5-18 heterocyclic or C 5-18 carbocyclyl, and each ring system is optionally unsubstituted or halogen, -CN, -OH, -NO 2 , carbonyl, =0, oxo, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 alkoxy, -NR 8 R 9 or -CH 2 NR 8 R 9 substituted; R 5 is selected from -H, halogen, -CN, -OH, -NR 8 R 9 , -N 3 , -NO 2 , C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl, C 6-10 arylalkyl, C 6-10 heteroaryl, C a 5-18 heterocyclyl or a C 5-18 carbocyclic group, and each ring system includes a monocyclic ring, a spiro ring, a bridged ring, a fused ring, and/or combinations thereof, and each of the groups is independently and optionally substituted Or not substituted; each R 8 and R 9 are independently selected from -H, halogen, -CN, -OH, -N 3 , -NO 2 , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , C 5-10 spiroheterocyclyl or C 5-10 carbocyclyl, and each of said The groups are independently substituted or unsubstituted. 根據請求項1所述的化合物，其中R1 選自-H、-F、-Cl、-Br、-I、-CN、-OH、-NH2 、取代或未取代的C1-3 烷氧基或取代或未取代的C1-3 烷基。The compound according to claim 1, wherein R 1 is selected from the group consisting of -H, -F, -Cl, -Br, -I, -CN, -OH, -NH 2 , substituted or unsubstituted C 1-3 alkoxy A substituted or unsubstituted C 1-3 alkyl group. 根據請求項1所述的化合物，其中R2 選自-H、-F、-Cl、 -Br、-I、-CN、-OH、-NH2 、取代或未取代的C1-3 烷氧基或取代或未取代的C1-3 烷基。The compound according to claim 1, wherein R 2 is selected from the group consisting of -H, -F, -Cl, -Br, -I, -CN, -OH, -NH 2 , substituted or unsubstituted C 1-3 alkoxy A substituted or unsubstituted C 1-3 alkyl group. 根據請求項1所述的化合物，其中R3 選自-H、-F、-Cl、 -Br、-CN、-OH、-NO2 、-NR8 R9 、-N(R8 )(CH2 )p NR8 R9 、-N(R8 )(CH2 )p R8 、-N(R8 )Gp R8 、-N(R8 )Gp NR8 R9 、-N(R8 )(C=O)q R8 、-N(R8 )(C=O)q NR8 R9 、-N(R8 )(C=O)q Gp R8 、-N(R8 )(C=O)q Gp NR8 R9 、-N(R8 )(C=O)q Gp (C=O)q R8 、-N(R8 )(C=O)q Gp (C=O)q NR8 R9 、-N(R8 )(C=O)q N(R8 )(C=O)q R8 、-N(R8 )(C=O)q N(R8 ) (C=O)q NR8 R9 、-N(R8 )(C=O)q N(R8 )Gq (C=O)p R8 、-N(R8 )(C=O)q N(R8 )Gp (C=O)q NR8 R9 、-(C=O)q R8 、-(C=O)q OR8 、 -(C=O)q NH2 、 -(C=O)q NR8 R9 、C1-6 烷基或C6-10 芳基，且每個基團獨立地任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自鹵素、-CN、-OH、-NH2 、-N3 、-NO2 、取代或未取代的C1-6 烷基或者取代或未取代的C1-6 烷氧基。The compound according to claim 1, wherein R 3 is selected from the group consisting of -H, -F, -Cl, -Br, -CN, -OH, -NO 2 , -NR 8 R 9 , -N(R 8 )(CH 2 ) p NR 8 R 9 , -N(R 8 )(CH 2 ) p R 8 , -N(R 8 )G p R 8 , -N(R 8 )G p NR 8 R 9 , -N(R 8 )(C=O) q R 8 , -N(R 8 )(C=O) q NR 8 R 9 , -N(R 8 )(C=O) q G p R 8 , -N(R 8 )(C=O) q G p NR 8 R 9 , -N(R 8 )(C=O) q G p (C=O) q R 8 , -N(R 8 )(C=O) q G p (C=O) q NR 8 R 9 , -N(R 8 )(C=O) q N(R 8 )(C=O) q R 8 , -N(R 8 )(C=O) q N(R 8 ) (C=O) q NR 8 R 9 , -N(R 8 )(C=O) q N(R 8 )G q (C=O) p R 8 , -N(R 8 ) (C=O) q N(R 8 )G p (C=O) q NR 8 R 9 , -(C=O) q R 8 , -(C=O) q OR 8 , -(C=O) q NH 2 , -(C=O) q NR 8 R 9 , C 1-6 alkyl or C 6-10 aryl, and each group is independently optionally substituted or unsubstituted by one or more substituents The substituents are each independently selected from the group consisting of halogen, -CN, -OH, -NH 2 , -N 3 , -NO 2 , substituted or unsubstituted C 1-6 alkyl or substituted or unsubstituted C 1- 6 alkoxy. 根據請求項4所述的化合物，其中p選自0或1。The compound according to claim 4, wherein p is selected from 0 or 1. 根據請求項4所述的化合物，其中q選自0、1或2。The compound according to claim 4, wherein q is selected from 0, 1, or 2. 根據請求項1所述的化合物，其中R3 選自-NH2 、、、、、、、或。The compound according to claim 1, wherein R 3 is selected from -NH 2 , , , , , , , or . 根據請求項1所述的化合物，其中R1 與R3 共同形成，或者R2 與R3 共同形成，5元雜芳環、6元雜芳環、7元雜芳環、8元雜芳環、5元雜環、6元雜環、7元雜環或8元雜環，且每個環系含有1、2、3或4個雜原子，所述雜原子選自N、O或S，且每個環系獨立地任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自-F、-Cl、-Br、-I、-CN、-OH、-NH2 、羰基、=O、氧代基、取代或未取代的C1-3 烷基、取代或未取代的C1-3 烷氧基、或-C(=O)R8 。The compound according to claim 1, wherein R 1 and R 3 are formed together, or R 2 and R 3 are co-formed, a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, a 7-membered heteroaryl ring, and an 8-membered heteroaryl ring. a 5-membered heterocyclic ring, a 6-membered heterocyclic ring, a 7-membered heterocyclic ring or an 8-membered heterocyclic ring, and each ring system contains 1, 2, 3 or 4 heteroatoms selected from N, O or S, And each ring system is independently or optionally substituted or unsubstituted with one or more substituents, each independently selected from -F, -Cl, -Br, -I, -CN, -OH, -NH 2 , carbonyl, =0, oxo, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1-3 alkoxy, or -C(=O)R 8 . 根據請求項8所述的化合物，其中R1 與R3 共同形成5元雜芳環、6元雜芳環、5元雜環或6元雜環，每個環系含有1或2個雜原子，所述雜原子選自N或O，且每個環系獨立地任意地被一個或多個取代基取代或不取代， 所述取代基分別獨立地選自-F、-Cl、-Br、-OH、-NH2 、-NH-甲基、-NH-乙基、-NH-丙基、-NH-異丙基、-NHOCH3 、羰基、=O、氧代基、甲基、乙基、丙基、異丙基、甲氧基、CHF2 、CH2 F、CF3 或-C(=O)R8 ；且每個甲基、乙基、丙基、異丙基、甲氧基、CHF2 、CH2 F或-C(=O)R8 獨立地任意地被一個或多個取代基取代或不取代，所述取代基選自-F、-Cl、-Br或-I。The compound according to claim 8, wherein R 1 and R 3 together form a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, a 5-membered heterocyclic ring or a 6-membered heterocyclic ring, each ring system having 1 or 2 hetero atoms The hetero atom is selected from N or O, and each ring system is independently or optionally substituted or unsubstituted with one or more substituents, each independently selected from -F, -Cl, -Br, -OH, -NH 2 , -NH-methyl, -NH-ethyl, -NH-propyl, -NH-isopropyl, -NHOCH 3 , carbonyl, =O, oxo, methyl, ethyl , propyl, isopropyl, methoxy, CHF 2 , CH 2 F, CF 3 or -C(=O)R 8 ; and each methyl, ethyl, propyl, isopropyl, methoxy group And CHF 2 , CH 2 F or -C(=O)R 8 are independently and optionally substituted or unsubstituted with one or more substituents selected from -F, -Cl, -Br or -I. 根據請求項8所述的化合物，其中R2 與R3 共同形成5元雜芳環、6元雜芳環、7元雜芳環、8元雜芳環、5元雜環、6元雜環、7元雜環、8元雜環、5元碳環、6元碳環、7元碳環或8元碳環，每個雜環系含有1或2個雜原子，所述雜原子選自N或O，且每個環系獨立地任意地被一個或多個取代基取代或不取代， 所述取代基分別獨立地選自-F、-Cl、-Br、-OH、-NH2 、-NH-甲基、-NH-乙基、-NH-丙基、-NH-異丙基、-NHOCH3 、羰基、=O、氧代基、甲基、乙基、丙基、異丙基、甲氧基、CHF2 、CH2 F、CF3 或-(C=O)R8 ；且每個甲基、乙基、丙基、異丙基、甲氧基、CHF2 、CH2 F或-(C=O)R8 獨立地任意地被一個或多個取代基取代或不取代，所述取代基選自-F、-Cl、-Br或-I。The compound according to claim 8, wherein R 2 and R 3 together form a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, a 7-membered heteroaryl ring, an 8-membered heteroaryl ring, a 5-membered heterocyclic ring, and a 6-membered heterocyclic ring. a 7-membered heterocyclic ring, an 8-membered heterocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, a 7-membered carbocyclic ring or an 8-membered carbocyclic ring, each heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of N or O, and each ring system is independently or optionally substituted or unsubstituted with one or more substituents, each independently selected from -F, -Cl, -Br, -OH, -NH 2 , -NH-methyl, -NH-ethyl, -NH-propyl, -NH-isopropyl, -NHOCH 3 , carbonyl, =O, oxo, methyl, ethyl, propyl, isopropyl , methoxy, CHF 2 , CH 2 F, CF 3 or -(C=O)R 8 ; and each methyl, ethyl, propyl, isopropyl, methoxy, CHF 2 , CH 2 F or - (C = O) R 8 is independently optionally substituted with one or more substituents or unsubstituted, the substituents are selected from -F, -Cl, -Br or -I. 根據請求項1所述的化合物，其中R4 選自-H、-F、-Cl、-CN、-OH、-NH2 、取代或未取代的C1-3 烷基、取代或未取代的C1-3 烷氧基、含有1、2或3個選自N或O雜原子的5元雜環、含有1、2或3個選自N或O雜原子的6元雜環、5元碳環或6元碳環；且每個環系獨立地任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自-F、-Cl、-Br、-CN、-OH、羰基、=O、氧代基、取代或未取代的C1-3 烷基、取代或未取代的C1-3 烷氧基、-NH2 、-NH-C1-3 烷基、-NH-C1-3 烷氧基、-C1-3 亞烷基-NH2 或-C1-3 亞烷基-NH-C1-3 烷基。The compound according to claim 1, wherein R 4 is selected from the group consisting of -H, -F, -Cl, -CN, -OH, -NH 2 , substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1-3 alkoxy, 5-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N or O, 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N or O, 5 yuan Carbocyclic or 6-membered carbocyclic ring; and each ring system is independently or optionally substituted or unsubstituted with one or more substituents, each independently selected from -F, -Cl, -Br, -CN, -OH, carbonyl, =0, oxo, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1-3 alkoxy, -NH 2 , -NH-C 1-3 alkyl , -NH-C 1-3 alkoxy, -C 1-3 alkylene-NH 2 or -C 1-3 alkylene-NH-C 1-3 alkyl. 根據請求項1所述的化合物，其中R4 選自-Cl、-NH2 、甲基或哌啶基，所述哌啶基任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自甲基、-NH2 或-CH2 NH2 。The compound according to claim 1, wherein R 4 is selected from -Cl, -NH 2 , methyl or piperidinyl, and the piperidinyl group is optionally substituted or unsubstituted with one or more substituents, the substitution The groups are each independently selected from methyl, -NH 2 or -CH 2 NH 2 . 根據請求項1所述的化合物，其中R5 選自-F、-Cl、-Br、-NR8 R9 、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、丙氧基、異丙氧基、6元雜芳基、7元雜芳基、8元雜芳基、9元雜芳基、6元雜環基、7元雜環基、8元雜環基、9元雜環基、10元雜環基、11元雜環基、12元雜環基、13元雜環基、14元雜環基、6元碳環基、7元碳環基、8元碳環基、9元碳環基、10元碳環基、11元碳環基、12元碳環基、13元碳環基或14元碳環基；且所述的每個含有雜原子的環系含有1、2或3個選自N、O或S的雜原子，每個環系包括單環、螺環、橋環、稠環及它們的組合；且上述每個基團獨立地任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自-F、-Cl、-Br、-I、-CN、-OH、-NO2 、-NH2 、羰基、=O、氧代基、取代或未取代的C1-3 烷基、取代或未取代的C1-3 烷氧基、取代或未取代的-(CH2 )k NR8 R9 、取代或未取代的-(CH2 )k NHCOOR8 或取代或未取代的-(C=O)R8 ；k選自0、1或2。The compound according to claim 1, wherein R 5 is selected from the group consisting of -F, -Cl, -Br, -NR 8 R 9 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, Propyloxy, isopropoxy, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 6-membered heterocyclic, 7-membered heterocyclic, 8-membered heterocyclic , 9-membered heterocyclic group, 10 membered heterocyclic group, 11-membered heterocyclic group, 12-membered heterocyclic group, 13-membered heterocyclic group, 14-membered heterocyclic group, 6-membered carbocyclic group, 7-membered carbocyclic group, 8 a carbocyclic group, a 9-membered carbocyclic group, a 10-membered carbocyclic group, an 11-membered carbocyclic group, a 12-membered carbocyclic group, a 13-membered carbocyclic group or a 14-membered carbocyclic group; and each of said hetero atom Ring system containing 1, 2 or 3 heteroatoms selected from N, O or S, each ring system comprising a monocyclic ring, a spiro ring, a bridged ring, a fused ring, and combinations thereof; and each of the above groups independently Optionally substituted or unsubstituted with one or more substituents, each independently selected from -F, -Cl, -Br, -I, -CN, -OH, -NO 2 , -NH 2 , carbonyl , =O, oxo, substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 1-3 alkoxy, substituted or unsubstituted -(CH 2 ) k NR 8 R 9 , substituted or unsubstituted -(CH 2 ) k NHCOOR 8 or substituted or unsubstituted -(C=O)R 8 ;k is selected from 0, 1 or 2. 根據請求項13所述的化合物，其中所述C1-3 烷基是甲基，所述述-(CH2 )k NHCOOR8 是-CH2 NHCOOBoc, or –NHCOOBoc, 所述-(CH2 )k NR8 R9 是 -CH2 NH2 或 -CH2 NH2 。The compound according to claim 13, wherein the C 1-3 alkyl group is a methyl group, the -(CH 2 ) k NHCOOR 8 is -CH 2 NHCOOBoc, or -NHCOOBoc, the -(CH 2 ) k NR 8 R 9 is -CH 2 NH 2 or -CH 2 NH 2 . 根據請求項13所述的化合物，其中所述單環包括或; 所述螺環包括或; 所述它們的組合包括、、、或。The compound according to claim 13 wherein the single ring comprises or The spiral ring includes or ; the combination of them includes , , , or . 根據請求項1所述的化合物，其中R5 選自； 每個R21 和R22 分別獨立地選自鹵素、 C1-3 烷基、-NH2 、-C1-3 亞烷基-NH2 、-C1-3 亞烷基-NH-C1-3 烷基、-C1-3 亞烷基-N(C1-3 烷基)2 、-NHBoc或-CH2 NHBoc；或者 R21 和R22 與它們共同連接的C原子一起形成5-10元的雜芳環、5-10元的碳環、5-10元的雜環、5-10元的螺雜環或5-10元稠合的雜環，且每個環系獨立地任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自鹵素、-CN、-OH、羰基、=O、氧代基、NH2 、C1-3 烷氧基、-C1-3 亞烷基-NH2 、-C1-3 亞烷基-NH-C1-3 烷基、-C1-3 亞烷基-N(C1-3 烷基)2 、-NHBoc、-CH2 NHBoc或C1-3 烷基。The compound according to claim 1, wherein R 5 is selected from Each of R 21 and R 22 is independently selected from the group consisting of halogen, C 1-3 alkyl, -NH 2 , -C 1-3 alkylene-NH 2 , -C 1-3 alkylene-NH-C 1-3 alkyl, -C 1-3 alkylene-N(C 1-3 alkyl) 2 , -NHBoc or -CH 2 NHBoc; or R 21 and R 22 together with the C atom to which they are attached form 5 a 10-membered heteroaryl ring, a 5-10 membered carbocyclic ring, a 5-10 membered heterocyclic ring, a 5-10 membered spiro heterocyclic ring or a 5-10 membered fused heterocyclic ring, and each ring system is independently Optionally substituted or unsubstituted with one or more substituents, each independently selected from the group consisting of halogen, -CN, -OH, carbonyl, =0, oxo, NH 2 , C 1-3 alkoxy , -C 1-3 alkylene-NH 2 , -C 1-3 alkylene-NH-C 1-3 alkyl, -C 1-3 alkylene-N(C 1-3 alkyl) 2 , -NHBoc, -CH 2 NHBoc or C 1-3 alkyl. 根據請求項16所述的化合物，其中R21 和R22 與它們共同連接的C原子一起形成5元雜芳環、6元雜芳環、7元雜芳環、8元雜芳環、 9元雜芳環、10元雜芳環、5元雜環、6元雜環、7元雜環、8元雜環、9元雜環、5元螺雜環、6元螺雜環、7元螺雜環、8元螺雜環、9元螺雜環、5元稠合雜環、6元稠合雜環、7元稠合雜環、8元稠合雜環、9元稠合雜環、或10元稠合雜環，且每個環系含有1、2或3個雜原子，所述雜原子選自N、O或S，且每個環系獨立地任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自鹵素、-CN、-OH、羰基、=O、氧代基、-NH2 、C1-3 烷氧基或C1-3 烷基。The compound according to claim 16, wherein R 21 and R 22 together with the C atom to which they are attached form a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, a 7-membered heteroaryl ring, an 8-membered heteroaryl ring, and 9 elements. Heteroaromatic ring, 10-membered heteroaryl ring, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 7-membered heterocyclic ring, 8-membered heterocyclic ring, 9-membered heterocyclic ring, 5-membered spiro heterocyclic ring, 6-membered spiro heterocyclic ring, 7-membered spiro a heterocyclic ring, an 8-membered spiro heterocyclic ring, a 9-membered spiro heterocyclic ring, a 5-membered fused heterocyclic ring, a 6-membered fused heterocyclic ring, a 7-membered fused heterocyclic ring, an 8-membered fused heterocyclic ring, a 9-membered fused heterocyclic ring, Or a 10-membered fused heterocyclic ring, and each ring system contains 1, 2 or 3 heteroatoms selected from N, O or S, and each ring system is independently and optionally substituted by one or more Substituted or unsubstituted, the substituents are each independently selected from halogen, -CN, -OH, carbonyl, =0, oxo, -NH 2 , C 1-3 alkoxy or C 1-3 alkyl . 根據請求項1所述的化合物，其中R5 選自-NH2 、、、、、、、、、、、、、、、、或者。The compound according to claim 1, wherein R 5 is selected from -NH 2 , , , , , , , , , , , , , , , , or . 根據請求項1所述的化合物，其中每 個R8 和R9 分別獨立地選自-H、甲基、叔丁基、-CH=CH2 、-N(CH3 )2 、或。The compound according to claim 1, wherein each of R 8 and R 9 is independently selected from -H, methyl, tert-butyl, -CH=CH 2 , -N(CH 3 ) 2 , or . 根據請求項1所述的化合物，其中X是O、S或者不存在。The compound according to claim 1, wherein X is O, S or absent. 根據請求項1所述的化合物，其中Y1 是N，Y2 是CR2 ，所述R2 是H、鹵素或C1-6 烷基；或者R2 與R3 共同形成5元雜芳環、6元雜芳環、7元雜芳環、8元雜芳環、5元雜環、6元雜環、7元雜環、8元雜環、5元碳環、6元碳環、7元碳環或8元碳環，每個含有雜原子的環系含有1個或2個選自N或O的雜原子，上述基團獨立地任意地被1個或多個基團取代或不取代，所述取代基選自-F、-Cl、-Br、-OH、-NH2 、-NH甲基、-NH乙基、-NH丙基、-NH異丙基、-NHOCH3 、羰基、 =O、氧代基、甲基、乙基、丙基、異丙基、甲氧基、CHF2 、CH2 F、CF3 或-(C=O)R8 ；上述每個甲基、乙基、丙基、異丙基、甲氧基、 CHF2 、CH2 F、CF3 或 -(C=O)R8 獨立地任意地被一個或多個取代基取代或不取代，所述取代基選自-F、-Cl、-Br或-I。The compound according to claim 1, wherein Y 1 is N, Y 2 is CR 2 , and R 2 is H, halogen or C 1-6 alkyl; or R 2 and R 3 together form a 5-membered heteroaryl ring , 6-membered heteroaryl ring, 7-membered heteroaryl ring, 8-membered heteroaryl ring, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 7-membered heterocyclic ring, 8-membered heterocyclic ring, 5-membered carbon ring, 6-membered carbon ring, 7 a carbocyclic ring or an 8-membered carbocyclic ring, each containing a hetero atom containing one or two heteroatoms selected from N or O, the above groups being independently optionally substituted by one or more groups or not Substituted, the substituent is selected from -F, -Cl, -Br, -OH, -NH 2 , -NH methyl, -NHethyl, -NH propyl, -NH isopropyl, -NHOCH 3 , carbonyl , =O, oxo, methyl, ethyl, propyl, isopropyl, methoxy, CHF 2 , CH 2 F, CF 3 or -(C=O)R 8 ; each of the above methyl groups, Ethyl, propyl, isopropyl, methoxy, CHF 2 , CH 2 F, CF 3 or -(C=O)R 8 are independently optionally substituted or unsubstituted with one or more substituents, The substituent is selected from -F, -Cl, -Br or -I. 根據請求項1所述的化合物，其中Y2 是N，Y1 是CR1 ，所述R1 選自-H、鹵素或 C1-6 烷基，或者R1 與R3 共同形成5元雜芳環、6元雜芳環、5元雜環或6元雜環，每個環系含有1個或2個選自N或O的雜原子，上述基團獨立地任意地被1個或多個基團取代或不取代，所述取代基選自-F、-Cl、-Br、-OH、-NH2 、-NH甲基、-NH乙基、-NH丙基、-NH異丙基、-NHOCH3 、羰基、=O、氧代基、甲基、乙基、丙基、異丙基、甲氧基、CHF2 、CH2 F、CF3 或-(C=O)R8 ；上述每個甲基、乙基、丙基、異丙基、甲氧基、 CHF2 、CH2 F、CF3 或-(C=O)R8 獨立地任意地被一個或多個取代基取代或不取代，所述取代基選自-F、-Cl、-Br或者-I。The compound according to claim 1, wherein Y 2 is N, Y 1 is CR 1 , R 1 is selected from -H, halogen or C 1-6 alkyl, or R 1 and R 3 together form a 5-membered hetero An aromatic ring, a 6-membered heteroaryl ring, a 5-membered heterocyclic ring or a 6-membered heterocyclic ring, each ring system containing 1 or 2 hetero atoms selected from N or O, the above groups being independently arbitrarily 1 or more Substituted or unsubstituted, the substituent is selected from -F, -Cl, -Br, -OH, -NH 2 , -NH methyl, -NHethyl, -NHpropyl, -NH isopropyl , -NHOCH 3 , carbonyl, =O, oxo, methyl, ethyl, propyl, isopropyl, methoxy, CHF 2 , CH 2 F, CF 3 or -(C=O)R 8 ; Each of the above methyl, ethyl, propyl, isopropyl, methoxy, CHF 2 , CH 2 F, CF 3 or -(C=O)R 8 is independently optionally substituted by one or more substituents With or without substitution, the substituent is selected from -F, -Cl, -Br or -I. 根據請求項1所述的化合物，其中所述化合物如式II所示：II 其中 Y1 選自N或CR25 ； Y2 選自N或C； R25 選自H、鹵素、C1-3 烷基、C1-3 烷氧基、C2-3 烯基或C2-3 炔基；環選自5-8元含有1、2、3或4個選自N、O或S雜原子的雜芳環、5-8元碳環、或5-8元含有1、2、3或4個選自N、O或S雜原子的雜環；每個環系獨立地任意地被一個或多個取代基取代或不取代，所述取代基選自鹵素、-CN、-OH、-NR8 R9 、-N3 、-NO2 、羰基、 =O、氧代基、C1-3 烷基、一個或多個鹵素取代的C1-3 烷基、C1-6 烷氧基、一個或多個鹵素取代的C1-6 烷氧基或-(C=O)R8 ； R31 選自-H、鹵素、-OH、-NH2 、-(C=O)C1-3 烷基、-CN、-NO2 、羰基、=O、氧代基、羧基、C1-3 烷基、一個或多個鹵素取代的C1-3 烷基、C1-3 烷氧基或一個或多個鹵素取代的C1-3 烷氧基； m選自0、1、2、3或4； R4 選自-H、鹵素、-NH2 、取代或未取代的C1-3 烷氧基或者取代或未取代的 C1-3 烷基； 每個R32 和R33 分別獨立地選自-H、鹵素、-OH、-NH2 、-CN、-NO2 、 -C1-3 亞烷基-NH2 、-C1-3 亞烷基-NH-C1-3 烷基、-C1-3 亞烷基-N(C1-3 烷基)2 、 -NHBoc、 -CH2 NHBoc、-NH-C1-3 烷基、-N(C1-3 烷基)2 、-NH-C1-3 烷氧基、-N(C1-3 烷氧基)2 、C1-3 烷基、一個或多個鹵素取代的C1-3 烷基、C1-3 烷氧基或一個或多個鹵素取代的C1-3 烷氧基；或者， R32 和R33 與它們共同連接的C原子一起形成5-8元含有1、2或3個選自N、O或S雜原子的雜芳環或5-8元含有1、2或3個選自N、O或S雜原子的雜環，且每個環系獨立地任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自鹵素、-CN、-OH、-NH2 、羰基、=O、氧代基、-CH2 NH2 、-C1-3 亞烷基-NH2 、-C1-3 亞烷基-NH-C1-3 烷基、-C1-3 亞烷基-N(C1-3 烷基)2 、-NHBoc、-CH2 NHBoc、-NH-C1-3 烷基、-N(C1-3 烷基)2 、-NH-C1-3 烷氧基、-N(C1-3 烷氧基)2 、取代或未取代的C1-3 烷基或者取代或未取代的C1-3 烷氧基。The compound according to claim 1, wherein the compound is as shown in formula II: Wherein Y 1 is selected from N or CR 25 ; Y 2 is selected from N or C; and R 25 is selected from H, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 2-3 alkenyl or C 2-3 alkynyl; The ring is selected from 5-8 members containing 1, 2, 3 or 4 heteroaryl rings selected from N, O or S heteroatoms, 5-8 membered carbocyclic rings, or 5-8 members containing 1, 2, 3 or 4 a heterocyclic ring selected from N, O or S heteroatoms; each ring system is independently or optionally substituted or unsubstituted with one or more substituents selected from the group consisting of halogen, -CN, -OH, -NR 8 R 9 , -N 3 , -NO 2 , carbonyl, =O, oxo, C 1-3 alkyl, one or more halogen-substituted C 1-3 alkyl, C 1-6 alkoxy, One or more halogen-substituted C 1-6 alkoxy groups or -(C=O)R 8 ; R 31 is selected from -H, halogen, -OH, -NH 2 , -(C=O)C 1-3 Alkyl, -CN, -NO 2 , carbonyl, =0, oxo, carboxy, C 1-3 alkyl, one or more halogen substituted C 1-3 alkyl, C 1-3 alkoxy or One or more halogen-substituted C 1-3 alkoxy groups; m is selected from 0, 1, 2 , 3 or 4; R 4 is selected from -H, halogen, -NH 2 , substituted or unsubstituted C 1-3 Alkoxy or substituted or unsubstituted C 1-3 alkyl; each R 32 and R 33 are independently selected from -H, halogen, -OH, -NH 2 , -CN, -NO 2 , -C 1 -3 alkylene-NH 2 , -C 1-3 alkylene-NH-C 1-3 alkyl, -C 1-3 alkylene-N (C 1-3 alkyl) 2 , -NHBoc, -CH 2 NHBoc, -NH-C 1-3 alkyl, -N(C 1-3 alkyl) 2 , -NH-C 1-3 alkoxy, - N (C 1-3 alkoxy) 2 , C 1-3 alkyl, one or more halogen-substituted C 1-3 alkyl, C 1-3 alkoxy or one or more halogen substituted C 1 -3 alkoxy; or, R 32 and R 33 together with the C atom to which they are attached form a 5-8 membered heteroaryl ring containing 1, 2 or 3 heteroatoms selected from N, O or S or 5-8 The element contains 1, 2 or 3 heterocyclic rings selected from N, O or S heteroatoms, and each ring system is independently or optionally substituted or unsubstituted with one or more substituents, which are independently selected From halogen, -CN, -OH, -NH 2 , carbonyl, =0, oxo, -CH 2 NH 2 , -C 1-3 alkylene-NH 2 , -C 1-3 alkylene-NH -C 1-3 alkyl, -C 1-3 alkylene-N(C 1-3 alkyl) 2 , -NHBoc, -CH 2 NHBoc, -NH-C 1-3 alkyl, -N(C 1-3 alkyl) 2 , -NH-C 1-3 alkoxy, -N(C 1-3 alkoxy) 2 , substituted or unsubstituted C 1-3 alkyl or substituted or unsubstituted C 1-3 alkoxy group. 根據請求項23所述的化合物，其中環選自5元雜芳環、6元雜芳環、7元雜芳環、5元雜環、6元雜環、7元雜環、5元碳環、6元碳環、7元碳環或8元碳環，且每個含有雜原子的環系含有1、2或3個雜原子，所述雜原子選自N、O或S。The compound according to claim 23, wherein The ring is selected from the group consisting of a 5-membered heteroaryl ring, a 6-membered heteroaryl ring, a 7-membered heteroaryl ring, a 5-membered heterocyclic ring, a 6-membered heterocyclic ring, a 7-membered heterocyclic ring, a 5-membered carbocyclic ring, a 6-membered carbocyclic ring, and a 7-membered carbocyclic ring. Or an 8-membered carbocyclic ring, and each ring system containing a hetero atom contains 1, 2 or 3 heteroatoms selected from N, O or S. 根據請求項23所述的化合物，其中環選自5元含有1或2個選自N或O雜原子的雜芳環、5元含有1或2個選自N或O雜原子的雜環、6元含有1或2個選自N或O雜原子的雜環或5元碳環。The compound according to claim 23, wherein The ring is selected from 5-membered heteroaryl rings containing 1 or 2 heteroatoms selected from N or O heteroatoms, 5-membered heterocyclic rings containing 1 or 2 heteroatoms selected from N or O, 6-membered containing 1 or 2 selected from N Or a heterocyclic or 5-membered carbon ring of an O hetero atom. 根據請求項23所述的化合物，其中R31 選自-H、-F、-Cl、-Br、-I、-OH、-NH2 、羰基、=O、氧代基、甲基、-(C=O)CH3 或者被-F、 -Cl、 -Br 或者 -I取代的甲基。The compound according to claim 23, wherein R 31 is selected from the group consisting of -H, -F, -Cl, -Br, -I, -OH, -NH 2 , carbonyl, =0, oxo, methyl, -( C=O)CH 3 or a methyl group substituted by -F, -Cl, -Br or -I. 根據請求項23所述的化合物，其中每個R32 和R33 獨立地選自-H、-F、-Cl、-OH、-NH2 、CN、-NO2 、-CH2 -NH2 、甲基或者被一個或多個-F、-Cl、-Br或者-I取代的甲基；或R32 和R33 與它們共同連接的C原子一起形成5元雜環、6元雜環或7元雜環，所述環系含有1或2個雜原子，所述雜原子選自N或O，且每個環系獨立地任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自-F、-Cl、-Br、-I、-CN、-OH、-NH2 、羰基、=O、氧代基、羧基、-N3 或者-NO2 。The compound according to claim 23, wherein each R 32 and R 33 are independently selected from the group consisting of -H, -F, -Cl, -OH, -NH 2 , CN, -NO 2 , -CH 2 -NH 2 , a methyl group or a methyl group substituted by one or more -F, -Cl, -Br or -I; or R 32 and R 33 together with the C atom to which they are attached form a 5-membered heterocyclic ring, a 6-membered heterocyclic ring or 7 a heterocyclic ring containing 1 or 2 heteroatoms selected from N or O, and each ring system is independently or optionally substituted or unsubstituted with one or more substituents, said substitution The groups are each independently selected from -F, -Cl, -Br, -I, -CN, -OH, -NH 2 , carbonyl, =0, oxo, carboxy, -N 3 or -NO 2 . 根據請求項23所述的化合物，其中每個R32 和R33 獨立地選自 -CH2 NH2 或-CH3 ；或者 R32 與R33 與他們連接的碳原子一起形成。The compound according to claim 23, wherein each R 32 and R 33 are independently selected from -CH 2 NH 2 or -CH 3 ; or R 32 and R 33 are formed together with the carbon atom to which they are attached . 根據請求項23所述的化合物，其中Y1 是N。The compound according to claim 23, wherein Y 1 is N. 根據請求項23所述的化合物，其中Y2 是C。The compound according to claim 23, wherein Y 2 is C. 根據請求項23所述的化合物，其中R25 是-H或-Cl。The compound according to claim 23, wherein R 25 is -H or -Cl. 根據請求項23所述的化合物，其中R4 是-NH2 。The compound according to claim 23, wherein R 4 is -NH 2 . 根據請求項1所述的化合物，其中所述化合物如式III所示：III 其中 X選自不存在或S； R26 選自-H、鹵素、取代或未取代的 C1-3 烷基或者取代或未取代的C1-3 烷氧基；環選自5-8元雜環，且每個環系獨立地含有1或2個雜原子，所述的雜原子選自N、O或S； R34 選自-H、鹵素、-OH、-NR35 R36 、-CN、-NO2 、羰基、=O、氧代基、取代或未取代的C1-3 烷基或者取代或未取代的C1-3 烷氧基； n選自0、1、2或3； R4 選自-H、鹵素、-NH2 、C1-6 烷基；或者R4 是5、6、7元雜環，每個環系獨立地含有1或2個N原子，且每個環系獨立地任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自鹵素、-C1-3 烷基或者-C1-3 亞烷基-NH2 ； 每個R35 和R36 分別獨立地選自-H、鹵素、-OH、-NH2 、-CN、-C1-3 亞烷基-NH2 、-NO2 、-CH2 NH2 、取代或未取代的C1-3 烷基或者取代或未取代的C1-3 烷氧基；或者， R35 和R36 與它們共同連接的C原子一起形成5-8元雜環，且每個環系獨立地含有1、2或3個雜原子，所述雜原子選自N、O或S，且每個環系獨立地任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自鹵素、-CN、-OH、-NH2 、取代或未取代的C1-3 烷基或者取代或未取代的C1-3 烷氧基。The compound according to claim 1, wherein the compound is as shown in formula III: Wherein X is selected from the absence or S; R 26 is selected from -H, halogen, substituted or unsubstituted C 1-3 alkyl or substituted or unsubstituted C 1-3 alkoxy; The ring is selected from a 5-8 membered heterocyclic ring, and each ring system independently contains 1 or 2 heteroatoms, said hetero atom being selected from N, O or S; R 34 is selected from -H, halogen, -OH, -NR 35 R 36 , -CN, -NO 2 , carbonyl, =0, oxo, substituted or unsubstituted C 1-3 alkyl or substituted or unsubstituted C 1-3 alkoxy; n selected from 0, 1, 2 or 3; R 4 is selected from -H, halogen, -NH 2 , C 1-6 alkyl; or R 4 is a 5, 6, 7-membered heterocyclic ring, each ring system independently containing 1 or 2 N atoms, and each ring system is independently or optionally substituted or unsubstituted with one or more substituents, each independently selected from halogen, -C 1-3 alkyl or -C 1-3 Alkylene-NH 2 ; each R 35 and R 36 are independently selected from -H, halogen, -OH, -NH 2 , -CN, -C 1-3 alkylene-NH 2 , -NO 2 , -CH 2 NH 2 , a substituted or unsubstituted C 1-3 alkyl group or a substituted or unsubstituted C 1-3 alkoxy group; or, R 35 and R 36 together with the C atom to which they are attached form 5-8 a heterocyclic ring, and each ring system independently contains 1, 2 or 3 heteroatoms selected from N, O or S, and each ring system is independently arbitrarily one or Substituents or substituted, the substituents are each independently selected from halogen, -CN, -OH, -NH 2, substituted or unsubstituted C 1-3 alkyl or C 1-3 substituted or unsubstituted Alkoxy. 根據請求項33所述的化合物，其中環選自5元雜環、6元雜環或7元雜環，且每個環系獨立地含有1個N原子。The compound according to claim 33, wherein The ring is selected from a 5-membered heterocyclic ring, a 6-membered heterocyclic ring or a 7-membered heterocyclic ring, and each ring system independently contains 1 N atom. 根據請求項33所述的化合物，其中每個R32 和R33 獨立地選自-H、-F、-Cl、-OH、-NH2 、-CN、-NO2 、-CH2 -NH2 、甲基、由1個或多個-F、-Cl、 -Br或-I取代的甲基，或者R35 和R36 與它們共同連接的C原子一起形成5元雜環、6元雜環或7元雜環，每個環系獨立地含有1個N原子，且每個環系獨立地任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自鹵素、-CN、-OH、-NH2 、羰基、=O、氧代基或者-CH2 NH2 。The compound according to claim 33, wherein each R 32 and R 33 are independently selected from the group consisting of -H, -F, -Cl, -OH, -NH 2 , -CN, -NO 2 , -CH 2 -NH 2 a methyl group, a methyl group substituted by one or more -F, -Cl, -Br or -I, or a combination of R 35 and R 36 with a C atom to which they are attached form a 5-membered heterocyclic ring and a 6-membered heterocyclic ring. Or a 7-membered heterocyclic ring, each ring system independently containing 1 N atom, and each ring system is independently or optionally substituted or unsubstituted with one or more substituents, each independently selected from halogen, -CN, -OH, -NH 2 , carbonyl, =O, oxo or -CH 2 NH 2 . 根據請求項33所述的化合物，其中R26 選自-H或-Cl。The compound according to claim 33, wherein R 26 is selected from -H or -Cl. 根據請求項33所述的化合物，其中R4 是-NH2 ，或者是含有1個N原子的6元雜環，且所述環系任意地被一個或多個取代基取代或不取代，所述取代基分別獨立地選自鹵素、-NH2 、甲基、乙基或者-CH2 NH2 。The compound according to claim 33, wherein R 4 is -NH 2 or a 6-membered heterocyclic ring containing 1 N atom, and the ring system is optionally substituted or unsubstituted with one or more substituents, The substituents are each independently selected from the group consisting of halogen, -NH 2 , methyl, ethyl or -CH 2 NH 2 . 根據請求項33所述的化合物，其中R34 選自-F、-COCH3 、羰基、=O、氧代基、-CH3 或-CF3 。The compound according to claim 33, wherein R 34 is selected from the group consisting of -F, -COCH 3 , carbonyl, =0, oxo, -CH 3 or -CF 3 . 根據請求項1所述的化合物，其中所述化合物是 1)(S)-N1 -(3-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-2-氯苯基)-N2 ,N2 -二甲基草醯胺鹽酸鹽； 2)N1 -(4-((3-胺基-5-(4-胺基-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-3-氯吡啶-2-基)-N2 ,N2 -二甲基草醯胺； 3) N-(3-((3-胺基-5-(4-胺基-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-2-氯苯基)-4-(2-(二甲基胺基)-2-氧代乙醯基)苯甲醯胺； 4) 6-((3-胺基-5-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-2H-苯並[b][1,4]惡嗪-3(4H)-酮； 5) 6-(3-胺基-5-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)-2H-苯並[b][1,4]惡嗪-3(4H)-酮； 6) 5-((2-胺基-3-氯吡啶-4-基)硫代)-N2 -(2-氮雜螺[4.5]癸烷-8-基)吡嗪-2,6-二胺； 7) (S)-1-(4-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-3,3-二氟吲哚啉-1-基)乙酮； 8) (S)-4-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-3,3-二氟吲哚啉-2-酮； 9) 4-((3-胺基-5-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫代)吲哚啉-2-酮； 10) (S)-4-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-3,3-二氟-1H-吡咯並[2,3-b]吡啶-2(3H)-酮； 11) (S)-4-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-3,3-二氟-1-甲基吲哚-2-酮； 12) (S)-4-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)吲哚啉-2,3-二酮鹽酸鹽； 13) 1-(4-((3-胺基-5-(4-(氨甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-3,3-二氟吲哚啉-1-基)乙酮； 14) 4-((3-胺基-5-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫代)吲哚啉-2,3-二酮； 15) 5-((2-胺基-3-氯吡啶-4-基)硫代)-6-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-胺； 16)N1 -(4-((3-胺基-5-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-3-氯吡啶-2-基)-N2 ,N2 -二甲基草醯胺； 17) ((1-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡嗪-2-基)-4-甲基哌啶-4-基)甲基)胺基甲酸叔丁酯； 18)(S)-N1 -(4-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-3-氯吡啶-2-基)-N2 ,N2 -二甲基草醯胺； 19)(S)-N1 -(3-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-2-氯苯基)-N2 ,N2 -二甲基草醯胺； 20)N1 -(3-((3-胺基-5-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-2-氯苯基)-N2 ,N2 -二甲基草醯胺； 21) N-(3-((3-胺基-5-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-2-氯苯基)-3-(2-(二甲基胺基)-2-氧代乙醯基)苯甲醯胺； 22) 2-(3-(3-(3-((3-胺基-5-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-2-氯苯基)脲基)苯基)-N,N-二甲基-2-氧代乙醯胺； 23) 2-(4-(3-(3-((3-胺基-5-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-2-氯苯基)脲基)苯基)-N,N-二甲基-2-氧代乙醯胺； 24) 6-(4-(胺基甲基)-4-甲基哌啶-1-基)-3-((3,4-二氫-2H-苯並[b][1,4]惡嗪-6-基)硫代)吡嗪-2-胺； 25) (1-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡嗪-2-基)-4-甲基哌啶-4-基)胺基甲酸叔丁酯； 26) (1-(5-((2-丙烯醯胺-3-氯吡啶-4-基)硫代)-6-胺基吡嗪-2-基)-4-甲基哌啶-4-基)胺基甲酸叔丁酯； 27) (1-(6-胺基-5-((3-氯-2-(2-(二甲基胺基)-2-氧代乙醯胺基)吡啶-4-基)硫代)吡嗪-2-基)-4-甲基哌啶-4-基)胺基甲酸叔丁酯； 28) (1-(6-胺基-5-((2-氯-3-(2-(二甲基胺基)-2-氧代乙醯胺基)苯基)硫代)吡嗪-2-基)-4-甲基哌啶-4-基)胺基甲酸叔丁酯； 29)N1 -(3-((3-胺基-5-(4-胺基-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-2-氯苯基)-N2 ,N2 -二甲基草醯胺； 30) (1-(6-胺基-5-((3-胺基-2-氯苯基)硫代)吡嗪-2-基)-4-甲基哌啶-4-基)胺基甲酸叔丁酯； 31) N-(3-((3-胺基-5-(4-胺基-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-2-氯苯基)-2-氧代-2-(4-甲苯基)乙醯胺； 32) (1-(5-((3-丙烯醯基-2-氯苯基)硫代)-6-胺基吡嗪-2-基)-4-甲基哌啶-4-基)胺基甲酸叔丁酯； 33) 6-(3-胺基-5-(4-胺基-4-甲基哌啶-1-基)吡嗪-2-基)-2H-苯並[b][1,4]惡嗪-3(4H)-酮； 34) N-(4-((3-胺基-5-(4-胺基-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-3-氯吡啶-2-基)-4-(2-(二甲基胺基)-2-氧代乙醯基)苯甲醯胺； 35) N-(4-((3-胺基-5-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-3-氯吡啶-2-基)-4-(2-(二甲基胺基)-2-氧代乙醯基)苯甲醯胺； 36) N-(3-((3-胺基-5-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-2-氯苯基)-4-(2-(二甲基胺基)-2-氧代乙醯基)苯甲醯胺； 37) 5-((2-胺基-3-氯吡啶-4-基)硫代)-N2 -環己基吡嗪-2,6-二胺； 38) (S)-8-(5-((1H-吡咯並[2,3-b]吡啶-4-基)硫代)-6-胺基吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 39) (S)-8-(6-胺基-5-((3,3-二甲基吲哚啉-4-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 40) (S)-8-(6-胺基-5-((3-氟-1H-吲哚-4-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 41) 5-((2-胺基-3-氯吡啶-4-基)硫代)-N2 -(4-(胺基甲基)-4-甲基環己基)吡嗪-2,6-二胺； 42) (S)-8-(5-((1H-吲哚-4-基)硫代)-6-胺基吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 43) (S)-1-(4-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-1H-吲哚-1-基)乙酮； 44) 5-((2-胺基-3-氯吡啶-4-基)硫代)-N2 -(4-胺基-4-甲基環己基)吡嗪-2,6-二胺； 45) (S)-6-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-2H-苯並[b][1,4]惡嗪-3(4H)-酮； 46) (S)-4-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-1,3,3-三甲基吲哚啉-2-酮； 47) (4S)-8-(6-胺基-5-((3-氟代吲哚啉-4-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 48) 1-(4-((3-胺基-5-((S)-4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-3-氟-3-甲基吲哚啉-1-基)乙酮； 49) (S)-8-(6-胺基-5-((3,3-二氟吲哚啉-4-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 50) 1-(4-((3-胺基-5-((S)-4-胺基-2-氧雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-3-甲基吲哚啉-1-基)乙酮； 51) (S)-8-(6-胺基-5-((8-氯-4,4-二氟-1,2,3,4-四氫喹啉-5-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 52) (4S)-8-(6-胺基-5-((8-氯-4-氟-1,2,3,4-四氫喹啉-5-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 53) (S)-8-(6-胺基-5-((3,3-二氟-1-甲基吲哚啉-4-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 54) (S)-6-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-3,3-二氟吲哚啉-2-酮； 55) 4-((3-胺基-5-((S)-4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-3-氟吲哚啉-2-酮； 56) (S)-8-(6-胺基-5-((3,3-二氟-2,3-二氫苯並呋喃-4-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 57) (S)-8-(6-胺基-5-((4,4-二氟苯並二氫吡喃-5-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 58) 4-((3-胺基-5-((S)-4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-3-氟-1-甲基-3-(三氟甲基)吲哚啉-2-酮； 59) (S)-6-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-7-氯吲哚啉-2-酮； 60) (S)-8-(6-胺基-5-((5-氯-3,4-二氫-2H-苯並[b][1,4]惡嗪-6-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 61) (S)-7-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-8-氯-3,4-二氫喹啉-2(1H)-酮； 62) (S)-6-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-5-氯-2H-苯並[b][1,4]惡嗪-3(4H)-酮； 63) (S)-2-(3-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-2-氯苯基)-N,N-二甲基-2-氧代乙醯胺； 64) 4-((3-胺基-5-(4-(胺基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫代)-3,3-二氟-1H-吡咯並[2,3-b]吡啶-2(3H)-酮； 65) (S)-4-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-1H-苯並[d]咪唑-2(3H)-酮； 66) (S)-4-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-1,3-二甲基-1H-苯並[d]咪唑-2(3H)-酮； 67) (S)-8-(6-胺基-5-((2,2-二氟-2,3-二氫-1H-苯並[d]咪唑-4-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 68) (S)-8-(6-胺基-5-((2,2-二氟-1,3-二甲基-2,3-二氫-1H-苯並[d]咪唑-4-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 69) (4S)-8-(6-胺基-5-((1-胺基-3,3-二氟-2,3-二氫-1H-茚-4-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 70) (S)-5-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)-2-甲基-[1,2,4]三氮唑並[4,3-a]吡啶-3(2H)-酮； 71) (S)-8-(6-胺基-5-((3,3-二氟-2-甲基-2,3-二氫-[1,2,4]三氮唑[4,3-a]吡啶-5-基)硫代)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺； 72) (S)-1-(4-((3-胺基-5-(4-胺基-2-氧雜-8-氮雜螺[4.5]癸烷-8-基)吡嗪-2-基)硫代)吲哚-1-基)乙酮； 73) 1'-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡嗪-2-基)六氫螺[環戊烷[b]呋喃-5,4'-哌啶]-4-胺； 74) 1'-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡嗪-2-基)螺[二環[3.1.0]己烷-3,4'-哌啶]-2-胺； 75) 1'-胺基-1-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡嗪-2-基)四氫螺[哌啶-4,2'-吡咯]-3'(1'H)-酮； 76) 1'-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡嗪-2-基)螺[二環[3.1.0]己烷-2,4'-哌啶]-3-胺。The compound according to claim 1, wherein the compound is 1) (S)-N 1 -(3-((3-amino-5-(4-amino-2-oxa-8-aza) Spiro[4.5]decane-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl) -N 2 ,N 2 -dimethylformamide hydrochloride; 2) N 1 - (4-((3-Amino-5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)- N 2 ,N 2 -dimethylxylamine; 3) N-(3-((3-amino-5-(4-amino-4-methylpiperidin-1-yl)pyrazine-2) -yl)thio)-2-chlorophenyl)-4-(2-(dimethylamino)-2-oxoethyl)benzamide; 4) 6-((3-amino) -5-(4-(Aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2H-benzo[b][1,4]oxazine- 3(4H)-one; 5) 6-(3-Amino-5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)-2H- Benzo[b][1,4]oxazin-3(4H)-one; 6) 5-((2-amino-3-chloropyridin-4-yl)thio) -N 2 -(2- Azaspiro[4.5]decane-8-yl)pyrazine-2,6-diamine; 7) (S)-1-(4-((3-amino-5-(4-amino-2) -oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl)thio)-3,3-difluoroindol-1-yl)ethanone; 8) ( S)-4-((3-Amino-5-(4-amino-2-oxa-8-azaspiro[4.5]decane-8 -yl)pyrazin-2-yl)thio)-3,3-difluoroporphyrin-2-one; 9) 4-((3-amino-5-(4-(aminomethyl))) 4-methylpiperidin-1-yl)pyrazin-2-yl)thio)porphyrin-2-one; 10) (S)-4-((3-amino-5-(4- Amino-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl)thio)-3,3-difluoro-1H-pyrrolo[2,3- b]pyridine-2(3H)-one; 11) (S)-4-((3-amino-5-(4-amino-2-oxa-8-azaspiro[4.5]decane- 8-yl)pyrazin-2-yl)thio)-3,3-difluoro-1-methylindol-2-one; 12) (S)-4-((3-amino-5-) (4-Amino-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl)thio)porphyrin-2,3-dione hydrochloride; 13) 1-(4-((3-Amino-5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3,3 -difluoroporphyrin-1-yl)ethanone; 14) 4-((3-amino-5-(4-(amino)methyl)-4-methylpiperidin-1-yl)pyrazine -2-yl)thio)porphyrin-2,3-dione; 15) 5-((2-amino-3-chloropyridin-4-yl)thio)-6-(4-(amine Methyl)-4-methylpiperidin-1-yl)pyrazin-2-amine; 16) N 1 -(4-((3-amino-5-(4-(aminomethyl))-) 4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl) -N 2 ,N 2 -dimethylxalamine; 17 ((1-(6-Amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl) )methyl)amino carboxylic acid tert-butyl ester; 18) (S)-N 1 -(4-((3-amino-5-(4-amino-2-oxa-8-azaspiro[4.5 ] decane-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl) -N 2 ,N 2 -dimethyl oxazinamide; 19) (S)-N 1 -(3-((3-Amino-5-(4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl)thio)- 2-chlorophenyl) -N 2 ,N 2 -dimethylxalamine; 20) N 1 -(3-(3-amino-5-(4-(aminomethyl))-4-) Isopiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl) -N 2 ,N 2 -dimethylxylamine; 21) N-(3-((3- Amino-5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-3-(2-( Dimethylamino)-2-oxoethyl)benzamide; 22) 2-(3-(3-(3-((3-amino-5-(4-(aminomethyl))) -4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)ureido)phenyl)-N,N-dimethyl-2-oxo Guanidine; 23) 2-(4-(3-(3-((3-Amino-5-(4-(amino)methyl)-4-methylpiperidin-1-yl)pyrazine-2 -yl)thio)-2-chlorophenyl)ureido)phenyl)-N,N-dimethyl-2-oxoethylamine; 24 6-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-3-((3,4-dihydro-2H-benzo[b][1,4]oxazine -6-yl)thio)pyrazine-2-amine; 25) (1-(6-Amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazine- Tert-butyl 2-yl)-4-methylpiperidin-4-yl)carbamate; 26) (1-(5-((2-propenylamine-3-chloropyridin-4-yl))thio) Tert-butyl-6-aminopyrazin-2-yl)-4-methylpiperidin-4-yl)carbazate; 27) (1-(6-Amino-5-((3-chloro) 2-(2-(Dimethylamino)-2-oxoethylamino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl Tert-butyl carbazate; 28) (1-(6-Amino-5-((2-chloro-3-(2-(dimethylamino))-2-oxoethylamino)benzene Tert-butyl thio)pyrazine-2-yl)-4-methylpiperidin-4-yl)carbazate; 29) N 1 -(3-((3-amino-5-(4) -amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl) -N 2 ,N 2 -dimethylformamide; 30) (1 -(6-Amino-5-((3-amino-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)carbamic acid tert-butyl ester 31) N-(3-((3-Amino-5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl -2-oxo-2-(4-methylphenyl)acetamide; 32) (1-(5-((3-Propyl)-2-chlorophenyl)thio)-6-aminopyrazin-2-yl)-4-methylpiperidin-4-yl)amine Tert-butyl carboxylic acid; 33) 6-(3-Amino-5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)-2H-benzo[b] [1,4]oxazin-3(4H)-one; 34) N-(4-((3-amino-5-(4-amino-4-methylpiperidin-1-yl)pyrazine) -2-yl)thio)-3-chloropyridin-2-yl)-4-(2-(dimethylamino)-2-oxoethyl)benzamide; 35) N-( 4-((3-Amino-5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridine-2- 4-(2-(dimethylamino)-2-oxoethyl)benzamide; 36) N-(3-((3-amino-5-(4-)amine Methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-4-(2-(dimethylamino)-2-oxo Benzyl hydrazide; 37) 5-((2-amino-3-chloropyridin-4-yl)thio) -N 2 -cyclohexylpyrazine-2,6-diamine; 38 (S)-8-(5-((1H-pyrrolo[2,3-b]pyridin-4-yl)thio)-6-aminopyrazin-2-yl)-2-oxa- 8-Azaspiro[4.5]decane-4-amine; 39) (S)-8-(6-Amino-5-((3,3-dimethylindol-4-yl)thio Pyrazin-2-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine; 40) (S)-8-(6- Amino-5-((3-fluoro-1H-indol-4-yl)thio)pyrazin-2-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine 41) 5-((2-Amino-3-chloropyridin-4-yl)thio) -N 2 -(4-(aminomethyl)-4-methylcyclohexyl)pyrazine-2, 6-diamine; 42) (S)-8-(5-((1H-indol-4-yl)thio)-6-aminopyrazin-2-yl)-2-oxa-8- Azaspiro[4.5]decane-4-amine; 43) (S)-1-(4-((3-amino-5-(4-amino-2-oxa-8-azaspiro[ 4.5]decane-8-yl)pyrazin-2-yl)thio)-1H-indol-1-yl)ethanone; 44) 5-((2-amino-3-chloropyridine-4- () thio) -N 2 -(4-amino-4-methylcyclohexyl)pyrazine-2,6-diamine; 45) (S)-6-((3-amino-5-( 4-Amino-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl)thio)-2H-benzo[b][1,4]oxazine -3(4H)-one; 46) (S)-4-((3-Amino-5-(4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl) Pyrazin-2-yl)thio)-1,3,3-trimethylindol-2-one; 47) (4S)-8-(6-amino-5-((3-fluoro) Phenanthion-4-yl)thio)pyrazine-2-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine; 48) 1-(4-((3) -amino-5-((S)-4-amino-2-oxo-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl)thio)-3-fluoro -3-methylindole Porphyrin-1-yl)ethanone; 49) (S)-8-(6-Amino-5-((3,3-difluoroindol-4-yl)thio)pyrazine-2- ))-2-oxa-8-azaspiro[4.5]decane-4-amine; 50) 1-(4-((3-amino-5-((S)))) -oxaspiro[4.5]decane-8-yl)pyrazin-2-yl)thio)-3-methylindol-1-yl)ethanone; 51) (S)-8-(6 -amino-5-((8-chloro-4,4-difluoro-1,2,3,4-tetrahydroquinolin-5-yl)thio)pyrazine-2-yl)-2-oxo Hetero-8-azaspiro[4.5]decane-4-amine; 52) (4S)-8-(6-amino-5-((8-chloro-4-fluoro-1,2,3,4) -tetrahydroquinolin-5-yl)thio)pyrazine-2-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine; 53) (S)-8-( 6-amino-5-((3,3-difluoro-1-methylindolino-4-yl)thio)pyrazin-2-yl)-2-oxa-8-azaspiro[ 4.5] decane-4-amine; 54) (S)-6-((3-amino-5-(4-amino-2-oxa-8-azaspiro[4.5]decane-8- Pyrazine-2-yl)thio)-3,3-difluoroporphyrin-2-one; 55) 4-((3-amino-5-((S)-4-amino)- 2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl)thio)-3-fluoroindol-2-one; 56) (S)-8- (6-Amino-5-((3,3-difluoro-2,3-dihydrobenzofuran-4-yl)thio)pyrazin-2-yl)-2-oxa-8-nitrogen Heterospiro[4.5]decane-4-amine; 57) ( S)-8-(6-Amino-5-((4,4-difluorochroman-5-yl)thio)pyrazine-2-yl)-2-oxa-8- Azaspiro[4.5]decane-4-amine; 58) 4-((3-Amino-5-((S)-4-amino-2-oxo-8-azaspiro[4.5]癸Alkan-8-yl)pyrazin-2-yl)thio)-3-fluoro-1-methyl-3-(trifluoromethyl)indol-2-one; 59) (S)-6- ((3-Amino-5-(4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl)thio)-7-chloropurine Porphyrin-2-one; 60) (S)-8-(6-Amino-5-((5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazine) -6-yl)thio)pyrazin-2-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine; 61) (S)-7-((3-amino) -5-(4-Amino-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl)thio)-8-chloro-3,4-dihydro Quinoline-2(1H)-one; 62) (S)-6-((3-Amino-5-(4-amino-2-oxa-8-azaspiro[4.5]decane-8 -yl)pyrazin-2-yl)thio)-5-chloro-2H-benzo[b][1,4]oxazin-3(4H)-one; 63) (S)-2-(3 -((3-Amino-5-(4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl)thio)-2-chloro Phenyl)-N,N-dimethyl-2-oxoethylamine; 64) 4-((3-Amino-5-(4-(aminomethyl)-4-methylpiperidine- 1-yl)pyrazin-2-yl)thio)-3,3-di -1H-pyrrolo[2,3-b]pyridine-2(3H)-one; 65) (S)-4-((3-amino-5-(4-amino-2-oxo-8) -azaspiro[4.5]decane-8-yl)pyrazin-2-yl)thio)-1H-benzo[d]imidazole-2(3H)-one; 66) (S)-4-( (3-Amino-5-(4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl)thio)-1,3-di methyl-1H-benzo[d]imidazole-2(3H)-one; 67) (S)-8-(6-amino-5-((2,2-difluoro-2,3-dihydro) -1H-benzo[d]imidazol-4-yl)thio)pyrazin-2-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine; 68) (S) 8-(6-Amino-5-((2,2-difluoro-1,3-dimethyl-2,3-dihydro-1H-benzo[d]imidazol-4-yl)thio Pyrazin-2-yl)-2-oxa-8-azaspiro[4.5]decane-4-amine; 69) (4S)-8-(6-amino-5-((1-amine) 3-,3-difluoro-2,3-dihydro-1H-indol-4-yl)thio)pyrazin-2-yl)-2-oxa-8-azaspiro[4.5]decane 4-amine; 70) (S)-5-((3-Amino-5-(4-amino-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazine -2-yl)thio)-2-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one; 71) (S)-8-( 6-Amino-5-((3,3-difluoro-2-methyl-2,3-dihydro-[1,2,4]triazole[4,3-a]pyridin-5-yl Thio)pyrazin-2-yl)-2-oxa-8-azaspiro[4.5] Alk-4-amine; 72) (S)-1-(4-((3-amino-5-(4-amino-2-oxa-8-azaspiro[4.5]decane-8-) Pyrazine-2-yl)thio)indol-1-yl)ethanone; 73) 1'-(6-amino-5-((2-amino-3-chloropyridin-4-yl) Thio)pyrazin-2-yl)hexahydrospiro[cyclopentane[b]furan-5,4'-piperidine]-4-amine; 74) 1'-(6-amino-5-( (2-Amino-3-chloropyridin-4-yl)thio)pyrazine-2-yl)spiro[bicyclo[3.1.0]hexane-3,4'-piperidinyl]-2-amine; 75) 1'-Amino-1-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)tetrahydrospiro[piperidine -4,2'-pyrrole]-3'(1'H)-one; 76) 1'-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio) Pyrazin-2-yl)spiro[bicyclo[3.1.0]hexane-2,4'-piperidine]-3-amine. 一種至少一種請求項1-39任一項所述的化合物或其藥學上可接受的鹽用於製備藥物的用途。Use of a compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament. 根據請求項40所述的用途，所述藥物用於治療由SHP2活性介導的病症。According to the use of claim 40, the medicament is for the treatment of a condition mediated by SHP2 activity. 根據請求項41所述的用途，所述由SHP2活性介導的病症是癌症、癌症轉移、心血管疾病、免疫學病症或眼部病症的治療或預防。According to the use of claim 41, the condition mediated by SHP2 activity is the treatment or prevention of cancer, cancer metastasis, cardiovascular disease, immunological condition or ocular condition. 根據請求項42所述的用途，所述由SHP2活性介導的病症是努南氏症候群、豹皮症候群、青少年骨髓單核細胞白血病、神經母細胞瘤、黑色素瘤、頭頸部鱗狀細胞癌、急性骨髓性白血病、乳癌、食道癌、肺癌、結腸癌、頭癌、胃癌、間變性大細胞淋巴瘤或成膠質細胞瘤。According to the use of claim 42, the condition mediated by SHP2 activity is Nunan's syndrome, leopard skin syndrome, adolescent bone marrow monocytogene leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma, Acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric cancer, anaplastic large cell lymphoma or glioblastoma. 一種藥物組合物，包含至少一種請求項1-39任一項所述的化合物和至少一種藥學上可接受的輔藥。A pharmaceutical composition comprising at least one compound of any one of claims 1-39 and at least one pharmaceutically acceptable adjuvant. 請求項44所述的藥物組合物，其中所述化合物與所述輔藥的重量比的範圍為約0.0001~約10。The pharmaceutical composition of claim 44, wherein the weight ratio of the compound to the adjuvant ranges from about 0.0001 to about 10. 一種請求項44所述的藥物組合物用於製備藥物的用途。Use of the pharmaceutical composition of claim 44 for the preparation of a medicament. 根據請求項46所述的用途，其中所述藥物組合物用於治療由SHP2活性介導的病症。The use of claim 46, wherein the pharmaceutical composition is for treating a condition mediated by SHP2 activity. 根據請求項47所述的用途，其中所述由SHP2活性介導的病症是癌症、癌症轉移、心血管疾病、免疫學病症或眼部病症的治療或預防。The use according to claim 47, wherein the condition mediated by SHP2 activity is the treatment or prevention of cancer, cancer metastasis, cardiovascular disease, immunological condition or ocular condition. 根據請求項47所述的用途，其中所述由SHP2活性介導的病症是努南氏症候群、豹皮症候群、青少年骨髓單核細胞白血病、神經母細胞瘤、黑色素瘤、頭頸部鱗狀細胞癌、急性骨髓性白血病、乳癌、食道癌、肺癌、結腸癌、頭癌、胃癌、間變性大細胞淋巴瘤或成膠質細胞瘤。The use according to claim 47, wherein the condition mediated by SHP2 activity is Nunan's syndrome, leopard skin syndrome, adolescent bone marrow monocytogene leukemia, neuroblastoma, melanoma, head and neck squamous cell carcinoma Acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, gastric cancer, anaplastic large cell lymphoma or glioblastoma.
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US11529347B2 (en) 2016-09-22 2022-12-20 Relay Therapeutics, Inc. SHP2 phosphatase inhibitors and methods of use thereof
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US11629145B2 (en) 2016-10-24 2023-04-18 D. E. Shaw Research, Llc SHP2 phosphatase inhibitors and methods of use thereof
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US11529347B2 (en) 2016-09-22 2022-12-20 Relay Therapeutics, Inc. SHP2 phosphatase inhibitors and methods of use thereof
US11629145B2 (en) 2016-10-24 2023-04-18 D. E. Shaw Research, Llc SHP2 phosphatase inhibitors and methods of use thereof
US11591336B2 (en) 2017-05-26 2023-02-28 D. E. Shaw Research, Llc Substituted pyrazolo[3,4-b]pyrazines as SHP2 phosphatase inhibitors
US11701354B2 (en) 2017-09-29 2023-07-18 D. E. Shaw Research, Llc Pyrazolo[3,4-b]pyrazine derivatives as SHP2 phosphatase inhibitors
US10934302B1 (en) 2018-03-21 2021-03-02 Relay Therapeutics, Inc. SHP2 phosphatase inhibitors and methods of use thereof
US11890281B2 (en) 2019-09-24 2024-02-06 Relay Therapeutics, Inc. SHP2 phosphatase inhibitors and methods of making and using the same
CN112574212A (en) * 2019-09-30 2021-03-30 上海拓界生物医药科技有限公司 Pyrimido five-membered nitrogen heterocyclic derivative, preparation method and medical application thereof
CN112724145A (en) * 2019-10-14 2021-04-30 杭州雷索药业有限公司 Pyrazine derivatives for inhibiting SHP2 activity
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