TW202115042A

TW202115042A - Aryl phosphorus oxide derivative inhibitors, preparation methods and applications thereof

Info

Publication number: TW202115042A
Application number: TW109121146A
Authority: TW
Inventors: 高鵬; 王少寶; 孫廣俊; 修文華; 譚松良; 蔡家強; 如迪包
Original assignee: 大陸商江蘇豪森藥業集團有限公司; 大陸商上海翰森生物醫藥科技有限公司
Priority date: 2019-06-21
Filing date: 2020-06-22
Publication date: 2021-04-16
Also published as: WO2020253862A1; CN112513029A; CN112513029B; CN112469713B; WO2020253860A1; CN112469713A

Abstract

The present invention relates to aryl phosphorus oxide derivative inhibitors, preparation methods and applications thereof. In particular, the present invention relates to compounds represented by the general formula (IA), their preparation methods and pharmaceutical compositions containing the compounds, and their use as EGFR inhibitors in the treatment of cancer and other related diseases.

Description

芳基磷氧化物類衍生物抑制劑、其製備方法和應用 Aryl phosphorus oxide derivative inhibitor, preparation method and application thereof

本發明屬於藥物合成領域，具體涉及一種芳基磷氧化物類衍生物抑制劑及其製備方法和應用。 The invention belongs to the field of drug synthesis, and specifically relates to an aryl phosphorus oxide derivative inhibitor and a preparation method and application thereof.

EGFR(Epidermal Growth Factor Receptor)是跨膜受體酪胺酸激酶ErbB家族中的一員，藉由與其配體表皮生長因子(EGF)或轉化生長因子α(TGFα)結合激活。激活的EGFR在細胞膜上形成同源二聚體，或與家族中其它受體(如ErbB-2，ErbB-3，或ErbB-4)形成異源二聚體，引起EGFR細胞內關鍵的酪胺酸殘基磷酸化，從而激活細胞內下游信號通路，在細胞增殖、生存及抗凋亡中發揮重要作用。EGFR的激活突變、過表達或基因擴增等可導致EGFR的過度激活，促進細胞向腫瘤細胞轉化，並在腫瘤細胞的增殖、侵襲、轉移以及血管形成中發揮重要作用，是抗癌藥物特別是肺癌治療藥物開發的重要靶點。 EGFR (Epidermal Growth Factor Receptor) is a member of the ErbB family of transmembrane receptor tyrosine kinases and is activated by binding to its ligand epidermal growth factor (EGF) or transforming growth factor alpha (TGFα). Activated EGFR forms a homodimer on the cell membrane, or forms a heterodimer with other receptors in the family (such as ErbB-2, ErbB-3, or ErbB-4), causing the key tyramine in EGFR cells Phosphorylation of acid residues activates downstream signaling pathways in cells and plays an important role in cell proliferation, survival and anti-apoptosis. EGFR activation mutation, overexpression or gene amplification can lead to excessive activation of EGFR, promote cell transformation into tumor cells, and play an important role in tumor cell proliferation, invasion, metastasis and angiogenesis. It is an anti-cancer drug, especially An important target for the development of lung cancer treatment drugs.

第一代EGFR小分子抑制劑包括吉非替尼(易瑞沙)和厄洛替尼(特羅凱)在肺癌治療中顯示出良好的療效，己作為一線藥物用於治療伴隨EGFR激活突變(包括L858R和delE746_A750)的非小細胞肺癌(NSCLC)。但經第一代小分子 EGFR抑制劑治療10-12月後，幾乎所有的NSCLC患者對第一代小分子抑制劑均產生耐藥性，其耐藥機制中有半數以上是由於EGFR看門基因殘基T790M的繼發突變導致。 The first generation of EGFR small molecule inhibitors, including gefitinib (Iressa) and erlotinib (Tracet), have shown good efficacy in the treatment of lung cancer. They have been used as first-line drugs to treat EGFR activating mutations ( Including L858R and delE746_A750) non-small cell lung cancer (NSCLC). But after the first generation of small molecules After 10-12 months of EGFR inhibitor treatment, almost all NSCLC patients are resistant to the first-generation small molecule inhibitors, and more than half of the resistance mechanisms are due to secondary mutations in the EGFR gatekeeper residue T790M resulting in.

奧希替尼(Osimertinib或AZD9291)是第三代EGFR TKI抑制劑，針對EGFR T790M突變導致的耐藥具有高響應率和良好治療效果，並於2015年11月獲得美國FDA加速批准上市，其在臨床上能有效治療EGFR T790M耐藥突變的晚期非小細胞肺癌患者。儘管奧希替尼在臨床上治療EGFR T790M突變的非小細胞肺癌取得了巨大的成功，患者在經過9~14個月治療後仍不可避免出現了耐藥的現象。經研究表明，高達20~40%的耐藥患者耐藥是由於EGFR C797S突變導致。EGFR C797S突變使797位的半肮胺酸轉變為絲胺酸，導致奧希替尼無法與EGFR蛋白形成共價結合健，從而引起耐藥。目前臨床還沒有針對EGFR C797S耐藥突變的有效抑制劑。因此，迫切需要開發新型高活性的EGFR抑制劑以解決EGFR C797S突變導致的藥物耐藥性問題。 Osimertinib (Osimertinib or AZD9291) is a third-generation EGFR TKI inhibitor. It has a high response rate and good therapeutic effect against drug resistance caused by EGFR T790M mutation. It was approved by the U.S. FDA for accelerated marketing in November 2015. Clinically, it can effectively treat patients with advanced non-small cell lung cancer with EGFR T790M resistance mutations. Although osimertinib has achieved great success in the clinical treatment of non-small cell lung cancer with EGFR T790M mutation, patients still inevitably develop drug resistance after 9 to 14 months of treatment. Studies have shown that up to 20-40% of drug-resistant patients are due to the EGFR C797S mutation. The EGFR C797S mutation converts the hemiglycine at position 797 to serine, causing osimertinib to fail to form a covalent bond with the EGFR protein, causing drug resistance. At present, there are no effective inhibitors against EGFR C797S resistance mutations in clinical practice. Therefore, there is an urgent need to develop new highly active EGFR inhibitors to solve the drug resistance problem caused by the EGFR C797S mutation.

諾華公司報導了針對EGFR C797S耐藥的化合物EAI0450，屬於一種EGFR變構抑制劑，在聯合EGFR單抗藥物如西妥昔單抗後，對L858R/T790M/C797S突變的小鼠體內藥效模型中顯示了較好的抗腫瘤效果，但該化合物單藥無效且不能抑制含deIE746_A750的C797S耐藥突變，未能進入臨床研究。2017年Ken Uchibori等報導了Brigatinib(AP26113)和EGFR單抗(如西妥昔單抗)聯用，能克服C797S這個突變導致的第三代EGFR抑制劑耐藥，在PC9(EGFR-C797S/T790M/del19)小鼠藥效模型顯示了良好的抗腫瘤藥效，但Brigatinib同樣面臨單藥體外活性低和體內無顯著抗腫瘤活性，同樣未有進一步臨床研究。 Novartis reported that the compound EAI0450, which is resistant to EGFR C797S, belongs to an EGFR allosteric inhibitor. After being combined with EGFR monoclonal antibodies such as cetuximab, it can be used in the in vivo pharmacodynamic model of L858R/T790M/C797S mutant mice It showed a good anti-tumor effect, but the compound was ineffective as a single agent and could not inhibit the C797S resistance mutation containing deIE746_A750, and failed to enter clinical studies. In 2017, Ken Uchibori et al. reported that the combination of Brigatinib (AP26113) and EGFR monoclonal antibodies (such as cetuximab) can overcome the third-generation EGFR inhibitor resistance caused by the C797S mutation. The /del19) mouse pharmacodynamic model showed good anti-tumor efficacy, but Brigatinib also faced low single-drug in vitro activity and no significant anti-tumor activity in vivo, and there was no further clinical research.

肺癌是威脅人類健康的重大疾病，肺癌死亡率己占所有惡性腫瘤首位。在我國，肺癌發病率逐年上升，每年新發病例70萬左右。我國肺癌伴有EGFR激活性突變的病例占所有NSCLC約35%左右，使用第一代或第三代EGFR抑制劑能發揮良好的治療效果，但後期都會產生新的耐藥突變，因此開發新一代抗耐藥的EGFR抑制劑具有巨大的臨床和市場價值。 Lung cancer is a major disease threatening human health, and the mortality rate of lung cancer has occupied the first place among all malignant tumors. In my country, the incidence of lung cancer is increasing year by year, with about 700,000 new cases each year. The lung cancer cases in my country with EGFR activating mutations account for about 35% of all NSCLC. The first or third generation EGFR inhibitors can exert good therapeutic effects, but new drug-resistant mutations will be generated later, so a new generation will be developed. Anti-drug resistance EGFR inhibitors have huge clinical and market value.

本發明的目的在於提供一種通式(IA)所示的化合物、其立體異構體或其藥學上可接受鹽，其化合物結構如下： The object of the present invention is to provide a compound represented by general formula (IA), its stereoisomers or pharmaceutically acceptable salts thereof, and the compound structure is as follows:

其中： among them:

X₁或Y₁各自獨立的選自鍵、-O-、-NR_AA-、-S-或-CR_AAR_BB-；較佳鍵、-O-、-NH-、-NCH₃-、-S-或-CH₂-； X ₁ or Y ₁ are each independently selected from bond, -O-, -NR _AA -, -S- or -CR _AA R _BB -; preferred bond, -O-, -NH-, -NCH ₃ -,- S- or -CH ₂ -;

環A1、環B1或環C1各自獨立的選自環烷基、雜環基、芳基或雜芳基，視需要進一步被選自氘、烷基、鹵烷基、鹵素、胺基、側氧基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、取代或未取代的環烷基、取代或未取代的雜環基、取代或未取代的芳基、取代或未取代的雜芳基、-(CH₂)_nP(=O)R_CCR_DD、-(CH₂)_nP(=S)R_CCR_DD、-(CH₂)_nS(O)_mRCC、-(CH₂)_nOR_CC、-(CH₂)_nNR_CCR_DD、-(CH₂)_nNR_CCC(O)R_DD、-NR_CCC(O)R_DD、-C(O)NR_CCR_DD、-N^-R_CCS(O)_mR_DD、-(CH₂)_nS(O)_mNR_CCR_DD、-(CH₂)_nC(O)R_CC、-NR_CCC(O)OR_DD、-(CH₂)_nS(O)_mR_CC或-(CH₂)_nNR_CCS(O)_mR_DD中的一個或多個取代基所取代； Ring A1, Ring B1, or Ring C1 are each independently selected from cycloalkyl, heterocyclic, aryl or heteroaryl, and optionally further selected from deuterium, alkyl, haloalkyl, halogen, amine, pendant oxygen Group, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted Substituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n P(=O)R _CC R _DD , -(CH ₂ ) _n P(=S)R _CC R _DD , -(CH ₂ ) _n S(O) _m RCC, -(CH ₂ ) _n OR _CC , -(CH ₂ ) _n NR _CC R _DD , -(CH ₂ ) _n NR _CC C(O)R _DD , -NR _CC C(O ) R _DD , -C(O)NR _CC R _DD , -N ^- R _CC S(O) _m R _DD , -(CH ₂ ) _n S(O) _m NR _CC R _DD , -(CH ₂ ) _n C One or more of (O)R _CC , -NR _CC C(O)OR _DD , -(CH ₂ ) _n S(O) _m R _CC or -(CH ₂ ) _n NR _CC S(O) _m R _DD Substituted by a substituent;

R_a選自氫、氘、羥基、胺基、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、硝基、羥基、氰基、烯基、炔基、環烷基、雜環基、側氧雜環基、芳基、雜芳基、-(CH₂)_nOR_CC、-(CH₂)_NNR_CCR_DD、-(CH₂)_nNR_CCC(O)R_DD、-NR_CCC(O)NR_DDR_EE、-C(O)NR_CCR_DD、-NR_CCS(O)_mR_DD、-(CH₂)_nS(O)_mNR_CCR_DD、-(CH₂)_nC(O)R_CC、-NR_CCC(O)OR_DD、-(CH₂)_nS(O)_mR_CC或-(CH₂)_nNR_CCS(O)_mR_DD；-(CH₂)_mNR_CCR_DD、-(CH₂)_mNR_CCC(O)R_DD、，其中該羥基、胺基烷基、鹵烷基、環烷基、雜環基、芳基和雜芳基，視需要進一步被選自氘、氘、烷基、鹵烷基、鹵素、取代或未取代的胺基、側氧基、硝基、氰基、羥基、取代或未取代的烯基、取代或未取代的炔基、烷氧基、鹵烷氧基、羥烷基、-(CH₂)_nC(O)R_CC、取代或未取代的環烷基、取代或未取代的雜環基、取代或未取代的芳基、取代或未取代的雜芳基、取代或未取代的側氧雜環基、螺環烷基、橋環烷基或稠環烷基中的一個或多個取代基所取代； R _a is selected from hydrogen, deuterium, hydroxy, amino, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halo, nitro, hydroxy, cyano, alkenyl group, alkynyl group, Cycloalkyl, heterocyclyl, pendant oxygen heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n OR _CC , -(CH ₂ ) _N NR _CC R _DD , -(CH ₂ ) _n NR _CC C (O)R _DD , -NR _CC C(O)NR _DD R _EE , -C(O)NR _CC R _DD , -NR _CC S(O) _m R _DD , -(CH ₂ ) _n S(O) _m NR _CC R _DD , -(CH ₂ ) _n C(O)R _CC , -NR _CC C(O)OR _DD , -(CH ₂ ) _n S(O) _m R _CC or -(CH ₂ ) _n NR _CC S(O) _m R _DD ; -(CH ₂ ) _m NR _CC R _DD , -(CH ₂ ) _m NR _CC C(O)R _DD , where the hydroxyl, aminoalkyl, haloalkyl, cycloalkane Group, heterocyclic group, aryl group and heteroaryl group, optionally further selected from deuterium, deuterium, alkyl, haloalkyl, halogen, substituted or unsubstituted amine, pendant oxy, nitro, cyano, Hydroxyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, -(CH ₂ ) _n C(O)R _CC , substituted or unsubstituted ring Alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted pendant oxygen heterocyclyl, spirocycloalkyl, bridged cycloalkyl or One or more substituents in the fused cycloalkyl group;

或者，R_a與環A1鏈接形成一個環烷基、雜環基、芳基或雜芳基，其中該環烷基、雜環基、芳基和雜芳基視需要進一步被選自氫、氘、烷基、鹵烷基、鹵素、胺基、側氧基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、環烷基、雜環基、-(CH₂)_nR_CC、芳基和雜芳基中的一個或多個取代基所取代； Alternatively, R _a and ring A1 are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from hydrogen, deuterium , Alkyl, haloalkyl, halogen, amino, pendant oxy, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic Substituted by one or more substituents in the group, -(CH ₂ ) _n R _{CC, aryl and heteroaryl;}

R_AA或R_BB各自獨立地選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、羥烷基、鹵烷氧基、鹵素、氰基、硝基、羥基、胺基、烯基、炔基、環烷基、雜環基、芳基或雜芳基，其中該烷基、氘代烷基、鹵烷基、烷氧基、羥烷基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基視需要進一步被選自氫、氘、取代或未取代的烷基、鹵素、羥基、取代或未取代的胺基、側氧基、硝基、氰基、取代或未取代烯基、取代或未取代炔基、取代或未取代烷氧基、取代或未取代羥烷基、取代或未取代的環烷基、取代或未取代的雜環基、取代或未取代的芳基和取代或未取代的雜芳基中的一個或多個取代基所取代； R _AA or R _BB are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amine Group, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amine, Pendant oxy, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted Or substituted by one or more substituents in an unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

或者，R_AA或R_BB與環A1或B1可鏈接形成一個環烷基、雜環基、芳基或雜芳基，其中該環烷基、雜環基、芳基和雜芳基視需要進一步被選自氫、氘、烷基、鹵烷基、鹵素、胺基、側氧基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代，較佳鏈接形成一個C_3-6環烷基、3-6員雜環基、C_3-6芳基或3-6員雜芳基，更較佳C_5-6環烷基、5-6員雜環基、C_5-6芳基或5-6員雜芳基； Alternatively, R _AA or R _BB and ring A1 or B1 may be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further Is selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amine, pendant oxy, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, Cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents, preferably linked to form a C _3-6 cycloalkyl, 3-6 membered heterocyclic group, C _3-6 Aryl or 3-6 membered heteroaryl, more preferably C _5-6 cycloalkyl, 5-6 membered heterocyclyl, C _5-6 aryl or 5-6 membered heteroaryl;

R_CC、R_DD或R_EE各自獨立地選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、羥烷基、鹵烷氧基、鹵素、氰基、硝基、羥基、胺基、烯基、炔基、環烷基、雜環基、芳基或雜芳基，其中該烷基、氘代烷基、鹵烷基、烷氧基、羥烷基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基，視需要進一步被選自氫、氘、取代或未取代的烷基、鹵素、羥基、取代或未取代的胺基、側氧基、硝基、氰基、取代或未取代烯基、取代或未取代炔基、取代或未取代烷氧基、取代或未取代羥烷基、取代或未取代的環烷基、取代或未取代的雜環基、取代或未取代的芳基和取代或未取代的雜芳基中的一個或多個取代基所取代； R _CC , R _DD or R _EE are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, Hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkane Oxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted The amino group, pendant oxy group, nitro group, cyano group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted alkoxy group, substituted or unsubstituted hydroxyalkyl group, substituted or unsubstituted ring Alkyl group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group are substituted by one or more substituents;

或者，R_CC、R_DD或R_EE任意兩個可鏈接形成一個環烷基、雜環基、芳基或雜芳基，其中該環烷基、雜環基、芳基和雜芳基，視需要進一步被選自氫、氘、烷基、鹵烷基、鹵素、胺基、側氧基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； Alternatively, _{any two of R CC} , R _DD or R _EE can be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are Need to be further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amine, pendant oxy, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl Substituted by one or more substituents in the group, cycloalkyl, heterocyclyl, aryl and heteroaryl;

m為0、1或2；且 m is 0, 1, or 2; and

n為0、1或2。 n is 0, 1, or 2.

本發明一個較佳的實施方案中，環A1、環B1或環C1各自獨立的選自環烷基、雜環基、芳基或雜芳基，視需要進一步被選自氘、烷基、鹵烷基、鹵素、胺基、側氧基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、取代或未取代的環烷基、取代或未取代的雜環基、取代或未取代的芳基、取代或未取代的雜芳基、-(CH₂)_nP(=O)R_CCR_DD、-(CH₂)_nP(=S)R_CCR_DD、-(CH₂)_nS(O)_mnR_CC、-(CH₂)_nOR_CC、-(CH₂)_nNR_CCR_DD、-(CH₂)_nNR_CCC(O)R_DD、-NR_CCC(O)R_DD、-C(O)NR_CCR_DD、-NR_CCS(O)_mR_DD、-(CH₂)_nS(O)_mNR_CCR_DD、-(CH₂)_nC(O)R_CC、-NR_CCC(O)OR_DD、-(CH₂)_nS(O)_mR_CC、-(CH₂)_nNR_CCS(O)_mR_DD或-(CH₂)_nC≡CR_CC中的一個或多個取代基所取代； In a preferred embodiment of the present invention, ring A1, ring B1, or ring C1 are each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally further selected from deuterium, alkyl, and halogen. Alkyl, halogen, amine, pendant oxy, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or Unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n P(=O)R _CC R _DD , -(CH ₂ ) _n P(=S ) R _CC R _DD , -(CH ₂ ) _n S(O) _mn R _CC , -(CH ₂ ) _n OR _CC , -(CH ₂ ) _n NR _CC R _DD , -(CH ₂ ) _n NR _CC C( O)R _DD , -NR _CC C(O)R _DD , -C(O)NR _CC R _DD , -NR _CC S(O) _m R _DD , -(CH ₂ ) _n S(O) _m NR _CC R _DD , -(CH ₂ ) _n C(O)R _CC , -NR _CC C(O)OR _DD , -(CH ₂ ) _n S(O) _m R _CC , -(CH ₂ ) _n NR _CC S(O ) _m R _DD or -(CH ₂ ) _n C≡CR _CC substituted by one or more substituents;

R_CC和R_DD各自獨立地選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、羥烷基、鹵烷氧基、鹵素、氰基、硝基、羥基、胺基、烯基、炔基、三甲基矽基、環烷基、雜環基、芳基或雜芳基，其中所述的烷基、氘代烷基、鹵烷基、烷氧基、羥烷基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基，視需要進一步被選自氫、氘、取代或未取代的烷基、鹵素、羥基、取代或未取代的胺基、側氧基、硝基、氰基、取代或未取代烯基、取代或未取代炔基、取代或未取代烷氧基、取代或未取代羥烷基、取代或未取代的環烷基、取代或未取代的雜環基、取代或未取代的芳基和取代或未取代的雜芳基中的一個或多個取代基所取代； R _CC and R _DD are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amine Group, alkenyl, alkynyl, trimethylsilyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxy Alkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, and hydroxy , Substituted or unsubstituted amino, pendant oxy, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted Or substituted by one or more substituents in unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

或者，R_CC和R_DD可鏈接形成一個環烷基、雜環基、芳基或雜芳基，其中所述的環烷基、雜環基、芳基和雜芳基，視需要進一步被選自氫、氘、烷基、鹵烷基、鹵素、胺基、側氧基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代。 Alternatively, R _CC and R _DD can be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are further selected as required From hydrogen, deuterium, alkyl, haloalkyl, halogen, amine, pendant oxy, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkane Substituted by one or more substituents in the group, heterocyclic group, aryl group and heteroaryl group.

本發明一個較佳的實施方案在於提供通式(IB)所示的化合物、其立體異構體或其藥學上可接受鹽，其結構如下： A preferred embodiment of the present invention is to provide a compound represented by general formula (IB), its stereoisomers or pharmaceutically acceptable salts thereof, the structure of which is as follows:

其中： among them:

X₁或Y₁各自獨立的選自-O-、-NR_AA-、-S-或-CR_AAR_BB-，較佳-O-、-NH-、-NCH₃-、-S-或-CH₂-； X ₁ or Y ₁ are each independently selected from -O-, -NR _AA -, -S- or -CR _AA R _BB -, preferably -O-, -NH-, -NCH ₃ -, -S- or- CH ₂ -;

M₂、M₃、M₄或M₅存在或不存在，存在時各自獨立的選自N、S、CH、或CR_aa，較佳O、S、N或CH； The _{presence or absence of M 2} , M ₃ , M ₄ or M ₅ , when present, are each independently selected from N, S, CH, or CR _aa , preferably O, S, N or CH;

M₀或M₁存在或不存在，存在時各自獨立的選自N、S、CH、NR_aa或CR_aaR_bb，較佳O、S、N或CH，更佳S、N或CH； The _{presence or absence of M 0} or M ₁ is independently selected from N, S, CH, NR _aa or CR _aa R _{bb when present} , preferably O, S, N or CH, more preferably S, N or CH;

環A選自環烷基或芳基，較佳苯基； Ring A is selected from cycloalkyl or aryl, preferably phenyl;

環D選自取代或未取代的環烷基、取代或未取代的雜環基、取代或未取代的芳基或取代或未取代的雜芳基，較佳取代或未取代的C_3-6環烷基、取代或未取代的3-6員雜環基、取代或未取代的C_5-6芳基或取代或未取代的5-6員雜芳基，更佳含有1-3個氮原子或氧原子的5-6員雜芳基或雜環基，進一步較佳

、

Ring D is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, preferably substituted or unsubstituted C _3-6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic group, substituted or unsubstituted C _5-6 aryl group or substituted or unsubstituted 5-6 membered heteroaryl group, more preferably containing 1-3 nitrogens 5-6 membered heteroaryl or heterocyclic group of atom or oxygen atom, further preferred

,

R獨立地選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、環烷基、雜環基、芳基或雜芳基，較佳氫、烷基或鹵素，更較佳氫、C_1-6烷基、氟、氯、溴或碘，進一步較佳氫、C_1-3烷基、氟、氯或溴； R is independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, ring Alkyl, heterocyclyl, aryl or heteroaryl, preferably hydrogen, alkyl or halogen, more preferably hydrogen, C _1-6 alkyl, fluorine, chlorine, bromine or iodine, still more preferably hydrogen, C _{1 -3} Alkyl, fluorine, chlorine or bromine;

R₁或R₅各自獨立的選自氫、氘、氧、氮、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、環烷基、雜環基、側氧雜環基、芳基、雜芳基、-(CH₂)_nOR_CC、-(CH₂)_nNR_CCR_DD、-(CH₂)_nNR_CCC(O)R_DD、-NR_CCC(O)NR_DDR_EE、-C(O)NR_CCR_DD、-NR_CCS(O)_mR_DD、-(CH₂)_nS(O)_mNR_CCR_DD、-(CH₂)_nC(O)R_CC、-NR_CCC(O)OR_DD、-(CH₂)_nS(O)_mR_CC或-(CH₂)_nNR_CCS(O)_mR_DD；其中該氧、氮、烷基、鹵烷基、環烷基、雜環基、芳基和雜芳基，視需要進一步被選自氘、氘、烷基、鹵烷基、鹵素、取代或未取代的胺基、側氧基、硝基、氰基、羥基、取代或未取代的烯基、取代或未取代的炔基、烷氧基、鹵烷氧基、羥烷基、-(CH₂)_nC(O)R_CC、取代或未取代的環烷基、取代或未取代的雜環基、取代或未取代的芳基、取代或未取代的雜芳基、取代或未取代的側氧雜環基、螺環烷基、橋環烷基或稠環烷基中的一個或多個取代基所取代； R ₁ or R ₅ are each independently selected from hydrogen, deuterium, oxygen, nitrogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyanide Group, alkenyl, alkynyl, cycloalkyl, heterocyclyl, pendant oxoheterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n OR _CC , -(CH ₂ ) _n NR _CC R _DD ,- (CH ₂ ) _n NR _CC C(O)R _DD , -NR _CC C(O)NR _DD R _EE , -C(O)NR _CC R _DD , -NR _CC S(O) _m R _DD , -(CH ₂ ) _n S(O) _m NR _CC R _DD , -(CH ₂ ) _n C(O)R _CC , -NR _CC C(O)OR _DD , -(CH ₂ ) _n S(O) _m R _CC or -(CH ₂ ) _n NR _CC S(O) _m R _DD ; wherein the oxygen, nitrogen, alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are further selected from Deuterium, deuterium, alkyl, haloalkyl, halogen, substituted or unsubstituted amine, pendant oxy, nitro, cyano, hydroxyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, alkane Oxy, haloalkoxy, hydroxyalkyl, -(CH ₂ ) _n C(O)R _CC , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group , Substituted or unsubstituted heteroaryl, substituted or unsubstituted pendant oxoheterocyclic group, spirocycloalkyl, bridged cycloalkyl or condensed cycloalkyl substituted by one or more substituents;

或者，R₁和R₅，或兩個相同或者不同的R₅鏈接形成一個環烷基、雜環基、芳基或雜芳基，其中該環烷基、雜環基、芳基和雜芳基，視需要進一步被選自氫、氘、烷基、鹵烷基、鹵素、胺基、側氧基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、環烷基、雜環基、-(CH₂)_nR_CC、芳基和雜芳基中的一個或多個取代基所取代； Alternatively, R ₁ and R ₅ , or two identical or different R _{5 are} linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are Group, optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amine, pendant oxy, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy , Hydroxyalkyl, cycloalkyl, heterocyclyl, -(CH ₂ ) _n R _CC , aryl and heteroaryl substituted by one or more substituents;

R₂選自-(CH₂)_nP(=O)R_aaR_bb、(CH₂)_nP(=S)R_aaR_bb或-(CH₂)_nS(O)_mR_aa； R _{2 is} selected from -(CH ₂ ) _n P(=O)R _aa R _bb , (CH ₂ ) _n P(=S)R _aa R _bb or -(CH ₂ ) _n S(O) _m R _aa ;

R₃和R₄各自獨立地選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、巰基、烷基取代巰基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的環烷基、取代或未取代的雜環基、取代或未取代的芳基或取代或未取代的雜芳基，較佳氫、烷基、鹵烷基、鹵素、羥基、巰基、烷氧基、-SR_aa或取代或未取代的炔基，更佳氫、C_1-6烷基、C_1-6鹵烷基、鹵素、羥基、巰基、C_1-6烷氧基、-SR_aa、C_2-6炔基、C_2-6烯基，所述C_1-6烷基、C_1-6鹵烷基、C_1-6烷氧基、-SR_aa、C_2-6炔基、C_2-6烯基，視需要進一步被C_3-6環烷基、C_1-6烷基或鹵素所取代，較佳氫、氯、溴、-SCH₃、

、

、

、環丙基或-CF₃； R ₃ and R ₄ are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, mercapto, Alkyl substituted mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted The substituted heteroaryl group is preferably hydrogen, alkyl, haloalkyl, halogen, hydroxy, mercapto, alkoxy, -SR _aa or substituted or unsubstituted alkynyl, more preferably hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, halogen, hydroxy, mercapto, C _1-6 alkoxy, -SR _aa , C _2-6 alkynyl, C _2-6 alkenyl, the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, -SR _aa , C _2-6 alkynyl, C _2-6 alkenyl, and C _3-6 cycloalkyl, C _1-6 alkane Group or halogen, preferably hydrogen, chlorine, bromine, -SCH ₃ ,

,

, Cyclopropyl or -CF ₃ ;

或者，R₃和R₄、R₃和Y₁鏈接形成一個環烷基、雜環基、芳基或雜芳基，其中該環烷基、雜環基、芳基和雜芳基，視需要進一步被選自氫、氘、烷基、鹵烷基、鹵素、胺基、側氧基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代，較佳取代或未取代的C_3-6環烷基、取代或未取代的3-6員雜環基、取代或未取代的C_5-6芳基或取代或未取代的5-6員雜芳基，更佳取代或未取代的含1-2個N、O或S原子的5-6員雜芳基，進一步較佳取代或未取代的吡咯基、取代或未取代的噻唑基、取代或未取代的吡啶基或取代或未取代的苯基； Alternatively, R ₃ and R ₄ , R ₃ and Y _{1 are} linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optional Further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amine, pendant oxy, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl , Cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents, preferably substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted 3-6 members Heterocyclyl, substituted or unsubstituted C _5-6 aryl or substituted or unsubstituted 5-6 membered heteroaryl, more preferably substituted or unsubstituted 5-containing 1-2 N, O or S atoms 6-membered heteroaryl, further preferably substituted or unsubstituted pyrrolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted pyridyl or substituted or unsubstituted phenyl;

R_aa或R_bb各自獨立地選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、羥烷基、鹵烷氧基、鹵素、氰基、硝基、羥基、胺基、烯基、炔基、側氧基、環烷基、雜環基、芳基或雜芳基，其中該烷基、氘代烷基、鹵烷基、烷氧基、羥烷基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基視需要進一步被選自氫、氘、取代或未取代的烷基、鹵素、羥基、取代或未取代的胺基、側氧基、側硫基、硝基、氰基、取代或未取代烯基、取代或未取代炔基、取代或未取代烷氧基、取代或未取代羥烷基、取代或未取代的環烷基、取代或未取代的雜環基、取代或未取代的芳基和取代或未取代的雜芳基中的一個或多個取代基所取代，較佳氫、烷基、環烷基、雜環基、側氧基或側硫基，更佳C_1-6烷基、C_3-6環烷基、3-6員雜環基、側氧基或側硫基，進一步較佳甲基、乙基、丙基、側氧基或側硫基； R _aa or R _bb are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amine Group, alkenyl group, alkynyl group, pendant oxy group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group, wherein the alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, hydroxyalkyl group, halo Alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted The amino group, pendant oxy group, pendant thio group, nitro group, cyano group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted alkoxy group, substituted or unsubstituted hydroxyalkyl group, substituted or Unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl are substituted by one or more substituents, preferably hydrogen, alkyl, Cycloalkyl, heterocyclic, pendant oxy or pendant thio, more preferably C _1-6 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic, pendant oxy or pendant thio, further Preferably methyl, ethyl, propyl, pendant oxy or pendant thio;

或者，R_aa或R_bb與磷原子鏈接形成一個雜環基或雜芳基，其中該雜環基和雜芳基，視需要進一步被選自氫原子、氘原子、烷基、鹵烷基、鹵素、胺基、側氧基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代，較佳3-6員雜環基，更佳 Alternatively, R _aa or R _{bb is} linked with a phosphorus atom to form a heterocyclic group or heteroaryl group, wherein the heterocyclic group and heteroaryl group are further selected from hydrogen atom, deuterium atom, alkyl group, haloalkyl group, Halogen, amino, pendant oxy, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl Is substituted by one or more substituents, preferably 3-6 membered heterocyclic group, more preferably

x為0、1或2； x is 0, 1 or 2;

y為0、1、2、3或4； y is 0, 1, 2, 3 or 4;

q為0、1或2； q is 0, 1 or 2;

m為0、1或2。 m is 0, 1, or 2.

本發明進一步較佳的實施方案中，R₁或R₅各自獨立的選自氫、氘、氧、氮、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、環烷基、雜環基、側氧雜環基、螺環烷基、橋環烷基、稠環烷基、橋雜環基、螺雜環基、稠雜環基、芳基、雜芳基、-(CH₂)_nOR_CC、-(CH₂)_nNR_CCR_DD、-(CH₂)_nNR_CCC(O)R_DD、-NR_CCC(O)NR_DDR_EE、-C(O)NR_CCR_DD、-NR_CCS(O)_mR_DD、-(CH₂)_nS(O)_mNR_CCR_DD、-(CH₂)_nC(O)R_CC、-NR_CCC(O)OR_DD、-(CH₂)_nS(O)_mR_CC、-(CH₂)_nNR_CCS(O)_mR_DD或-(CH₂)_nC≡CR_CC；其中該氧、氮、烷基、鹵烷基、環烷基、雜環基、芳基和雜芳基，視需要進一步被選自氘、氘、烷基、鹵烷基、鹵素、取代或未取代的胺基、側氧基、硝基、氰基、羥基、取代或未取代的烯基、取代或未取代的炔基、烷氧基、鹵烷氧基、羥烷基、-(CH₂)_nC(O)R_CC、取代或未取代的環烷基、取代或未取代的雜環基、取代或未取代的芳基、取代或未取代的雜芳基、取代或未取代的側氧雜環基、螺環烷基、橋環烷基或稠環烷基中的一個或多個取代基所取代； In a further preferred embodiment of the present invention, R ₁ or R ₅ are each independently selected from hydrogen, deuterium, oxygen, nitrogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen , Amine, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, pendant oxygen heterocyclic group, spirocycloalkyl, bridged cycloalkyl, fused ring alkyl, bridged heterocycle Group, spiro heterocyclic group, fused heterocyclic group, aryl, heteroaryl, -(CH ₂ ) _n OR _CC , -(CH ₂ ) _n NR _CC R _DD , -(CH ₂ ) _n NR _CC C(O )R _DD , -NR _CC C(O)NR _DD R _EE , -C(O)NR _CC R _DD , -NR _CC S(O) _m R _DD , -(CH ₂ ) _n S(O) _m NR _CC R _DD , -(CH ₂ ) _n C(O)R _CC , -NR _CC C(O)OR _DD , -(CH ₂ ) _n S(O) _m R _CC , -(CH ₂ ) _n NR _CC S( O) _m R _DD or -(CH ₂ ) _n C≡CR _CC ; wherein the oxygen, nitrogen, alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are further selected as required From deuterium, deuterium, alkyl, haloalkyl, halogen, substituted or unsubstituted amine, pendant oxy, nitro, cyano, hydroxyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, Alkoxy, haloalkoxy, hydroxyalkyl, -(CH ₂ ) _n C(O)R _CC , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl Substituted by one or more substituents in the group, substituted or unsubstituted heteroaryl, substituted or unsubstituted pendant oxoheterocyclic group, spirocycloalkyl, bridged cycloalkyl, or condensed cycloalkyl;

或者，R₁和R₅，或兩個相同或者不同的R₅鏈接形成一個環烷基、雜環基、芳基或雜芳基，其中該環烷基、雜環基、芳基和雜芳基，視需要進一步被選自氫、氘、烷基、鹵烷基、鹵素、胺基、側氧基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、環烷基、雜環基、-(CH₂)_nR_CC、-(CH₂)_nNR_CCR_DD、-(CH₂)_nC(O)R_CC、芳基和雜芳基中的一個或多個取代基所取代。 Alternatively, R ₁ and R ₅ , or two identical or different R _{5 are} linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are Group, optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amine, pendant oxy, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy , Hydroxyalkyl, cycloalkyl, heterocyclyl, -(CH ₂ ) _n R _CC , -(CH ₂ ) _n NR _CC R _DD , -(CH ₂ ) _n C(O)R _CC , aryl and hetero One or more substituents in the aryl group are substituted.

本發明的目的在於提供一種通式(I)所示的化合物、其立體異構體或其藥學上可接受鹽，其中，通式(I)所示的化合物結構如下： The object of the present invention is to provide a compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, wherein the structure of the compound represented by general formula (I) is as follows:

其中： among them:

M₁、M₂和M₃各自相同或者不同，各自獨立的選自O、N、S、CH、NR_aa或CR_aaR_bb； M ₁ , M ₂ and M ₃ are the same or different, and are independently selected from O, N, S, CH, NR _aa or CR _aa R _bb ;

環A選自環烷基或芳基； Ring A is selected from cycloalkyl or aryl;

R獨立地選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、環烷基、雜環基、芳基或雜芳基； R is independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, ring Alkyl, heterocyclyl, aryl or heteroaryl;

R₁選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、環烷基、雜環基、芳基、雜芳基、-(CH₂)_nOR_aa、 -(CH₂)_nNR_aaR_bb、-NR_aaC(O)R_bb、-NR_aaC(O)NR_bbR_cc、-C(O)NR_aaR_bb、-NR_aaS(O)_mR_bb、-(CH₂)_nS(O)_mNR_aaR_bb、-(CH₂)_nC(O)R_aa、-NR_aaC(O)OR_bb、-(CH₂)_nS(O)_mR_aa或-(CH₂)_nNR_aaS(O)_mR_bb，其中該烷基、鹵烷基、環烷基、雜環基、芳基和雜芳基視需要進一步被選自氫、氘、烷基、鹵烷基、鹵素、胺基、側氧基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、取代或未取代的環烷基、取代或未取代的雜環基、取代或未取代的芳基、取代或未取代的雜芳基中的一個或多個取代基所取代； R _{1 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, aryl, heteroaryl, -(CH ₂ ) _n OR _aa , -(CH ₂ ) _n NR _aa R _bb , -NR _aa C(O)R _bb , -NR _aa C(O) NR _bb R _cc , -C(O)NR _aa R _bb , -NR _aa S(O) _m R _bb , -(CH ₂ ) _n S(O) _m NR _aa R _bb , -(CH ₂ ) _n C( O) R _aa , -NR _aa C(O)OR _bb , -(CH ₂ ) _n S(O) _m R _aa or -(CH ₂ ) _n NR _aa S(O) _m R _bb , wherein the alkyl group, Haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amine, pendant oxy, nitro, cyano, Hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted One or more substituents in the substituted heteroaryl group;

R₃和R₄相同或不同，且各自獨立地選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、環烷基、雜環基、芳基或雜芳基； R ₃ and R _{4 are the} same or different, and are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, Cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

R₅選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、環烷基、雜環基、芳基、雜芳基、-(CH₂)_nOR_aa、-(CH₂)_nNR_aaR_bb、-NR_aaC(O)R_bb、-NR_aaC(O)NR_bbR_cc、-C(O)NR_aaR_bb、-NR_aaS(O)_mR_bb、-(CH₂)_nS(O)_mNR_aaR_bb、-(CH₂)_nC(O)R_aa、-NR_aaC(O)OR_bb、-(CH₂)_nS(O)_mR_aa或-(CH₂)_nNR_aaS(O)_mR_bb； R _{5 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, aryl, heteroaryl, -(CH ₂ ) _n OR _aa , -(CH ₂ ) _n NR _aa R _bb , -NR _aa C(O)R _bb , -NR _aa C(O) NR _bb R _cc , -C(O)NR _aa R _bb , -NR _aa S(O) _m R _bb , -(CH ₂ ) _n S(O) _m NR _aa R _bb , -(CH ₂ ) _n C( O) R _aa , -NR _aa C(O)OR _bb , -(CH ₂ ) _n S(O) _m R _aa or -(CH ₂ ) _n NR _aa S(O) _m R _bb ;

或者，R₁和R₅、或兩個相同或者不同的R₅鏈接形成一個環烷基、雜環基、芳基或雜芳基，其中該環烷基、雜環基、芳基和雜芳基視需要進一步被選自氫、氘、烷基、鹵烷基、鹵素、胺基、側氧基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； Alternatively, R ₁ and R ₅ , or two identical or different R _{5 are} linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are The group is optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amine, pendant oxy, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, Substituted by one or more substituents in hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R_aa、R_bb和R_cc各自獨立地選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、羥烷基、鹵烷氧基、鹵素、氰基、硝基、羥基、胺基、烯基、炔基、環烷基、雜環基、芳基或雜芳基，其中該烷基、氘代烷基、鹵烷基、烷氧基、羥烷基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基視需要進一步被選自氫、氘、取代或未取代的烷基、鹵素、羥基、取代或未取代的胺基、側氧基、硝基、氰基、取代或未取代烯基、取代或未取代炔基、取代或未取代烷氧基、取代或未取代羥烷基、取代或未取代的環烷基、取代或未取代的雜環基、取代或未取代的芳基和取代或未取代的雜芳基中的一個或多個取代基所取代； R _aa , R _bb and R _cc are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, Hydroxyl, amino, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkane Oxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted Amino, pendant oxy, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkane Substituted by one or more substituents in the group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, and substituted or unsubstituted heteroaryl group;

或者，R_aa、R_bb和R_cc中任意兩個可鏈接形成一個環烷基、雜環基、芳基或雜芳基，其中該環烷基、雜環基、芳基和雜芳基視需要進一步被選自氫、氘、烷基、鹵烷基、鹵素、胺基、側氧基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； Alternatively, _{any two of R aa} , R _bb and R _cc may be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be Need to be further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amine, pendant oxy, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl Substituted by one or more substituents in the group, cycloalkyl, heterocyclyl, aryl and heteroaryl;

x為0、1或2； x is 0, 1 or 2;

y為0、1、2、3或4； y is 0, 1, 2, 3 or 4;

q為0、1或2； q is 0, 1 or 2;

n為0、1或2；且 n is 0, 1 or 2; and

m為0、1或2。 m is 0, 1, or 2.

本發明進一步較佳的實施方案中，R₁選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、環烷基、雜環基、芳基、雜芳基、-(CH₂)_nOR_aa、-(CH₂)_nNR_aaR_bb、-NR_aaC(O)R_bb、-NR_aaC(O)NR_bbR_cc、-C(O)NR_aaR_bb、-NR_aaS(O)_mR_bb、-(CH₂)_nS(O)_mNR_aaR_bb、- (CH₂)_nC(O)R_aa、-NR_aaC(O)OR_bb、-(CH₂)_nS(O)_mR_aa、-(CH₂)_nNR_aaS(O)_mR_bb或-(CH₂)_nC≡CR_CC，其中該烷基、鹵烷基、環烷基、雜環基、芳基和雜芳基視需要進一步被選自氫、氘、側氧基、烷基、鹵烷基、鹵素、胺基、側氧基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、取代或未取代的環烷基、取代或未取代的雜環基、取代或未取代的芳基、取代或未取代的雜芳基中的一個或多個取代基所取代； In a further preferred embodiment of the present invention, R _{1 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano Group, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n OR _aa , -(CH ₂ ) _n NR _aa R _bb , -NR _aa C(O) R _bb , -NR _aa C(O)NR _bb R _cc , -C(O)NR _aa R _bb , -NR _aa S(O) _m R _bb , -(CH ₂ ) _n S(O) _m NR _aa R _bb ,-(CH ₂ ) _n C(O)R _aa , -NR _aa C(O)OR _bb , -(CH ₂ ) _n S(O) _m R _aa , -(CH ₂ ) _n NR _aa S(O ) _m R _bb or -(CH ₂ ) _n C≡CR _CC , wherein the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further selected from hydrogen, deuterium, side Oxy, alkyl, haloalkyl, halogen, amino, pendant oxy, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted Is substituted by one or more substituents in the cycloalkyl group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, and substituted or unsubstituted heteroaryl group;

R₃和R₄相同或不同，且各自獨立地選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、取代或未取代的炔基、環烷基、雜環基、芳基、雜芳基或-SR_aa； R ₃ and R _{4 are the} same or different, and are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, Cyano, alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or -SR _aa ;

R₅選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、環烷基、雜環基、芳基、雜芳基、-(CH₂)_nOR_aa、-(CH₂)_nNR_aaR_bb、-NR_aaC(O)R_bb、-NR_aaC(O)NR_bbR_cc、-C(O)NR_aaR_bb、-NR_aaS(O)_mR_bb、-(CH₂)_nS(O)_mNR_aaR_bb、-(CH₂)_nC(O)R_aa、-NR_aaC(O)OR_bb、-(CH₂)_nS(O)_mR_aa、-(CH₂)_nNR_aaS(O)_mR_bb或-(CH₂)_nC≡CR_aa； R _{5 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, aryl, heteroaryl, -(CH ₂ ) _n OR _aa , -(CH ₂ ) _n NR _aa R _bb , -NR _aa C(O)R _bb , -NR _aa C(O) NR _bb R _cc , -C(O)NR _aa R _bb , -NR _aa S(O) _m R _bb , -(CH ₂ ) _n S(O) _m NR _aa R _bb , -(CH ₂ ) _n C( O)R _aa , -NR _aa C(O)OR _bb , -(CH ₂ ) _n S(O) _m R _aa , -(CH ₂ ) _n NR _aa S(O) _m R _bb or -(CH ₂ ) _n C≡CR _aa ;

或者，R₁和R₅，或兩個相同或者不同的R₅鏈接形成一個環烷基、雜環基、芳基或雜芳基，其中該環烷基、雜環基、芳基和雜芳基視需要進一步被選自氫原子、氘原子、烷基、鹵烷基、鹵素、胺基、側氧基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、環烷基、取代或未取代的雜環基、芳基、雜芳基、-(CH₂)_nR_aa、-(CH₂)_nNR_aaR_bb和-(CH₂)_nC(O)R_aa中的一個或多個取代基所取代； Alternatively, R ₁ and R ₅ , or two identical or different R _{5 are} linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are The group is optionally selected from hydrogen atom, deuterium atom, alkyl group, haloalkyl group, halogen, amino group, pendant oxy group, nitro group, cyano group, hydroxyl group, alkenyl group, alkynyl group, alkoxy group, haloalkoxy group Group, hydroxyalkyl, cycloalkyl, substituted or unsubstituted heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n R _aa , -(CH ₂ ) _n NR _aa R _bb and -(CH ₂ ) _n C(O)R _aa is substituted by one or more substituents;

R_aa、R_bb和R_cc各自獨立地選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、羥烷基、鹵烷氧基、鹵素、氰基、硝基、羥基、胺基、烯基、炔基、三甲基矽基、環烷基、雜環基、芳基或雜芳基，其中該烷基、氘代烷基、鹵烷基、烷氧基、羥烷基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基視需要進一步被選自氫、氘、取代或未取代的烷基、鹵素、羥基、取代或未取代的胺基、側氧基、硝基、氰基、取代或未取代烯基、取代或未取代炔基、取代或未取代烷氧基、取代或未取代羥烷基、取代或未取代的環烷基、取代或未取代的雜環基、取代或未取代的芳基和取代或未取代的雜芳基中的一個或多個取代基所取代； R _aa , R _bb and R _cc are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, Hydroxyl, amino, alkenyl, alkynyl, trimethylsilyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, Hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, and hydroxy , Substituted or unsubstituted amino, pendant oxy, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted Or substituted by one or more substituents in unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

或者，R_aa、R_bb和R_cc中任意兩個可鏈接形成一個環烷基、雜環基、芳基或雜芳基，視需要進一步被選自氫、氘、烷基、鹵烷基、鹵素、胺基、側氧基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； Alternatively, _{any two of R aa} , R _bb and R _cc can be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, and optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, Halogen, amino, pendant oxy, nitro, cyano, hydroxyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl Is substituted by one or more substituents in;

所述

可以為飽和或不飽和環。 Said

It can be a saturated or unsaturated ring.

本發明較佳的實施方案為提供一種通式(IA)進一步為通式(G)所示： The preferred embodiment of the present invention is to provide a general formula (IA) further represented by the general formula (G):

其中： among them:

環D選自雜環基； Ring D is selected from heterocyclyl;

環B存在或不存在，存在時選自環烷基、雜環基、芳基或雜芳基；較佳C_3-8單環環烷基、橋環烷基、螺環烷基、稠環烷基、3-8員單環雜環基、橋雜環基、螺雜環基、稠雜環基、芳基或3-8員雜芳基；更佳含1-2個N或O原子的5-7員雜環基、橋雜環基、螺雜環基或稠雜環基；進一步較佳以下基團： The presence or absence of ring B is selected from cycloalkyl, heterocyclic, aryl or heteroaryl; preferably C _3-8 monocyclic cycloalkyl, bridged cycloalkyl, spirocycloalkyl, fused ring Alkyl group, 3-8 membered monocyclic heterocyclic group, bridged heterocyclic group, spiro heterocyclic group, fused heterocyclic group, aryl group or 3-8 membered heteroaryl group; preferably containing 1-2 N or O atoms 5-7 membered heterocyclic group, bridged heterocyclic group, spiro heterocyclic group or fused heterocyclic group; further preferred are the following groups:

R選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、環烷基、雜環基、芳基或雜芳基；較佳氫、鹵素或C_1-6烷基； R is selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkyl , Heterocyclyl, aryl or heteroaryl; preferably hydrogen, halogen or C _1-6 alkyl;

R₂選自-(CH₂)_nP(=O)R_aaR_bb、(CH₂)_nP(=S)R_aaR_bb或-(CH₂)_nS(O)_m1R_aa； R _{2 is} selected from -(CH ₂ ) _n P(=O)R _aa R _bb , (CH ₂ ) _n P(=S)R _aa R _bb or -(CH ₂ ) _n S(O) _m1 R _aa ;

R₃選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、取代或未取代的炔基、環烷基、雜環基、芳基、雜芳基或-SR_aa；較佳氫、鹵素、氰基、C_1-6烷基或C_1-6鹵烷基； R _{3 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, substituted or unsubstituted Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or -SR _aa ; preferably hydrogen, halogen, cyano, C _1-6 alkyl or C _1-6 haloalkyl;

R₄選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、取代或未取代的炔基、環烷基、雜環基、芳基、雜芳基或-SR_aa；較佳氫、鹵素、氰基、C_1-6烷基或C_1-6鹵烷基； R _{4 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, substituted or unsubstituted Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or -SR _aa ; preferably hydrogen, halogen, cyano, C _1-6 alkyl or C _1-6 haloalkyl;

R₅選自氫、鹵素、氰基、C_1-6烷基、C_1-6鹵烷基、C_2-6烯基、C_2-4炔基或-(CH₂)_nOR_aa；或者，兩個R₅相連形成一個C_3-8環烷基或3-12員雜環基； R _{5 is} selected from hydrogen, halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-4 alkynyl or -(CH ₂ ) _n OR _aa ; or , Two R _{5 are} connected to form a C _3-8 cycloalkyl group or a 3-12 membered heterocyclic group;

R₈選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、側氧基、環烷基、雜環基、芳基或雜芳基；較佳氫、鹵素、羥基、氰基C_1-6烷基、C_1-6烷氧基或側氧基； R _{8 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, pendant oxygen Group, cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably hydrogen, halogen, hydroxy, cyano C _1-6 alkyl, C _1-6 alkoxy or pendant oxy;

或者，R₅和R₈鏈接形成一個環烷基、雜環基、芳基或雜芳基，其中該環烷基、雜環基、芳基和雜芳基視需要進一步被選自氫原子、氘原子、烷基、鹵烷基、鹵素、胺基、側氧基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； Alternatively, R ₅ and R _{8 are} linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic group, aryl and heteroaryl group are optionally further selected from hydrogen atoms, Deuterium atoms, alkyl groups, haloalkyl groups, halogens, amine groups, pendant oxy groups, nitro groups, cyano groups, hydroxyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, cycloalkyl groups, Substituted by one or more substituents in heterocyclic group, aryl group and heteroaryl group;

R₉選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、側氧基、羥烷基、環烷基、雜環基、芳基、雜芳基、羥基取代的烷基、氰基取代的烷基、-(CH₂)_nR_aa、-(CH₂)_nOR_aa、-(CH₂)_nNR_aaR_bb、-(CH₂)_nC(O)R_aa、-(CH₂)_nS(O)_mR_aa、-(CH₂)_nNR_aaS(O)_mR_bb或-(CH₂)_nNR_aaC(O)R_bb； R _{9 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, pendant oxygen Group, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxy-substituted alkyl, cyano-substituted alkyl, -(CH ₂ ) _n R _aa , -(CH ₂ ) _n OR _aa , -(CH ₂ ) _n NR _aa R _bb , -(CH ₂ ) _n C(O)R _aa , -(CH ₂ ) _n S(O) _m R _aa , -(CH ₂ ) _n NR _aa S( O) _m R _bb or -(CH ₂ ) _n NR _aa C(O)R _bb ;

較佳氫、鹵素、羥基、C_1-6烷基、C_1-6烷基氰基、C_1-6鹵烷基、C_1-6烷氧基、鹵C_1-6烷氧基、C_1-6羥烷基、C_3-6環烷基、C_3-6雜環基、C_1-6羥基取代的烷基、C_1-6氰基取代的烷基、-(CH₂)_nR_aa、-(CH₂)_nOR_aa、-(CH₂)_nNR_aaR_bb、-(CH₂)_nC(O)R_aa、-(CH₂)_nS(O)_mR_aa、-(CH₂)_nNR_aaS(O)_mR_bb或-(CH₂)_nNR_aaC(O)R_bb； Preferably hydrogen, halogen, hydroxy, C _1-6 alkyl, C _1-6 alkyl cyano, C _1-6 haloalkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _1-6 hydroxy substituted alkyl, C _1-6 cyano substituted alkyl, -(CH ₂ ) _n R _aa , -(CH ₂ ) _n OR _aa , -(CH ₂ ) _n NR _aa R _bb , -(CH ₂ ) _n C(O)R _aa , -(CH ₂ ) _n S(O) _m R _aa , -(CH ₂ ) _n NR _aa S(O) _m R _bb or -(CH ₂ ) _n NR _aa C(O)R _bb ;

進一步較佳氫、鹵素、羥基、C_1-3烷基、C_1-3鹵烷基、C_1-3烷氧基、鹵C_1-3烷氧基、C_1-3羥烷基、C_3-6環烷基、C_3-6雜環基、C_1-3羥基取代的烷基、C_1-3氰基取代的烷基、-(CH₂)_nOC_1-3烷基、-(CH₂)_nC(O)C_1-3烷基、-(CH₂)_nC(O)OC_1-3烷基、-(CH₂)_nC(O)C_3-6環烷基、-(CH₂)_nC(O)OC_1-3烷基、-(CH₂)_nNC_1-3-3-6員雜環基、- (CH₂)_nN(C_1-3烷基)₂、-(CH₂)_nNHC_1-3烷基、-(CH₂)_nN(C_1-3烷基)、-(CH₂)_nNHC(O)C_1-3烷基或-(CH₂)_nS(O)₂C_1-3烷基；更佳氫、甲基、乙基、羧基、-CH₂OH、HOCH₂CH₂-、CH₃OCH₂-、CH₃OCH₂CH₂-、CH₂FCH₂-、CNCH₂-、(CH₃)₂N-、(CH₃CH₂)₂N-、(CH₃)₂SO₂-、CH₃CH₂O-、CH₃CH₂NH-、CH₃(O)C(CH₃)N-、CH₃(O)CNH-、(CH₃CH₂)(CH₃)N-、CH₃(O)C-、CH₃O(O)C-、環丙基或甲醯基； More preferably hydrogen, halogen, hydroxy, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _1-3 hydroxy substituted alkyl, C _1-3 cyano substituted alkyl, -(CH ₂ ) _n OC _1-3 alkyl,- (CH ₂ ) _n C(O)C _1-3 alkyl, -(CH ₂ ) _n C(O)OC _1-3 alkyl, -(CH ₂ ) _n C(O)C _3-6 cycloalkyl , -(CH ₂ ) _n C(O)OC _1-3 alkyl, -(CH ₂ ) _n NC _1-3 -3-6-membered heterocyclic group,-(CH ₂ ) _n N(C _1-3 alkane Group) ₂ , -(CH ₂ ) _n NHC _1-3 alkyl, -(CH ₂ ) _n N(C _1-3 alkyl), -(CH ₂ ) _n NHC(O)C _1-3 alkyl or -(CH ₂ ) _n S(O) ₂ C _1-3 alkyl; more preferably hydrogen, methyl, ethyl, carboxyl, -CH ₂ OH, HOCH ₂ CH ₂ -, CH ₃ OCH ₂ -, CH ₃ OCH ₂ CH ₂ -, CH ₂ FCH ₂ -, CNCH ₂ -, (CH ₃ ) ₂ N-, (CH ₃ CH ₂ ) ₂ N-, (CH ₃ ) ₂ SO ₂ -, CH ₃ CH ₂ O-, CH ₃ CH ₂ NH-, CH ₃ (O)C(CH ₃ )N-, CH ₃ (O)CNH-, (CH ₃ CH ₂ )(CH ₃ )N-, CH ₃ (O)C-, CH ₃ O(O)C-, cyclopropyl or methanoyl;

R₁₃選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、側氧基、羥烷基、環烷基、雜環基、芳基或雜芳基；較佳氫、鹵素、氰基、C_1-6烷基或C_1-6鹵烷基； R _{13 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, pendant oxygen Group, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably hydrogen, halogen, cyano, C _1-6 alkyl or C _1-6 haloalkyl;

R_aa、R_bb或R_cc各自獨立的選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、側氧基、三甲基矽基、取代或未取代的環烷基、取代或未取代的雜環基、取代或未取代的芳基或取代或未取代的雜芳基；較佳氫、C_1-6烷基、取代或未取代的C_1-6烷氧基、一個或多個鹵原子取代的C_1-6烷基、取代或未取代的3-6員雜環基或取代或未取代的C_3-6環烷基；更佳氫、甲基、乙基、環丙基、環丁基、甲氧基、乙氧基、三甲基矽基、氟、氯、溴、

、

或

； R _aa , R _bb or R _cc are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano , Alkenyl, alkynyl, pendant oxy, trimethylsilyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl group; preferably hydrogen, C _1-6 alkyl group, a substituted or unsubstituted C _1-6 alkoxy group, substituted with one or more halogen atoms, a C _1-6 alkyl group, a substituted or unsubstituted 3-6 membered Heterocyclic group or substituted or unsubstituted C _3-6 cycloalkyl; more preferably hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, trimethylsilyl, fluorine , Chlorine, bromine,

,

or

；

y為0、1、2、3或4； y is 0, 1, 2, 3 or 4;

n為0、1、2、3或4； n is 0, 1, 2, 3 or 4;

m1為0、1、2、3或4； m1 is 0, 1, 2, 3 or 4;

z為0、1、2、3或4； z is 0, 1, 2, 3 or 4;

p為0、1、2、3或4； p is 0, 1, 2, 3 or 4;

u為0、1、2、3或4；且 u is 0, 1, 2, 3 or 4; and

q為0、1或2。 q is 0, 1, or 2.

本發明更進一步較佳的實施方案在於提供一種通式(II)所示的化合物、其立體異構體或其藥學上可接受鹽，其結構如下： A further preferred embodiment of the present invention is to provide a compound represented by general formula (II), its stereoisomers or pharmaceutically acceptable salts thereof, the structure of which is as follows:

本發明還提供了一種較佳方案，其為通式(IV)所示的化合物、其立體異構體或其藥學上可接受鹽，其結構如下： The present invention also provides a preferred solution, which is a compound represented by general formula (IV), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:

本發明還提供了一種較佳方案，通式(G)進一步為通式(G-1)所示： The present invention also provides a better solution, and the general formula (G) is further represented by the general formula (G-1):

本發明還提供另一較佳的實施方案，其為通式(IG)所示的化合物、其立體異構體或其藥學上可接受鹽，其結構如下： The present invention also provides another preferred embodiment, which is a compound represented by general formula (IG), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:

其中： among them:

R₁₃選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、側氧基、羥烷基、環烷基、雜環基、芳基或雜芳基； R _{13 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, pendant oxygen Group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group;

u為0、1、2、3或4；且 u is 0, 1, 2, 3 or 4; and

i為0、1或2。 i is 0, 1, or 2.

本發明還提供另一較佳的實施方案，其為通式(VII)所示的化合物、其立體異構體或其藥學上可接受鹽，其結構如下： The present invention also provides another preferred embodiment, which is a compound represented by general formula (VII), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:

本發明還提供另一較佳的實施方案，其為(VIII-B)所示的化合物、其立體異構體或其藥學上可接受鹽，其結構如下： The present invention also provides another preferred embodiment, which is the compound represented by (VIII-B), its stereoisomer or its pharmaceutically acceptable salt, and its structure is as follows:

其中： among them:

環F選自取代或未取代的環烷基或取代或未取代的雜環基，較佳取代或未取代的C_4-7環烷基或取代或未取代的5-7員雜環基，進一步較佳哌啶基、四氫吡咯基、環丁基、環戊基、環己基、四氫呋喃基或四氫吡喃基； Ring F is selected from substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclic group, preferably substituted or unsubstituted C _4-7 cycloalkyl or substituted or unsubstituted 5-7 membered heterocyclic group, More preferably piperidinyl, tetrahydropyrrolyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl or tetrahydropyranyl;

R₁₂選自氫原子、氘原子、烷基、鹵烷基、鹵素、胺基、側氧基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、取代或未取代的環烷基、取代或未取代的雜環基、取代或未取代的芳基、取代或未取代的雜芳基、-(CH₂)_nR_aa、-(CH₂)_nNR_aaR_bb或-(CH₂)_nC(O)R_aa，較佳氫、C_1-6烷基、取代或未取代的雜環基、-(CH₂)_nR_aa、-(CH₂)_nNR_aaR_bb或-(CH₂)_nC(O)R_aa； R _{12 is} selected from hydrogen atom, deuterium atom, alkyl group, haloalkyl group, halogen, amino group, pendant oxy group, nitro group, cyano group, hydroxyl group, alkenyl group, alkynyl group, alkoxy group, haloalkoxy group, hydroxyl group Alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n R _aa , -(CH ₂ ) _n NR _aa R _bb or -(CH ₂ ) _n C(O)R _aa , preferably hydrogen, C _1-6 alkyl, substituted or unsubstituted heterocyclic group, -(CH ₂ ) _n R _aa , -(CH ₂ ) _n NR _aa R _bb or -(CH ₂ ) _n C(O)R _aa ;

s為0、1、2、3或4。 s is 0, 1, 2, 3, or 4.

本發明還提供了一種較佳方案，環B選自含有一個或兩個選自氮原子或氧原子的4-6員單環雜環基或含有一個或兩個選自氮原子或氧原子的7-9員稠環雜環基，較佳含有一個選自氮原子或氧原子的4-6員單環雜環基或含有兩個選自氮原子或氧原子的7-9員稠環雜環基。 The present invention also provides a preferred solution. Ring B is selected from 4-6 membered monocyclic heterocyclic groups containing one or two nitrogen atoms or oxygen atoms or containing one or two nitrogen atoms or oxygen atoms. A 7-9 membered fused ring heterocyclic group preferably contains a 4-6 membered monocyclic heterocyclic group selected from a nitrogen atom or an oxygen atom or two 7-9 membered fused ring heterocyclic groups selected from a nitrogen atom or an oxygen atom Ring base.

本發明還提供了一種較佳方案，所述的各通式所示的化合物、其立體異構體或其藥學上可接受鹽，其中通式(IB)以及通式(I)中： The present invention also provides a preferred solution. The compounds represented by the general formulas, their stereoisomers or their pharmaceutically acceptable salts, wherein in the general formula (IB) and the general formula (I):

環A選自如下基團： Ring A is selected from the following groups:

通式(G)、通式(G-1)、通式(IG)以及通式(VII)中： In general formula (G), general formula (G-1), general formula (IG) and general formula (VII):

環B選自如下基團： Ring B is selected from the following groups:

本發明還提供了一種較佳方案，該各通式所示的化合物、其立體異構體或其藥學上可接受鹽，其中通式(IB)以及通式(I)： The present invention also provides a preferred solution. The compounds represented by the general formulas, their stereoisomers or their pharmaceutically acceptable salts, wherein the general formula (IB) and the general formula (I):

環A選自如下基團： Ring A is selected from the following groups:

通式(G)、通式(G-1)、通式(IG)以及通式(VII)中， In general formula (G), general formula (G-1), general formula (IG) and general formula (VII),

環B選自如下基團： Ring B is selected from the following groups:

本發明還提供了一種較佳方案，所述環D選自3-8員雜環基；較佳5-6員雜環基，更佳含有2-3個選自氮或氧原子的5-6員雜環基。 The present invention also provides a preferred solution. The ring D is selected from 3-8 membered heterocyclic groups; preferably 5-6 membered heterocyclic groups, and more preferably contains 2-3 5-members selected from nitrogen or oxygen atoms. 6-membered heterocyclic group.

本發明還提供了一種較佳方案，所述的各通式、其立體異構體或其藥學上可接受的鹽，其中，R₉選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、側氧基、羥烷基、環烷基、雜環基、芳基、雜芳基、-(CH₂)_nC(O)R_aa、-(CH₂)_nC(O)OR_aa、-(CH₂)_nR_aa、-(CH₂)_nOR_aa、-(CH₂)_nNR_aaR_bb、-(CH₂)_nNR_aaC(O)R_bb或-(CH₂)_nS(O)_mR_aa； The present invention also provides a preferred solution. The general formulas, their stereoisomers or their pharmaceutically acceptable salts, wherein R _{9 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, halogen Alkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, pendant oxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, Heteroaryl, -(CH ₂ ) _n C(O)R _aa , -(CH ₂ ) _n C(O)OR _aa , -(CH ₂ ) _n R _aa , -(CH ₂ ) _n OR _aa , -( CH ₂ ) _n NR _aa R _bb , -(CH ₂ ) _n NR _aa C(O)R _bb or -(CH ₂ ) _n S(O) _m R _aa ;

較佳氫、氘、C_1-6烷基、C_1-6烷基氰基、C_1-6鹵烷基、C_1-6烷氧基、鹵C_1-6烷氧基、鹵素、羥基、C_1-6羥烷基、C_3-6環烷基、C_3-6雜環基、-(CH₂)_nOR_aa、-(CH₂)_nC(O)R_aa、-(CH₂)_nNR_aaR_bb、-(CH₂)_nC(O)OR_aa、-(CH₂)_nNR_aaC(O)R_bb或-(CH₂)_nS(O)_mR_aa； Preferably hydrogen, deuterium, C _1-6 alkyl, C _1-6 alkyl cyano, C _1-6 haloalkyl, C _1-6 alkoxy, halogen C _1-6 alkoxy, halogen, hydroxyl , C _1-6 hydroxyalkyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, -(CH ₂ ) _n OR _aa , -(CH ₂ ) _n C(O)R _aa , -(CH ₂ ) _n NR _aa R _bb , -(CH ₂ ) _n C(O)OR _aa , -(CH ₂ ) _n NR _aa C(O)R _bb or -(CH ₂ ) _n S(O) _m R _aa ;

進一步較佳氫、氘、C_1-3烷基、C_1-3烷基氰基、C_1-3鹵烷基、C_1-3烷氧基、鹵C_1-3烷氧基、鹵素、羥基、C_1-3羥烷基、C_3-6環烷基、C_3-6雜環基、-(CH₂)_nOC_1-3烷基、-(CH₂)_nC(O)C_1-3烷基、-(CH₂)_nC(O)OC_1-3烷基、-(CH₂)_nC(O)C_3-6環烷基、-(CH₂)_nC(O)OR_aa、-(CH₂)_nNHC_3-6環烷基、-(CH₂)_nN(C_1-3烷基)₂、-(CH₂)_nNHC_1-3烷基、-(CH₂)_nN(C_1-3烷基)(C_3-6環烷基)、-(CH₂)_nN(C_1-3烷基)(C_3-6雜環基)、-(CH₂)_nN(C_1-3烷基)C(O)C_1-3烷基、-(CH₂)_nNHC(O)C_1-3烷基、-(CH₂)_nSC_1-3烷基、-(CH₂)_nS(O)C_1-3烷基或-(CH₂)_nS(O)₂C_1-3烷基。 More preferably hydrogen, deuterium, C _1-3 alkyl, C _1-3 alkyl cyano, C _1-3 haloalkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, halogen, Hydroxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, -(CH ₂ ) _n OC _1-3 alkyl, -(CH ₂ ) _n C(O)C _1-3 alkyl, -(CH ₂ ) _n C(O)OC _1-3 alkyl, -(CH ₂ ) _n C(O)C _3-6 cycloalkyl, -(CH ₂ ) _n C(O )OR _aa , -(CH ₂ ) _n NHC _3-6 cycloalkyl, -(CH ₂ ) _n N(C _1-3 alkyl) ₂ , -(CH ₂ ) _n NHC _1-3 alkyl, -( CH ₂ ) _n N(C _1-3 alkyl)(C _3-6 cycloalkyl), -(CH ₂ ) _n N(C _1-3 alkyl)(C _3-6 heterocyclyl), -( CH ₂ ) _n N(C _1-3 alkyl) C(O)C _1-3 alkyl, -(CH ₂ ) _n NHC(O)C _1-3 alkyl, -(CH ₂ ) _n SC _{1- 3} alkyl, -(CH ₂ ) _n S(O)C _1-3 alkyl or -(CH ₂ ) _n S(O) ₂ C _1-3 alkyl.

本發明還提供了一種更佳方案，R₉選自氫、鹵素、羥基、C_1-3烷基、氰基取代的C_1-3烷基、C_1-3鹵烷基、C_1-3烷氧基、鹵C_1-3烷氧基、C_1-3羥烷基、C_3-6環烷基、C_3-6雜環基、-(CH₂)_nOC_1-3烷基、-(CH₂)_nC(O)C_1-3烷基、-(CH₂)_nC(O)OC_1-3烷基、-(CH₂)_nC(O)C_3-6環烷基、-(CH₂)_nC(O)OC_1-3烷基、-(CH₂)_nNC_1-3-3-6員雜環基、-(CH₂)_nN(C_1-3烷基)₂、-(CH₂)_nNHC_1-3烷基、-(CH₂)_nN(C_1-3烷基)、-(CH₂)_nNHC(O)C_1-3烷基或-(CH₂)_nS(O)₂C_1-3烷基； The present invention also provides a better solution, R _{9 is} selected from hydrogen, halogen, hydroxyl, C _1-3 alkyl, cyano substituted C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 Alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, -(CH ₂ ) _n OC _1-3 alkyl, -(CH ₂ ) _n C(O)C _1-3 alkyl, -(CH ₂ ) _n C(O)OC _1-3 alkyl, -(CH ₂ ) _n C(O)C _3-6 cycloalkane Group, -(CH ₂ ) _n C(O)OC _1-3 alkyl, -(CH ₂ ) _n NC _1-3 -3-6-membered heterocyclic group, -(CH ₂ ) _n N(C _1-3 Alkyl) ₂ , -(CH ₂ ) _n NHC _1-3 alkyl, -(CH ₂ ) _n N(C _1-3 alkyl), -(CH ₂ ) _n NHC(O)C _1-3 alkyl Or -(CH ₂ ) _n S(O) ₂ C _1-3 alkyl;

較佳氫、甲基、乙基、羧基、-CH₂OH、HOCH₂CH₂-、CH₃OCH₂-、CH₃OCH₂CH₂-、CH₂FCH₂-、CNCH₂-、(CH₃)₂N-、(CH₃CH₂)₂N-、(CH₃)₂SO₂-、CH₃CH₂O-、CH₃CH₂NH-、CH₃(O)C(CH₃)N-、CH₃(O)CNH-、(CH₃CH₂)(CH₃)N-、CH₃(O)C-、CH₃O(O)C-、環丙基或甲醯基。 Preferred hydrogen, methyl, ethyl, carboxyl, -CH ₂ OH, HOCH ₂ CH ₂ -, CH ₃ OCH ₂ -, CH ₃ OCH ₂ CH ₂ -, CH ₂ FCH ₂ -, CNCH ₂ -, (CH ₃ ) ₂ N-, (CH ₃ CH ₂ ) ₂ N-, (CH ₃ ) ₂ SO ₂ -, CH ₃ CH ₂ O-, CH ₃ CH ₂ NH-, CH ₃ (O)C(CH ₃ )N- , CH ₃ (O)CNH-, (CH ₃ CH ₂ )(CH ₃ )N-, CH ₃ (O)C-, CH ₃ O(O)C-, cyclopropyl or methanoyl.

本發明還提供了一種較佳方案，R_aa、R_bb或R_cc各自獨立的選自氫、C_1-6烷基、取代或未取代的C_1-6烷氧基、一個或多個鹵原子取代的C_1-6烷基、取代或未取代的3-6員雜環基或取代或未取代的C_3-6環烷基；更佳氫、甲基、乙基、環丙基、環丁基、甲氧基、乙氧基、三甲基矽基、氟、氯、溴、

、

或

。 The present invention also provides a preferred solution, R _aa , R _bb or R _cc are each independently selected from hydrogen, C _1-6 alkyl, substituted or unsubstituted C _1-6 alkoxy, one or more halogens Atom-substituted C _1-6 alkyl, substituted or unsubstituted 3-6 membered heterocyclic group or substituted or unsubstituted C _3-6 cycloalkyl; more preferably hydrogen, methyl, ethyl, cyclopropyl, Cyclobutyl, methoxy, ethoxy, trimethylsilyl, fluorine, chlorine, bromine,

,

or

.

本發明還提供了一種較佳方案，該各通式、其立體異構體或其藥學上可接受的鹽，其中， The present invention also provides a preferred solution, each of the general formula, its stereoisomers or pharmaceutically acceptable salts thereof, wherein:

R選自氫、鹵素或C_1-6烷基； R is selected from hydrogen, halogen or C _1-6 alkyl;

R₁選自取代的或未取代的3-12員雜環基、-(CH₂)_nOR_aa或-(CH₂)_nNR_aaR_bb； R _{1 is} selected from a substituted or unsubstituted 3-12 membered heterocyclic group, -(CH ₂ ) _n OR _aa or -(CH ₂ ) _n NR _aa R _bb ;

R₃選自氫或鹵素； R _{3 is} selected from hydrogen or halogen;

R₄選自氫； R _{4 is} selected from hydrogen;

R₅選自氫、C_1-6烷基、C_1-6鹵烷基、C_2-6烯基、C_2-4炔基、鹵素、氰基或-(CH₂)_nOR_aa，或者，兩個R₅相連形成一個C_3-8環烷基或3-12員雜環基； R _{5 is} selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-4 alkynyl, halogen, cyano or -(CH ₂ ) _n OR _aa , or , Two R _{5 are} connected to form a C _3-8 cycloalkyl group or a 3-12 membered heterocyclic group;

R₆和R₇自獨立的選自氫或3-12員雜環基，其中該3-12員雜環基視需要進一步被選自氫、氘、C_1-6烷基、C_1-6鹵烷基、鹵素、羥基、胺基、氰基、側氧基、C_3-8環烷基、3-12雜環基、-(CH₂)_nR_aa、-(CH₂)_nC(O)R_aa和-(CH₂)_nOR_aa中的一個或多個取代基所取代； R ₆ and R _{7 are} independently selected from hydrogen or 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group is optionally further selected from hydrogen, deuterium, C _1-6 alkyl, C _1-6 Haloalkyl, halogen, hydroxyl, amino, cyano, pendant oxy, C _3-8 cycloalkyl, 3-12 heterocyclic group, -(CH ₂ ) _n R _aa , -(CH ₂ ) _n C( O) R _aa and -(CH ₂ ) _n OR _aa are substituted by one or more substituents;

或者，R₆和R₇相連形成一個3-12員雜環基，其中該3-12員雜環基視需要進一步被選自氫、氘、C_1-6烷基、C_1-6鹵烷基、鹵素、羥基、胺基、氰基、側氧基、C_3-8環烷基、3-12雜環基、-(CH₂)_nOR_aa、-(CH₂)_nC(O)R_aa和-(CH₂)_nOR_aa中的一個或多個取代基所取代； Alternatively, R ₆ and R _{7 are} connected to form a 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group is optionally further selected from hydrogen, deuterium, C _1-6 alkyl, C _1-6 haloalkane Group, halogen, hydroxyl, amino, cyano, pendant oxy, C _3-8 cycloalkyl, 3-12 heterocyclic group, -(CH ₂ ) _n OR _aa , -(CH ₂ ) _n C(O) R _aa and -(CH ₂ ) _n OR _aa are substituted by one or more substituents;

R₈選自氫、氘、C_1-6烷基、C_1-6氘代烷基、C_1-6鹵烷基、鹵素、胺基、羥基、氰基或側氧基； R _{8 is} selected from hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, halogen, amino, hydroxyl, cyano or pendant oxy;

或者，R₅和R₈鏈接形成一個C_3-8環烷基，其中該C_3-8環烷基視需要進一步被選自氫、氘、C_1-6烷基、C_1-6鹵烷基、鹵素、胺基、側氧基、氰基和羥基中的一個或多個取代基所取代； Alternatively, R ₅ and R _{8 are} linked to form a C _3-8 cycloalkyl group, wherein the C _3-8 cycloalkyl group is optionally further selected from hydrogen, deuterium, C _1-6 alkyl, and C _1-6 haloalkanes. Substituted by one or more substituents in the group, halogen, amine, pendant oxy, cyano and hydroxy;

R₉選自氫、氘、C_1-6烷基、C_1-6氘代烷基、C_1-6鹵烷基、鹵素、胺基、羥基、氰基、側氧基、羥烷基、C_3-8環烷基、3-12員雜環基、-(CH₂)_nC(O)R_aa、-(CH₂)_nR_aa、-(CH₂)_nOR_aa或-(CH₂)_nNR_aaR_bb； R _{9 is} selected from hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, halogen, amino, hydroxyl, cyano, pendant oxy, hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclic group, -(CH ₂ ) _n C(O)R _aa , -(CH ₂ ) _n R _aa , -(CH ₂ ) _n OR _aa or -(CH ₂ ) _n NR _aa R _bb ;

R_aa和R_bb各自獨立地選自氫、氘、氰基、C_1-6烷基、C_1-6氘代烷基、C_1-6鹵烷基或取代或未取代的C_3-8環烷基。 R _aa and R _bb are each independently selected from hydrogen, deuterium, cyano, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl or substituted or unsubstituted C _3-8 Cycloalkyl.

環D為5-6員含氧雜環基；較佳5-6員含雙氧雜環基；更佳

或

； Ring D is a 5-6 membered oxygen-containing heterocyclic group; preferably a 5-6 membered dioxyheterocyclic group; more preferably

or

；

環B為3-8員雜環基；較佳3-8員單環雜環基或3-8員並環雜環基；跟較佳 Ring B is a 3-8 membered heterocyclic group; preferably a 3-8 membered monocyclic heterocyclic group or a 3-8 membered bicyclic heterocyclic group;

R₂選自-(CH₂)_nP(=O)R_aaR_bb； R _{2 is} selected from -(CH ₂ ) _n P(=O)R _aa R _bb ;

R₃選自氫、鹵素、-SR_aa或C_1-6鹵烷基；更佳溴； R _{3 is} selected from hydrogen, halogen, -SR _aa or C _1-6 haloalkyl; more preferably bromine;

R₄選自氫； R _{4 is} selected from hydrogen;

R₅選自氫、C_1-6烷基、C_1-6鹵烷基、C_2-6烯基、C_2-4炔基、鹵素、氰基或-(CH₂)_nOR_aa，或者，兩個R₅相連形成一個C_3-8環烷基或5-6員雜環基； R _{5 is} selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-4 alkynyl, halogen, cyano or -(CH ₂ ) _n OR _aa , or , Two R _{5 are} connected to form a C _3-8 cycloalkyl group or a 5-6 membered heterocyclic group;

R₈選自氫； R _{8 is} selected from hydrogen;

R₉選自氫、氘、鹵素、氰基、C_1-6烷基、C_1-6氘代烷基、C_1-6羥基取代烷基、C_1-6氰基取代烷基、C_1-6鹵烷基、-(CH₂)_nR_aa、-(CH₂)_nOR_aa、-(CH₂)_nC(O)R_aa、-(CH₂)_nS(O)_mR_aa或-(CH₂)_nNR_aaR_bb； R _{9 is} selected from hydrogen, deuterium, halogen, cyano, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 hydroxy substituted alkyl, C _1-6 cyano substituted alkyl, C _{1 -6} haloalkyl, -(CH ₂ ) _n R _aa , -(CH ₂ ) _n OR _aa , -(CH ₂ ) _n C(O)R _aa , -(CH ₂ ) _n S(O) _m R _aa Or -(CH ₂ ) _n NR _aa R _bb ;

R_aa和R_bb各自獨立地選自氫、氘、鹵素、氰基、C_1-6烷基、C_1-6氘代烷基、C_1-6鹵烷基或3-6員雜環基。 R _aa and R _bb are each independently selected from hydrogen, deuterium, halogen, cyano, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, or 3-6 membered heterocyclic group .

本發明還提供了一種更佳方案，通式(I)、通式(G)、通式(G-1)、通式(IG)以及通式(VII)中， The present invention also provides a better solution. In general formula (I), general formula (G), general formula (G-1), general formula (IG) and general formula (VII),

R₂選自-P(=O)(CH₃)₂或-P(=S)(CH₃)₂； R _{2 is} selected from -P(=O)(CH ₃ ) ₂ or -P(=S)(CH ₃ ) ₂ ;

R₃選自氫或鹵素； R _{3 is} selected from hydrogen or halogen;

R₅選自氫、鹵素、氰基、C_1-6烷基、C_1-6烷氧基、C_1-6鹵烷基、C_2-6烯基、或C_2-4炔基，或者，兩個R₅相連形成一個C_3-8環烷基或3-12員雜環基； R _{5 is} selected from hydrogen, halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _2-6 alkenyl, or C _2-4 alkynyl, or , Two R _{5 are} connected to form a C _3-8 cycloalkyl group or a 3-12 membered heterocyclic group;

R₈選自氫、氘、C_1-6烷基、C_1-6氘代烷基、C_1-6鹵烷基、鹵素、胺基、羥基、氰基或側氧基。 R _{8 is} selected from hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, halogen, amino, hydroxyl, cyano or pendant oxy.

R₃選自氫或鹵素； R _{3 is} selected from hydrogen or halogen;

R₅選自氫、鹵素、氰基、C_1-3烷基、C_1-3烷氧基、C_1-3鹵烷基、C_2-3烯基、或C_2-4炔基，或者，兩個R₅相連形成一個C_3-6環烷基或5-6員雜環基； R _{5 is} selected from hydrogen, halogen, cyano, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, C _2-3 alkenyl, or C _2-4 alkynyl, or , Two R _{5 are} connected to form a C _3-6 cycloalkyl group or a 5-6 membered heterocyclic group;

本發明還涉及一種通式(A)所示的化合物、其立體異構體或其藥學上可接受鹽： The present invention also relates to a compound represented by general formula (A), its stereoisomers or pharmaceutically acceptable salts thereof:

其中： among them:

i為0、1、2、3或4； i is 0, 1, 2, 3 or 4;

u為0、1、2、3或4；且 u is 0, 1, 2, 3 or 4; and

q為0、1或2。 q is 0, 1, or 2.

本發明還涉及一種通式(A-1)所示的化合物、其立體異構體或其藥學上可接受鹽： The present invention also relates to a compound represented by general formula (A-1), its stereoisomers or pharmaceutically acceptable salts thereof:

其中： among them:

X1為鹵素、胺基、硼酸或硼酸酯；較佳氯或溴； X1 is halogen, amino, boric acid or boric acid ester; preferably chlorine or bromine;

R_aa或R_bb各自獨立的選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、側氧基、三甲基矽基、取代或未取代的環烷基、取代或未取代的雜環基、取代或未取代的芳基或取代或未取代的雜芳基，較佳C_1-3烷基。 R _aa or R _bb are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl , Alkynyl, pendant oxy, trimethylsilyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, more Preferably C _1-3 alkyl.

i為0、1、2、3或4； i is 0, 1, 2, 3 or 4;

u為0、1、2、3或4；且 u is 0, 1, 2, 3 or 4; and

q為0、1或2。 q is 0, 1, or 2.

本發明還涉及一種通式(A-2)所示的化合物、其立體異構體或其藥學上可接受鹽： The present invention also relates to a compound represented by general formula (A-2), its stereoisomers or pharmaceutically acceptable salts thereof:

其中： among them:

R₃選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、取代或未取代的炔基、環烷基、雜環基、芳基、雜芳基或-SR_aa；較佳氫、鹵素、氰基、C_1-6烷基、C_1-6鹵烷基或-SR_aa； R _{3 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxyl, cyano, alkenyl, substituted or unsubstituted Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or -SR _aa ; preferably hydrogen, halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl or -SR _aa ;

R₅選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、氰基取代的烷基、烯基、炔基、環烷基、雜環基、芳基、雜芳基、-(CH₂)_nOR_aa、-(CH₂)_nNR_aaR_bb、-NR_aaC(O)R_bb、-NR_aaC(O)NR_bbR_cc、 -C(O)NR_aaR_bb、-NR_aaS(O)_mR_bb、-(CH₂)_nS(O)_mNR_aaR_bb、-(CH₂)_nC(O)R_aa、-NR_aaC(O)OR_bb、-(CH₂)_nS(O)_mR_aa、-(CH₂)nNR_aaS(O)_mR_bb或-(CH₂)_nC≡CR_aa，較佳氫、烷基、烷氧基、鹵烷基、鹵素、胺基、硝基、氰基、氰基取代的烷基、烯基、炔基、-NR_aaC(O)R_bb或-(CH₂)_nC≡CR_aa，更佳氫、C_1-6烷基、C_1-6烷氧基、C_1-6鹵烷基、鹵素、胺基、硝基、氰基、氰基取代的烷基、C_2-4烯基、C_2-4炔基、-NR_aaC(O)R_bb或-(CH₂)_nC≡CR_aa，進一步較佳氫、甲基、乙基、丙基、甲氧基、乙氧基、乙烯基、乙炔基、氰基、胺基、硝基、氟、氯、溴、鹵甲基、鹵乙基、-CH₂CN、-NR_aaC(O)R_bb或-(CH₂)_nC≡CR_aa； R _{5 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, cyano substituted alkyl, alkene Group, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n OR _aa , -(CH ₂ ) _n NR _aa R _bb , -NR _aa C(O)R _bb , -NR _aa C(O)NR _bb R _cc , -C(O)NR _aa R _bb , -NR _aa S(O) _m R _bb , -(CH ₂ ) _n S(O) _m NR _aa R _bb ,- (CH ₂ ) _n C(O)R _aa , -NR _aa C(O)OR _bb , -(CH ₂ ) _n S(O) _m R _aa , -(CH ₂ )nNR _aa S(O) _m R _bb Or -(CH ₂ ) _n C≡CR _aa , preferably hydrogen, alkyl, alkoxy, haloalkyl, halogen, amine, nitro, cyano, cyano substituted alkyl, alkenyl, alkynyl , -NR _aa C(O)R _bb or -(CH ₂ ) _n C≡CR _aa , more preferably hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, halogen , Amine, nitro, cyano, cyano substituted alkyl, C _2-4 alkenyl, C _2-4 alkynyl, -NR _aa C(O)R _bb or -(CH ₂ ) _n C≡CR _aa , more preferably hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, vinyl, ethynyl, cyano, amino, nitro, fluorine, chlorine, bromine, halomethyl, halogen Ethyl, -CH ₂ CN, -NR _aa C(O)R _bb or -(CH ₂ ) _n C≡CR _aa ;

或者，兩個相同或者不同的R₅鏈接形成一個環烷基、雜環基、芳基或雜芳基，其中該環烷基、雜環基、芳基和雜芳基，視需要進一步被選自氫原子、氘原子、烷基、鹵烷基、鹵素、胺基、側氧基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、環烷基、雜環基、芳基、雜芳基、-(CH₂)_nR_aa、-(CH₂)_nNR_aaR_bb和-(CH₂)_nC(O)R_aa中的一個或多個取代基所取代；較佳C_3-6環烷基、3-6員雜環基；更佳C_4-6環烷基、5-6員雜環基；進一步較佳環丁基、環戊基、哌啶基、四氫吡咯基、四氫呋喃基或四氫吡喃基； Alternatively, two identical or different R _{5 are} linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are further selected as required From hydrogen atom, deuterium atom, alkyl group, haloalkyl group, halogen, amine group, pendant oxy group, nitro group, cyano group, hydroxyl group, alkenyl group, alkynyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, Cycloalkyl, heterocyclyl, aryl, heteroaryl, one of -(CH ₂ ) _n R _aa , -(CH ₂ ) _n NR _aa R _bb and -(CH ₂ ) _n C(O)R _aa Or more substituents; preferably C _3-6 cycloalkyl, 3-6 membered heterocyclic group; more preferably C _4-6 cycloalkyl, 5-6 membered heterocyclic group; more preferably cyclobutyl , Cyclopentyl, piperidinyl, tetrahydropyrrolyl, tetrahydrofuranyl or tetrahydropyranyl;

R₆和R₇各自獨立地選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、環烷基、雜環基、芳基或雜芳基，其中該烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基，視需要進一步被選自氫、氘、烷基、鹵烷基、鹵素、胺基、側氧基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； R ₆ and R ₇ are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl , Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, aryl group and heteroaryl group, optionally further selected from hydrogen, deuterium, alkyl, haloalkyl, halogen, amine, pendant oxy, nitro, cyano, hydroxy, alkenyl, Substituted by one or more substituents of alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

或者，R₆和R₇鏈接形成一個側氧基、環烷基、雜環基、芳基或雜芳基，其中該環烷基、雜環基、芳基和雜芳基視需要進一步被選自氫原子、氘原子、烷基、鹵烷基、鹵素、胺基、側氧基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； Alternatively, R ₆ and R _{7 are} linked to form a pendant oxy group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group, wherein the cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further selected as necessary From hydrogen atom, deuterium atom, alkyl group, haloalkyl group, halogen, amine group, pendant oxy group, nitro group, cyano group, hydroxyl group, alkenyl group, alkynyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, Substituted by one or more substituents in cycloalkyl, heterocyclyl, aryl and heteroaryl;

R₈選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、側氧基、環烷基、雜環基、芳基或雜芳基；較佳氫、C_1-6烷基、C_1-6烷氧基、鹵素、羥基、氰基或側氧基； R _{8 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, pendant oxygen Group, cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably hydrogen, C _1-6 alkyl, C _1-6 alkoxy, halogen, hydroxy, cyano or pendant oxy;

R_aa、R_bb或R_cc各自獨立的選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、側氧基、三甲基矽基、取代或未取代的環烷基、取代或未取代的雜環基、取代或未取代的芳基或取代或未取代的雜芳基，較佳氫、C_1-6烷基、取代或未取代的C_1-6烷氧基、一個或多個鹵原子取代的C_1-6烷基、取代或未取代的3-6員雜環基或取代或未取代的C_3-6環烷基，更佳氫、甲基、乙基、環丙基、環丁基、甲氧基、乙氧基、三甲基矽基、氟、氯、溴、

、

或

； R _aa , R _bb or R _cc are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano , Alkenyl, alkynyl, pendant oxy, trimethylsilyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl group, preferably hydrogen, C _1-6 alkyl group, a substituted or unsubstituted C _1-6 alkoxy group, substituted with one or more halogen atoms, a C _1-6 alkyl group, a substituted or unsubstituted 3-6 membered Heterocyclic group or substituted or unsubstituted C _3-6 cycloalkyl, more preferably hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, trimethylsilyl, fluorine , Chlorine, bromine,

,

or

；

i為0、1、2、3或4； i is 0, 1, 2, 3 or 4;

u為0、1、2、3或4； u is 0, 1, 2, 3 or 4;

q為0、1或2； q is 0, 1 or 2;

n為0、1、2、3或4； n is 0, 1, 2, 3 or 4;

m為0、1或2； m is 0, 1 or 2;

m1為0、1或2； m1 is 0, 1 or 2;

y為0、1、2、3或4；且 y is 0, 1, 2, 3 or 4; and

p為0、1或2。 p is 0, 1, or 2.

本發明還涉及一種製備如請求項23所述的通式(A-1)所示的化合物、其立體異構體或其藥學上可接受鹽的方法，其特徵在於包含如下步驟： The present invention also relates to a method for preparing the compound represented by general formula (A-1), its stereoisomers or pharmaceutically acceptable salts thereof as described in claim 23, characterized by comprising the following steps:

通式(A)所示的化合物與通式(A-3)所示的化合物反應，得到通式(A-1)所示的目標化合物； The compound represented by the general formula (A) reacts with the compound represented by the general formula (A-3) to obtain the target compound represented by the general formula (A-1);

其中： among them:

X2為鹵素、胺基、硼酸或硼酸酯；較佳氯或溴。 X2 is halogen, amino, boric acid or boric acid ester; preferably chlorine or bromine.

本發明還涉及一種製備如請求項24所述的通式(A-2)所示的化合物、其立體異構體或其藥學上可接受鹽的方法，其特徵在於包含如下步驟： The present invention also relates to a method for preparing the compound represented by general formula (A-2), its stereoisomers or pharmaceutically acceptable salts thereof as described in claim 24, characterized by comprising the following steps:

通式(A-1)所示的化合物與通式(A-4)所示的化合物反應，得到通式(A-2)所示的目標化合物； The compound represented by the general formula (A-1) reacts with the compound represented by the general formula (A-4) to obtain the target compound represented by the general formula (A-2);

其中： among them:

X3為鹵素、胺基、硼酸或硼酸酯；較佳氯、溴或胺基。 X3 is halogen, amine group, boric acid or boric acid ester; preferably chlorine, bromine or amine group.

本發明還涉及一種製備如請求項10所述的通式(G-1)所示的化合物、其立體異構體或其藥學上可接受鹽的方法，其特徵在於包含如下步驟： The present invention also relates to a method for preparing the compound represented by general formula (G-1), its stereoisomers or pharmaceutically acceptable salts thereof as described in claim 10, characterized by comprising the following steps:

通式(A-2)所示的化合物與含環B的化合物反應，得到通式(G-1)所示的目標化合物； The compound represented by the general formula (A-2) reacts with the compound containing ring B to obtain the target compound represented by the general formula (G-1);

環B選自環烷基、雜環基、芳基或雜芳基；較佳C3-8單環環烷基、橋環烷基、螺環烷基、稠環烷基、3-8員單環雜環基、橋雜環基、螺雜環基、稠雜環基、芳基或3-8員雜芳基；更佳含1-2個N或O原子的5-7員雜環基、橋雜環基、螺雜環基或稠雜環基；進一步較佳以下基團： Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably C3-8 monocyclic cycloalkyl, bridged cycloalkyl, spirocycloalkyl, condensed cycloalkyl, 3-8 membered monocyclic Cyclic heterocyclic group, bridged heterocyclic group, spiro heterocyclic group, fused heterocyclic group, aryl group or 3-8 membered heteroaryl group; more preferably 5-7 membered heterocyclic group containing 1-2 N or O atoms , Bridged heterocyclic group, spiro heterocyclic group or fused heterocyclic group; further preferred are the following groups:

本發明還提供了一種較佳方案，還涉及一種醫藥組成物，其包括治療有效劑量的所示的各通式所示化合物及其立體異構體或其藥學上可接受的鹽以及一種或多種藥學上可接受的載體、稀釋劑或賦形劑。 The present invention also provides a better solution, and also relates to a pharmaceutical composition, which includes a therapeutically effective dose of the compound represented by the general formula and its stereoisomers or pharmaceutically acceptable salts thereof, and one or more A pharmaceutically acceptable carrier, diluent or excipient.

本發明還提供了一種較佳方案，還涉及該各通式化合物、及其立體異構體或其藥學上可接受的鹽，或該醫藥組成物在製備MEK抑制劑、EGFR抑制劑和EGFR單抗及其聯用相關藥物中的應用。 The present invention also provides a better solution, and also relates to the compounds of the general formulas, and their stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition is used in the preparation of MEK inhibitors, EGFR inhibitors and EGFR monomers. Anti- and its combination in the application of related drugs.

本發明還提供了一種較佳方案，還涉及該各通式所示的化合物及其立體異構體或其藥學上可接受的鹽，或該醫藥組成物在製備治癌症相關疾病中的應用；其中該癌症疾病選自肺癌。 The present invention also provides a preferred solution, and also relates to the compounds represented by the general formulas and their stereoisomers or pharmaceutically acceptable salts thereof, or the application of the pharmaceutical composition in the preparation and treatment of cancer-related diseases; Wherein the cancer disease is selected from lung cancer.

本發明進一步涉及各通式所示的化合物、其立體異構體或其藥學上可接受的鹽，或其醫藥組成物在製備治療癌症相關疾病的方法。 The present invention further relates to a method for preparing the compound represented by each general formula, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition for the treatment of cancer-related diseases.

本發明還涉及治療癌症相關疾病的方法，其包括向該哺乳動物施用治療有效量的本發明的化合物或其藥學上可接受的鹽、酯、前藥、溶劑化物、水合物或衍生物。 The present invention also relates to a method for treating cancer-related diseases, which comprises administering to the mammal a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

在一些實施方案中，本方法涉及諸如癌症相關病症的治療。 In some embodiments, the method involves the treatment of disorders such as cancer.

以上方法所述的癌症選自乳腺癌、自宮頸癌、結腸癌、肺癌、胃癌、直腸癌、胰腺癌、腦癌、肝癌、實體瘤、神經膠質瘤、神經膠母細胞瘤、白血病、淋巴瘤或骨髓瘤；較佳非小細胞肺癌。 The cancer described in the above method is selected from breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumor, glioma, glioblastoma, leukemia, lymphoma Or myeloma; preferably non-small cell lung cancer.

本文提供的治療方法包括向受試者施用治療有效量的本發明的化合物。在一個實施方案中，本發明提供了治療哺乳動物中包括癌症相關疾病症的方法。該方法包括向該哺乳動物施用治療有效量的本發明的化合物，或其藥學上可接受的鹽、酯、前藥、溶劑化物、水合物或衍生物。 The treatment methods provided herein include administering to a subject a therapeutically effective amount of a compound of the invention. In one embodiment, the present invention provides a method of treating a disease including cancer-related diseases in a mammal. The method includes administering to the mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof.

[發明的詳細說明][Detailed Description of the Invention]

除非有相反陳述，在說明書和請求項書中使用的術語具有下述含義。 Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

術語“烷基”指飽和脂肪族烴基團，其為包含1至20個碳原子的直鏈或支鏈基團，較佳含有1至8個碳原子的烷基，更佳1至6個碳原子的烷基，最更佳1至3個碳原子的烷基。非限制性實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各種支鏈異構體等。更佳的是含有1至6個碳原子的低級烷基，非限制性實施例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，當被取代時，取代基可以在任何可使用的連接點上被取代，所述取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、側氧基、羧基或羧酸酯基，本發明較佳甲基、乙基、異丙基、第三丁基、鹵烷基、氘代烷基、烷氧基取代的烷基和羥基取代的烷基。 The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbons An alkyl group having 1 to 3 carbon atoms is most preferred. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, second butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-di Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4 -Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferably, it is a lower alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, and Dibutyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl Group, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methyl Benzylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups, which are independently selected from Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, pendant oxy, carboxyl or carboxylate group, preferably methyl, ethyl, isopropyl and tertiary butyl in the present invention Group, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

術語“伸烷基”是指烷基的一個氫原子進一步被取代，例如：“亞甲基”指-CH₂-、“伸乙基”指-(CH₂)₂-、“伸丙基”指-(CH₂)₃-、“伸丁基”指-(CH₂)₄-等。術語“烯基”指由至少由兩個碳原子和至少一個碳-碳雙鍵組成的如上定義的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基。 The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" refers to -CH ₂ -, "ethylene" refers to -(CH ₂ ) ₂ -, "propylene" Refers to -(CH ₂ ) ₃ -, "butylene" refers to -(CH ₂ ) ₄ -and so on. The term "alkenyl" refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3 -Butenyl etc. The alkenyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkylthio , Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio.

術語“環烷基”指飽和或部分不飽和單環或多環環狀烴取代基，環烷基環包含3至20個碳原子，較佳包含3至12個碳原子，更佳包含3至6個碳原子。單環環烷基的非限制性實例包括環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環己二烯基、環庚基、環庚三烯基、環辛基等；多環環烷基包括螺環、稠環和橋環的環烷基，較佳環丙基、環丁基、環己基、環戊基和環庚基。 The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.

術語“螺環烷基”指5至20員的單環之間共用一個碳原子(稱螺原子)的多環基團，其可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。較佳為6至14員，更佳為7至10員。根據環與環之間共用螺原子的數目將螺環烷基分為單螺環烷基、雙螺環烷基或多螺環烷基，較佳為單螺環烷基和雙螺環烷基。更佳為4員/4員、4員/5員、4員/6員、5員/5員或5員/6員單螺環烷基。螺環烷基的非限制性實例包括： The term "spirocycloalkyl" refers to a polycyclic group that shares one carbon atom (called a spiro atom) between monocyclic rings with 5 to 20 members. It may contain one or more double bonds, but none of the rings have complete conjugation. Π electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between the ring and the ring, the spirocycloalkyl is classified into a single spirocycloalkyl, a dispirocycloalkyl, or a polyspirocycloalkyl, preferably a single spirocycloalkyl and a bispirocycloalkyl . More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

也包含單螺環烷基與雜環烷基共用螺原子的螺環烷基，非限制性實例包括： It also includes a spirocycloalkyl group in which a single spirocycloalkyl and a heterocycloalkyl share a spiro atom, non-limiting examples include:

術語“稠環烷基”指5至20員，系統中的每個環與體系中的其他環共享毗鄰的一對碳原子的全碳多環基團，其中一個或多個環可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。較佳為6至14員，更佳為7至10員。根據組成環的數目可以分為雙環、三環、四環或多環稠環烷基，較佳為雙環或三環，更佳為5員/5員或5員/6員雙環烷基。稠環烷基的非限制性實例包括：

和

。 The term "fused cycloalkyl" refers to an all-carbon polycyclic group consisting of 5 to 20 members. Each ring in the system shares an adjacent pair of carbon atoms with other rings in the system. One or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyls, preferably bicyclic or tricyclic, and more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl. Non-limiting examples of fused cycloalkyl groups include:

with

.

術語“橋環烷基”指5至20員，任意兩個環共用兩個不直接連接的碳原子的全碳多環基團，其可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。較佳為6至14員，更佳為7至10員。根據組成環的數目可以分為雙環、三環、四環或多環橋環烷基，較佳為雙環、三環或四環，更有選為雙環或三環。橋環烷基的非限制性實例包括： The term "bridged cycloalkyl" refers to a 5- to 20-member, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has a complete Conjugated π electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

該環烷基環可以稠合於芳基、雜芳基或雜環烷基環上，其中與母體結構連接在一起的環為環烷基，非限制性實例包括茚滿基、四氫萘基、苯并環庚烷基等。環烷基可以是視需要取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、側氧基、羧基或羧酸酯基。 The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected with the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl , Benzocycloheptanyl, etc. Cycloalkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, pendant oxy group, carboxyl group or carboxylate group.

術語“雜環基”指飽和或部分不飽和單環或多環環狀烴取代基，其包含3至20個環原子，其中一個或多個環原子為選自氮、氧或S(O)_m(其中m是整數0至2)的雜原子，但不包括-O-O-、-O-S-或-S-S-的環部分，其餘環原子為碳。較佳包含3至12個環原子，其中1~4個是雜原子；更佳包含3至8個環原子；進一步較佳包含1-3氮原子的3-8員雜環基，最佳5-6員雜環基，視需要地，被1-2個氧原子、硫原子、側氧基取代，包括含氮單環雜環基、含氮螺雜環基、含氮稠雜環基、含氧單環雜環基、含氧螺雜環基或含氧稠雜環基。 The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) _m (wherein m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 8 ring atoms; further preferably contains 3-8 membered heterocyclic groups containing 1-3 nitrogen atoms, most preferably 5 The -6 membered heterocyclic group is optionally substituted by 1-2 oxygen atoms, sulfur atoms, and pendant oxy groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spiro heterocyclic groups, nitrogen-containing fused heterocyclic groups, An oxygen-containing monocyclic heterocyclic group, an oxygen-containing spiro heterocyclic group or an oxygen-containing fused heterocyclic group.

單環雜環基的非限制性實例包括吡咯烷基、咪唑烷基、四氫呋喃基、四氫噻吩基、二氫咪唑基、二氫呋喃基、二氫吡唑基、二氫吡咯基、哌啶基、哌嗪基、嗎啉基、硫嗎啉基、高哌嗪基、吡喃基等，較佳哌啶基和哌嗪基。多環雜環基包括螺環、稠環和橋環的雜環基；其中涉及到的螺環、稠環和橋環的雜環基視需要與其他基團藉由單鍵相連接，或者藉由環上的任意兩個或者兩個以上的原子與其他環烷基、雜環基、芳基和雜芳基進一步並環連接。 Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably piperidinyl and piperazinyl. Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic rings involved The group is optionally connected to other groups by a single bond, or is further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups via any two or more atoms on the ring.

術語“螺雜環基”指5至20員的單環之間共用一個原子(稱螺原子)的多環雜環基團，其中一個或多個環原子為選自氮、氧或S(O)_m(其中m是整數0至2)的雜原子，其餘環原子為碳。其可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。較佳為6至14員，更佳為7至10員。根據環與環之間共用螺原子的數目將螺雜環基分為單螺雜環基、雙螺雜環基或多螺雜環基，較佳為單螺雜環基和雙螺雜環基。更佳為4員/4員、4員/5員、4員/6員、5員/5員或5員/6員單螺雜環基。螺雜環基的非限制性實例包括： The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group sharing one atom (called a spiro atom) between monocyclic rings of 5 to 20 members, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) _{Heteroatoms of m} (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between the ring and the ring, the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group . More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members monospiroheterocyclic groups. Non-limiting examples of spiroheterocyclic groups include:

術語“稠雜環基”指5至20員，系統中的每個環與體系中的其他環共享毗鄰的一對原子的多環雜環基團，一個或多個環可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統，其中一個或多個環原子為選自氮、氧或S(O)_m(其中m是整數0至2)的雜原子，其餘環原子為碳。較佳為6至14員，更佳為7至10員。根據組成環的數目可以分為雙環、三環、四環或多環稠雜環基，較佳為雙環或三環，更佳為5員/5員或5員/6員雙環稠雜環基。稠雜環基的非限制性實例包括： The term "fused heterocyclic group" refers to a polycyclic heterocyclic group with 5 to 20 members. Each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated π-electron system, where one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), and the rest of the ring The atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group . Non-limiting examples of fused heterocyclic groups include:

術語“橋雜環基”指5至14員，任意兩個環共用兩個不直接連接的原子的多環雜環基團，其可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統，其中一個或多個環原子為選自氮、氧或S(O)_m(其中m是整數0至2)的雜原子，其餘環原子為碳。較佳為6至14員，更佳為7至10員。根據組成環的數目可以分為雙環、三環、四環或多環橋雜環基，較佳為雙環、三環或四環，更有選為雙環或三環。橋雜環基的非限制性實例包括： The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group with 5 to 14 members, and any two rings share two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common A conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) _m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

該雜環基環可以稠合於芳基、雜芳基或環烷基環上，其中與母體結構連接在一起的環為雜環基，其非限制性實例包括： The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:

和

等。

with

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雜環基可以是視需要取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、側氧基、羧基或羧酸酯基。 The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, pendant oxy, carboxy, or carboxylate.

術語“芳基”指具有共軛的π電子體系的6至14員全碳單環或稠合多環(也就是共享毗鄰碳原子對的環)基團，較佳為6至10員，例如苯基和萘基。更佳苯基。該芳基環可以稠合於雜芳基、雜環基或環烷基環上，包括苯并3-8員環烷基、苯并3-8員雜烷基，較佳苯并3-6員環烷基、苯并3-6員雜烷基，其中雜環基為含1-3氮原子、氧原子、硫原子的雜環基；或者還包含含苯環的三員含氮稠環。 The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group with a conjugated π-electron system, preferably 6 to 10 members, for example Phenyl and naphthyl. More preferably phenyl. The aryl ring can be fused on a heteroaryl, heterocyclic or cycloalkyl ring, including benzo 3-8 membered cycloalkyl, benzo 3-8 membered heteroalkyl, preferably benzo 3-6 Membered cycloalkyl group, benzo 3-6 membered heteroalkyl group, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, and sulfur atoms; or it also contains a three-membered nitrogen-containing fused ring containing a benzene ring .

其中與母體結構連接在一起的環為芳基環，其非限制性實例包括： The ring connected to the parent structure is an aryl ring, and non-limiting examples include:

芳基可以是取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、羧基或羧酸酯基。 The aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkylthio , Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, carboxy, or carboxylate.

術語“雜芳基”指包含1至4個雜原子、5至14個環原子的雜芳族體系，其中雜原子選自氧、硫和氮。雜芳基較佳為5至10員，更佳為5員或6員，例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，較佳為***基、噻吩基、咪唑基、吡唑基或嘧啶基、噻唑基；更有選***基、吡咯基、噻吩基、噻唑基和嘧啶基。該雜芳基環可以稠合於芳基、雜環基或環烷基環上，其中與母體結構連接在一起的環為雜芳基環，其非限制性實例包括： The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, Tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably triazolyl, pyrrole Group, thienyl, thiazolyl and pyrimidinyl. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

雜芳基可以是視需要取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、羧基或羧酸酯基。 The heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, carboxyl group or carboxylate group.

術語“烷氧基”指-O-(烷基)和-O-(非取代的環烷基)，其中烷基的定義如上所述。烷氧基的非限制性實例包括：甲氧基、乙氧基、丙氧基、丁氧基、環丙氧基、環丁氧基、環戊氧基、環己氧基。烷氧基可以是視需要取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、羧基或羧酸酯基。 The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where the definition of alkyl is as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, carboxyl group or carboxylate group.

“鹵烷基”指被一個或多個鹵素取代的烷基，其中烷基如上所定義。 "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.

“鹵烷氧基”指被一個或多個鹵素取代的烷氧基，其中烷氧基如上所定義。 "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.

“羥烷基”指被羥基取代的烷基，其中烷基如上所定義。 "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.

“烯基”指鏈烯基，又稱烯烴基，其中該烯基可以進一步被其他相關基團取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、羧基或羧酸酯基。 "Alkenyl" refers to alkenyl, also known as alkenyl, where the alkenyl may be further substituted by other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino , Halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio , Carboxyl or carboxylate.

“炔基”指(CH≡C-)，其中該炔基可以進一步被其他相關基團取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、羧基或羧酸酯基。 "Alkynyl" refers to (CH≡C-), where the alkynyl group can be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen , Mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl Or carboxylate group.

“羥基”指-OH基團。 "Hydroxy" refers to the -OH group.

“鹵素”指氟、氯、溴或碘。 "Halogen" refers to fluorine, chlorine, bromine or iodine.

“胺基”指-NH₂。 "Amino" refers to -NH ₂ .

“氰基”指-CN。 "Cyano" refers to -CN.

“硝基”指-NO₂。 "Nitro" refers to -NO ₂ .

“羧基”指-C(O)OH。 "Carboxy" refers to -C(O)OH.

“THF”指四氫呋喃。 "THF" means tetrahydrofuran.

“EtOAc”指乙酸乙酯。 "EtOAc" refers to ethyl acetate.

“MeOH”指甲醇。 "MeOH" means methanol.

“DMF”指N、N-二甲基甲醯胺。 "DMF" refers to N, N-dimethylformamide.

“TFA”指三氟乙酸。 "TFA" means trifluoroacetic acid.

“MeCN”指乙晴。 "MeCN" means Otoharu.

“DMA”指N,N-二甲基乙醯胺。 "DMA" refers to N,N-dimethylacetamide.

“Et₂O”指***。 "Et ₂ O" means diethyl ether.

“DCE”指1,2二氯乙烷。 "DCE" refers to 1,2 dichloroethane.

“DIPEA”指N,N-二異丙基乙胺。 "DIPEA" refers to N,N-diisopropylethylamine.

“NBS”指N-溴琥珀醯亞胺。 "NBS" refers to N-bromosuccinimide.

“NIS”指N-碘丁二醯亞胺。 "NIS" refers to N-iodosuccinimide.

“Cbz-Cl”指氯甲酸苄酯。 "Cbz-Cl" refers to benzyl chloroformate.

“Pd₂(dba)₃”指三(二亞苄基丙酮)二鈀。 "Pd ₂ (dba) ₃ "refers to tris(dibenzylideneacetone) dipalladium.

“Dppf”指1,1’-雙二苯基膦二茂鐵。 "Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.

“HATU”指2-(7-氧化苯并***)-N,N,N’,N’-四甲基脲六氟磷酸鹽。 "HATU" refers to 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.

“KHMDS”指六甲基二矽基胺基鉀。 "KHMDS" refers to potassium hexamethyldisilazide.

“LiHMDS”指雙三甲基矽基胺基鋰。 "LiHMDS" refers to lithium bistrimethylsilylamide.

“MeLi”指甲基鋰。 "MeLi" refers to methyl lithium.

“n-BuLi”指正丁基鋰。 "N-BuLi" refers to n-butyl lithium.

“NaBH(OAc)₃”指三乙醯氧基硼氫化鈉。 "NaBH(OAc) ₃ "means sodium triacetoxyborohydride.

“X選自A、B、或C”、“X選自A、B和C”、“X為A、B或C”、“X為A、B和C”等不同用語均表達了相同的意義，即表示X可以是A、B、C中的任意一種或幾種。 "X is selected from A, B, or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and other terms all express the same Meaning, which means that X can be any one or more of A, B, and C.

本發明所述的氫原子均可被其同位素氘所取代，本發明涉及的實施例化合物中的任一氫原子也均可被氘原子取代。 The hydrogen atoms described in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

“視需要”或“視需要地”意味著隨後所描述的事件或環境可以但不必發生，該說明包括該事件或環境發生或不發生的場合。例如，“視需要被烷基取代的雜環基團”意味著烷基可以但不必須存在，該說明包括雜環基團被烷基取代的情形和雜環基團不被烷基取代的情形。 "As needed" or "as needed" means that the event or environment described later can but does not have to occur, and the description includes occasions where the event or environment occurs or does not occur. For example, "optionally alkylated "Substituted heterocyclic group" means that an alkyl group may but does not have to be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.

“取代的”指基團中的一個或多個氫原子，較佳為最多5個，更佳為1~3個氫原子彼此獨立地被相應數目的取代基取代。不言而喻，取代基僅處在它們的可能的化學位置，本領域技術人員能夠在不付出過多努力的情況下確定(藉由實驗或理論)可能或不可能的取代。例如，具有游離氫的胺基或羥基與具有不飽和(如烯屬)鍵的碳原子結合時可能是不穩定的。 "Substituted" refers to one or more hydrogen atoms in the group, preferably at most 5, and more preferably 1 to 3 hydrogen atoms are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amine group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

“醫藥組成物”表示含有一種或多種本文所述化合物或其生理學上/可藥用的鹽或前體藥物與其他化學組分的混合物，以及其他組分例如生理學/可藥用的載體和賦形劑。醫藥組成物的目的是促進對生物體的給藥，利於活性成分的吸收進而發揮生物活性。 "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers And excipients. The purpose of the medicinal composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

“可藥用鹽”是指本發明化合物的鹽，這類鹽用於哺乳動物體內時具有安全性和有效性，且具有應有的生物活性。 "Pharmaceutically acceptable salt" refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has due biological activity.

以下結合實施例進一步描述本發明，但這些實施例並非限制著本發明的範圍。 The present invention is further described below in conjunction with examples, but these examples do not limit the scope of the present invention.

[實施例] [Example]

本發明的化合物結構是藉由核磁共振(NMR)或/和液質聯用色譜(LC-MS)來確定的。NMR化學位移(δ)以百萬分之一(ppm)的單位給出。NMR的測定是用Bruker AVANCE-400核磁儀，測定溶劑為氘代二甲基亞碸(DMSO-d ₆)，氘代甲醇(CD₃OD)和氘代氯仿(CDCl₃)，內標為四甲基矽烷(TMS)。 The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in units of parts per million (ppm). NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO- d ₆ ), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ), and the internal standard was tetramethylsulfonate (DMSO- d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ). Methyl Silane (TMS).

液質聯用色譜LC-MS的測定用Agilent 1200 Infinity Series質譜儀。HPLC的測定使用安捷倫1200DAD高壓液相色譜儀(Sunfire C18 150×4.6mm色譜管柱)和Waters 2695-2996高壓液相色譜儀(Gimini C18 150×4.6mm色譜管柱)。 The liquid mass spectrometry LC-MS was measured with an Agilent 1200 Infinity Series mass spectrometer. HPLC determination uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6mm chromatographic column).

薄層層析矽膠板使用煙臺黃海HSGF254或青島GF254矽膠板，TLC採用的規格是0.15mm~0.20mm，薄層層析分離純化產品採用的規格是0.4mm~0.5mm。管柱層析一般使用煙臺黃海矽膠200~300目矽膠為載體。 The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specifications used for TLC are 0.15mm~0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm~0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

本發明實施例中的起始原料是已知的並且可以在市場上買到，或者可以採用或按照本領域已知的方法來合成。 The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by using or following methods known in the art.

在無特殊說明的情況下，本發明的所有反應均在連續的磁力攪拌下，在乾燥氮氣或氬氣氛下進行，溶劑為乾燥溶劑，反應溫度單位為攝氏度。 Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius.

中間體的製備1 Preparation of intermediate 1

(6-胺基-2,3-二氫苯并[b][1,4]二噁英-5-基)二甲基膦氧化的製備 (6-Amino-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) dimethylphosphine oxidation preparation

第一步：2-溴-6-甲氧基-3-硝基苯酚的製備 The first step: the preparation of 2-bromo-6-methoxy-3-nitrophenol

往2-甲氧基-5-硝基苯酚(2g,11.8mmol)的DCM(20mL)溶液中加入NBS(2.1g,11.8mmol)，室溫攪拌一小時後，向反應中加入CH₂Cl₂與水分液，有機相減壓濃縮後管柱層析分離得到標題化合物2-溴-6-甲氧基-3-硝基苯酚(1.5g，收率：51%)。 Add NBS (2.1g, 11.8mmol) to the solution of 2-methoxy-5-nitrophenol (2g, 11.8mmol) in DCM (20mL). After stirring for one hour at room temperature, CH ₂ Cl _{2 was added to the reaction.} Liquid with water, the organic phase was concentrated under reduced pressure and column chromatography was separated to obtain the title compound 2-bromo-6-methoxy-3-nitrophenol (1.5g, yield: 51%).

MS m/z(ESI)：245.9[M-H]^-. MS m/z(ESI): 245.9 [MH] ^- .

第二步：3-溴-4-硝基苯-1,2-二酚的製備 Step 2: Preparation of 3-bromo-4-nitrobenzene-1,2-diphenol

-78℃下往2-溴-6-甲氧基-3-硝基苯酚(500mg,2.0mmol)的二氯甲烷溶液(5mL)中，加入BBr₃(1M,2.6mL,2.6mmol)的二氯甲烷溶液，攪拌2小時後，緩慢升至室溫，攪拌過夜。冷卻至0℃，向反應中緩慢滴加MeOH(5ml)，有機相減壓濃縮後管柱層析分離得到標題化合物3-溴-4-硝基苯-1,2-二酚(410mg,收率：87%)。 To the dichloromethane solution (5mL) of 2-bromo-6-methoxy-3-nitrophenol (500mg, 2.0mmol) at -78℃, add BBr ₃ (1M, 2.6mL, 2.6mmol) The methyl chloride solution was stirred for 2 hours, then slowly warmed to room temperature and stirred overnight. After cooling to 0°C, MeOH (5ml) was slowly added dropwise to the reaction. The organic phase was concentrated under reduced pressure and then column chromatography was separated to obtain the title compound 3-bromo-4-nitrobenzene-1,2-diphenol (410mg, yield). Rate: 87%).

MS m/z(ESI)：231.9[M-H]^-. MS m/z(ESI): 231.9[MH] ^- .

第三步：5-溴-6-硝基-2,3-二氫苯并[b][1,4]二噁烷的製備 The third step: Preparation of 5-bromo-6-nitro-2,3-dihydrobenzo[b][1,4]dioxane

3-溴-4-硝基苯-1,2-二酚(410mg,1.75mmol)，碳酸鉀(0.73g,5.26mmol)，1,2-二溴乙烷(1.32g,7.0mmol)混合於DMF(5mL)中，在90℃下攪拌過夜，冷卻，加入大量乙酸乙酯稀釋。有機相用飽和食鹽水洗滌多次，然後無水硫酸鈉乾燥，減壓濃縮有機溶劑後管柱層析得到標題化合物5-溴-6-硝基-2,3-二氫苯并[b][1,4]二噁英(200mg，收率：44%)。 3-Bromo-4-nitrobenzene-1,2-diphenol (410mg, 1.75mmol), potassium carbonate (0.73g, 5.26mmol), 1,2-dibromoethane (1.32g, 7.0mmol) were mixed in In DMF (5 mL), stir overnight at 90°C, cool, and dilute by adding a large amount of ethyl acetate. The organic phase was washed with saturated brine several times, and then dried over anhydrous sodium sulfate. The organic solvent was concentrated under reduced pressure and then column chromatography was used to obtain the title compound 5-bromo-6-nitro-2,3-dihydrobenzo[b][ 1,4] Dioxin (200 mg, yield: 44%).

MS m/z(ESI)：257.9[M-H]^-. MS m/z(ESI): 257.9 [MH] ^- .

第四步：5-溴-2,3-二氫苯并[b][1,4]二噁烷-6-胺的製備 Step 4: Preparation of 5-bromo-2,3-dihydrobenzo[b][1,4]dioxane-6-amine

5-溴-6-硝基-2,3-二氫苯并[b][1,4]二噁烷(200mg,0.77mmol)溶於乙醇(9mL)和水(3mL)，加入還原鐵粉(343mg,6.1mmol)和氯化銨(82mg,1.5mmol)，回流反應3h。反應液過濾，濾液減壓濃縮後得到標題化合物5-溴-2,3-二氫苯并[b][1,4]二噁英-6-胺(170mg，收率：96%)。 5-Bromo-6-nitro-2,3-dihydrobenzo[b][1,4]dioxane (200mg, 0.77mmol) dissolved in ethanol (9mL) and water (3mL), added reduced iron powder (343mg, 6.1mmol) and ammonium chloride (82mg, 1.5mmol), react under reflux for 3h. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 5-bromo-2,3-dihydrobenzo[b][1,4]dioxin-6-amine (170 mg, yield: 96%).

MS m/z(ESI)：230.2[M+H]⁺. MS m/z(ESI): 230.2[M+H] ⁺ .

第五步：(6-胺基-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 Step 5: Preparation of (6-amino-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidation

5-溴-2,3-二氫苯并[b][1,4]二噁烷-6-胺(0.16g,0.7mmol)，二甲基氧化磷(108mg,1.39mmol)，磷酸鉀(295mg,1.39mmol)混合於N,N-二甲基甲醯胺(5mL)中，加入醋酸鈀(31mg,0.14mmol)和Xantphos(161mg,0.28mmol)，N2除氧5分鐘，然後微波加熱至145℃反應3小時。反應冷卻至室溫，減壓濃縮有機溶劑後管柱層析分離得到標題化合物(6-胺基-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化(83mg，收率：52%)。 5-bromo-2,3-dihydrobenzo[b][1,4]dioxane-6-amine (0.16g, 0.7mmol), dimethyl phosphorous oxide (108mg, 1.39mmol), potassium phosphate ( 295mg, 1.39mmol) was mixed in N,N-dimethylformamide (5mL), palladium acetate (31mg, 0.14mmol) and Xantphos (161mg, 0.28mmol) were added, N2 deoxygenated for 5 minutes, and then heated to React at 145°C for 3 hours. The reaction was cooled to room temperature, the organic solvent was concentrated under reduced pressure and column chromatography was separated to obtain the title compound (6-amino-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) Dimethylphosphine oxidation (83mg, yield: 52%).

¹H NMR(400MHz,CDCl₃)δ 1.72(s,3H),1.75(s,3H),4.09-4.13(m,2H),4.15-4.23(m,2H),5.41-5.85(m,2H),6.07-6.15(m,1H),6.72(d，J=6.8,1H)；MS m/z(ESI)：228.2[M+H]⁺. ¹ H NMR(400MHz, CDCl ₃ ) δ 1.72(s,3H),1.75(s,3H),4.09-4.13(m,2H),4.15-4.23(m,2H),5.41-5.85(m,2H) ,6.07-6.15(m,1H),6.72(d, J =6.8,1H); MS m/z(ESI): 228.2[M+H] ⁺ .

中間體的製備2 Preparation of intermediate 2

2-甲氧基-5-甲基-4-(1,4-二氧雜-8-氮雜螺[4.5]癸烷-8-基)苯胺 2-Methoxy-5-methyl-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)aniline

第一步：8-(5-甲氧基-2-甲基-4-硝基苯基)-1,4-二氧雜-8-氮雜螺[4.5]癸烷的製備 Step 1: Preparation of 8-(5-methoxy-2-methyl-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane

往1-氟-5-甲氧基-2-甲基-4-硝基苯(1.1g,5.9mmol)和4-哌啶酮縮乙二醇(3.4g,23.9mmol)的DMSO(15mL)溶液中加入K₂CO₃(1.6g,11.9mmol)，120℃攪拌過夜。反應液冷卻至室溫，減壓濃縮有機溶劑後管柱層析分離得到標題化合物8-(5-甲氧基-2-甲基-4-硝基苯基)-1,4-二氧雜-8-氮雜螺[4.5]癸烷(1.3g，收率：71%)。 To 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene (1.1g, 5.9mmol) and 4-piperidone ethylene ketal (3.4g, 23.9mmol) in DMSO (15mL) _{K 2} CO ₃ (1.6 g, 11.9 mmol) was added to the solution, and the solution was stirred overnight at 120°C. The reaction solution was cooled to room temperature, the organic solvent was concentrated under reduced pressure, and then column chromatography was separated to obtain the title compound 8-(5-methoxy-2-methyl-4-nitrophenyl)-1,4-dioxa -8-Azaspiro[4.5]decane (1.3g, yield: 71%).

MS m/z(ESI)：309.2[M+H]⁺. MS m/z(ESI): 309.2[M+H] ⁺ .

第二步：2-甲氧基-5-甲基-4-(1,4-二氧雜-8-氮雜螺[4.5]癸烷-8-基)苯胺的製備 Step 2: Preparation of 2-methoxy-5-methyl-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)aniline

8-(5-甲氧基-2-甲基-4-硝基苯基)-1,4-二氧雜-8-氮雜螺[4.5]癸烷(500mg,1.62mmol)溶於甲醇(10mL)，四氫呋喃(3mL)中，加入Pd/C(100mg)，氫氣氛圍下室溫攪拌5h。反應液過濾，濾液減壓濃縮後得到標題化合物2-甲氧基-5-甲基-4-(1,4-二氧雜-8-氮雜螺[4.5]癸烷-8-基)苯胺(433mg，收率：96%)。 8-(5-Methoxy-2-methyl-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (500mg, 1.62mmol) dissolved in methanol ( 10 mL), tetrahydrofuran (3 mL), add Pd/C (100 mg), and stir at room temperature for 5 h under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 2-methoxy-5-methyl-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)aniline (433mg, yield: 96%).

MS m/z(ESI)：279.2[M+H]⁺. MS m/z(ESI): 279.2[M+H] ⁺ .

實施例1 Example 1

(6-((5-溴-2-((2-甲氧基-4-(4-(3-(甲氧基甲基)吖丁啶-1-基)哌啶-1-基)-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidine-1-yl)piperidin-1-yl)- 5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidized preparation

第一步：(6-((5-溴-2-氯嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 The first step: (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) Preparation of dimethyl phosphine oxidation

室溫條件下，5-溴-2,4-二氯嘧啶(2.27g,10mmol)，(6-胺基-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化(2.27g,10mmol)，磷酸鉀(2.76g,20 mmol)混合於第三戊醇(20mL)中，微波90℃反應1h。反應冷卻至室溫，減壓濃縮有機溶劑後管柱層析分離得到標題化合物(6-((5-溴-2-氯嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化(3.25g，收率：78%)。 At room temperature, 5-bromo-2,4-dichloropyrimidine (2.27g, 10mmol), (6-amino-2,3-dihydrobenzo[b][1,4]dioxane-5 -Base) dimethyl phosphine oxidation (2.27g, 10mmol), potassium phosphate (2.76g, 20 mmol) was mixed with tertiary amyl alcohol (20 mL), and reacted in a microwave at 90°C for 1 h. The reaction was cooled to room temperature, the organic solvent was concentrated under reduced pressure and column chromatography was separated to obtain the title compound (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo [b] [1,4] Dioxan-5-yl)dimethylphosphine oxidation (3.25 g, yield: 78%).

¹H NMR(400MHz,DMSO-d ⁶)δ 1.81(s,3H),1.85(s,3H),4.24-4.39(m,4H),7.13(d,J=9.2Hz,1H),7.89-7.98(m,1H),8.44(d,J=1.8Hz,1H),12.26(s,1H)；MS m/z(ESI)：417.9[M+H]⁺. ¹ H NMR (400MHz, DMSO- d ⁶ ) δ 1.81 (s, 3H), 1.85 (s, 3H), 4.24-4.39 (m, 4H), 7.13 (d, J = 9.2 Hz, 1H), 7.89-7.98 (m,1H),8.44(d, J =1.8Hz,1H),12.26(s,1H); MS m/z(ESI): 417.9[M+H] ⁺ .

第二步：(6-((5-溴-2-((2-甲氧基-5-甲基-4-(1,4-二氧雜-8-氮雜螺[4.5]癸烷-8-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 The second step: (6-((5-bromo-2-((2-methoxy-5-methyl-4-(1,4-dioxa-8-azaspiro[4.5]decane- 8-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidized preparation

室溫條件下，(6-((5-溴-2-氯嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化(1.0g,2.4mmol)，2-甲氧基-5-甲基-4-(1,4-二氧雜-8-氮雜螺[4.5]癸烷-8-基)苯胺(1.0g,3.6mmol)，對甲苯磺酸(0.62g,3.6mmol)混合於乙二醇(40mL)中，升溫至90℃反應2h。反應冷卻至室溫，加入飽和碳酸氫鈉水溶液，用乙酸乙酯萃取，分離有機相並用飽和食鹽水洗滌，有機相用無水硫酸鈉乾燥，過濾乾燥劑後減壓濃縮有機溶劑，管柱層析分離得到標題化合物(6-((5-溴-2-((2-甲氧基-5-甲基-4-(1,4-二氧雜-8-氮雜螺[4.5]癸烷-8-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化(1.34g，收率：85%)。 At room temperature, (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl ) Dimethylphosphine oxide (1.0g, 2.4mmol), 2-methoxy-5-methyl-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl ) Aniline (1.0 g, 3.6 mmol), p-toluenesulfonic acid (0.62 g, 3.6 mmol) were mixed in ethylene glycol (40 mL), and the temperature was raised to 90° C. to react for 2 hours. The reaction was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, the organic phase was separated and washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered and the organic solvent was concentrated under reduced pressure, and column chromatography The title compound (6-((5-bromo-2-((2-methoxy-5-methyl-4-(1,4-dioxa-8-azaspiro[4.5]decane- 8-yl)phenyl)amino)pyridine (Pyridin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxide (1.34g, yield: 85%).

¹H NMR(400MHz,DMSO-d ⁶)δ 1.74-1.85(m,10H),2.14(s,3H),2.91(t,J=5.4Hz,4H),3.77(s,3H)，3.93(s,4H),4.24(s,2H),4.32(s,2H),6.73(s,1H),6.81(d,J=9.2Hz,1H),7.46(s,1H),7.94(d,J=15.0Hz,2H),8.10(s,1H),11.62(s,1H)；MS m/z(ESI)：660.2[M+H]⁺. ¹ H NMR(400MHz,DMSO- d ⁶ ) δ 1.74-1.85(m,10H), 2.14(s,3H), 2.91(t, J =5.4Hz,4H), 3.77(s,3H), 3.93(s ,4H),4.24(s,2H),4.32(s,2H),6.73(s,1H),6.81(d, J =9.2Hz,1H),7.46(s,1H),7.94(d, J = 15.0Hz,2H),8.10(s,1H),11.62(s,1H); MS m/z(ESI): 660.2[M+H] ⁺ .

第三步：1-(4-((5-溴-4-((5-(二甲基磷基)-2,3-二氫苯并[b][1,4]二噁烷-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-甲基苯基)哌啶-4-酮的製備 The third step: 1-(4-((5-bromo-4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1,4]dioxane-6 -Yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-one

室溫條件下，(6-((5-溴-2-((2-甲氧基-5-甲基-4-(1,4-二氧雜-8-氮雜螺[4.5]癸烷-8-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化(1.34g,2.03mmol)混合於醋酸/水(12mL/12mL)中，升溫至90℃反應2h。反應冷卻至室溫，減壓濃縮反應液，加入飽和碳酸氫鈉水溶液，用乙酸乙酯萃取，合併有機相並用無水硫酸鈉乾燥，過濾乾燥劑後減壓濃縮有機溶劑，管柱層析分離得到標題化合物1-(4-((5-溴-4-((5-(二甲基磷基)-2,3-二氫苯并[b][1,4]二噁烷-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-甲基苯基)哌啶-4-酮(1.2g,收率：96%)。 At room temperature, (6-((5-bromo-2-((2-methoxy-5-methyl-4-(1,4-dioxa-8-azaspiro[4.5]decane -8-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxide (1.34g, 2.03mmol) was mixed in acetic acid/water (12mL/12mL), heated to 90°C and reacted for 2h. The reaction was cooled to room temperature, the reaction solution was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, the desiccant was filtered, the organic solvent was concentrated under reduced pressure, and the column chromatography was separated. The title compound 1-(4-((5-bromo-4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1,4]dioxane-6-yl )Amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-one (1.2g, yield: 96%).

MS m/z(ESI)：616.2[M+H]⁺. MS m/z(ESI): 616.2[M+H] ⁺ .

第四步：(6-((5-溴-2-((2-甲氧基-4-(4-(3-(甲氧基甲基)吖丁啶-1-基)哌啶-1-基)-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 The fourth step: (6-((5-bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidine-1-yl)piperidine-1 -Yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethyl Preparation of Phosphine Oxidation

室溫條件下，1-(4-((5-溴-4-((5-(二甲基磷基)-2,3-二氫苯并[b][1,4]二噁烷-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-甲基苯基)哌啶-4-酮(0.8g,1.3mmol)，3-(甲氧基甲基)吖丁啶三氟醋酸鹽(0.42g,1.95mmol)和醋酸(0.1mL)混溶於二氯乙烷(20mL)中，攪拌30分鐘，加入三乙醯氧基硼氫化鈉(0.55g,2.6mmol)室溫攪拌過夜。加入飽和碳酸氫鈉水溶液，用二氯甲烷萃取，有機相用無水硫酸鈉乾燥，過濾乾燥劑後減壓濃縮有機溶劑，管柱層析分離得到標題化合物(6-((5-溴-2-((2-甲氧基-4-(4-(3-(甲氧基甲基)吖丁啶-1-基)哌啶-1-基)-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化(0.56g，收率：62%)。 At room temperature, 1-(4-((5-bromo-4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1,4]dioxane- 6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-one (0.8g, 1.3mmol), 3-(methoxy (Methyl)azetidine trifluoroacetate (0.42g, 1.95mmol) and acetic acid (0.1mL) are miscible in dichloroethane (20mL), stirred for 30 minutes, add sodium triacetoxyborohydride (0.55 g, 2.6mmol) Stir at room temperature overnight. Saturated aqueous sodium bicarbonate solution was added, extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered, the organic solvent was concentrated under reduced pressure, and the column chromatography was separated to obtain the title compound (6-((5-bromo-2- ((2-Methoxy-4-(4-(3-(methoxymethyl)azetidin-1-yl)piperidin-1-yl)-5-methylphenyl)amino)pyrimidine -4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxide (0.56g, yield: 62%).

¹H NMR(400MHz,DMSO-d ⁶)δ 1.26-1.38(m,2H),1.69-1.77(m,2H),1.78(s,3H),1.81(s,3H),2.07-2.22(m,4H),2.56-2.66(m,3H),2.83-2.92(m,1H),2.96-3.05(m,2H),3.15-3.19(m,2H),3.23-3.27(m,3H),3.42-3.46(m,2H),3.76(s,3H),4.07-4.13 (m,1H),4.24(s,2H),4.32(s,2H),6.69(s,1H),6.80(d,J=9.0Hz,1H),7.43(s,1H),7.91-7.98(m,2H),8.10(s,1H),11.62(s,1H)；MS m/z(ESI)：701.2[M+H]⁺. ¹ H NMR (400MHz, DMSO- d ⁶ ) δ 1.26-1.38 (m, 2H), 1.69-1.77 (m, 2H), 1.78 (s, 3H), 1.81 (s, 3H), 2.07-2.22 (m, 4H),2.56-2.66(m,3H),2.83-2.92(m,1H),2.96-3.05(m,2H),3.15-3.19(m,2H),3.23-3.27(m,3H),3.42- 3.46(m, 2H), 3.76(s, 3H), 4.07-4.13 (m, 1H), 4.24(s, 2H), 4.32(s, 2H), 6.69(s, 1H), 6.80(d, J = 9.0Hz,1H),7.43(s,1H),7.91-7.98(m,2H),8.10(s,1H),11.62(s,1H); MS m/z(ESI): 701.2[M+H] ⁺ .

實施例2 Example 2

(6-((5-溴-2-((4-(4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2- (Methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidation preparation

第一步：第三-丁基4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-羧酸酯的製備 The first step: the preparation of tertiary-butyl 4-(3-(dimethylamino)azetidine-1-yl)piperidine-1-carboxylate

室溫條件下，將第三-丁基4-羰基哌啶-1-羧酸酯(500mg，2.51mmol)和N,N-二甲基吖丁啶-3-胺(302mg，3.01mmol)溶於1,2-二氯乙烷(15mL)中，加入2滴醋酸，攪拌5分鐘，加入三乙醯氧基硼氫化鈉(1.06g，5.02mmol)，室溫攪拌過夜，然後加入飽和碳酸氫鈉溶液淬滅反應，用二氯甲烷萃取三次。合併有機相，有機相用無水硫酸鈉乾燥，過濾乾燥劑後減壓濃縮有機溶劑後管柱層析分離得到標題化合物第三-丁基4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-羧酸酯(610mg，收率：86%)。 At room temperature, dissolve tert-butyl 4-carbonylpiperidine-1-carboxylate (500 mg, 2.51 mmol) and N,N-dimethylazetidine-3-amine (302 mg, 3.01 mmol) In 1,2-dichloroethane (15mL), add 2 drops of acetic acid, stir for 5 minutes, add sodium triacetoxyborohydride (1.06g, 5.02mmol), stir at room temperature overnight, then add saturated hydrogen carbonate The reaction was quenched with sodium solution and extracted with dichloromethane Take three times. Combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter the desiccant, concentrate the organic solvent under reduced pressure, and separate by column chromatography to obtain the title compound tert-butyl 4-(3-(dimethylamino)azetidine- 1-yl)piperidine-1-carboxylate (610 mg, yield: 86%).

¹H NMR(400MHz,CDCl₃)δ 1.14-1.23(m,2H),1.44(s,9H),1.62-1.70(m,2H),2.12(s,6H),2.81-2.89(m,6H),3.48-3.53(m,2H),4.03-3.87(m,2H)；MS m/z(ESI)：284.1[M+H]⁺. ¹ H NMR (400MHz, CDCl ₃ ) δ 1.14-1.23 (m, 2H), 1.44 (s, 9H), 1.62-1.70 (m, 2H), 2.12 (s, 6H), 2.81-2.89 (m, 6H) ,3.48-3.53(m,2H),4.03-3.87(m,2H); MS m/z(ESI): 284.1[M+H] ⁺ .

第二步：N,N-二甲基-1-(哌啶-4-基)吖丁啶-3-胺的製備 Step 2: Preparation of N,N-dimethyl-1-(piperidin-4-yl)azetidine-3-amine

室溫條件下，將第三-丁基4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-羧酸酯(610mg，2.16mmol)溶於鹽酸二噁烷(10mL)中，室溫攪拌過夜，減壓濃縮有機溶劑後得到標題化合物N,N-二甲基-1-(哌啶-4-基)吖丁啶-3-胺粗品直接用於下一步反應。 At room temperature, dissolve tert-butyl 4-(3-(dimethylamino)azetidin-1-yl)piperidine-1-carboxylate (610mg, 2.16mmol) in dioxane hydrochloride (10mL), stirred at room temperature overnight, and concentrated the organic solvent under reduced pressure to obtain the title compound N,N-dimethyl-1-(piperidin-4-yl)azetidine-3-amine crude product and used directly in the next step reaction.

MS m/z(ESI)：184.1[M+H]⁺. MS m/z(ESI): 184.1[M+H] ⁺ .

第三步：1-(1-(2-溴-5-甲氧基-4-硝基苯基)哌啶-4-基)-N,N-二甲基吖丁啶-3-胺的製備 The third step: 1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)-N,N-dimethylazetidine-3-amine preparation

室溫條件下，將1-溴-2-氟-4-甲氧基-5-硝基苯(300mg,1.2mmol)N,N-二甲基-1-(哌啶-4-基)吖丁啶-3-胺粗品(220mg,1.2mmol)和碳酸鉀(497mg,3.6mmol)溶於N,N-二甲基甲醯胺(8mL)中，升溫至60℃攪拌過夜，向反應體系中加入水，用乙酸乙酯萃取三次。合併有機相，然後有機相用無水硫酸鈉乾燥，過濾乾燥劑，減壓濃縮有機溶劑後管柱層析分離得到標題化合物1-(1-(2-溴-5-甲氧基-4-硝基苯基)哌啶-4-基)-N,N-二甲基吖丁啶-3-胺(430mg，收率：87%)。 At room temperature, the 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (300mg, 1.2mmol) N,N-dimethyl-1-(piperidin-4-yl) acridine The crude butidine-3-amine (220mg, 1.2mmol) and potassium carbonate (497mg, 3.6mmol) were dissolved in N,N-dimethylformamide (8mL), heated to 60°C and stirred overnight, and added to the reaction system Water was added and extracted three times with ethyl acetate. Combine the organic phases, then dry the organic phase with anhydrous sodium sulfate, filter the desiccant, concentrate the organic solvent under reduced pressure, and separate by column chromatography to obtain the title compound 1-(1-(2-bromo-5-methoxy-4-nitro) (Phenyl)piperidin-4-yl)-N,N-dimethylazetidine-3-amine (430 mg, yield: 87%).

MS m/z(ESI)：413.1[M+H]⁺. MS m/z(ESI): 413.1[M+H] ⁺ .

第四步：1-(1-(5-甲氧基-4-硝基-2-乙烯基苯基)哌啶-4-基)-N,N-二甲基吖丁啶-3-胺的製備 The fourth step: 1-(1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)-N,N-dimethylazetidine-3-amine Preparation

室溫條件下，將1-(1-(2-溴-5-甲氧基-4-硝基苯基)哌啶-4-基)-N,N-二甲基吖丁啶-3-胺(430mg,1.04mmol)，乙烯基三氟硼酸鉀(279mg,2.08mmol)，[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(76mg,0.104mmol)，碳酸銫(1.01g,3.12 mmol)溶於二氧六環/水(10mL/1.5mL)中，氮氣置換三次，升溫至90℃攪拌過夜，向反應體系中加入水，用乙酸乙酯萃取三次。合併有機相，然後有機相用無水硫酸鈉乾燥，過濾乾燥劑，減壓濃縮有機溶劑後管柱層析分離得到標題化合物1-(1-(5-甲氧基-4-硝基-2-乙烯基苯基)哌啶-4-基)-N,N-二甲基吖丁啶-3-胺(230mg，收率：61%)。 At room temperature, the 1-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)-N,N-dimethylazetidine-3- Amine (430mg, 1.04mmol), potassium vinyl trifluoroborate (279mg, 2.08mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (76mg, 0.104mmol), Cesium carbonate (1.01g, 3.12 mmol) was dissolved in dioxane/water (10mL/1.5mL), replaced with nitrogen three times, heated to 90°C and stirred overnight, water was added to the reaction system, and extracted three times with ethyl acetate. The organic phases were combined, and the organic phases were dried over anhydrous sodium sulfate, the desiccant was filtered, the organic solvent was concentrated under reduced pressure, and the column chromatography was separated to obtain the title compound 1-(1-(5-methoxy-4-nitro-2- Vinylphenyl)piperidin-4-yl)-N,N-dimethylazetidine-3-amine (230 mg, yield: 61%).

MS m/z(ESI)：361.1[M+H]⁺. MS m/z(ESI): 361.1[M+H] ⁺ .

第五步：1-(1-(4-胺基-2-乙基-5-甲氧苯基)哌啶-4-基)-N,N-二甲基吖丁啶-3-胺的製備 The fifth step: 1-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-N,N-dimethylazetidine-3-amine preparation

室溫條件下，將1-(1-(5-甲氧基-4-硝基-2-乙烯基苯基)哌啶-4-基)-N,N-二甲基吖丁啶-3-胺(230mg,0.64mmol)溶於甲醇(10mL)中，氮氣置換三次，加入鈀/碳(46mg)，氫氣氛下室溫攪拌過夜，過濾除去催化劑，減壓濃縮有機溶劑得到標題化合物1-(1-(4-胺基-2-乙基-5-甲氧苯基)哌啶-4-基)-N,N-二甲基吖丁啶-3-胺(210mg，收率：98%)。 At room temperature, the 1-(1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)-N,N-dimethylazetidine-3 -Amine (230mg, 0.64mmol) was dissolved in methanol (10mL), replaced with nitrogen three times, palladium/carbon (46mg) was added, stirred overnight under hydrogen atmosphere at room temperature, the catalyst was removed by filtration, and the organic solvent was concentrated under reduced pressure to obtain the title compound 1- (1-(4-Amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-N,N-dimethylazetidine-3-amine (210mg, yield: 98 %).

MS m/z(ESI)：333.1[M+H]⁺. MS m/z(ESI): 333.1[M+H] ⁺ .

參考實施例1的第二步，將製備得到的1-(1-(4-胺基-2-乙基-5-甲氧苯基)哌啶-4-基)-N,N-二甲基吖丁啶-3-胺與(6-((5-溴-2-氯嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化反應製備目標產物(6-((5-溴-2-((4-(4- (3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化。 Referring to the second step of Example 1, the prepared 1-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-N,N-dimethyl Azetidine-3-amine and (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxane -5-yl) dimethylphosphine oxidation reaction to prepare the target product (6-((5-bromo-2-((4-(4- (3-(Dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)- 2,3-Dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidation.

¹H NMR(400MHz,CD₃OD)δ 0.98-1.07(m,3H),1.47-1.60(m,2H),1.87(s,3H),1.91(s,3H),1.96-2.05(m,2H),2.24(s,6H),2.50-2.59(m,2H),2.71-2.83(m,4H),3.03-3.10(m,2H),3.12-3.19(m,1H),3.47-3.58(m,2H),3.84(d,J=1.7Hz,2H),3.90-3.97(m,2H),4.26-4.32(m,2H),4.33-4.39(m,2H),6.77(s,1H),6.88-6.94(m,1H),7.75(d,J=1.6Hz,1H),7.79-7.84(m,1H),8.07(s,1H)；MS m/z(ESI)：714.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 0.98-1.07 (m, 3H), 1.47-1.60 (m, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 1.96-2.05 (m, 2H) ), 2.24(s, 6H), 2.50-2.59(m, 2H), 2.71-2.83(m, 4H), 3.03-3.10(m, 2H), 3.12-3.19(m, 1H), 3.47-3.58(m ,2H),3.84(d, J =1.7Hz,2H),3.90-3.97(m,2H),4.26-4.32(m,2H),4.33-4.39(m,2H),6.77(s,1H), 6.88-6.94(m,1H),7.75(d, J =1.6Hz,1H),7.79-7.84(m,1H),8.07(s,1H); MS m/z(ESI): 714.2[M+H ] ⁺ .

實施例3 Example 3

(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-8-氟-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-8-fluoro-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidation preparation

(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-8-氟-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例2。 (6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-8-fluoro-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidation preparation method Refer to Example 2.

MS m/z(ESI)：732.2[M+H]⁺. MS m/z(ESI): 732.2[M+H] ⁺ .

實施例4 Example 4

(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-7-氟-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-7-fluoro-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidation preparation

(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-7-氟-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例2。 (6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-7-fluoro-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) dimethylphosphine oxidation preparation method Refer to Example 2.

MS m/z(ESI)：732.2[M+H]⁺. MS m/z(ESI): 732.2[M+H] ⁺ .

實施例5 Example 5

(6-((5-溴-2-((5-乙基-3-氟-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((5-ethyl-3-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidine-1- (Phenyl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) dimethylphosphine oxidation preparation

(6-((5-溴-2-((5-乙基-3-氟-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例2。 (6-((5-Bromo-2-((5-ethyl-3-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidine-1- (Yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) dimethylphosphine oxidation preparation method Refer to Example 2.

MS m/z(ESI)：732.2[M+H]⁺. MS m/z(ESI): 732.2[M+H] ⁺ .

實施例6 Example 6

(6-((5-溴-2-((3-乙基-2-氟-6-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((3-ethyl-2-fluoro-6-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidine-1- (Phenyl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) dimethylphosphine oxidation preparation

(6-((5-溴-2-((3-乙基-2-氟-6-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例2。 (6-((5-Bromo-2-((3-ethyl-2-fluoro-6-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidine-1- (Yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) dimethylphosphine oxidation preparation method Refer to Example 2.

MS m/z(ESI)：732.2[M+H]⁺. MS m/z(ESI): 732.2[M+H] ⁺ .

實施例7 Example 7

(5-((5-溴-2-((5-乙炔基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)苯并[d][1,3]二噁唑-4-基)二甲基膦氧化的製備 (5-((5-Bromo-2-((5-ethynyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxazol-4-yl)dimethylphosphine oxidation preparation

(5-((5-溴-2-((5-乙炔基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)苯并[d][1,3]二噁唑-4-基)二甲基膦氧化的製備方法參照實施例1。 (5-((5-Bromo-2-((5-ethynyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxazol-4-yl)dimethylphosphine oxidation The preparation method refers to Example 1.

MS m/z(ESI)：696.2[M+H]⁺. MS m/z(ESI): 696.2[M+H] ⁺ .

實施例8 Example 8

(5-((5-溴-2-((5-乙炔基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,2-二氟苯并[d][1,3]二噁唑-4-基)二甲基膦氧化的製備 (5-((5-Bromo-2-((5-ethynyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)dimethylphosphine oxidation preparation

(5-((5-溴-2-((5-乙炔基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,2-二氟苯并[d][1,3]二噁唑-4-基)二甲基膦氧化的製備方法參照實施例1。 (5-((5-Bromo-2-((5-ethynyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)dimethylphosphine oxidized preparation method refer to Example 1 .

MS m/z(ESI)：732.2[M+H]⁺. MS m/z(ESI): 732.2[M+H] ⁺ .

實施例9 Example 9

(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-((3aR,6aS)-5-甲基六氫吡咯并[3,4-c]吡咯-2(1H)-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c ]Pyrrol-2(1H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]二Oxidation of oxan-5-yl) dimethylphosphine

(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-((3aR,6aS)-5-甲基六氫吡咯并[3,4-c]吡咯-2(1H)-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c ]Pyrrol-2(1H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]二Refer to Example 1 for the preparation method of oxan-5-yl)dimethylphosphine oxidation.

MS m/z(ESI)：726.3[M+H]⁺. MS m/z(ESI): 726.3[M+H] ⁺ .

實施例10 Example 10

(6-((5-氯-2-((2-甲氧基-5-甲基-4-(4-((3aR,6aS)-5-甲基六氫吡咯并[3,4-c]吡咯-2(1H)-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Chloro-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c ]Pyrrol-2(1H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]二Oxidation of oxan-5-yl) dimethylphosphine

(6-((5-氯-2-((2-甲氧基-5-甲基-4-(4-((3aR,6aS)-5-甲基六氫吡咯并[3,4-c]吡咯-2(1H)-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((5-Chloro-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c ]Pyrrol-2(1H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]二Refer to Example 1 for the preparation method of oxan-5-yl)dimethylphosphine oxidation.

MS m/z(ESI)：682.3[M+H]⁺. MS m/z(ESI): 682.3[M+H] ⁺ .

實施例11 Example 11

(6-((2-((2-甲氧基-5-甲基-4-(4-((3aR,6aS)-5-甲基六氫吡咯并[3,4-c]吡咯-2(1H)-基)哌啶-1-基)苯基)胺基)-5-(三氟甲基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((2-((2-Methoxy-5-methyl-4-(4-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrole-2 (1H)-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo(b)( Preparation of 1,4]dioxan-5-yl)dimethylphosphine oxidation

(6-((2-((2-甲氧基-5-甲基-4-(4-((3aR,6aS)-5-甲基六氫吡咯并[3,4-c]吡咯-2(1H)-基)哌啶-1-基)苯基)胺基)-5-(三氟甲基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((2-((2-Methoxy-5-methyl-4-(4-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrole-2 (1H)-yl)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo(b)( Refer to Example 1 for the preparation method of 1,4]dioxan-5-yl)dimethylphosphine oxidation.

MS m/z(ESI)：716.3[M+H]⁺. MS m/z(ESI): 716.3[M+H] ⁺ .

實施例12 Example 12

2-(1-(1-(4-((5-溴-4-((5-(二甲基磷基)-2,3-二氫苯并[b][1,4]二噁烷-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-甲基苯基)哌啶-4-基)吖丁啶-3-基)乙醯腈的製備 2-(1-(1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)-2,3-dihydrobenzo[b][1,4]dioxane -6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile preparation

2-(1-(1-(4-((5-溴-4-((5-(二甲基磷基)-2,3-二氫苯并[b][1,4]二噁烷-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-甲基苯基)哌啶-4-基)吖丁啶-3-基)乙醯腈的製備方法參照實施例1。 2-(1-(1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)-2,3-dihydrobenzo[b][1,4]dioxane -6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile Refer to Example 1 for the preparation method.

¹H NMR(400MHz,CD₃OD)δ 1.49-1.51(m,3H),1.91-1.93(m,9H),2.12(s,3H),2.57-2.59(m,1H),2.69-2.72(m,2H),2.78-2.80(m,2H),2.89-2.93(m,1H),3.12-3.15(m,2H),3.78-3.81(m,2H),3.84(s,3H),4.33-4.36(m,4H),6.72(s,1H),6.91-6.95(m,1H),7.70-7.76(m,1H),7.88-7.91(m,1H),8.06(s,1H)；MS m/z(ESI)：696.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 1.49-1.51 (m, 3H), 1.91-1.93 (m, 9H), 2.12 (s, 3H), 2.57-2.59 (m, 1H), 2.69-2.72 (m , 2H), 2.78-2.80 (m, 2H), 2.89-2.93 (m, 1H), 3.12-3.15 (m, 2H), 3.78-3.81 (m, 2H), 3.84 (s, 3H), 4.33-4.36 (m,4H),6.72(s,1H),6.91-6.95(m,1H),7.70-7.76(m,1H),7.88-7.91(m,1H),8.06(s,1H); MS m/ z(ESI): 696.2[M+H] ⁺ .

實施例13 Example 13

2-(1-(1-(4-((5-氯-4-((5-(二甲基磷基)-2,3-二氫苯并[b][1,4]二噁烷-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-甲基苯基)哌啶-4-基)吖丁啶-3-基)乙醯腈的製備 2-(1-(1-(4-((5-chloro-4-((5-(dimethylphosphoryl)-2,3-dihydrobenzo[b][1,4]dioxane -6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile preparation

2-(1-(1-(4-((5-氯-4-((5-(二甲基磷基)-2,3-二氫苯并[b][1,4]二噁烷-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-甲基苯基)哌啶-4-基)吖丁啶-3-基)乙醯腈的製備方法參照實施例1。 2-(1-(1-(4-((5-chloro-4-((5-(dimethylphosphoryl)-2,3-dihydrobenzo[b][1,4]dioxane -6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile Refer to Example 1 for the preparation method.

¹H NMR(400MHz,CD₃OD)δ 1.46-1.49(m,2H),1.90-1.93(m,8H),2.15-2.19(m,3H),2.37-2.39(m,1H),2.62-2.78(m,4H),2.85-2.89(m,1H),3.06-3.21(m,4H),3.63-3.66(m,2H),3.83(s,3H),4.32-4.38(m,4H),6.72(s,1H),6.89-6.91(m,1H),7.69-7.73(m,1H),7.96-8.10(m,2H)；MS m/z(ESI)：652.3[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 1.46-1.49 (m, 2H), 1.90-1.93 (m, 8H), 2.15-2.19 (m, 3H), 2.37-2.39 (m, 1H), 2.62-2.78 (m,4H),2.85-2.89(m,1H),3.06-3.21(m,4H),3.63-3.66(m,2H),3.83(s,3H),4.32-4.38(m,4H),6.72 (s,1H),6.89-6.91(m,1H),7.69-7.73(m,1H),7.96-8.10(m,2H); MS m/z(ESI): 652.3[M+H] ⁺ .

實施例14 Example 14

2-(1-(1-(4-((4-((5-(二甲基磷基)-2,3-二氫苯并[b][1,4]二噁烷-6-基)胺基)-5-(三氟甲基)嘧啶-2-基)胺基)-5-甲氧基-2-甲基苯基)哌啶-4-基)吖丁啶-3-基)乙醯腈的製備 2-(1-(1-(4-((4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1,4]dioxane-6-yl )Amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl ) Preparation of Acetonitrile

2-(1-(1-(4-((4-((5-(二甲基磷基)-2,3-二氫苯并[b][1,4]二噁烷-6-基)胺基)-5-(三氟甲基)嘧啶-2-基)胺基)-5-甲氧基-2-甲基苯基)哌啶-4-基)吖丁啶-3-基)乙醯腈的製備方法參照實施例1。 2-(1-(1-(4-((4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1,4]dioxane-6-yl )Amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl ) Refer to Example 1 for the preparation method of acetonitrile.

MS m/z(ESI)：686.3[M+H]⁺. MS m/z(ESI): 686.3[M+H] ⁺ .

實施例15 Example 15

(6-((5-溴-2-((4-(4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) dimethylphosphine oxidation preparation

(6-((5-溴-2-((4-(4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) dimethylphosphine oxidation preparation Refer to Example 1 for the method.

¹H NMR(400MHz,CD₃OD)δ 1.54-1.61(m,2H),1.89-1.91(m,6H),2.07-2.08(m,2H),2.12(s,3H),2.30(s,6H),2.72-2.79(m,2H),3.04-3.06(m,2H),3.15-3.18(m,2H),3.82-3.88(m,5H),4.05-4.18(m,2H),4.32-4.39(m,4H),6.71(s,1H),6.90-6.93(m,1H),7.71(s,1H),7.88-7.92(m,1H),8.06(s,1H)；MS m/z(ESI)：700.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 1.54-1.61 (m, 2H), 1.89-1.91 (m, 6H), 2.07-2.08 (m, 2H), 2.12 (s, 3H), 2.30 (s, 6H) ), 2.72-2.79(m, 2H), 3.04-3.06(m, 2H), 3.15-3.18(m, 2H), 3.82-3.88(m, 5H), 4.05-4.18(m, 2H), 4.32-4.39 (m,4H),6.71(s,1H),6.90-6.93(m,1H),7.71(s,1H),7.88-7.92(m,1H),8.06(s,1H); MS m/z( ESI): 700.2[M+H] ⁺ .

實施例16 Example 16

(6-((5-溴-2-((4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((4-(4-(3-ethoxyazetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methyl (Phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidation preparation

(6-((5-溴-2-((4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((5-Bromo-2-((4-(4-(3-ethoxyazetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methyl (Phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidation preparation method refer to the implementation example 1.

¹H NMR(400MHz,CD₃OD)δ 1.22(t,J=7.0Hz,3H),1.53-1.64(m,2H),1.87(s,3H),1.90(s,3H),2.00-2.08(m,2H),2.11(s,3H),2.64-2.75(m,2H),2.91-3.01(m,1H),3.11-3.18(m,2H),3.48-3.57(m,2H),3.73-3.79(m,2H),3.83(s,3H),4.15-4.23(m,2H),4.25-4.38(m,5H),6.70(s,1H),6.89(d,J=9.1Hz,1H),7.71(s,1H),7.84-7.91(m,1H),8.05(s,1H)；MS m/z(ESI)：701.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 1.22 (t, J =7.0Hz, 3H), 1.53-1.64 (m, 2H), 1.87 (s, 3H), 1.90 (s, 3H), 2.00-2.08 ( m,2H),2.11(s,3H),2.64-2.75(m,2H),2.91-3.01(m,1H),3.11-3.18(m,2H),3.48-3.57(m,2H),3.73- 3.79(m,2H),3.83(s,3H),4.15-4.23(m,2H),4.25-4.38(m,5H),6.70(s,1H),6.89(d, J =9.1Hz,1H) ,7.71(s,1H),7.84-7.91(m,1H),8.05(s,1H); MS m/z(ESI): 701.2[M+H] ⁺ .

實施例17 Example 17

(S)-(6-((5-溴-2-((4-(4-(3-(二甲胺基)吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (S)-(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy 5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine Oxidation preparation

(S)-(6-((5-溴-2-((4-(4-(3-(二甲胺基)吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (S)-(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy 5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine Refer to Example 1 for the preparation method of oxidation.

¹H NMR(400MHz,CD₃OD)δ 1.80-1.83(m,2H),1.88-1.90(m,6H),2.09-2.11(m,6H),2.30(s,1H),2.62(s,6H),2.72-2.79(m,3H),3.14-3.18(m,4H),3.25-3.29(m,1H),3.34-3.47(m,2H),3.83(s,3H),4.31-4.33(m,4H),6.69(s,1H),6.88-6.91(m,1H),7.70(s,1H),7.87-7.89(m,1H),8.05(s,1H)；MS m/z(ESI)：714.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 1.80-1.83 (m, 2H), 1.88-1.90 (m, 6H), 2.09-2.11 (m, 6H), 2.30 (s, 1H), 2.62 (s, 6H) ), 2.72-2.79 (m, 3H), 3.14-3.18 (m, 4H), 3.25-3.29 (m, 1H), 3.34-3.47 (m, 2H), 3.83 (s, 3H), 4.31-4.33 (m ,4H),6.69(s,1H),6.88-6.91(m,1H),7.70(s,1H),7.87-7.89(m,1H),8.05(s,1H); MS m/z(ESI) : 714.2[M+H] ⁺ .

實施例18 Example 18

(R)-(6-((5-溴-2-((4-(4-(3-(二甲胺基)吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (R)-(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy 5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine Oxidation preparation

(R)-(6-((5-溴-2-((4-(4-(3-(二甲胺基)吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (R)-(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy 5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine Refer to Example 1 for the preparation method of oxidation.

實施例19 Example 19

(S)-(6-((5-溴-2-((4-(4-(3-乙氧基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (S)-(6-((5-Bromo-2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) dimethylphosphine oxidation preparation

(S)-(6-((5-溴-2-((4-(4-(3-乙氧基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (S)-(6-((5-Bromo-2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) dimethylphosphine oxidation preparation Refer to Example 1 for the method.

¹H NMR(400MHz,CD₃OD)δ 1.22(t,J=7.0Hz,3H),1.90-1.96(m,8H),2.15(s,3H),2.22-2.28(m,4H),2.75-2.82(m,2H),3.18-3.22(m,3H),3.41-3.46(m,3H),3.50-3.59(m,4H),3.84(s,3H),4.25-4.38(m,5H),6.71(s,1H),6.91-6.96(m,1H),7.73(s,1H),7.90-7.93(m,1H),8.06(s,1H)；MS m/z(ESI)：715.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 1.22 (t, J = 7.0Hz, 3H), 1.90-1.96 (m, 8H), 2.15 (s, 3H), 2.22-2.28 (m, 4H), 2.75 2.82 (m, 2H), 3.18-3.22 (m, 3H), 3.41-3.46 (m, 3H), 3.50-3.59 (m, 4H), 3.84 (s, 3H), 4.25-4.38 (m, 5H), 6.71(s,1H),6.91-6.96(m,1H),7.73(s,1H),7.90-7.93(m,1H),8.06(s,1H); MS m/z(ESI): 715.2[M +H] ⁺ .

實施例20 Example 20

(R)-(6-((5-溴-2-((4-(4-(3-乙氧基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (R)-(6-((5-Bromo-2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) dimethylphosphine oxidation preparation

(R)-(6-((5-溴-2-((4-(4-(3-乙氧基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (R)-(6-((5-Bromo-2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) dimethylphosphine oxidation preparation Refer to Example 1 for the method.

實施例21 Example 21

(6-((5-氯-2-((4-(4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Chloro-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) dimethylphosphine oxidation preparation

(6-((5-氯-2-((4-(4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((5-Chloro-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) dimethylphosphine oxidation preparation Refer to Example 1 for the method.

¹H NMR(400MHz,CD₃OD)δ 1.53-1.56(m,2H),1.89-1.91(m,6H),1.98-2.01(m,2H),2.14(s,3H),2.23(s,6H),2.69-2.71(m,3H),3.06-3.22(m,3H),3.40-3.51(m,2H),3.79-3.91(m,5H),4.22-4.38(m,4H),6.72(s,1H),6.89-6.91(m,1H),7.70(s,1H),7.95(s,1H),8.03-8.09(m,1H)；MS m/z(ESI)：656.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 1.53-1.56 (m, 2H), 1.89-1.91 (m, 6H), 1.98-2.01 (m, 2H), 2.14 (s, 3H), 2.23 (s, 6H) ), 2.69-2.71 (m, 3H), 3.06-3.22 (m, 3H), 3.40-3.51 (m, 2H), 3.79-3.91 (m, 5H), 4.22-4.38 (m, 4H), 6.72 (s ,1H),6.89-6.91(m,1H),7.70(s,1H),7.95(s,1H),8.03-8.09(m,1H); MS m/z(ESI): 656.2[M+H] ⁺ .

實施例22 Example 22

(6-((5-氯-2-((4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Chloro-2-((4-(4-(3-ethoxyazetidine-1-yl)piperidin-1-yl)-2-methoxy-5-methyl (Phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidation preparation

(6-((5-氯-2-((4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((5-Chloro-2-((4-(4-(3-ethoxyazetidine-1-yl)piperidin-1-yl)-2-methoxy-5-methyl (Phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidation preparation method refer to the implementation example 1.

MS m/z(ESI)：657.2[M+H]⁺. MS m/z(ESI): 657.2[M+H] ⁺ .

實施例23 Example 23

(S)-(6-((5-氯-2-((4-(4-(3-(二甲胺基)吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (S)-(6-((5-chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy 5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine Oxidation preparation

(S)-(6-((5-氯-2-((4-(4-(3-(二甲胺基)吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (S)-(6-((5-chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy 5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine Refer to Example 1 for the preparation method of oxidation.

MS m/z(ESI)：670.2[M+H]⁺. MS m/z(ESI): 670.2[M+H] ⁺ .

實施例24 Example 24

(R)-(6-((5-氯-2-((4-(4-(3-(二甲胺基)吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (R)-(6-((5-chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy 5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine Oxidation preparation

(R)-(6-((5-氯-2-((4-(4-(3-(二甲胺基)吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (R)-(6-((5-chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy 5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine Refer to Example 1 for the preparation method of oxidation.

MS m/z(ESI)：670.2[M+H]⁺. MS m/z(ESI): 670.2[M+H] ⁺ .

實施例25 Example 25

(S)-(6-((5-氯-2-((4-(4-(3-乙氧基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (S)-(6-((5-chloro-2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) dimethylphosphine oxidation preparation

(S)-(6-((5-氯-2-((4-(4-(3-乙氧基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (S)-(6-((5-chloro-2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) dimethylphosphine oxidation preparation Refer to Example 1 for the method.

MS m/z(ESI)：671.2[M+H]⁺. MS m/z(ESI): 671.2[M+H] ⁺ .

實施例26 Example 26

(R)-(6-((5-氯-2-((4-(4-(3-乙氧基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (R)-(6-((5-chloro-2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) dimethylphosphine oxidation preparation

(R)-(6-((5-氯-2-((4-(4-(3-乙氧基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (R)-(6-((5-chloro-2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) dimethylphosphine oxidation preparation Refer to Example 1 for the method.

MS m/z(ESI)：671.2[M+H]⁺. MS m/z(ESI): 671.2[M+H] ⁺ .

實施例27 Example 27

(6-((2-((4-(4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)-5-(三氟甲基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5-methylbenzene (Yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethyl Preparation of Phosphine Oxidation

(6-((2-((4-(4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)-5-(三氟甲基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5-methylbenzene (Yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethyl Refer to Example 1 for the preparation method of phosphine oxidation.

MS m/z(ESI)：690.2[M+H]⁺. MS m/z(ESI): 690.2[M+H] ⁺ .

實施例28 Example 28

(6-((2-((4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)-5-(三氟甲基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((2-((4-(4-(3-ethoxyazetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amine Yl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxide Preparation

(6-((2-((4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)-5-(三氟甲基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((2-((4-(4-(3-ethoxyazetidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amine Yl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxide Refer to Example 1 for the preparation method.

MS m/z(ESI)：691.2[M+H]⁺. MS m/z(ESI): 691.2[M+H] ⁺ .

實施例29 Example 29

(S)-(6-((2-((4-(4-(3-(二甲胺基)吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)-5-(三氟甲基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (S)-(6-((2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl ) Preparation of dimethyl phosphine oxidation

(S)-(6-((2-((4-(4-(3-(二甲胺基)吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)-5-(三氟甲基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (S)-(6-((2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl ) Refer to Example 1 for the preparation method of dimethylphosphine oxidation.

MS m/z(ESI)：704.2[M+H]⁺. MS m/z(ESI): 704.2[M+H] ⁺ .

實施例30 Example 30

(R)-(6-((2-((4-(4-(3-(二甲胺基)吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)-5-(三氟甲基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (R)-(6-((2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl ) Preparation of dimethyl phosphine oxidation

(R)-(6-((2-((4-(4-(3-(二甲胺基)吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)-5-(三氟甲基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (R)-(6-((2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5- (Methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl ) Refer to Example 1 for the preparation method of dimethylphosphine oxidation.

MS m/z(ESI)：704.2[M+H]⁺. MS m/z(ESI): 704.2[M+H] ⁺ .

實施例31 Example 31

(S)-(6-((2-((4-(4-(3-乙氧基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)-5-(三氟甲基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (S)-(6-((2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylbenzene (Yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethyl Preparation of Phosphine Oxidation

(S)-(6-((2-((4-(4-(3-乙氧基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)-5-(三氟甲基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (S)-(6-((2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylbenzene (Yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethyl Refer to Example 1 for the preparation method of phosphine oxidation.

MS m/z(ESI)：705.2[M+H]⁺. MS m/z(ESI): 705.2[M+H] ⁺ .

實施例32 Example 32

(R)-(6-((2-((4-(4-(3-乙氧基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)-5-(三氟甲基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (R)-(6-((2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylbenzene (Yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethyl Preparation of Phosphine Oxidation

(R)-(6-((2-((4-(4-(3-乙氧基吡咯烷-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)-5-(三氟甲基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (R)-(6-((2-((4-(4-(3-ethoxypyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5-methylbenzene (Yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethyl Refer to Example 1 for the preparation method of phosphine oxidation.

MS m/z(ESI)：705.2[M+H]⁺. MS m/z(ESI): 705.2[M+H] ⁺ .

實施例33 Example 33

(6-((5-溴-2-((7-甲氧基-2-(四氫呋喃-3-基)-1,2,3,4-四氫異喹啉-6-基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((7-methoxy-2-(tetrahydrofuran-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino) Preparation of pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidation

(6-((5-溴-2-((7-甲氧基-2-(四氫呋喃-3-基)-1,2,3,4-四氫異喹啉-6-基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((5-Bromo-2-((7-methoxy-2-(tetrahydrofuran-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino) The preparation method of pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidation refers to Example 1.

MS m/z(ESI)：630.2[M+H]⁺. MS m/z(ESI): 630.2[M+H] ⁺ .

實施例34 Example 34

(6-((5-溴-2-((7-甲氧基-2-(1-甲基吡咯烷-3-基)-1,2,3,4-四氫異喹啉-6-基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((7-methoxy-2-(1-methylpyrrolidin-3-yl)-1,2,3,4-tetrahydroisoquinoline-6- (Amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidation preparation

(6-((5-溴-2-((7-甲氧基-2-(1-甲基吡咯烷-3-基)-1,2,3,4-四氫異喹啉-6-基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((5-Bromo-2-((7-methoxy-2-(1-methylpyrrolidin-3-yl)-1,2,3,4-tetrahydroisoquinoline-6- (Amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidized preparation method refer to Examples 1.

MS m/z(ESI)：643.2[M+H]⁺. MS m/z(ESI): 643.2[M+H] ⁺ .

實施例35 Example 35

(6-((5-溴-2-((7-甲氧基-1,2,3,4-四氫異喹啉-6-基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)amino)- Preparation of 2,3-Dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine by oxidation

(6-((5-溴-2-((7-甲氧基-1,2,3,4-四氫異喹啉-6-基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((5-Bromo-2-((7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)amino)- Refer to Example 1 for the preparation method of 2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidation.

MS m/z(ESI)：560.1[M+H]⁺. MS m/z(ESI): 560.1[M+H] ⁺ .

實施例36 Example 36

(6-((5-溴-2-((6-甲氧基-1,2,3,4-四氫異喹啉-7-基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)- Preparation of 2,3-Dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine by oxidation

(6-((5-溴-2-((6-甲氧基-1,2,3,4-四氫異喹啉-7-基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((5-Bromo-2-((6-methoxy-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino)- Refer to Example 1 for the preparation method of 2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidation.

MS m/z(ESI)：560.1[M+H]⁺. MS m/z(ESI): 560.1[M+H] ⁺ .

實施例37 Example 37

(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦硫化的製備 (6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine sulfide preparation

(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦硫化的製備方法參照實施例2。 (6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine vulcanization preparation method refer to Example 2 .

MS m/z(ESI)：730.2[M+H]⁺. MS m/z(ESI): 730.2[M+H] ⁺ .

實施例38 Example 38

(6-((5-溴-2-((4-(4-(3-(乙基(甲基)胺基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((4-(4-(3-(ethyl(methyl)amino)azetidin-1-yl)piperidin-1-yl)-2-methyl (Oxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethyl Preparation of phosphine oxidation

(6-((5-溴-2-((4-(4-(3-(乙基(甲基)胺基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((5-Bromo-2-((4-(4-(3-(ethyl(methyl)amino)azetidin-1-yl)piperidin-1-yl)-2-methyl (Oxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethyl Refer to Example 1 for the preparation method of phosphine oxidation.

¹H NMR(400MHz,CD₃OD)δ 1.14(t,J=7.2Hz,3H),1.52-1.63(m,2H),1.87(s,3H),1.91(s,3H),1.99-2.09(m,2H),2.12(s,3H),2.29(s,3H),2.48-2.57(m,2H),2.66-2.77(m,2H),2.83-2.93(m,1H),3.08-3.18(m,2H),3.38-3.45(m,1H),3.63-3.71(m,2H),3.84(s,3H),4.00-4.07(m,2H),4.22-4.40(m,4H),6.71(s,1H),6.88-6.95(m,1H),7.71(s,1H),7.85-7.92(m,1H),8.06(s,1H)；MS m/z(ESI)：714.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 1.14 (t, J = 7.2Hz, 3H), 1.52-1.63 (m, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 1.99-2.09 ( m, 2H), 2.12 (s, 3H), 2.29 (s, 3H), 2.48-2.57 (m, 2H), 2.66-2.77 (m, 2H), 2.83-2.93 (m, 1H), 3.08-3.18 ( m, 2H), 3.38-3.45 (m, 1H), 3.63-3.71 (m, 2H), 3.84 (s, 3H), 4.00-4.07 (m, 2H), 4.22-4.40 (m, 4H), 6.71 ( s,1H),6.88-6.95(m,1H),7.71(s,1H),7.85-7.92(m,1H),8.06(s,1H); MS m/z(ESI): 714.2[M+H ] ⁺ .

實施例39 Example 39

(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基-1,4-重氮基庚環-1-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazoheptan-1-yl)piper (Pyridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine Oxidation preparation

(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(4-甲基-1,4-重氮基庚環-1-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazoheptan-1-yl)piper (Pyridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine Refer to Example 1 for the preparation method of oxidation.

¹H NMR(400MHz,CD₃OD)δ 1.73-1.84(m,2H),1.85-1.97(m,8H),2.00-2.10(m,2H),2.14(s,3H),2.64-2.74(m,2H),2.78-2.86(m,4H),3.01-3.07(m,2H),3.09-3.18(m,4H),3.19-3.23(m,2H),3.25-3.29(m,2H),3.83(s,3H),4.25-4.39(m,4H),6.70(s,1H),6.90(d,J=9.1Hz,1H),7.68(s,1H),7.86-7.93(m,1H),8.05(s,1H)；MS m/z(ESI)：714.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 1.73-1.84 (m, 2H), 1.85-1.97 (m, 8H), 2.00-2.10 (m, 2H), 2.14 (s, 3H), 2.64-2.74 (m ,2H),2.78-2.86(m,4H),3.01-3.07(m,2H),3.09-3.18(m,4H),3.19-3.23(m,2H),3.25-3.29(m,2H),3.83 (s,3H),4.25-4.39(m,4H),6.70(s,1H),6.90(d, J =9.1Hz,1H),7.68(s,1H),7.86-7.93(m,1H), 8.05(s,1H); MS m/z(ESI): 714.2[M+H] ⁺ .

實施例40 Example 40

(6-((2-((4-(4-(1,4-噁吖庚環-4-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)-5-溴嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((2-((4-(4-(1,4-oxazepan-4-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amine (Yl)-5-bromopyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidation preparation

(6-((2-((4-(4-(1,4-噁吖庚環-4-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)-5-溴嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((2-((4-(4-(1,4-oxazepan-4-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amine (Base)-5-bromopyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidation preparation method refer to the implementation example 1.

¹H NMR(400MHz,CD₃OD)δ 1.84-1.94(m,8H),2.02-2.10(m,4H),2.15(s,3H),2.69-2.79(m,2H),3.08-3.26(m,7H),3.80-3.88(m,7H),4.26-4.39(m,4H),6.72(s,1H),6.91(d,J=9.1Hz,1H),7.70(s,1H),7.86-7.92(m,1H),8.06(s,1H)；MS m/z(ESI)：701.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 1.84-1.94 (m, 8H), 2.02-2.10 (m, 4H), 2.15 (s, 3H), 2.69-2.79 (m, 2H), 3.08-3.26 (m ,7H),3.80-3.88(m,7H),4.26-4.39(m,4H),6.72(s,1H),6.91(d, J =9.1Hz,1H),7.70(s,1H),7.86- 7.92(m,1H),8.06(s,1H); MS m/z(ESI): 701.2[M+H] ⁺ .

實施例41 Example 41

(6-((2-((4-(4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)胺基)-5-(三氟甲基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl )Amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethyl Preparation of phosphine oxidation

(6-((2-((4-(4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)胺基)-5-(三氟甲基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例2。 (6-((2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl )Amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethyl Refer to Example 2 for the preparation method of phosphine oxidation.

¹H NMR(400MHz,CD₃OD)δ 0.94-1.04(m,3H),1.51-1.60(m,2H),1.84(s,3H),1.88(s,3H),1.98-2.07(m,2H),2.26(s,6H),2.46-2.55(m,2H),2.70-2.81(m,2H), 3.04-3.12(m,2H),3.17-3.23(m,2H),3.57-3.65(m,2H),3.84(s,3H),3.99(t,J=8.1Hz,2H),4.26-4.33(m,2H),4.33-4.41(m,2H),6.77(s,1H),6.89(d,J=9.1Hz,1H),7.54-7.64(m,1H),7.72(s,1H),8.25(s,1H)；MS m/z(ESI)：704.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 0.94-1.04 (m, 3H), 1.51-1.60 (m, 2H), 1.84 (s, 3H), 1.88 (s, 3H), 1.98-2.07 (m, 2H) ), 2.26(s, 6H), 2.46-2.55(m, 2H), 2.70-2.81(m, 2H), 3.04-3.12(m, 2H), 3.17-3.23(m, 2H), 3.57-3.65(m ,2H),3.84(s,3H),3.99(t, J =8.1Hz,2H),4.26-4.33(m,2H),4.33-4.41(m,2H),6.77(s,1H),6.89( d, J =9.1Hz,1H),7.54-7.64(m,1H),7.72(s,1H),8.25(s,1H); MS m/z(ESI): 704.2[M+H] ⁺ .

實施例42 Example 42

2-(1-(1-(4-((4-((5-(二甲基磷基)-2,3-二氫苯并[b][1,4]二噁烷-6-基)胺基)-5-(甲硫基)嘧啶-2-基)胺基)-5-甲氧基-2-甲基苯基)哌啶-4-基)吖丁啶-3-基)乙醯腈的製備 2-(1-(1-(4-((4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1,4]dioxane-6-yl )Amino)-5-(methylthio)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl) Preparation of Acetonitrile

2-(1-(1-(4-((4-((5-(二甲基磷基)-2,3-二氫苯并[b][1,4]二噁烷-6-基)胺基)-5-(甲硫基)嘧啶-2-基)胺基)-5-甲氧基-2-甲基苯基)哌啶-4-基)吖丁啶-3-基)乙醯腈的製備方法參照實施例1。 2-(1-(1-(4-((4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1,4]dioxane-6-yl )Amino)-5-(methylthio)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)azetidine-3-yl) Refer to Example 1 for the preparation method of acetonitrile.

¹H NMR(400MHz,CD₃OD)δ 1.51-1.61(m,2H),1.87(s,3H),1.91(s,3H),1.99-2.07(m,2H),2.13(s,3H),2.29(s,3H),2.67-2.76(m,2H),2.81-2.95(m,3H),3.07-3.19(m,3H),3.65-3.73(m,2H),3.85(s,3H),4.02-4.10(m,2H),4.26-4.31(m,4H),6.72(s,1H),6.91(d,J=9.1Hz,1H),7.75(s,1H),7.89-7.96(m,1H),8.11(s,1H)；MS m/z(ESI)：664.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 1.51-1.61 (m, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 1.99-2.07 (m, 2H), 2.13 (s, 3H), 2.29(s,3H),2.67-2.76(m,2H),2.81-2.95(m,3H),3.07-3.19(m,3H),3.65-3.73(m,2H),3.85(s,3H), 4.02-4.10(m,2H),4.26-4.31(m,4H),6.72(s,1H),6.91(d, J =9.1Hz,1H),7.75(s,1H),7.89-7.96(m, 1H),8.11(s,1H); MS m/z(ESI): 664.2[M+H] ⁺ .

實施例43 Example 43

(6-((2-((4-(4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)胺基)-5-(甲硫基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl )Amino)-5-(methylthio)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine Oxidation preparation

(6-((2-((4-(4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)胺基)-5-(甲硫基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例2。 (6-((2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl )Amino)-5-(methylthio)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine Refer to Example 2 for the preparation method of oxidation.

¹H NMR(400MHz,CD₃OD)δ 1.01(t,J=7.5Hz,3H),1.51-1.63(m,2H),1.87(s,3H),1.91(s,3H),1.99-2.08(m,2H),2.24-2.32(m,9H),2.50-2.58(m,2H),2.70-2.80(m,2H),2.85-2.96(m,1H),3.03-3.13(m,2H),3.20-3.28(m,1H),3.64-3.71(m,2H),3.85(s,3H),3.98-4.08(m,2H),4.25-4.40(m,4H),6.77(s,1H),6.91(d,J=9.1Hz,1H),7.79-7.88(m,2H),8.12(s,1H)；MS m/z(ESI)：682.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 1.01 (t, J = 7.5Hz, 3H), 1.51-1.63 (m, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 1.99-2.08 ( m, 2H), 2.24-2.32 (m, 9H), 2.50-2.58 (m, 2H), 2.70-2.80 (m, 2H), 2.85-2.96 (m, 1H), 3.03-3.13 (m, 2H), 3.20-3.28 (m, 1H), 3.64-3.71 (m, 2H), 3.85 (s, 3H), 3.98-4.08 (m, 2H), 4.25-4.40 (m, 4H), 6.77 (s, 1H), 6.91(d, J =9.1Hz,1H),7.79-7.88(m,2H),8.12(s,1H); MS m/z(ESI): 682.2[M+H] ⁺ .

實施例44 Example 44

(6-((5-溴-2-((5-乙炔基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((5-ethynyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidation preparation

(6-((5-溴-2-((5-乙炔基-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例2。 (6-((5-Bromo-2-((5-ethynyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidized preparation method refer to Example 2 .

MS m/z(ESI)：710.2[M+H]⁺. MS m/z(ESI): 710.2[M+H] ⁺ .

實施例45 Example 45

(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(3-(甲氧基甲基)吖丁啶-1-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(3-(methoxymethyl)azetidine-1-yl)piperidine- 1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidized preparation

(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-(3-(甲氧基甲基)吖丁啶-1-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例2。 (6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(3-(methoxymethyl)azetidine-1-yl)piperidine- 1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidized Refer to Example 2 for the preparation method.

¹H NMR(400MHz,CD₃OD)δ 1.02(t,J=7.5Hz,3H),1.53-1.64(m,2H),1.87(s,3H),1.91(s,3H),2.02-2.09(m,2H),2.49-2.60(m,2H),2.71-2.81(m,2H),2.97-3.13(m,4H),3.44(s,3H),3.52(d,J=4.5Hz,2H),3.84(s,3H),3.87-3.91(m,2H),4.08(t,J=9.4Hz,2H),4.26-4.33(m,2H),4.33-4.40(m,2H),6.77(s,1H),6.91(d,J=9.2Hz,1H),7.77(s,1H),7.79-7.84(m,1H),8.07(s,1H)；MS m/z(ESI)：715.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 1.02 (t, J = 7.5 Hz, 3H), 1.53-1.64 (m, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 2.02-2.09 ( m,2H),2.49-2.60(m,2H),2.71-2.81(m,2H),2.97-3.13(m,4H),3.44(s,3H),3.52(d, J =4.5Hz,2H) ,3.84(s,3H),3.87-3.91(m,2H),4.08(t, J =9.4Hz,2H),4.26-4.33(m,2H),4.33-4.40(m,2H),6.77(s ,1H),6.91(d, J =9.2Hz,1H),7.77(s,1H),7.79-7.84(m,1H),8.07(s,1H); MS m/z(ESI): 715.2[M +H] ⁺ .

實施例46 Example 46

2-(1-(1-(4-((5-溴-4-((5-(二甲基磷基)-2,3-二氫苯并[b][1,4]二噁烷-6-基)胺基)嘧啶-2-基)胺基)-2-乙基-5-甲氧苯基)哌啶-4-基)吖丁啶-3-基)乙醯腈的製備 2-(1-(1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)-2,3-dihydrobenzo[b][1,4]dioxane -6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile

2-(1-(1-(4-((5-溴-4-((5-(二甲基磷基)-2,3-二氫苯并[b][1,4]二噁烷-6-基)胺基)嘧啶-2-基)胺基)-2-乙基-5-甲氧苯基)哌啶-4-基)吖丁啶-3-基)乙醯腈的製備方法參照實施例2。 2-(1-(1-(4-((5-Bromo-4-((5-(dimethylphosphoryl)-2,3-dihydrobenzo[b][1,4]dioxane -6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)azetidine-3-yl)acetonitrile Refer to Example 2 for the method.

¹H NMR(400MHz,CD₃OD)δ 1.01(t,J=7.5Hz,3H),1.50-1.60(m,2H),1.87(s,3H),1.91(s,3H),1.96-2.04(m,2H),2.50-2.58(m,2H),2.71-2.79(m,2H),2.80-2.87(m,3H),3.03-3.12(m,3H),3.58-3.68(m,2H),3.84(s,3H),3.97-4.06(m,2H),4.25-4.31(m,4H),6.76(s,1H),6.90(d,J=9.1Hz,1H),7.74-7.83(m,2H),8.07(s,1H)；MS m/z(ESI)：710.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 1.01 (t, J = 7.5Hz, 3H), 1.50-1.60 (m, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 1.96-2.04 ( m, 2H), 2.50-2.58 (m, 2H), 2.71-2.79 (m, 2H), 2.80-2.87 (m, 3H), 3.03-3.12 (m, 3H), 3.58-3.68 (m, 2H), 3.84(s,3H),3.97-4.06(m,2H),4.25-4.31(m,4H),6.76(s,1H),6.90(d, J =9.1Hz,1H),7.74-7.83(m, 2H), 8.07(s,1H); MS m/z(ESI): 710.2[M+H] ⁺ .

實施例47 Example 47

(6-((5-溴-2-((4-(4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-(三氟甲基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5 -(Trifluoromethyl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethyl Preparation of phosphine oxidation

(6-((5-溴-2-((4-(4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-(三氟甲基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5 -(Trifluoromethyl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethyl Refer to Example 1 for the preparation method of phosphine oxidation.

¹H NMR(400MHz，CD₃OD)δ 1.51-1.62(m,2H),1.88(s,3H),1.91(s,3H),2.00-2.07(m,2H),2.28(s,6H),2.85(t,J=11.3Hz,2H),2.91-3.02(m,1H),3.04-3.12(m,2H),3.21-3.27(m,1H),3.67-3.75(m,2H),3.94(s,3H),4.02-4.08(m,2H),4.26-4.32(m,2H),4.33-4.39(m,2H),6.89(d,J=9.1Hz,1H),7.07(s,1H),7.81-7.86(m,1H),8.13(s,1H),8.21(s,1H)；MS m/z(ESI)：754.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 1.51-1.62 (m, 2H), 1.88 (s, 3H), 1.91 (s, 3H), 2.00-2.07 (m, 2H), 2.28 (s, 6H), 2.85(t, J =11.3Hz,2H),2.91-3.02(m,1H),3.04-3.12(m,2H),3.21-3.27(m,1H),3.67-3.75(m,2H),3.94( s,3H),4.02-4.08(m,2H),4.26-4.32(m,2H),4.33-4.39(m,2H),6.89(d, J =9.1Hz,1H),7.07(s,1H) ,7.81-7.86(m,1H),8.13(s,1H),8.21(s,1H); MS m/z(ESI): 754.2[M+H] ⁺ .

實施例48 Example 48

(5-((5-溴-2-((4-(4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)苯并[d][1,3]二噁唑-4-基)二甲基膦氧化的製備 (5-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxazol-4-yl)dimethylphosphine oxidation preparation

(5-((5-溴-2-((4-(4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)苯并[d][1,3]二噁唑-4-基)二甲基膦氧化的製備方法參照實施例1。 (5-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxazol-4-yl)dimethylphosphine oxidation The preparation method refers to Example 1.

¹H NMR(400MHz,CD₃OD)δ 1.58-1.61(m,2H),1.86-1.88(m,6H),1.90-1.92(m,1H),2.04-2.07(m,2H),2.12-2.15(m,3H),2.20-2.37(m,6H),2.70-2.75(m,2H),2.92-2.95(m,1H),3.13-3.16(m,2H),3.61-3.77(m,2H),3.84(s,3H),3.97-4.14(m,2H),6.07(s,2H),6.71(s,1H),6.92-6.95(m,1H),7.70(s,1H),7.74-7.87(m,1H),8.07(s,1H)；MS m/z(ESI)：686.2[M+H]⁺. ¹ H NMR(400MHz,CD ₃ OD) δ 1.58-1.61(m,2H),1.86-1.88(m,6H),1.90-1.92(m,1H),2.04-2.07(m,2H),2.12-2.15 (m,3H),2.20-2.37(m,6H),2.70-2.75(m,2H),2.92-2.95(m,1H),3.13-3.16(m,2H),3.61-3.77(m,2H) ,3.84(s,3H),3.97-4.14(m,2H),6.07(s,2H),6.71(s,1H),6.92-6.95(m,1H),7.70(s,1H),7.74-7.87 (m,1H),8.07(s,1H); MS m/z(ESI): 686.2[M+H] ⁺ .

實施例49 Example 49

(5-((5-溴-2-((4-(4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)胺基)嘧啶-4-基)胺基)苯并[d][1,3]二噁唑-4-基)二甲基膦氧化的製備 (5-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2- (Methoxyphenyl) amino) pyrimidin-4-yl) amino) benzo[d][1,3] dioxazol-4-yl) dimethylphosphine oxidation preparation

(5-((5-溴-2-((4-(4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)胺基)嘧啶-4-基)胺基)苯并[d][1,3]二噁唑-4-基)二甲基膦氧化的製備方法參照實施例2。 (5-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2- (Methoxyphenyl) amino) pyrimidin-4-yl) amino) benzo[d] [1,3] dioxazol-4-yl) dimethyl phosphine oxidation method refer to Example 2.

¹H NMR(400MHz,CD₃OD)δ 1.01(t,J=7.2Hz,3H),1.41-1.58(m,2H),1.86-1.89(m,6H),2.01-2.03(m,2H),2.25(s,6H),2.52-2.55(m,2H),2.76-2.78(m,3H),3.05-3.08(m,2H),3.12-3.24(m,1H),3.57-3.59(m,2H),3.84(s,3H),3.96-3.99(m,2H),6.07(s,2H),6.76(s,1H),6.91-6.93(m,1H),7.61-7.78(m,2H),8.08(s,1H)；MS m/z(ESI)：700.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 1.01 (t, J = 7.2Hz, 3H), 1.41-1.58 (m, 2H), 1.86-1.89 (m, 6H), 2.01-2.03 (m, 2H), 2.25(s,6H),2.52-2.55(m,2H),2.76-2.78(m,3H),3.05-3.08(m,2H),3.12-3.24(m,1H),3.57-3.59(m,2H) ), 3.84(s,3H),3.96-3.99(m,2H),6.07(s,2H),6.76(s,1H),6.91-6.93(m,1H),7.61-7.78(m,2H), 8.08(s,1H); MS m/z(ESI): 700.2[M+H] ⁺ .

實施例50 Example 50

(6-((2-((5-溴-4-(4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-2-甲氧苯基)胺基)-5-氯嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((2-((5-Bromo-4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxyphenyl) Amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) dimethylphosphine oxidation preparation

(6-((2-((5-溴-4-(4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-2-甲氧苯基)胺基)-5-氯嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((2-((5-Bromo-4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxyphenyl) Amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidation preparation method reference Example 1.

MS m/z(ESI)：720.2[M+H]⁺. MS m/z(ESI): 720.2[M+H] ⁺ .

實施例51 Example 51

(6-((2-((5-溴-4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-2-甲氧苯基)胺基)-5-氯嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((2-((5-Bromo-4-(4-(3-ethoxyazetidine-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino) Preparation of -5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidation

(6-((2-((5-溴-4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-2-甲氧苯基)胺基)-5-氯嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((2-((5-Bromo-4-(4-(3-ethoxyazetidine-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino) -5-Chloropyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidized preparation method refer to Example 1 .

MS m/z(ESI)：721.2[M+H]⁺. MS m/z(ESI): 721.2[M+H] ⁺ .

實施例52 Example 52

(6-((5-氯-2-((4-(4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Chloro-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2- (Methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidation preparation

(6-((5-氯-2-((4-(4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-5-乙基-2-甲氧苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例2。 (6-((5-Chloro-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-5-ethyl-2- (Methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) dimethylphosphine oxidation preparation method Refer to Example 2.

¹H NMR(400MHz,CD₃OD)δ 0.96-1.11(m,3H),1.48-1.63(m,2H),1.88(s,3H),1.91(s,3H),1.99-2.08(m,2H),2.27(s,6H),2.50-2.64(m,2H),2.66-2.96(m,4H),3.04-3.12(m,2H),3.16-3.25(m,2H),3.55-3.66(m,2H),3.85(s,3H),3.94-4.05(m,2H),4.23-4.31(m,2H),4.33-4.40(m,2H),6.78(s,1H),6.86-6.93(m,1H),7.76(d,J=4.4Hz,1H),7.93-8.01(m,2H)；MS m/z(ESI)：670.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 0.96-1.11 (m, 3H), 1.48-1.63 (m, 2H), 1.88 (s, 3H), 1.91 (s, 3H), 1.99-2.08 (m, 2H) ), 2.27(s, 6H), 2.50-2.64(m, 2H), 2.66-2.96(m, 4H), 3.04-3.12(m, 2H), 3.16-3.25(m, 2H), 3.55-3.66(m ,2H),3.85(s,3H),3.94-4.05(m,2H),4.23-4.31(m,2H),4.33-4.40(m,2H),6.78(s,1H),6.86-6.93(m ,1H),7.76(d, J =4.4Hz,1H),7.93-8.01(m,2H); MS m/z(ESI): 670.2[M+H] ⁺ .

實施例53 Example 53

(6-((5-溴-2-((4-(4-(3-氟-3-(羥甲基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((4-(4-(3-fluoro-3-(hydroxymethyl)azetidine-1-yl)piperidin-1-yl)-2-methoxy 5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine Oxidation preparation

(6-((5-溴-2-((4-(4-(3-氟-3-(羥甲基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((5-Bromo-2-((4-(4-(3-fluoro-3-(hydroxymethyl)azetidine-1-yl)piperidin-1-yl)-2-methoxy 5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine Refer to Example 1 for the preparation method of oxidation.

¹H NMR(400MHz,DMSO-d ⁶)δ 1.35-1.38(m,2H),1.79-1.81(m,8H),2.11(s,3H),2.22-2.25(m,1H),2.58-2.71(m,3H),2.96-3.01(m,5H),3.68-2.71(m,2H),3.76(s,3H),4.28-4.31(m,4H),6.70(s,1H),6.80-6.83(m,1H),7.43(s,1H),7.93-7.95(m2H),8.10(s,1H),11.62(s,1H)；MS m/z(ESI)：705.2[M+H]⁺. ¹ H NMR (400MHz, DMSO- d ⁶ ) δ 1.35-1.38 (m, 2H), 1.79-1.81 (m, 8H), 2.11 (s, 3H), 2.22-2.25 (m, 1H), 2.58-2.71 ( m, 3H), 2.96-3.01 (m, 5H), 3.68-2.71 (m, 2H), 3.76 (s, 3H), 4.28-4.31 (m, 4H), 6.70 (s, 1H), 6.80-6.83 ( m,1H),7.43(s,1H),7.93-7.95(m2H),8.10(s,1H),11.62(s,1H); MS m/z(ESI): 705.2[M+H] ⁺ .

實施例54 Example 54

(6-((5-溴-2-((5-乙基-4-(4-(3-氟-3-(羥甲基)吖丁啶-1-基)哌啶-1-基)-2-甲氧苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((5-ethyl-4-(4-(3-fluoro-3-(hydroxymethyl)azetidine-1-yl)piperidin-1-yl) -2-Methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxide Preparation

(6-((5-溴-2-((5-乙基-4-(4-(3-氟-3-(羥甲基)吖丁啶-1-基)哌啶-1-基)-2-甲氧苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例2。 (6-((5-Bromo-2-((5-ethyl-4-(4-(3-fluoro-3-(hydroxymethyl)azetidine-1-yl)piperidin-1-yl) -2-Methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxide Refer to Example 2 for the preparation method.

¹H NMR(400MHz,CD₃OD)δ 1.02(t,J=7.6Hz,3H),1.49-1.64(m,2H),1.87(s,3H),1.91(s,3H),2.00(d,J=13.4Hz,2H),2.54(q,J=7.5Hz,2H),2.75(t,J=11.5Hz,3H),3.07(d,J=11.7Hz,2H),3.71-3.85(m,7H),3.97(dd,J=15.7,10.4Hz,2H),4.29(s,2H),4.36(s,2H),6.77(s,1H),6.90(d,J=9.1Hz,1H),7.75(s,1H),7.81(dd,J=9.2,4.5Hz,1H),8.07(s,1H)；MS m/z(ESI)：719.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 1.02 (t, J =7.6Hz, 3H), 1.49-1.64 (m, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 2.00 (d, J =13.4Hz,2H),2.54(q, J =7.5Hz,2H),2.75(t, J =11.5Hz,3H),3.07(d, J =11.7Hz,2H),3.71-3.85(m, 7H), 3.97(dd, J =15.7, 10.4Hz, 2H), 4.29(s, 2H), 4.36(s, 2H), 6.77(s, 1H), 6.90(d, J =9.1Hz, 1H), 7.75(s,1H),7.81(dd, J =9.2,4.5Hz,1H),8.07(s,1H); MS m/z(ESI): 719.2[M+H] ⁺ .

實施例55 Example 55

(6-((5-溴-2-((4-(4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,2-二甲基-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2,3-dihydrobenzo[b][1,4]dioxan-5-yl ) Preparation of dimethyl phosphine oxidation

(6-((5-溴-2-((4-(4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,2-二甲基-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2,3-dihydrobenzo[b][1,4]dioxan-5-yl ) Refer to Example 1 for the preparation method of dimethylphosphine oxidation.

MS m/z(ESI)：728.2[M+H]⁺. MS m/z(ESI): 728.2[M+H] ⁺ .

實施例56 Example 56

(6-((5-溴-2-((4-(4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-3,3-二甲基-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxan-5-yl ) Preparation of dimethyl phosphine oxidation

(6-((5-溴-2-((4-(4-(3-(二甲胺基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-3,3-二甲基-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((5-Bromo-2-((4-(4-(3-(dimethylamino)azetidine-1-yl)piperidin-1-yl)-2-methoxy-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxan-5-yl ) Refer to Example 1 for the preparation method of dimethylphosphine oxidation.

MS m/z(ESI)：728.2[M+H]⁺. MS m/z(ESI): 728.2[M+H] ⁺ .

實施例57 Example 57

(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-((3aR,6aS)-四氫-1H-呋喃并[3,4-c]吡咯-5(3H)-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-tetrahydro-1H-furo[3,4-c] Pyrrole-5(3H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]diox Alk-5-yl) dimethyl phosphine oxidation preparation

第一步：(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-((3aR,6aS)-四氫-1H-呋喃并[3,4-c]吡咯-5(3H)-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 The first step: (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-tetrahydro-1H-furo[3, 4-c]pyrrole-5(3H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1, 4] Preparation of dioxan-5-yl) dimethyl phosphine oxidation

室溫條件下，1-(4-((5-溴-4-((5-(二甲基磷基)-2,3-二氫苯并[b][1,4]二噁烷-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-甲基苯基)哌啶-4-酮(0.25g,0.41mmol)，(3aR,6aS)-六氫-1H-呋喃并[3,4-c]吡咯(0.07g,0.61mmol)和醋酸(3滴)混溶於二氯乙烷(10mL)中，攪拌30分鐘，加入三乙醯氧基硼氫化鈉(0.17g,0.81mmol)，室溫攪拌過夜，向反應液中加入飽和碳酸氫鈉水溶液，用二氯甲烷萃取，分離有機相，用無水硫酸鈉乾燥，過濾後減壓濃縮有機溶劑，管柱層析分離得到標題化合物(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-((3aR,6aS)-四氫-1H-呋喃并[3,4-c]吡咯-5(3H)-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化(0.17g，收率：58%)。 At room temperature, 1-(4-((5-bromo-4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1,4]dioxane- 6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-one (0.25g, 0.41mmol), (3aR,6aS)- Hexahydro-1H-furo[3,4-c]pyrrole (0.07g, 0.61mmol) and acetic acid (3 drops) were mixed in dichloroethane (10mL), stirred for 30 minutes, and added triacetoxy Sodium borohydride (0.17g, 0.81mmol), stirred at room temperature overnight, add saturated aqueous sodium bicarbonate to the reaction solution, extract with dichloromethane, separate the organic phase, dry with anhydrous sodium sulfate, filter and concentrate the organic solvent under reduced pressure , Column chromatography was separated to obtain the title compound (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-tetrahydro-1H- Furo[3,4-c]pyrrole-5(3H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[ b] [1,4] Dioxan-5-yl)dimethylphosphine oxidation (0.17 g, yield: 58%).

¹H NMR(400MHz,DMSO-d ⁶)δ 1.49-1.62(m,2H),1.78(s,3H),1.81(s,3H),1.89-1.95(m,2H),2.04-2.15(m,4H),2.38-2.43(m,2H),2.58-2.72(m,6H),3.02-3.07(m,2H),3.35-3.43(m,2H),3.72-3.80(m,5H),4.24(s,2H),4.32(s,2H),6.70(s,1H),6.80(d,J=8.8Hz,1H),7.43(s,1H),7.91-7.97(m,2H),8.10(s,1H),11.62(s,1H)；MS m/z(ESI)：713.2[M+H]⁺. ¹ H NMR (400MHz, DMSO- d ⁶ ) δ 1.49-1.62 (m, 2H), 1.78 (s, 3H), 1.81 (s, 3H), 1.89-1.95 (m, 2H), 2.04-2.15 (m, 4H), 2.38-2.43 (m, 2H), 2.58-2.72 (m, 6H), 3.02-3.07 (m, 2H), 3.35-3.43 (m, 2H), 3.72-3.80 (m, 5H), 4.24 ( s, 2H), 4.32 (s, 2H), 6.70 (s, 1H), 6.80 (d, J = 8.8 Hz, 1H), 7.43 (s, 1H), 7.91-7.97 (m, 2H), 8.10 (s ,1H),11.62(s,1H); MS m/z(ESI): 713.2[M+H] ⁺ .

實施例58 Example 58

(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-((3aR,6aS)-四氫-1H-呋喃并[3,4-c]吡咯-5(3H)-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-((3aR,6aS)-tetrahydro-1H-furo[3,4-c] Pyrrole-5(3H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]diox Alk-5-yl) dimethyl phosphine oxidation preparation

(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-((3aR,6aS)-四氫-1H-呋喃并[3,4-c]吡咯-5(3H)-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例2。 (6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-((3aR,6aS)-tetrahydro-1H-furo[3,4-c] Pyrrole-5(3H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]diox Refer to Example 2 for the preparation method of alkyl-5-yl)dimethylphosphine oxidation.

¹H NMR(400MHz,CD₃OD)δ 1.03(t,J=7.6Hz,3H),1.87-1.91(m,8H),2.17-2.19(m,2H),2.56-2.58(m,2H),2.77-2.79(m,2H),2.90(s,3H),3.08-3.11(m 4H),3.65-3.68(m,4H),3.83-3.86(m,5H),4.32-4.35(m,4H),6.76(s,1H),6.91-6.93(m,1H),7.80-7.83(m,2H),8.07(s,1H)；MS m/z(ESI)：727.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 1.03 (t, J =7.6Hz, 3H), 1.87-1.91 (m, 8H), 2.17-2.19 (m, 2H), 2.56-2.58 (m, 2H), 2.77-2.79(m,2H),2.90(s,3H),3.08-3.11(m 4H),3.65-3.68(m,4H),3.83-3.86(m,5H),4.32-4.35(m,4H) ,6.76(s,1H),6.91-6.93(m,1H),7.80-7.83(m,2H),8.07(s,1H); MS m/z(ESI): 727.2[M+H] ⁺ .

實施例59 Example 59

(6-((5-溴-2-((5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-2,3-二氫苯并呋喃-7-基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzene Furan-7-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidized preparation

第一步：5-甲基-2,3-二氫苯并呋喃的製備 Step 1: Preparation of 5-methyl-2,3-dihydrobenzofuran

往5-甲基苯并呋喃(3.0g,22.7mmol)的甲醇溶液(30mL)中加入Pd/C(300mg,10wt%)，在氫氣氛下，常溫常壓，攪拌過夜。用矽藻土濾除不溶物，濾液減壓濃縮有機溶劑，管柱層析分離得到標題化合物5-甲基-2,3-二氫苯并呋喃(2.70g，收率：89%)。 Pd/C (300mg, 10wt%) was added to a methanol solution (30mL) of 5-methylbenzofuran (3.0g, 22.7mmol), and stirred overnight under a hydrogen atmosphere at room temperature and pressure. The insoluble matter was filtered off with celite, the filtrate was concentrated under reduced pressure and the organic solvent was concentrated, and column chromatography was separated to obtain the title compound 5-methyl-2,3-dihydrobenzofuran (2.70 g, yield: 89%).

第二步：5-甲基-7-硝基-2,3-二氫苯并呋喃的製備 Step 2: Preparation of 5-methyl-7-nitro-2,3-dihydrobenzofuran

冰水浴下，往5-甲基-2,3-二氫苯并呋喃(2.70g,20.1mmol)的TFA溶液(40mL)裡分批加入NaNO₂(1.36g,19.7mmol)，然後繼續在冰水浴下攪拌兩小時。向反應中加入冰水，然後用DCM萃取多次，合併有機相，依次用飽和碳酸氫鈉水溶液和飽和食鹽水洗滌，分離有機相用無水硫酸鈉乾燥，過濾後減壓濃縮有機溶劑，管柱層析分離得到標題化合物5-甲基-7-硝基-2,3-二氫苯并呋喃(900mg，收率：25%)。 _{In an ice-water bath, add NaNO 2} (1.36g, 19.7mmol) to the TFA solution (40mL) of 5-methyl-2,3-dihydrobenzofuran (2.70g, 20.1mmol) in batches, and then continue to place it on ice. Stir under a water bath for two hours. Ice water was added to the reaction, and then extracted with DCM for several times. The organic phases were combined, washed with saturated aqueous sodium bicarbonate solution and saturated brine successively, separated the organic phase and dried with anhydrous sodium sulfate, filtered, and concentrated the organic solvent under reduced pressure. Chromatographic separation gave the title compound 5-methyl-7-nitro-2,3-dihydrobenzofuran (900mg, yield: 25%).

第三步：5-甲基-2,3-二氫苯并呋喃-7-胺的製備 The third step: Preparation of 5-methyl-2,3-dihydrobenzofuran-7-amine

往5-甲基-7-硝基-2,3-二氫苯并呋喃(900mg,5.03mmol)的甲醇溶液(30mL)中加入Pd/C(100mg,10wt%)，在氫氣氛下，常溫常壓，攪拌過夜。用矽藻土濾除不溶物，濾液濃縮，管柱層析分離得到標題化合物5-甲基-2,3-二氫苯并呋喃-7-胺(670mg，收率：89%)。 Add Pd/C (100mg, 10wt%) to a methanol solution (30mL) of 5-methyl-7-nitro-2,3-dihydrobenzofuran (900mg, 5.03mmol), under a hydrogen atmosphere, at room temperature At normal pressure, stir overnight. The insoluble matter was filtered off with Celite, the filtrate was concentrated, and column chromatography was separated to obtain the title compound 5-methyl-2,3-dihydrobenzofuran-7-amine (670mg, yield: 89%).

MS m/z(ESI)：150.1[M+H]⁺. MS m/z(ESI): 150.1[M+H] ⁺ .

第四步：4-溴-5-甲基-2,3-二氫苯并呋喃-7-胺的製備 The fourth step: preparation of 4-bromo-5-methyl-2,3-dihydrobenzofuran-7-amine

-30℃下，往5-甲基-2,3-二氫苯并呋喃-7-胺(650mg,4.36mmol)的DMF溶液(20mL)裡分批加入NBS(466mg,2.62mmol)，反應緩慢升至室溫，並在室溫下繼續攪拌兩小時。用EtOAc稀釋反應液後，用飽和食鹽水洗滌多次，濾液用無水硫酸鈉乾燥，減壓濃縮有機溶劑，管柱層析分離得到標題化合物4-溴-5-甲基-2,3-二氫苯并呋喃-7-胺(600mg，收率：60%)。 At -30℃, add NBS (466mg, 2.62mmol) to the DMF solution (20mL) of 5-methyl-2,3-dihydrobenzofuran-7-amine (650mg, 4.36mmol) in batches, the reaction is slow Warm to room temperature and continue stirring at room temperature for two hours. After diluting the reaction solution with EtOAc, it was washed with saturated brine several times, the filtrate was dried over anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure, and the title compound 4-bromo-5-methyl-2,3-di was obtained by column chromatography. Hydrobenzofuran-7-amine (600 mg, yield: 60%).

MS m/z(ESI)：228.0[M+H]⁺. MS m/z(ESI): 228.0[M+H] ⁺ .

第五步：N-(4-溴-5-甲基-2,3-二氫苯并呋喃-7-基)乙醯胺的製備 Step 5: Preparation of N-(4-bromo-5-methyl-2,3-dihydrobenzofuran-7-yl)acetamide

冰水浴下，往4-溴-5-甲基-2,3-二氫苯并呋喃-7-胺(400mg,1.75mmol)的二氯甲烷溶液(10mL)裡依次滴加入乙酸酐(0.233mL,2.46mmol)和DIPEA(0.864mL,5.25mmol)，反應然後緩慢升至室溫，並在室溫下繼續攪拌兩小時。減壓濃縮反應液，管柱層析分離純化得到標題化合物N-(4-溴-5-甲基-2,3-二氫苯并呋喃-7-基)乙醯胺(385mg，收率：81%)。 Under an ice-water bath, add acetic anhydride (0.233mL) to the dichloromethane solution (10mL) of 4-bromo-5-methyl-2,3-dihydrobenzofuran-7-amine (400mg, 1.75mmol). , 2.46 mmol) and DIPEA (0.864 mL, 5.25 mmol), the reaction was then slowly raised to room temperature, and stirring was continued for two hours at room temperature. The reaction solution was concentrated under reduced pressure, and column chromatography was separated and purified to obtain the title compound N-(4-bromo-5-methyl-2,3-dihydrobenzofuran-7-yl)acetamide (385mg, yield: 81%).

MS m/z(ESI)：270.0[M+H]⁺. MS m/z(ESI): 270.0[M+H] ⁺ .

第六步：N-(5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-2,3-二氫苯并呋喃-7-基)乙醯胺的製備 The sixth step: N-(5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzofuran-7-yl ) Preparation of Acetamide

往N-(4-溴-5-甲基-2,3-二氫苯并呋喃-7-基)乙醯胺(385mg,1.43mmol)和1-甲基-4-(哌啶-4-基)哌嗪(783mg,4.28mmol)的THF溶液(10mL)裡，依次加入醋酸鈀(48mg,0.215mmol)、Johnphos(128mg,0.430mmol)和LiHMDS(1M in THF,4.3mL)，氮氣保護下，微波115℃下反應2小時。反應冷卻至室溫，濃縮反應液，管柱層析分離得到標題化合物N-(5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-2,3-二氫苯并呋喃-7-基)乙醯胺(225mg，收率：42%)。 To N-(4-bromo-5-methyl-2,3-dihydrobenzofuran-7-yl)acetamide (385mg, 1.43mmol) and 1-methyl-4-(piperidine-4- Pyrazine (783mg, 4.28mmol) in THF (10mL), add palladium acetate (48mg, 0.215mmol), Johnphos (128mg, 0.430mmol) and LiHMDS (1M in THF, 4.3mL) in sequence under nitrogen protection , React under microwave at 115°C for 2 hours. The reaction was cooled to room temperature, the reaction solution was concentrated, and column chromatography was separated to obtain the title compound N-(5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) -2,3-Dihydrobenzofuran-7-yl)acetamide (225 mg, yield: 42%).

MS m/z(ESI)：373.3[M+H]⁺. MS m/z(ESI): 373.3[M+H] ⁺ .

第七步：5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-2,3-二氫苯并呋喃-7-胺的製備 Step 7: Preparation of 5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzofuran-7-amine

往N-(5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-2,3-二氫苯并呋喃-7-基)乙醯胺(125mg,0.336mmol)的乙醇溶液(10mL)裡小心加入濃硫酸(1mL)，加熱回流下攪拌一小時，冷卻，濃縮，用DCM溶解，再依次用飽和碳酸氫鈉水溶液、飽和食鹽水洗滌，乾燥，管柱層析，得標題化合物5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-2,3-二氫苯并呋喃-7-胺(80mg，收率：72%)。 To N-(5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzofuran-7-yl)acetone Carefully add concentrated sulfuric acid (1mL) to the ethanol solution (10mL) of amine (125mg, 0.336mmol), stir under reflux for one hour, cool, concentrate, dissolve with DCM, and wash with saturated sodium bicarbonate aqueous solution and saturated brine in turn , Drying, and column chromatography to obtain the title compound 5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzofuran -7-amine (80mg, yield: 72%).

MS m/z(ESI)：331.2[M+H]⁺. MS m/z(ESI): 331.2[M+H] ⁺ .

(6-((5-溴-2-((5-甲基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-2,3-二氫苯并呋喃-7-基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((5-Bromo-2-((5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2,3-dihydrobenzene Furan-7-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethylphosphine oxidized Refer to Example 1 for the preparation method.

¹H NMR(400MHz,CD₃OD)δ 1.70(d,J=12.0Hz,2H),1.87(s,3H),1.91(s,3H),2.00(d,J=13.2Hz,3H),2.16(s,3H),2.53(s,3H),2.60-2.65(m,1H),2.73-3.17(m, 13H),4.27(s,2H),4.34(d,J=4.3Hz,2H),4.48(t,J=8.6Hz,2H),6.84(d,J=9.3Hz,1H),7.30(s,1H),7.97(d,J=9.3Hz,1H),8.03(s,1H)；MS m/z(ESI)：712.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 1.70 (d, J =12.0Hz, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 2.00 (d, J =13.2Hz, 3H), 2.16 (s,3H),2.53(s,3H),2.60-2.65(m,1H),2.73-3.17(m, 13H), 4.27(s,2H), 4.34(d, J =4.3Hz,2H), 4.48(t, J =8.6Hz,2H),6.84(d, J =9.3Hz,1H),7.30(s,1H),7.97(d,J=9.3Hz,1H),8.03(s,1H); MS m/z(ESI): 712.2[M+H] ⁺ .

實施例60 Example 60

1-((3aR,6aS)-5-(1-(4-((5-溴-4-((5-(二甲基磷基)-2,3-二氫苯并[b][1,4]二噁烷-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-甲基苯基)哌啶-4-基)六氫吡咯并[3,4-c]吡咯-2(1H)-基)乙烷-1-酮的製備 1-((3aR,6aS)-5-(1-(4-((5-bromo-4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1 ,4]Dioxan-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)hexahydropyrrolo[3 ,4-c]pyrrole-2(1H)-yl)ethane-1-one

1-((3aR,6aS)-5-(1-(4-((5-溴-4-((5-(二甲基磷基)-2,3-二氫苯并[b][1,4]二噁烷-6-基)胺基)嘧啶-2-基)胺基)-5-甲氧基-2-甲基苯基)哌啶-4-基)六氫吡咯并[3,4-c]吡咯-2(1H)-基)乙烷-1-酮的製備方法參照實施例1。 1-((3aR,6aS)-5-(1-(4-((5-bromo-4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1 ,4]Dioxan-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)hexahydropyrrolo[3 The preparation method of ,4-c]pyrrole-2(1H)-yl)ethane-1-one refers to Example 1.

¹H NMR(400MHz,CD₃OD)δ 1.78-1.90(m,5H),1.91(s,3H),2.09(s,3H),2.12-2.22(m,5H),2.73(t,J=11.8Hz,2H),2.97-3.23(m,7H),3.54-3.67(m,5H),3.75-3.82(m,1H),3.84(s,3H),4.25-4.32(m,2H),4.33-4.39(m,2H),6.71(s,1H),6.91(d,J=9.1Hz,1H),7.72(s,1H),7.87-7.92(m,1H),8.06(s,1H)；MS m/z(ESI)：754.2[M+H]⁺. ¹ H NMR(400MHz,CD ₃ OD) δ 1.78-1.90(m,5H),1.91(s,3H),2.09(s,3H),2.12-2.22(m,5H),2.73(t, J =11.8 Hz, 2H), 2.97-3.23 (m, 7H), 3.54-3.67 (m, 5H), 3.75-3.82 (m, 1H), 3.84 (s, 3H), 4.25-4.32 (m, 2H), 4.33- 4.39(m,2H),6.71(s,1H),6.91(d, J =9.1Hz,1H),7.72(s,1H),7.87-7.92(m,1H),8.06(s,1H); MS m/z(ESI): 754.2[M+H] ⁺ .

實施例61 Example 61

1-((3aR,6aS)-5-(1-(4-((5-溴-4-((5-(二甲基磷基)-2,3-二氫苯并[b][1,4]二噁烷-6-基)胺基)嘧啶-2-基)胺基)-2-乙基-5-甲氧苯基)哌啶-4-基)六氫吡咯并[3,4-c]吡咯-2(1H)-基)乙烷-1-酮的製備 1-((3aR,6aS)-5-(1-(4-((5-bromo-4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1 ,4]Dioxan-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)hexahydropyrrolo[3, Preparation of 4-c]pyrrole-2(1H)-yl)ethane-1-one

1-((3aR,6aS)-5-(1-(4-((5-溴-4-((5-(二甲基磷基)-2,3-二氫苯并[b][1,4]二噁烷-6-基)胺基)嘧啶-2-基)胺基)-2-乙基-5-甲氧苯基)哌啶-4-基)六氫吡咯并[3,4-c]吡咯-2(1H)-基)乙烷-1-酮的製備方法參照實施例2。 1-((3aR,6aS)-5-(1-(4-((5-bromo-4-((5-(dimethylphosphorus)-2,3-dihydrobenzo[b][1 ,4]Dioxan-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)hexahydropyrrolo[3, Refer to Example 2 for the preparation method of 4-c]pyrrole-2(1H)-yl)ethane-1-one.

¹H NMR(400MHz,CD₃OD)δ 1.02(t,J=7.7Hz,3H),1.81-1.93(m,8H),2.09(s,3H),2.18(d,J=10.5Hz,2H),2.56(q,J=7.5Hz,2H),2.78(t,J=11.6Hz,2H),2.95-3.20(m,7H),3.52-3.68(m,5H),3.77(d,J=9.6Hz,1H),3.84(s,3H),4.29(s,2H),4.36(s,2H),6.76(s,1H),6.90(d,J=9.2Hz,1H),7.79-7.83(m,2H),8.07(s,1H)；MS m/z(ESI)：768.2[M+H]⁺ ¹ H NMR(400MHz, CD ₃ OD) δ 1.02(t, J =7.7Hz,3H), 1.81-1.93(m,8H), 2.09(s,3H), 2.18(d, J =10.5Hz,2H) ,2.56(q, J =7.5Hz,2H),2.78(t, J =11.6Hz,2H),2.95-3.20(m,7H),3.52-3.68(m,5H),3.77(d, J =9.6 Hz, 1H), 3.84 (s, 3H), 4.29 (s, 2H), 4.36 (s, 2H), 6.76 (s, 1H), 6.90 (d, J = 9.2 Hz, 1H), 7.79-7.83 (m ,2H),8.07(s,1H); MS m/z(ESI): 768.2[M+H] ⁺

實施例62 Example 62

(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-((3aR,6aS)-5-(甲磺醯)六氫吡咯并[3,4-c]吡咯-2(1H)-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-5-(methylsulfonyl)hexahydropyrrolo[3, 4-c]pyrrole-2(1H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1, 4] Preparation of dioxan-5-yl) dimethyl phosphine oxidation

(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-((3aR,6aS)-5-(甲磺醯)六氫吡咯并[3,4-c]吡咯-2(1H)-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-((3aR,6aS)-5-(methylsulfonyl)hexahydropyrrolo[3, 4-c]pyrrole-2(1H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1, 4] Refer to Example 1 for the preparation method of dioxan-5-yl)dimethylphosphine oxidation.

¹H NMR(400MHz,CD₃OD)δ 1.85-1.97(m,8H),2.14(s,3H),2.17-2.30(m,2H),2.74(t,J=11.9Hz,2H),2.96(s,3H),3.04-3.26(m,7H),3.34-3.49(m,3H),3.80-3.91(m,5H),4.28(d,J=4.9Hz,2H),4.35(d,J=4.9Hz,2H),6.70(s,1H),6.90(d,J=9.1Hz,1H),7.72(s,1H),7.88(dd,J=9.5,4.4Hz,1H),8.06(s,1H)；MS m/z(ESI)：790.2[M+H]⁺ ¹ H NMR (400MHz, CD ₃ OD) δ 1.85-1.97 (m, 8H), 2.14 (s, 3H), 2.17-2.30 (m, 2H), 2.74 (t, J =11.9 Hz, 2H), 2.96 ( s,3H),3.04-3.26(m,7H),3.34-3.49(m,3H),3.80-3.91(m,5H), 4.28(d, J =4.9Hz,2H), 4.35(d, J = 4.9Hz, 2H), 6.70 (s, 1H), 6.90 (d, J = 9.1 Hz, 1H), 7.72 (s, 1H), 7.88 (dd, J = 9.5, 4.4 Hz, 1H), 8.06 (s, 1H); MS m/z(ESI): 790.2[M+H] ⁺

實施例63 Example 63

(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-((3aR,6aS)-5-(甲磺醯)六氫吡咯并[3,4-c]吡咯-2(1H)-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-((3aR,6aS)-5-(methylsulfonyl)hexahydropyrrolo[3, 4-c]pyrrole-2(1H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1, 4] Preparation of dioxan-5-yl) dimethyl phosphine oxidation

(6-((5-溴-2-((5-乙基-2-甲氧基-4-(4-((3aR,6aS)-5-(甲磺醯)六氫吡咯并[3,4-c]吡咯-2(1H)-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例2。 (6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-((3aR,6aS)-5-(methylsulfonyl)hexahydropyrrolo[3, 4-c]pyrrole-2(1H)-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1, 4] Refer to Example 2 for the preparation method of dioxan-5-yl)dimethylphosphine oxidation.

MS m/z(ESI)：804.2[M+H]⁺ MS m/z(ESI): 804.2[M+H] ⁺

實施例64 Example 64

(5-((5-溴-2-((4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)苯并[d][1,3]二噁唑-4-基)二甲基膦氧化的製備 (5-((5-Bromo-2-((4-(4-(3-ethoxyazetidine-1-yl)piperidin-1-yl)-2-methoxy-5-methyl (Phenyl) amino) pyrimidin-4-yl) amino) benzo[d][1,3] dioxazol-4-yl) dimethylphosphine oxidation preparation

(5-((5-溴-2-((4-(4-(3-乙氧基吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)苯并[d][1,3]二噁唑-4-基)二甲基膦氧化的製備方法參照實施例1。 (5-((5-Bromo-2-((4-(4-(3-ethoxyazetidine-1-yl)piperidin-1-yl)-2-methoxy-5-methyl (Phenyl)amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxazol-4-yl)dimethylphosphine oxidized preparation method refer to Example 1.

¹H NMR(400MHz,CD₃OD)δ 1.23(t,J=7.1Hz,3H),1.53-1.64(m,2H),1.84(s,3H),1.88(s,3H),2.03-2.14(m,5H),2.72(t,J=11.7Hz,2H),3.06-3.19(m,3H),3.49-3.58(m,2H),3.84(s,3H),3.88-3.95(m,2H),4.25-4.38(m,3H),6.07(s,2H),6.71(s,1H),6.93(d,J=8.7Hz,1H),7.71(s,1H),7.74-7.81(m,1H),8.08(s,1H)；MS m/z(ESI)：687.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 1.23 (t, J =7.1Hz, 3H), 1.53-1.64 (m, 2H), 1.84 (s, 3H), 1.88 (s, 3H), 2.03-2.14 ( m, 5H), 2.72 (t, J =11.7 Hz, 2H), 3.06-3.19 (m, 3H), 3.49-3.58 (m, 2H), 3.84 (s, 3H), 3.88-3.95 (m, 2H) ,4.25-4.38(m,3H),6.07(s,2H),6.71(s,1H),6.93(d, J =8.7Hz,1H),7.71(s,1H),7.74-7.81(m,1H) ),8.08(s,1H); MS m/z(ESI): 687.2[M+H] ⁺ .

實施例65 Example 65

(5-((5-溴-2-((2-甲氧基-4-(4-(3-(甲氧基甲基)吖丁啶-1-基)哌啶-1-基)-5-甲基苯基)胺基)嘧啶-4-基)胺基)苯并[d][1,3]二噁唑-4-基)二甲基膦氧化的製備 (5-((5-Bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidin-1-yl)piperidin-1-yl)- Preparation of 5-methylphenyl)amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxazol-4-yl)dimethylphosphine oxidation

(5-((5-溴-2-((2-甲氧基-4-(4-(3-(甲氧基甲基)吖丁啶-1-基)哌啶-1-基)-5-甲基苯基)胺基)嘧啶-4-基)胺基)苯并[d][1,3]二噁唑-4-基)二甲基膦氧化的製備方法參照實施例1。 (5-((5-Bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidin-1-yl)piperidin-1-yl)- The preparation method of 5-methylphenyl)amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxazol-4-yl)dimethylphosphine oxidation refers to Example 1.

¹H NMR(400MHz,CD₃OD)δ 1.55-1.68(m,2H),1.86-1.89(m,6H),2.09-2.11(m,5H),2.72-2.76(m,2H),3.15-3.18(m,4H),3.45(s,3H),3.52-3.54(m,2H),3.84(s, 3H),3.99-4.13(m,2H),4.20-4.31(m,2H),6.07-6.09(m,2H),6.71(s,1H),6.93-6.96(m,1H),7.63-7.88(m,2H),8.07(s,1H)；MS m/z(ESI)：687.2[M+H]⁺. ¹ H NMR(400MHz,CD ₃ OD) δ 1.55-1.68(m,2H),1.86-1.89(m,6H),2.09-2.11(m,5H),2.72-2.76(m,2H),3.15-3.18 (m, 4H), 3.45 (s, 3H), 3.52-3.54 (m, 2H), 3.84 (s, 3H), 3.99-4.13 (m, 2H), 4.20-4.31 (m, 2H), 6.07-6.09 (m,2H),6.71(s,1H),6.93-6.96(m,1H),7.63-7.88(m,2H),8.07(s,1H); MS m/z(ESI): 687.2[M+ H] ⁺ .

實施例66 Example 66

(6-((5-溴-2-((2-甲氧基-4-(4-(3-(甲氧基甲基)吖丁啶-1-基)哌啶-1-基)-5-甲基苯基)胺基)嘧啶-4-基)胺基)-3,3-二甲基-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidine-1-yl)piperidin-1-yl)- 5-methylphenyl)amino)pyrimidin-4-yl)amino)-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxane-5- Base) dimethyl phosphine oxidation preparation

(6-((5-溴-2-((2-甲氧基-4-(4-(3-(甲氧基甲基)吖丁啶-1-基)哌啶-1-基)-5-甲基苯基)胺基)嘧啶-4-基)胺基)-3,3-二甲基-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((5-Bromo-2-((2-methoxy-4-(4-(3-(methoxymethyl)azetidine-1-yl)piperidin-1-yl)- 5-methylphenyl)amino)pyrimidin-4-yl)amino)-3,3-dimethyl-2,3-dihydrobenzo[b][1,4]dioxane-5- Refer to Example 1 for the preparation method of oxy) dimethyl phosphine.

¹H NMR(400MHz,CD₃OD)δ 1.35(s,6H),1.50-1.63(m,2H),1.89(s,3H),1.93(s,3H),1.98-2.06(m,2H),2.11(s,3H),2.71(t,J=11.7Hz,2H),2.92-3.01(m,2H),3.11-3.18(m,2H),3.43(s,3H),3.49-3.54(m,2H),3.74-3.81(m,2H),3.84(s,3H),3.95-4.07(m,4H),6.72(s,1H),6.88(d,J=9.1Hz,1H),7.74(s,1H),7.87-7.93(m,1H),8.06(s,1H)；MS m/z(ESI)：687.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 1.35 (s, 6H), 1.50-1.63 (m, 2H), 1.89 (s, 3H), 1.93 (s, 3H), 1.98-2.06 (m, 2H), 2.11(s,3H),2.71(t, J =11.7Hz,2H),2.92-3.01(m,2H),3.11-3.18(m,2H),3.43(s,3H),3.49-3.54(m, 2H), 3.74-3.81(m, 2H), 3.84(s, 3H), 3.95-4.07(m, 4H), 6.72(s, 1H), 6.88(d, J = 9.1Hz, 1H), 7.74(s ,1H),7.87-7.93(m,1H),8.06(s,1H); MS m/z(ESI): 687.2[M+H] ⁺ .

實施例67 Example 67

(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(3-(甲基(噁丁環-3-基)胺基)吖丁啶-1-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(3-(methyl(oxbutan-3-yl)amino)azetidine -1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxane-5- Base) dimethyl phosphine oxidation preparation

(6-((5-溴-2-((2-甲氧基-5-甲基-4-(4-(3-(甲基(噁丁環-3-基)胺基)吖丁啶-1-基)哌啶-1-基)苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(3-(methyl(oxbutan-3-yl)amino)azetidine -1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxane-5- Refer to Example 1 for the preparation method of oxy) dimethyl phosphine.

¹H NMR(400MHz,CD₃OD)δ 1.50-1.65(m,2H),1.87(s,3H),1.91(s,3H),1.99-2.07(m,2H),2.11(s,3H),2.22(s,3H),2.64-2.74(m,2H),2.90-3.00(m,1H),3.08-3.18(m,2H),3.37-3.46(m,1H),3.73-3.81(m,3H),3.83(s,3H),3.95-4.04(m,2H),4.24-4.39(m,4H),4.60-4.70(m,4H),6.69(s,1H),6.89(d,J=9.1Hz,1H),7.71(s,1H),7.84-7.91(m,1H),8.05(s,1H)；MS m/z(ESI)：742.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 1.50-1.65 (m, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 1.99-2.07 (m, 2H), 2.11 (s, 3H), 2.22(s,3H),2.64-2.74(m,2H),2.90-3.00(m,1H),3.08-3.18(m,2H),3.37-3.46(m,1H),3.73-3.81(m,3H) ), 3.83(s, 3H), 3.95-4.04(m, 2H), 4.24-4.39(m, 4H), 4.60-4.70(m, 4H), 6.69(s, 1H), 6.89(d, J = 9.1 Hz,1H),7.71(s,1H),7.84-7.91(m,1H),8.05(s,1H); MS m/z(ESI): 742.2[M+H] ⁺ .

實施例68 Example 68

(6-((5-溴-2-((4-(4-(3-氟-3-(2-羥基丙烷-2-基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((4-(4-(3-fluoro-3-(2-hydroxypropan-2-yl)azetidine-1-yl)piperidin-1-yl) -2-Methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl ) Preparation of dimethyl phosphine oxidation

(6-((5-溴-2-((4-(4-(3-氟-3-(2-羥基丙烷-2-基)吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((5-Bromo-2-((4-(4-(3-fluoro-3-(2-hydroxypropan-2-yl)azetidine-1-yl)piperidin-1-yl) -2-Methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl ) Refer to Example 1 for the preparation method of dimethylphosphine oxidation.

¹H NMR(400MHz,CD₃OD)δ 1.23-1.25(m,6H),1.63-1.65(m,2H),1.89-1.91(m,6H),2.02-2.21(m,5H),2.71-2.73(m,2H),3.12-3.16(m,3H),3.84(s,3H),4.11-4.13(m 2H),4.36-4.39(m,6H),6.72(s,1H),6.91-6.93(m,1H),7.72(s,1H),7.87-7.89(m,1H),8.06(s,1H)；MS m/z(ESI)：733.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 1.23-1.25 (m, 6H), 1.63-1.65 (m, 2H), 1.89-1.91 (m, 6H), 2.02-2.21 (m, 5H), 2.71-2.73 (m,2H),3.12-3.16(m,3H),3.84(s,3H),4.11-4.13(m 2H),4.36-4.39(m,6H),6.72(s,1H),6.91-6.93( m,1H),7.72(s,1H),7.87-7.89(m,1H),8.06(s,1H); MS m/z(ESI): 733.2[M+H] ⁺ .

實施例69 Example 69

(6-((5-溴-2-((5-乙基-4-(4-(3-氟-3-(2-羥基丙烷-2-基)吖丁啶-1-基)哌啶-1-基)-2-甲氧苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((5-ethyl-4-(4-(3-fluoro-3-(2-hydroxypropan-2-yl)azetidine-1-yl)piperidine -1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) Preparation of dimethyl phosphine oxidation

(6-((5-溴-2-((5-乙基-4-(4-(3-氟-3-(2-羥基丙烷-2-基)吖丁啶-1-基)哌啶-1-基)-2-甲氧苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例2。 (6-((5-Bromo-2-((5-ethyl-4-(4-(3-fluoro-3-(2-hydroxypropan-2-yl)azetidine-1-yl)piperidine -1-yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl) Refer to Example 2 for the preparation method of dimethylphosphine oxidation.

¹H NMR(400MHz,CD₃OD)δ 1.03(t,J=7.6Hz,3H),1.23-1.26(m,6H),1.60-1.65(m,2H),1.91-1.93(m,6H),2.03-2.05(m,2H),2.56-2.58(m,2H),2.75-2.78(m,3H),3.08-3.12(m,2H),3.78-3.96(m,5H),4.12-4.16(m,2H),4.22-4.48(m,4H),6.78(s,1H),6.91-6.93(m,1H),7.63-7.90(m,2H),8.08(s,1H)；MS m/z(ESI)：747.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 1.03 (t, J =7.6Hz, 3H), 1.23-1.26 (m, 6H), 1.60-1.65 (m, 2H), 1.91-1.93 (m, 6H), 2.03-2.05(m,2H),2.56-2.58(m,2H),2.75-2.78(m,3H),3.08-3.12(m,2H),3.78-3.96(m,5H),4.12-4.16(m ,2H),4.22-4.48(m,4H),6.78(s,1H),6.91-6.93(m,1H),7.63-7.90(m,2H),8.08(s,1H); MS m/z( ESI): 747.2[M+H] ⁺ .

實施例70 Example 70

(6-((5-溴-2-((4-(4-(3-(2-氟乙基)-3-羥基吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備 (6-((5-Bromo-2-((4-(4-(3-(2-fluoroethyl)-3-hydroxyazetidine-1-yl)piperidin-1-yl)-2- Methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethyl Preparation of Phosphine Oxidation

(6-((5-溴-2-((4-(4-(3-(2-氟乙基)-3-羥基吖丁啶-1-基)哌啶-1-基)-2-甲氧基-5-甲基苯基)胺基)嘧啶-4-基)胺基)-2,3-二氫苯并[b][1,4]二噁烷-5-基)二甲基膦氧化的製備方法參照實施例1。 (6-((5-Bromo-2-((4-(4-(3-(2-fluoroethyl)-3-hydroxyazetidine-1-yl)piperidin-1-yl)-2- Methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)dimethyl Refer to Example 1 for the preparation method of phosphine oxidation.

¹H NMR(400MHz,CD₃OD)δ 1.56-1.67(m,2H),1.88(s,3H),1.92(s,3H),2.03-2.11(m,2H),2.12-2.18(m,4H),2.20-2.26(m,1H),2.73(t,J=11.7Hz,3H),3.11-3.20(m,2H),3.81-3.89(m,4H),4.08-4.14(m,2H),4.25-4.31(m,2H),4.33-4.38(m,2H),4.55-4.66(m,3H),4.75(t,J=5.6Hz,1H),6.72(s,1H),6.92(d,J=9.2Hz,1H),7.72(s,1H),7.87-7.93(m,1H),8.07(s,1H)；MS m/z(ESI)：719.2[M+H]⁺. ¹ H NMR (400MHz, CD ₃ OD) δ 1.56-1.67 (m, 2H), 1.88 (s, 3H), 1.92 (s, 3H), 2.03-2.11 (m, 2H), 2.12-2.18 (m, 4H) ), 2.20-2.26(m,1H), 2.73(t, J =11.7Hz,3H),3.11-3.20(m,2H),3.81-3.89(m,4H),4.08-4.14(m,2H), 4.25-4.31(m,2H),4.33-4.38(m,2H),4.55-4.66(m,3H), 4.75(t, J =5.6Hz,1H), 6.72(s,1H), 6.92(d, J =9.2Hz,1H),7.72(s,1H),7.87-7.93(m,1H),8.07(s,1H); MS m/z(ESI): 719.2[M+H] ⁺ .

生物學測試評價Biological test evaluation

以下結合測試例進一步描述解釋本發明，但這些實施例並非意味著限制本發明的範圍。 The following further describes and explains the present invention in conjunction with test examples, but these examples are not meant to limit the scope of the present invention.

測試例1、本發明化合物對EGFR野生型、EGFR del746-750/T790M/C797S和EGFR L858R/T790M/C797S突變激酶抑制活性的測定Test Example 1. Determination of the inhibitory activity of the compounds of the present invention on EGFR wild-type, EGFR del746-750/T790M/C797S and EGFR L858R/T790M/C797S mutant kinases

實驗目的：該測試例的目的是測試化合物對EGFR野生型、EGFR del746-750/T790M/C797S和EGFR L858R/T790M/C797S突變激酶的抑制活性。 Experimental purpose: The purpose of this test example is to test the inhibitory activity of the compound against EGFR wild-type, EGFR del746-750/T790M/C797S and EGFR L858R/T790M/C797S mutant kinases.

實驗儀器：離心機(5810R)購自Eppendorf公司，移液器購自Eppendorf或Rainin公司，酶標儀購自美國BioTek公司，型號為SynergyH1全功能酶標儀。 Experimental instrument: a centrifuge (5810R) was purchased from Eppendorf, a pipette was purchased from Eppendorf or Rainin, and a microplate reader was purchased from BioTek, USA, and the model was SynergyH1 full-function microplate reader.

實驗方法：本實驗採用Cisbio公司的HTRF激酶測定方法(Cisbio#62TK0PEB)，受質多肽TK和ATP在酪胺酸激酶EGFR野生型、EGFR del746-750/T790M/C797S或EGFR L858R/T790M/C797S突變存在的條件下發生催化反應，受質被磷酸化，藉由測定反應中生成的磷酸化受質的含量來表徵激酶的活性，並得出化合物對EGFR野生型、EGFR del746-750/T790M/C797S或EGFR L858R/T790M/C797S突變激酶活性抑制的半數抑制濃度IC₅₀。 Experimental method: This experiment uses Cisbio's HTRF kinase assay method (Cisbio#62TK0PEB). The substrate peptides TK and ATP are in the tyrosine kinase EGFR wild-type, EGFR del746-750/T790M/C797S or EGFR L858R/T790M/C797S mutation The catalytic reaction occurs under the existing conditions, and the substrate is phosphorylated. The activity of the kinase is characterized by determining the content of the phosphorylated substrate generated in the reaction, and the compound is found to be EGFR wild-type, EGFR del746-750/T790M/C797S or EGFR L858R / T790M / C797S mutant half maximal inhibitory concentration IC ₅₀ of inhibition of kinase activity.

具體實驗操作如下： The specific experiment operation is as follows:

激酶反應在白色384孔板(Perkin Elmer#6008280)中進行，每孔加入1~5μL用含1% DMSO的ddH₂O稀釋的不同濃度的化合物，陽性對照孔加入1~5μL含1% DMSO的ddH₂O，然後每孔加入1~5μL用Dilution buffer(5×激酶緩衝液，MgCl₂ 6.65mM，MnCl₂ 1.33mM，DTT 1.33mM)稀釋的0.5~5nM 4×EGFR野生型、EGFR del746-750/T790M/C797S或EGFR L858R/T790M/C797S突變的激酶溶液，陰性對照孔加入1~5μL的Dilution buffer，所有孔加入1~5μL用10×Dilution buffer配製的4μM 4×受質TK溶液，最後加入1~5μL用Dilution buffer稀釋的24μM 4×ATP溶液啟動反應，室溫反應120分鐘後，每孔加入10μL檢測液(TK抗體16nM，XL665 0.5μM)室溫避光反應20分鐘後用BioTek Synergy H1酶標儀檢測化學發光值。 Kinase reaction is carried out in a white 384-well plate (Perkin Elmer#6008280), each well is added with 1~5μL _{of compounds of different concentrations diluted with ddH 2} O containing 1% DMSO, and 1~5μL of 1% DMSO is added to the positive control well. ddH ₂ O, then add 1~5μL to each well diluted 0.5~5nM 4×EGFR wild type, EGFR del746-750 _{in Dilution buffer (5×kinase buffer, MgCl 2} 6.65mM, MnCl _{2 1.33mM, DTT 1.33mM)} /T790M/C797S or EGFR L858R/T790M/C797S mutant kinase solution, add 1~5μL of Dilution buffer to the negative control wells, add 1~5μL of 4μM 4×substrate TK solution prepared with 10×Dilution buffer to all wells, and finally add Start the reaction with 1~5μL 24μM 4×ATP solution diluted in Dilution buffer. After reacting at room temperature for 120 minutes, add 10μL of detection solution (TK antibody 16nM, XL665 0.5μM) to each well and react at room temperature and avoid light for 20 minutes, then use BioTek Synergy H1 The microplate reader detects the chemiluminescence value.

實驗數據處理方法： Experimental data processing method:

藉由於板上陽性對照孔(DMSO對照孔)和陰性對照孔(不添加激酶)計算使用化合物處理的孔的百分比抑制數據{%抑制率=100-[(測試化合物值-陰性對照值)]/(陽性對照值-陰性對照值)×100}。使用GraphPad prism擬合不同濃度和相應百分比抑制率數據至4參數非線性邏輯公式計算出IC₅₀值，具體數據如下表所示： Calculate the percentage inhibition data of the wells treated with the compound based on the positive control wells (DMSO control wells) and negative control wells (no kinase added) on the plate {% inhibition rate=100-[(test compound value-negative control value)]/ (Positive control value-negative control value)×100}. Use GraphPad prism to fit data of different concentrations and corresponding percentage inhibition rates to a 4-parameter non-linear logic formula to calculate the IC ₅₀ value. The specific data are shown in the following table:

實驗結論： Experimental results:

藉由以上方案得出，本發明所示的實施例化合物對EGFR突變的激酶活性具有較強的抑制作用，而對EGFR野生型激酶活性抑制作用較小，對比數據可知，本發明系列實施例化合物對EGFR突變的/野生型激酶活性的抑制具有高選擇性。 According to the above scheme, the example compounds of the present invention have a strong inhibitory effect on the kinase activity of EGFR mutations, but have less inhibitory effect on the EGFR wild-type kinase activity. The comparative data shows that the series of example compounds of the present invention It has high selectivity for the inhibition of EGFR mutant/wild-type kinase activity.

測試例2、本發明化合物對EGFR del746-750/C797S和EGFRL858R/C797S突變的激酶抑制活性的測定Test Example 2. Determination of the kinase inhibitory activity of the compounds of the present invention on EGFR del746-750/C797S and EGFRL858R/C797S mutations

實驗目的：該測試例的目的是測試化合物對EGFR del746-750/C797S和EGFR L858R/C797S突變激酶的抑制活性。 Experimental purpose: The purpose of this test case is to test the inhibitory activity of the compound against EGFR del746-750/C797S and EGFR L858R/C797S mutant kinases.

實驗方法：本實驗採用Cisbio公司的HTRF激酶測定方法(Cisbio#62TK0PEB)，受質多肽TK和ATP在酪胺酸激酶EGFR del746-750/C797S或EGFR L858R/C797S突變存在的條件下發生催化反應，受質被磷酸化，藉由測定反應中生成的磷酸化受質的含量來表徵激酶的活性，並得出化合物對EGFR del746-750/C797S或EGFR L858R/C797S突變激酶活性抑制的半數抑制濃度IC₅₀。 Experimental method: This experiment uses Cisbio's HTRF kinase assay method (Cisbio#62TK0PEB). The substrate polypeptide TK and ATP undergo a catalytic reaction in the presence of tyrosine kinase EGFR del746-750/C797S or EGFR L858R/C797S mutations. The substrate is phosphorylated, the activity of the kinase is characterized by measuring the content of the phosphorylated substrate generated in the reaction, and the half inhibitory concentration IC of the compound's inhibition of EGFR del746-750/C797S or EGFR L858R/C797S mutant kinase activity is obtained. ₅₀ .

具體實驗操作如下： The specific experiment operation is as follows:

激酶反應在白色384孔板(Perkin Elmer#6008280)中進行，每孔加入1~5μL用含1% DMSO的ddH₂O稀釋的不同濃度的化合物，陽性對照孔加入1~5μL含1% DMSO的ddH₂O，然後每孔加入1~5μL用Dilution buffer(5×激酶緩衝液，MgCl₂ 6.65mM，MnCl₂ 1.33mM，DTT 1.33mM)稀釋的0.5~5nM 4×EGFR del746-750/C797S或EGFR L858R/C797S突變的激酶溶液，陰性對照孔加入1~5 μL的Dilution buffer，所有孔加入1~5μL用10×Dilution buffer配製的4μM 4×受質TK溶液，最後加入1~5μL用Dilution buffer稀釋的24μM 4×ATP溶液啟動反應，室溫反應120分鐘後，每孔加入10μL檢測液(TK抗體16nM,XL665 0.5μM)室溫避光反應20分鐘後用BioTek Synergy H1酶標儀檢測化學發光值。 Kinase reaction is carried out in a white 384-well plate (Perkin Elmer#6008280), each well is added with 1~5μL _{of compounds of different concentrations diluted with ddH 2} O containing 1% DMSO, and 1~5μL of 1% DMSO is added to the positive control well. ddH ₂ O, then add 1~5μL to each well diluted 0.5~5nM 4×EGFR del746-750/C797S or EGFR _{in Dilution buffer (5×kinase buffer, MgCl 2} 6.65mM, MnCl _{2 1.33mM, DTT 1.33mM)} For L858R/C797S mutant kinase solution, add 1~5 μL of Dilution buffer to the negative control wells, add 1~5 μL of 4 μM 4× substrate TK solution prepared with 10×Dilution buffer to all wells, and finally add 1~5 μL to dilute with Dilution buffer Start the reaction with the 24μM 4×ATP solution. After reacting at room temperature for 120 minutes, add 10μL of detection solution (TK antibody 16nM, XL665 0.5μM) to each well, and react for 20 minutes in the dark at room temperature. Then use the BioTek Synergy H1 microplate reader to detect the chemiluminescence value .

實驗數據處理方法： Experimental data processing method:

實驗結論： Experimental results:

藉由以上方案得出，本發明所示的實施例化合物對EGFR del746-750/C797S或EGFR L858R/C797S突變的激酶活性具有較強的抑制作用 Based on the above scheme, the compound of the examples shown in the present invention has a strong inhibitory effect on the kinase activity of EGFR del746-750/C797S or EGFR L858R/C797S mutation

測試例3：細胞增殖抑制實驗Test Example 3: Cell Proliferation Inhibition Experiment

實驗目的：該測試例的目的是測試化合物對細胞的增殖抑制活性。 Experimental purpose: The purpose of this test case is to test the compound's inhibitory activity on cell proliferation.

實驗儀器：移液器購自Eppendorf公司，CO₂培養箱購自美國Thermo公司，酶標儀購自美國BioTek公司，型號為SynergyH1全功能酶標儀。 Experimental instrument: the pipette was purchased from Eppendorf, the CO ₂ incubator was purchased from the American Thermo company, and the microplate reader was purchased from the American BioTek company, and the model was SynergyH1 full-function microplate reader.

實驗方法：本實驗採用CTG(CELL TITER-GLO)發光法檢測化合物對A431細胞和Ba/F3(EGFR del746-750/T790M/C797S)細胞的增殖抑制活性，並得出化合物對細胞增殖活性的半數抑制濃度IC₅₀。 Experimental method: In this experiment, the CTG (CELL TITER-GLO) luminescence method was used to detect the compound's proliferation inhibitory activity on A431 cells and Ba/F3 (EGFR del746-750/T790M/C797S) cells, and the compound's half of the cell proliferation activity was obtained. Inhibition concentration IC ₅₀ .

具體實驗操作如下： The specific experiment operation is as follows:

對於A431細胞：第一天，在96孔檢測板中鋪入90μL A431細胞懸液，每孔細胞個數為3000個，其中陰性對照不加細胞，將板放入含5% CO₂的37℃培養箱中培養過夜。第二天，每孔加入10μL梯度稀釋好的化合物溶液，陽性和陰性對照孔只加入含DMSO的10μL培養基，將板放入二氧化碳培養箱孵育72小時。培養72h後，向細胞板的每個孔中加入50μL Cell Titer Glo，避光震盪2min後靜置10min；之後在BioTek Synergy H1酶標儀檢測發光值，藉由化學發光信號值計算抑制率，根據不同濃度的抑制率藉由曲線擬合得出化合物的IC₅₀。 For A431 cells: On the first day, spread 90μL of A431 cell suspension in a 96-well test plate, with 3000 cells per well. The negative control does not add cells, and the plate is placed at 37°C _{with 5% CO 2} Cultivate overnight in an incubator. On the next day, add 10 μL of the diluted compound solution to each well, add only 10 μL of medium containing DMSO to the positive and negative control wells, and place the plate in a carbon dioxide incubator for 72 hours. After culturing for 72 hours, add 50μL Cell Titer Glo to each well of the cell plate, shake for 2 minutes in the dark, and then stand for 10 minutes; then detect the luminescence value on the BioTek Synergy H1 microplate reader, and calculate the inhibition rate based on the chemiluminescence signal value. _{The IC 50 of the} compound was obtained by curve fitting for the inhibition rate of different concentrations.

對於Ba/F3(EGFR del746-750/T790M/C797S)懸浮細胞： For Ba/F3 (EGFR del746-750/T790M/C797S) suspension cells:

在96孔檢測板中鋪入90μL Ba/F3細胞懸液，每孔細胞個數為3000個，其中陰性對照不加細胞；靜置2h後每孔加入10μL梯度稀釋好的化合物溶液，陽性和陰性對照孔只加入含DMSO的10μL培養基，放入二氧化碳培養箱培養72小時後同前述A431細胞的方法進行CTG檢測。 Spread 90μL of Ba/F3 cell suspension in a 96-well test plate, the number of cells per well is 3000, and the negative control does not add cells; after standing for 2h, add 10μL of the compound solution with gradient dilution to each well, positive and negative Only 10μL of medium containing DMSO was added to the control wells, and then placed in a carbon dioxide incubator for 72 hours and then subjected to CTG detection using the same A431 cell method described above.

實驗數據處理方法： Experimental data processing method:

藉由板上陽性對照孔(DMSO對照孔)和陰性對照孔(不加細胞)計算使用化合物處理的孔的百分比抑制數據{%抑制率=100-[(測試化合物值-陰性對照值)]/(陽性對照值-陰性對照值)×100}。使用GraphPad prism擬合不同濃度和相應百分比抑制率數據至4參數非線性邏輯公式計算出IC₅₀值，具體數據如下表所示： Calculate the percentage inhibition data of the wells treated with the compound from the positive control wells (DMSO control wells) and negative control wells (without cells) on the plate {% inhibition rate=100-[(test compound value-negative control value)]/ (Positive control value-negative control value)×100}. Use GraphPad prism to fit data of different concentrations and corresponding percentage inhibition rates to a 4-parameter non-linear logic formula to calculate the IC ₅₀ value. The specific data are shown in the following table:

實驗結論： Experimental results:

藉由以上方案得出，本發明所示的實施例化合物在Ba/F3(EGFR del746-750/T790M/C797S)突變細胞增殖活性的抑制試驗中具有良好的抑制作用，而對A431細胞具有較弱的抑制作用，對比數據可知，本發明系列實施例化合物對Ba/F3(EGFR del746-750/T790M/C797S)突變細胞增殖活性的抑制具有高選擇性。 According to the above scheme, the compound of the examples of the present invention has a good inhibitory effect in the inhibition test of the proliferation activity of Ba/F3 (EGFR del746-750/T790M/C797S) mutant cells, but has a weaker effect on A431 cells. According to the comparative data, it can be seen that the compounds of the series of examples of the present invention have high selectivity in inhibiting the proliferation activity of Ba/F3 (EGFR del746-750/T790M/C797S) mutant cells.

測試例4、本發明化合物對細胞EGFR磷酸化抑制作用的測定Test Example 4. Determination of the inhibitory effect of the compound of the present invention on cell EGFR phosphorylation

實驗目的：該測試例的目的是測試化合物對細胞EGFR磷酸化的抑制活性。 Experimental purpose: The purpose of this test case is to test the compound's inhibitory activity on cell EGFR phosphorylation.

實驗儀器：微孔板振盪器(88880024)購自Thermo Scientific^TM公司，離心機(5702R)購自Eppendorf公司，移液器購自Eppendorf公司，酶標儀購自美國Biotech公司，型號為SynergyH1全功能酶標儀。 Experimental instrument: Microplate shaker (88880024) was purchased from Thermo Scientific ^TM company, centrifuge (5702R) was purchased from Eppendorf company, pipette was purchased from Eppendorf company, microplate reader was purchased from American Biotech company, the model was SynergyH1 full function Microplate reader.

實驗試劑：Phospho-EGFR(Tyr1068)LANCE Ultra TR-FRET Cellular Detection Kit(Perkin Elmer TRF4016C)內含(5X)LANCE Ultra Lysis Buffer 1，LANCE Ultra Eu-labeled Anti-EGFR(Y1068)Antibody，LANCE Ultra ULight-labeled Anti-EGFR Antibody,EGF(Thermo fisher PHG0311)； Experimental reagents: Phospho-EGFR (Tyr1068) LANCE Ultra TR-FRET Cellular Detection Kit (Perkin Elmer TRF4016C) contains (5X) LANCE Ultra Lysis Buffer 1, LANCE Ultra Eu-labeled Anti-EGFR (Y1068) Antibody, LANCE Ultra ULight- labeled Anti-EGFR Antibody, EGF (Thermo fisher PHG0311);

實驗方法：本實驗採用Ba/F3(EGFR del746-750/T790M/C797S)細胞系，藉由EGF刺激激活EGFR信號通路，檢測化合物對其下游EGFR(Y1068)磷酸化的抑制活性，並得出化合物對EGFR信號通路活性的半數抑制濃度IC₅₀。 Experimental method: In this experiment, the Ba/F3 (EGFR del746-750/T790M/C797S) cell line was used, and the EGFR signaling pathway was activated by EGF stimulation, and the inhibitory activity of the compound on its downstream EGFR (Y1068) phosphorylation was detected, and the compound was obtained The half inhibitory concentration IC _{50 for the} activity of EGFR signaling pathway.

具體實驗操作如下： The specific experiment operation is as follows:

384孔檢測板中鋪入Ba/F3(EGFR del746-750/T790M/C797S)細胞3-12μL，每孔細胞個數為100-300K，加入2μL梯度稀釋好的化合物溶液，室溫，350rpm,孵育2小時。2小時後加入2μL EGF，EGF終濃度50nM，室溫震盪15min。加入2-5μL(5X)LANCE Ultra Lysis Buffer 1溶液，室溫震盪2h。2h後加入5μL終濃度為0.5nM的LANCE Ultra Eu-labeled Anti-EGFR(Y1068)Antibody(PerkinElmer)和終濃度為5nM的LANCE Ultra ULight-labeled Anti-EGFR Antibody(PerkinElmer)溶液，室溫孵育過夜。酶標儀測定各板孔的665nm螢光信號值，藉由螢光信號值計算抑制率，根據不同濃度的抑制率藉由曲線擬合得出化合物的IC₅₀。 Place 3-12μL of Ba/F3 (EGFR del746-750/T790M/C797S) cells in a 384-well detection plate, the number of cells in each well is 100-300K, add 2μL of the compound solution with gradient dilution, room temperature, 350rpm, incubate 2 hours. After 2 hours, add 2μL of EGF, the final concentration of EGF is 50nM, and shake at room temperature for 15min. Add 2-5μL (5X) LANCE Ultra Lysis Buffer 1 solution and shake at room temperature for 2h. After 2 hours, 5 μL of LANCE Ultra Eu-labeled Anti-EGFR (Y1068) Antibody (PerkinElmer) with a final concentration of 0.5 nM and LANCE Ultra ULight-labeled Anti-EGFR Antibody (PerkinElmer) with a final concentration of 5 nM were added, and incubated overnight at room temperature. The microplate reader measures the 665nm fluorescence signal value of each well, and calculates the inhibition rate from the fluorescence signal value. According to the inhibition rate of different concentrations, the IC _{50 of the} compound is obtained by curve fitting.

實驗數據處理方法： Experimental data processing method:

藉由於板上陽性對照孔(DMSO對照孔)和陰性對照孔(不加細胞)計算使用化合物處理的孔的百分比抑制數據{%抑制率=100-[(測試化合物值-陰性對照值)]/(陽性對照值-陰性對照值)×100}。使用GraphPad prism擬合不同濃度和相應百分比抑制率數據至4參數非線性邏輯公式計算出IC₅₀值。 Calculate the percentage inhibition data of the wells treated with the compound based on the positive control wells (DMSO control wells) and negative control wells (without cells) on the plate {% inhibition rate=100-[(test compound value-negative control value)]/ (Positive control value-negative control value)×100}. Use GraphPad prism to fit the data of different concentrations and corresponding percentage inhibition rates to a 4-parameter non-linear logic formula to calculate the IC ₅₀ value.

實驗結論： Experimental results:

藉由以上方案得出，本發明所示的實施例化合物對Ba/F3(EGFR del746-750/T790M/C797S)細胞的EGFR磷酸化具有良好的抑制作用。 Based on the above scheme, the compound of the examples shown in the present invention has a good inhibitory effect on EGFR phosphorylation of Ba/F3 (EGFR del746-750/T790M/C797S) cells.

測試例5：Balb/C小鼠藥物代謝動力學測定Test Example 5: Balb/C mouse pharmacokinetic determination

5.1研究目的： 5.1 Research purpose:

以Balb/C小鼠為受試動物，研究化合物實施例，在5mg/kg劑量下口服給藥在小鼠體內血漿的藥物代謝動力學行為。 Balb/C mice were used as the test animals to study the pharmacokinetic behavior of the compound examples in the plasma of mice administered orally at a dose of 5 mg/kg.

5.2試驗方案 5.2 Test plan

5.2.1試驗藥品： 5.2.1 Test drugs:

本發明實施例化合物，自製。 The example compounds of the present invention are self-made.

5.2.2試驗動物： 5.2.2 Experimental animals:

Balb/C Mouse(6隻/實施例)，雄性，上海傑思捷實驗動物有限公司，動物生產許可證號(SCXK(滬)2013-0006 N0.311620400001794)。 Balb/C Mouse (6 mice/example), male, Shanghai Jiesjie Experimental Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006 N0.311620400001794).

5.2.3製劑處方： 5.2.3 Formulation prescription:

0.5%CMC-Na(1%Tween80)，超聲溶解，配製為澄清溶液或均一混懸液。 0.5% CMC-Na (1% Tween80), dissolve by ultrasonic, prepare as clear solution or homogeneous suspension.

5.2.4給藥： 5.2.4 Administration:

Balb/C小鼠(6隻/實施例)，雄性；禁食一夜後分別p.o.，劑量為5mg/kg，給藥體積10mL/kg。 Balb/C mice (6 mice/example), male; p.o. after fasting overnight, the dose was 5 mg/kg, and the administration volume was 10 mL/kg.

5.2.5樣品採集： 5.2.5 Sample collection:

小鼠給藥前和給藥後，在0、0.5、1、2、4、6、8和24小時，採用眼眶採血0.1mL，置於EDTA-K₂試管中，4℃ 6000rpm離心6min分離血漿，於-80℃保存。 _{Before and after the administration of the mice, at 0, 0.5, 1, 2} , 4, 6, 8 and 24 hours, 0.1 mL of blood was collected from the orbit, placed in an EDTA-K 2 test tube, and centrifuged at 4°C at 6000 rpm for 6 minutes to separate plasma , Store at -80℃.

5.2.6樣品處理： 5.2.6 Sample processing:

1)血漿樣品40μL加入160μL乙腈沉澱，混合後3500×g離心5~20分鐘。 1) 40μL of plasma sample was precipitated with 160μL of acetonitrile, mixed and centrifuged at 3500×g for 5-20 minutes.

2)取處理後上清溶液100μL進行LC/MS/MS分析待測化合物的濃度。 2) Take 100 μL of the supernatant solution after treatment and analyze the concentration of the test compound by LC/MS/MS.

5.2.7液相分析 5.2.7 Liquid phase analysis

●液相條件：Shimadzu LC-20AD泵 ●Liquid phase conditions: Shimadzu LC-20AD pump

●質譜條件：AB Sciex API 4000質譜儀 ● Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

●色譜管柱：phenomenex Gemiu 5um C18 50×4.6mm ●Chromatography column: phenomenex Gemiu 5um C18 50×4.6mm

●移動相：A液為0.1%甲酸水溶液，B液為乙腈 ●Mobile phase: A solution is 0.1% formic acid aqueous solution, B solution is acetonitrile

●流速：0.8mL/min ●Flow rate: 0.8mL/min

●洗脫時間：0-4.0分鐘，洗脫液如下： ●Elution time: 0-4.0 minutes, the eluent is as follows:

5.3試驗結果與分析 5.3 Test results and analysis

藥物代謝動力學主要參數用WinNonlin 6.1計算得到，小鼠藥物代謝實驗結果見下表： The main parameters of pharmacokinetics are calculated with WinNonlin 6.1, and the results of the mouse drug metabolism experiment are shown in the following table:

實驗結論： Experimental results:

從表中小鼠藥物代謝實驗結果可以看出，本發明實施例化合物表現出良好的代謝性質，暴露量AUC和最大血藥濃度C_max都表現良好。 From the results of the mouse drug metabolism experiment in the table, it can be seen that the compounds of the examples of the present invention exhibit good metabolic properties, and both the exposure amount AUC and the maximum blood drug concentration C _max perform well.

測試例6：本發明實施例化合物的體內藥效試驗Test Example 6: In vivo efficacy test of the compound of the example of the present invention

6.1實驗目的 6.1 Purpose of the experiment

藉由體內藥效實驗篩選出藥效較為明顯且毒副作用較小的化合物。 Through in vivo drug efficacy experiments, compounds with more obvious drug effects and less toxic and side effects are screened out.

6.2實驗主要儀器和材料 6.2 The main instruments and materials of the experiment

6.2.1儀器： 6.2.1 Apparatus:

6.2.2試劑： 6.2.2 Reagents:

6.2.3動物： 6.2.3 Animals:

NOD/SCID小鼠，6-8週，♀，購自江蘇集萃藥康生物科技有限公司。 NOD/SCID mice, 6-8 weeks, ♀, purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.

6.3實驗步驟 6.3 Experimental procedure

6.3.1細胞培養 6.3.1 Cell culture

PC9(EGFR Del19/T790M/C797S)細胞培養在含10%胎牛血清的RPMI1640培養液中。收集指數生長期的PC9(EGFR Del19/T790M/C797S)細胞。 PC9 (EGFR Del19/T790M/C797S) cells were cultured in RPMI1640 medium containing 10% fetal calf serum. PC9 (EGFR Del19/T790M/C797S) cells in the exponential growth phase were collected.

6.3.2細胞接種 6.3.2 Cell seeding

實驗小鼠於右側背部皮下(小鼠右側背部，前肢附近的皮下)接種1×10⁷PC9(EGFR Del19/T790M/C797S)細胞，細胞重懸在1：1的PBS與基質膠中(0.1ml/只)，定期觀察腫瘤生長情況，腫瘤細胞接種當天定義為第0天。 ^{Experimental mice were inoculated with 1×10 7} PC9 (EGFR Del19/T790M/C797S) cells subcutaneously on the right back (right back of the mouse, subcutaneous near the forelimb), and the cells were resuspended in 1:1 PBS and Matrigel (0.1ml /Only), regular observation of tumor growth, the day of tumor cell inoculation is defined as day 0.

6.3.3荷瘤鼠量瘤、分組、給藥 6.3.3 Tumor measurement, grouping and administration of tumor-bearing mice

a, day7測量腫瘤體積數據，並選擇腫瘤體積在100-200mm³範圍的小鼠，按照平均體積140mm³，根據腫瘤大小和小鼠體重隨機分組給藥。 a. Measure the tumor volume data on day7, and select mice with tumor volume in the ^{range of 100-200mm 3} , according to the average volume of 140mm ³ , randomized administration according to tumor size and mouse body weight.

c,根據分組結果，開始給予測試藥物(給藥方式：口服給藥；給藥體積：10mL/kg；給藥頻率：1次/天；給藥週期：21天；溶媒：0.5% HPMC)。 c. According to the grouping results, start to give the test drug (administration method: oral administration; dosing volume: 10 mL/kg; dosing frequency: 1 time/day; dosing cycle: 21 days; vehicle: 0.5% HPMC).

d,開始給予測試藥物後每週兩次量瘤、稱重。 d. Measure the tumor and weigh the tumor twice a week after starting to give the test drug.

e,實驗結束後安樂死動物。 e. Euthanize the animals after the experiment.

f,用Excel等軟件處理數據。化合物抑瘤率TGI(%)的計算：TGI%=[1-(T_i-T₀)/(C_i-C₀)]×100%；其中，T_i為給藥組第i天瘤體積，T₀為給藥組分組當天瘤體積，C_i為溶劑對照組第i天瘤體積，C₀為溶劑對照組分組當天瘤體積。 f, Use Excel and other software to process the data. Calculation of compound tumor inhibition rate TGI (%): TGI%=[1-(T _i -T ₀ )/(C _i -C ₀ )]×100%; where T _i is the tumor volume on the i day of the administration group , T ₀ is the tumor volume on the day of the administration group, C _i is the tumor volume on the i day _{of the solvent control group, and C 0} is the tumor volume on the day of the solvent control group.

6.4試驗數據如下表： 6.4 The test data is as follows:

6.5實驗結果 6.5 Experimental results

從上述結果中可以看出，本專利的上述化合物有較好的抑瘤率，且安全性較好。 It can be seen from the above results that the above-mentioned compounds of this patent have better tumor inhibition rate and better safety.

Claims

一種通式(IB)所示的化合物、其立體異構體或其藥學上可接受鹽， A compound represented by general formula (IB), its stereoisomers or pharmaceutically acceptable salts thereof,

其中： among them:

X₁或Y₁各自獨立的選自-O-、-NR_AA-、-S-或-CR_AAR_BB-；較佳-O-、-NH-、-NCH₃-、-S-或-CH₂-； X ₁ or Y ₁ are each independently selected from -O-, -NR _AA -, -S- or -CR _AA R _BB -; preferably -O-, -NH-, -NCH ₃ -, -S- or- CH ₂ -;

M₂、M₃、M₄或M₅存在或不存在，存在時各自獨立的選自N、S、CH或CR_aa；較佳O、S、N或CH； The _{presence or absence of M 2} , M ₃ , M ₄ or M ₅ , when present, are each independently selected from N, S, CH or CR _aa ; preferably O, S, N or CH;

M₀或M₁存在或不存在，存在時各自獨立的選自N、S、CH、NR_aa或CR_aaR_bb；較佳O、S、N或CH，更佳S、N或CH； The _{presence or absence of M 0} or M ₁ is independently selected from N, S, CH, NR _aa or CR _aa R _{bb when present} ; preferably O, S, N or CH, more preferably S, N or CH;

環D選自取代或未取代的環烷基、取代或未取代的雜環基、取代或未取代的芳基或取代或未取代的雜芳基；較佳取代或未取代的C_3-6環烷基、取代或未取代的3-6員雜環基、取代或未取代的C_5-6芳基或取代或未取代的5-6員雜芳基，更佳含有1-3個氮原子或氧原子的5-6員雜芳基或雜環基，進一步較佳

、

Ring D is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; preferably substituted or unsubstituted C _3-6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclic group, substituted or unsubstituted C _5-6 aryl group or substituted or unsubstituted 5-6 membered heteroaryl group, more preferably containing 1-3 nitrogens 5-6 membered heteroaryl or heterocyclic group of atom or oxygen atom, further preferred

,

R獨立地選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、環烷基、雜環基、芳基或雜芳基，較佳氫、烷基或鹵素，更佳氫、C_1-6烷基、氟、氯、溴或碘，進一步較佳氫、C_1-3烷基、氟、氯或溴； R is independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, ring Alkyl, heterocyclyl, aryl or heteroaryl, preferably hydrogen, alkyl or halogen, more preferably hydrogen, C _1-6 alkyl, fluorine, chlorine, bromine or iodine, still more preferably hydrogen, C _{1- 3} Alkyl, fluorine, chlorine or bromine;

R₁或R₅各自獨立的選自氫、氘、氧、氮、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、環烷基、雜環基、側氧雜環基、螺環烷基、橋環烷基、稠環烷基、橋雜環基、螺雜環基、稠雜環基、芳基、雜芳基、-(CH₂)_nOR_CC、-(CH₂)_nNR_CCR_DD、-(CH₂)_nNR_CCC(O)R_DD、 R ₁ or R ₅ are each independently selected from hydrogen, deuterium, oxygen, nitrogen, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyanide Group, alkenyl, alkynyl, cycloalkyl, heterocyclyl, pendant oxoheterocyclic group, spirocycloalkyl, bridged cycloalkyl, fused ring alkyl, bridged heterocyclyl, spiroheterocyclic group, fused heterocyclic ring Group, aryl, heteroaryl, -(CH ₂ ) _n OR _CC , -(CH ₂ ) _n NR _CC R _DD , -(CH ₂ ) _n NR _CC C(O)R _DD ,

-NR_CCC(O)NR_DDR_EE、-C(O)NR_CCR_DD、-NR_CCS(O)_mR_DD、-(CH₂)_nS(O)_mNR_CCR_DD、-(CH₂)_nC(O)R_CC、-NR_CCC(O)OR_DD、-(CH₂)_nS(O)_mR_CC或-(CH₂)_nNR_CCS(O)_mR_DD；其中該氧、氮、烷基、鹵烷基、環烷基、雜環基、芳基和雜芳基，視需要進一步被選自氘、氘、烷基、鹵烷基、鹵素、取代或未取代的胺基、側氧基、硝基、氰基、羥基、取代或未取代的烯基、取代或未取代的炔基、烷氧基、鹵烷氧基、羥烷基、-(CH₂)_nC(O)R_CC、取代或未取代的環烷基、取代或未取代的雜環基、取代或未取代的芳基、取代或未取代的雜芳基、取代或未取代的側氧雜環基、螺環烷基、橋環烷基或稠環烷基中的一個或多個取代基所取代； -NR _CC C(O)NR _DD R _EE , -C(O)NR _CC R _DD , -NR _CC S(O) _m R _DD , -(CH ₂ ) _n S(O) _m NR _CC R _DD ,- (CH ₂ ) _n C(O)R _CC , -NR _CC C(O)OR _DD , -(CH ₂ ) _n S(O) _m R _CC or -(CH ₂ ) _n NR _CC S(O) _m R _DD ; wherein the oxygen, nitrogen, alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are further selected from deuterium, deuterium, alkyl, haloalkyl, halogen, and substituted Or unsubstituted amino, pendant oxy, nitro, cyano, hydroxyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, -( CH ₂ ) _n C(O)R _CC , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Is substituted by one or more substituents in the pendant oxoheterocyclic group, spirocycloalkyl, bridged cycloalkyl or fused ring alkyl;

、

、

、環丙基或-CF₃； R ₃ and R ₄ are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, mercapto, Alkyl substituted mercapto, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted The substituted heteroaryl group is preferably hydrogen, alkyl, haloalkyl, halogen, hydroxy, mercapto, alkoxy, -SR _aa or substituted or unsubstituted alkynyl, more preferably hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, halogen, hydroxy, mercapto, C _1-6 alkoxy, -SR _aa , C _2-6 alkynyl, C _2-6 alkenyl, the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, -SR _aa , C _2-6 alkynyl, C _2-6 alkenyl, and C _3-6 cycloalkyl, C _1-6 alkane Group or halogen, preferably hydrogen, chlorine, bromine, -SCH ₃ ,

,

, Cyclopropyl or -CF ₃ ;

R_aa或R_bb各自獨立地選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、羥烷基、鹵烷氧基、鹵素、氰基、硝基、羥基、胺基、烯基、炔基、側氧基、環烷基、雜環基、芳基或雜芳基，其中該烷基、氘代烷基、鹵烷基、烷氧基、羥烷基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基，視需要進一步被選自氫、氘、取代或未取代的烷基、鹵素、羥基、取代或未取代的胺基、側氧基、側硫基、硝基、氰基、取代或未取代烯基、取代或未取代炔基、取代或未取代烷氧基、取代或未取代羥烷基、取代或未取代的環烷基、取代或未取代的雜環基、取代或未取代的芳基和取代或未取代的雜芳基中的一個或多個取代基所取代，較佳氫、烷基、環烷基、雜環基、側氧基或側硫基，更佳C_1-6烷基、C_3-6環烷基、3-6員雜環基、側氧基或側硫基，進一步較佳甲基、乙基、丙基、側氧基或側硫基； R _aa or R _bb are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxyl, amine Group, alkenyl group, alkynyl group, pendant oxy group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group, wherein the alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, hydroxyalkyl group, halo Alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further selected from hydrogen, deuterium, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted Substituted amino, pendant oxy, pendant thio, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group substituted by one or more substituents, preferably hydrogen, alkyl , Cycloalkyl, heterocyclic, pendant oxy or pendant thio, more preferably C _1-6 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclic, pendant oxy or pendant thio, More preferably methyl, ethyl, propyl, pendant oxy or pendant thio;

x為0-2的整數； x is an integer of 0-2;

y為0-4的整數； y is an integer from 0-4;

q為0-2的整數； q is an integer of 0-2;

m為0-2的整數。 m is an integer of 0-2.

一種通式(I)所示的化合物、其立體異構體或其藥學上可接受鹽，其結構如下： A compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, and its structure is as follows:

其中： among them:

M₁、M₂和M₃各自獨立的選自O、N、S、CH、NR_aa或CR_aaR_bb； M ₁ , M ₂ and M ₃ are each independently selected from O, N, S, CH, NR _aa or CR _aa R _bb ;

環A選自環烷基或芳基； Ring A is selected from cycloalkyl or aryl;

R₁選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、環烷基、雜環基、芳基、雜芳基、-(CH₂)_nOR_aa、-(CH₂)_nNR_aaR_bb、-NR_aaC(O)R_bb、-NR_aaC(O)NR_bbR_cc、-C(O)NR_aaR_bb、-NR_aaS(O)_mR_bb、-(CH₂)_nS(O)_mNR_aaR_bb、-(CH₂)_nC(O)R_aa、-NR_aaC(O)OR_bb、-(CH₂)_nS(O)_mR_aa或-(CH₂)_nNR_aaS(O)_mR_bb，其中該烷基、鹵烷基、環烷基、雜環基、芳基和雜芳基，視需要進一步被選自氫、氘、側氧基、烷基、鹵烷基、鹵素、胺基、側氧基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、取代或未取代的環烷基、取代或未取代的雜環基、取代或未取代的芳基、取代或未取代的雜芳基中的一個或多個取代基所取代； R _{1 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, cycloalkane Group, heterocyclic group, aryl, heteroaryl, -(CH ₂ ) _n OR _aa , -(CH ₂ ) _n NR _aa R _bb , -NR _aa C(O)R _bb , -NR _aa C(O) NR _bb R _cc , -C(O)NR _aa R _bb , -NR _aa S(O) _m R _bb , -(CH ₂ ) _n S(O) _m NR _aa R _bb , -(CH ₂ ) _n C( O) R _aa , -NR _aa C(O)OR _bb , -(CH ₂ ) _n S(O) _m R _aa or -(CH ₂ ) _n NR _aa S(O) _m R _bb , wherein the alkyl group, Haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further selected from hydrogen, deuterium, pendant oxy, alkyl, haloalkyl, halogen, amine, pendant oxy, nitro Group, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl Substituted by one or more substituents in the heteroaryl group, substituted or unsubstituted heteroaryl group;

或者，R₁和R₅，或兩個相同或者不同的R₅鏈接形成一個環烷基、雜環基、芳基或雜芳基，其中該環烷基、雜環基、芳基和雜芳基視需要進一步被選自氫原子、氘原子、烷基、鹵烷基、鹵素、胺基、側氧基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； Alternatively, R ₁ and R ₅ , or two identical or different R _{5 are} linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are The group is optionally selected from hydrogen atom, deuterium atom, alkyl group, haloalkyl group, halogen, amino group, pendant oxy group, nitro group, cyano group, hydroxyl group, alkenyl group, alkynyl group, alkoxy group, haloalkoxy group. Substituted by one or more substituents in the group, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

x為0-2的整數； x is an integer of 0-2;

y為0-4的整數； y is an integer from 0-4;

q為0-2的整數； q is an integer of 0-2;

n為0-2的整數；且 n is an integer of 0-2; and

m為0-2的整數。 m is an integer of 0-2.

如請求項1所述的化合物、其立體異構體或其藥學上可接受鹽，其中，該通式(IB)進一步為通式(G)所示： The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the general formula (IB) is further represented by the general formula (G):

其中： among them:

環D選自雜環基； Ring D is selected from heterocyclyl;

或者，R₅和R₈鏈接形成一個環烷基、雜環基、芳基或雜芳基，視需要進一步被選自氫原子、氘原子、烷基、鹵烷基、鹵素、胺基、側氧基、硝基、氰基、羥基、烯基、炔基、烷氧基、鹵烷氧基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； Alternatively, R ₅ and R _{8 are} linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, optionally further selected from hydrogen atom, deuterium atom, alkyl group, haloalkyl group, halogen, amine group, side One or more of oxy, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituent substituted;

R₉選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、側氧基、羥烷基、環烷基、雜環基、芳基、雜芳基、羥基取代的烷基、氰基取代的烷基、-(CH₂)_nR_aa、-(CH₂)_nOR_aa、- (CH₂)_nNR_aaR_bb、-(CH₂)_nC(O)R_aa、-(CH₂)_nS(O)_mR_aa、-(CH₂)_nNR_aaS(O)_mR_bb或-(CH₂)_nNR_aaC(O)R_bb； R _{9 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, pendant oxygen Group, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxy-substituted alkyl, cyano-substituted alkyl, -(CH ₂ ) _n R _aa , -(CH ₂ ) _n OR _aa ,-(CH ₂ ) _n NR _aa R _bb , -(CH ₂ ) _n C(O)R _aa , -(CH ₂ ) _n S(O) _m R _aa , -(CH ₂ ) _n NR _aa S( O) _m R _bb or -(CH ₂ ) _n NR _aa C(O)R _bb ;

較佳地R₉選自氫、鹵素、羥基、C_1-6烷基、氰基取代的C_1-6烷基、C_1-6鹵烷基、C_1-6烷氧基、鹵C_1-6烷氧基、C_1-6羥烷基、C_3-6環烷基、C_3-6雜環基、-(CH₂)_nR_aa、-(CH₂)_nOR_aa、-(CH₂)_nNR_aaR_bb、-(CH₂)_nC(O)R_aa、-(CH₂)_nS(O)_mR_aa、-(CH₂)_nNR_aaS(O)_mR_bb或-(CH₂)_nNR_aaC(O)R_bb； Preferably R _{9 is} selected from hydrogen, halogen, hydroxyl, C _1-6 alkyl, cyano substituted C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, halo C _{1 -6} alkoxy, C _1-6 hydroxyalkyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, -(CH ₂ ) _n R _aa , -(CH ₂ ) _n OR _aa , -( CH ₂ ) _n NR _aa R _bb , -(CH ₂ ) _n C(O)R _aa , -(CH ₂ ) _n S(O) _m R _aa , -(CH ₂ ) _n NR _aa S(O) _m R _bb or -(CH ₂ ) _n NR _aa C(O)R _bb ;

R_aa、R_bb或R_cc各自獨立的選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、側氧基、三甲基矽基、取代或未取代的環烷基、取代或未取代的雜環基、取代或未取代的芳基或取代或未取代的雜芳基； R _aa , R _bb or R _cc are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano , Alkenyl, alkynyl, pendant oxy, trimethylsilyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl base;

y為0-4的整數； y is an integer from 0-4;

n為0-4的整數； n is an integer from 0-4;

m1為0-4的整數； m1 is an integer of 0-4;

z為0-4的整數； z is an integer of 0-4;

p為0-4的整數； p is an integer from 0-4;

u為0-4的整數；且 u is an integer from 0-4; and

q為0-2的整數。 q is an integer of 0-2.

如請求項2所述的化合物，其立體異構體或其藥學上可接受鹽，其中，該通式(I)進一步為通式(II)所示： The compound according to claim 2, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the general formula (I) is further represented by the general formula (II):

如請求項2所述的化合物、其立體異構體或其藥學上可接受鹽，其中，該通式(I)進一步為通式(IV)所示： The compound according to claim 2, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the general formula (I) is further represented by the general formula (IV):

如請求項3所述的化合物、其立體異構體或其藥學上可接受鹽，其中，該通式(G)進一步為通式(G-1)所示： The compound according to claim 3, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the general formula (G) is further represented by the general formula (G-1):

根據請求項1所述的化合物、其立體異構體或其藥學上可接受鹽，其中，該通式(IB)進一步為通式(IG)所示： The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein the general formula (IB) is further represented by the general formula (IG):

其中： among them:

R₃選自氫或鹵素； R _{3 is} selected from hydrogen or halogen;

R₅各自獨立地選自氫、C_1-6烷基、C_1-6鹵烷基、C_2-6烯基、C_2-4炔基、鹵素、氰基或-(CH₂)_nOR_aa，或者，兩個R₅相連形成一個C_3-8環烷基或3-12員雜環基； R _{5 is} each independently selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-4 alkynyl, halogen, cyano or -(CH ₂ ) _n OR _aa , or, two R _{5 are} connected to form a C _3-8 cycloalkyl group or a 3-12 membered heterocyclic group;

R₉選自氫、氘、C_1-6烷基、C_1-6氘代烷基、C_1-6鹵烷基、鹵素、胺基、羥基、氰基、側氧基、羥烷基、C_3-8環烷基、3-12員雜環基、-(CH₂)_nC(O)R_aa、-(CH₂)_nR_aa、-(CH₂)_nOR_aa或-(CH₂)_nNR_aaR_bb；n為0-2的整數； R _{9 is} selected from hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, halogen, amino, hydroxyl, cyano, pendant oxy, hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, -(CH ₂ ) _n C(O)R _aa , -(CH ₂ ) _n R _aa , -(CH ₂ ) _n OR _aa or -(CH ₂ ) _n NR _aa R _bb ; n is an integer of 0-2;

R_aa和R_bb各自獨立地選自氫、氘、氰基、C_1-6烷基、C_1-6氘代烷基、C_1-6鹵烷基或取代或未取代的C_3-8環烷基； R _aa and R _bb are each independently selected from hydrogen, deuterium, cyano, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl or substituted or unsubstituted C _3-8 Cycloalkyl

q為0-2的整數； q is an integer of 0-2;

y為0-4的整數； y is an integer from 0-4;

z為0-4的整數； z is an integer of 0-4;

u為0-4的整數；且 u is an integer from 0-4; and

i為0-2的整數。 i is an integer of 0-2.

如請求項2或7所述的化合物，其立體異構體或其藥學上可接受鹽，其中，該通式進一步為通式(VII)所示： The compound according to claim 2 or 7, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the general formula is further represented by general formula (VII):

如請求項2所述的化合物，其立體異構體或其藥學上可接受鹽，其中，該通式(I)進一步為通式((VIII-B)所示： The compound according to claim 2, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the general formula (I) is further represented by the general formula ((VIII-B):

其中： among them:

s為0-4的整數。 s is an integer from 0-4.

如請求項1至2中任一項所述的化合物、其立體異構體或其藥學上可接受鹽，其中， The compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 2, wherein

環A選自如下基團： Ring A is selected from the following groups:

如請求項2、3、6至8中任一項所述的化合物、其立體異構體或其藥學上可接受鹽，其中，環B選自含有一個或兩個選自氮原子或氧原子的4-6員單環雜環基或含有一個或兩個選自氮原子或氧原子的7-9員稠環雜環基，較佳如下基團： The compound according to any one of claims 2, 3, 6 to 8, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein ring B is selected from containing one or two selected from nitrogen atoms or oxygen atoms The 4-6 membered monocyclic heterocyclic group or the 7-9 membered fused ring heterocyclic group containing one or two nitrogen atoms or oxygen atoms, preferably the following groups:

如請求項3、6至8中任一項所述的化合物、其立體異構體或其藥學上可接受鹽，其中， The compound according to any one of claims 3 and 6 to 8, its stereoisomer or pharmaceutically acceptable salt thereof, wherein:

環B選自如下基團： Ring B is selected from the following groups:

如請求項1或3所述的化合物、其立體異構體或其藥學上可接受鹽，其中， The compound according to claim 1 or 3, its stereoisomer or pharmaceutically acceptable salt thereof, wherein

環D選自3-8員雜環基；較佳5-6員雜環基，更佳含有2-3個選自氮或氧原子的5-6員雜環基。 Ring D is selected from 3-8 membered heterocyclic groups; preferably 5-6 membered heterocyclic groups, more preferably containing 2-3 5-6 membered heterocyclic groups selected from nitrogen or oxygen atoms.

如請求項3、6至8中任一項所述的化合物、其立體異構體或其藥學上可接受鹽，其中，R₉選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、側氧基、羥烷基、環烷基、雜環基、芳基、雜芳基、-(CH₂)_nC(O)R_aa、-(CH₂)_nC(O)OR_aa、-(CH₂)_nR_aa、-(CH₂)_nOR_aa、-(CH₂)_nNR_aaR_bb、-(CH₂)_nNR_aaC(O)R_bb或-(CH₂)_nS(O)_mR_aa； The compound according to any one of claims 3 and 6 to 8, its stereoisomer or pharmaceutically acceptable salt thereof, wherein R _{9 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkane Group, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl, alkynyl, pendant oxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, hetero Aryl, -(CH ₂ ) _n C(O)R _aa , -(CH ₂ ) _n C(O)OR _aa , -(CH ₂ ) _n R _aa , -(CH ₂ ) _n OR _aa , -(CH ₂ ) _n NR _aa R _bb , -(CH ₂ ) _n NR _aa C(O)R _bb or -(CH ₂ ) _n S(O) _m R _aa ;

如請求項3、6至8中任一項所述的化合物、其立體異構體或其藥學上可接受鹽，其中，R₉選自氫、鹵素、羥基、C_1-3烷基、氰基取代的C_1-3烷基、C_1-3鹵烷基、C_1-3烷氧基、鹵C_1-3烷氧基、C_1-3羥烷基、C_3-6環烷基、C_3-6雜環基、-(CH₂)_nOC_1-3烷基、-(CH₂)_nC(O)C_1-3烷基、-(CH₂)_nC(O)OC_1-3烷基、-(CH₂)_nC(O)C_3-6環烷基、-(CH₂)_nC(O)OC_1-3烷基、-(CH₂)_nNC_1-3-3-6員雜環基、-(CH₂)_nN(C_1-3烷基)₂、-(CH₂)nNHC_1-3烷基、-(CH₂)_nN(C_1-3烷基)、-(CH₂)_nNHC(O)C_1-3烷基或-(CH₂)_nS(O)₂C_1-3烷基； The compound according to any one of claims 3, 6 to 8, its stereoisomer or pharmaceutically acceptable salt thereof, wherein R _{9 is} selected from hydrogen, halogen, hydroxy, C _1-3 alkyl, cyano Group substituted C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl , C _3-6 heterocyclyl, -(CH ₂ ) _n OC _1-3 alkyl, -(CH ₂ ) _n C(O)C _1-3 alkyl, -(CH ₂ ) _n C(O)OC _1-3 alkyl, -(CH ₂ ) _n C(O)C _3-6 cycloalkyl, -(CH ₂ ) _n C(O)OC _1-3 alkyl, -(CH ₂ ) _n NC _{1- 3} -3-6-membered heterocyclic group, -(CH ₂ ) _n N(C _1-3 alkyl) ₂ , -(CH ₂ )nNHC _1-3 alkyl, -(CH ₂ ) _n N(C _{1- 3} alkyl), -(CH ₂ ) _n NHC(O)C _1-3 alkyl or -(CH ₂ ) _n S(O) ₂ C _1-3 alkyl;

如請求項3、6至8中任一項所述的化合物、其立體異構體或其藥學上可接受鹽，其中，R_aa、R_bb或R_cc各自獨立的選自氫、C_1-6烷基、取代或未取代的C_1-6烷氧基、一個或多個鹵原子取代的C_1-6烷基、取代或未取代的3-6員雜環基或取代或未取代的C_3-6環烷基；更佳氫、甲基、乙基、環丙基、環丁基、甲氧基、乙氧基、三甲基矽基、氟、氯、溴、

、

或

。 The compound according to any one of claims 3 and 6 to 8, its stereoisomer or pharmaceutically acceptable salt thereof, wherein R _aa , R _bb or R _cc are each independently selected from hydrogen, C _{1- 6} alkyl group, a substituted or unsubstituted C _1-6 alkoxy group, substituted with one or more halogen atoms, C _1-6 alkyl, substituted or unsubstituted 3-6 membered heterocyclyl group or a substituted or unsubstituted C _3-6 cycloalkyl; more preferably hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, trimethylsilyl, fluorine, chlorine, bromine,

,

or

.

如請求項1至16中任一項所述的化合物、其立體異構體或其藥學上可接受的鹽，其中， The compound according to any one of claims 1 to 16, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein

R₃選自氫或鹵素； R _{3 is} selected from hydrogen or halogen;

R₄選自氫； R _{4 is} selected from hydrogen;

或者，R₅和R₈鏈接形成一個C_3-8環烷基，視需要進一步被選自氫、氘、C_1-6烷基、C_1-6鹵烷基、鹵素、胺基、側氧基、氰基和羥基中的一個或多個取代基所取代； Alternatively, R ₅ and R _{8 are} linked to form a C _3-8 cycloalkyl group, optionally further selected from hydrogen, deuterium, C _1-6 alkyl, C _1-6 haloalkyl, halogen, amino, pendant oxygen Substituted by one or more substituents in the group, cyano group and hydroxyl group;

如請求項1至17中任一項所述的化合物、其立體異構體或其藥學上可接受的鹽，其中， The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein

環D為5-6員含氧雜環基；較佳5-6員含雙氧雜環基；更佳

或

or

；

環B為3-8員雜環基；較佳3-8員單環雜環基或3-8員並環雜環基；更佳 Ring B is a 3-8 membered heterocyclic group; preferably a 3-8 membered monocyclic heterocyclic group or a 3-8 membered bicyclic heterocyclic group; more preferably

R₄選自氫； R _{4 is} selected from hydrogen;

R₈選自氫； R _{8 is} selected from hydrogen;

如請求項2、3、6至8中任一項所述的化合物、其立體異構體或其藥學上可接受鹽，其中， The compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 2, 3, 6 to 8, wherein:

R₃選自氫或鹵素； R _{3 is} selected from hydrogen or halogen;

如請求項1至19中任一項所述的化合物、其立體異構體或其藥學上可接受的鹽，其中，該化合物具體結構如下： The compound according to any one of claims 1 to 19, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the specific structure of the compound is as follows:

一種通式(A)所示的化合物、其立體異構體或其藥學上可接受鹽， A compound represented by general formula (A), its stereoisomers or pharmaceutically acceptable salts thereof,

其中： among them:

R_aa或R_bb各自獨立的選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、烯基、炔基、側氧基、三甲基矽基、取代或未取代的環烷基、取代或未取代的雜環基、取代或未取代的芳基或取代或未取代的雜芳基； R _aa or R _bb are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, alkenyl , Alkynyl, pendant oxy, trimethylsilyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

i為0-4的整數； i is an integer from 0-4;

u為0-4的整數；且 u is an integer from 0-4; and

q為0-2的整數。 q is an integer of 0-2.

一種通式(A-1)所示的化合物、其立體異構體或其藥學上可接受鹽， A compound represented by general formula (A-1), its stereoisomers or pharmaceutically acceptable salts thereof,

其中： among them:

i為0-4的整數； i is an integer from 0-4;

u為0-4的整數；且 u is an integer from 0-4; and

q為0-2的整數。 q is an integer of 0-2.

一種通式(A-2)所示的化合物、其立體異構體或其藥學上可接受鹽， A compound represented by general formula (A-2), its stereoisomers or pharmaceutically acceptable salts thereof,

其中： among them:

R₅選自氫、氘、烷基、氘代烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、胺基、硝基、羥基、氰基、氰基取代的烷基、烯基、炔基、環烷基、雜環基、芳基、雜芳基、-(CH₂)_nOR_aa、-(CH₂)_nNR_aaR_bb、-NR_aaC(O)R_bb、-NR_aaC(O)NR_bbR_cc、-C(O)NR_aaR_bb、-NR_aaS(O)_mR_bb、-(CH₂)_nS(O)_mNR_aaR_bb、-(CH₂)_nC(O)R_aa、-NR_aaC(O)OR_bb、-(CH₂)_nS(O)_mR_aa、-(CH₂)_nNR_aaS(O)_mR_bb或-(CH₂)_nC≡CR_aa，較佳氫、烷基、烷氧基、鹵烷基、鹵素、胺基、硝基、氰基、氰基取代的烷基、烯基、炔基、-NR_aaC(O)R_bb或-(CH₂)_nC≡CR_aa，更佳氫、C_1-6烷基、C_1-6烷氧基、C_1-6鹵烷基、鹵素、胺基、硝基、氰基、氰基取代的烷基、C_2-4烯基、C_2-4炔基、-NR_aaC(O)R_bb或-(CH₂)_nC≡CR_aa，進一步較佳氫、甲基、乙基、丙基、甲氧基、乙氧基、乙烯基、乙炔基、氰基、胺基、硝基、氟、氯、溴、鹵甲基、鹵乙基、-CH₂CN、-NR_aaC(O)R_bb或-(CH₂)_nC≡CR_aa； R _{5 is} selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxyl, cyano, cyano substituted alkyl, alkene Group, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n OR _aa , -(CH ₂ ) _n NR _aa R _bb , -NR _aa C(O)R _bb , -NR _aa C(O)NR _bb R _cc , -C(O)NR _aa R _bb , -NR _aa S(O) _m R _bb , -(CH ₂ ) _n S(O) _m NR _aa R _bb ,- (CH ₂ ) _n C(O)R _aa , -NR _aa C(O)OR _bb , -(CH ₂ ) _n S(O) _m R _aa , -(CH ₂ ) _n NR _aa S(O) _m R _bb or -(CH ₂ ) _n C≡CR _aa , preferably hydrogen, alkyl, alkoxy, haloalkyl, halogen, amine, nitro, cyano, cyano substituted alkyl, alkenyl, alkyne Group, -NR _aa C(O)R _bb or -(CH ₂ ) _n C≡CR _aa , more preferably hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, Halogen, amine, nitro, cyano, cyano substituted alkyl, C _2-4 alkenyl, C _2-4 alkynyl, -NR _aa C(O)R _bb or -(CH ₂ ) _n C≡ CR _aa , more preferably hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, vinyl, ethynyl, cyano, amine, nitro, fluorine, chlorine, bromine, halomethyl, Haloethyl, -CH ₂ CN, -NR _aa C(O)R _bb or -(CH ₂ ) _n _{C≡CR aa} ;

、

或

,

or

；

i為0-4的整數； i is an integer from 0-4;

u為0-4的整數； u is an integer from 0-4;

q為0-2的整數； q is an integer of 0-2;

n為0-4的整數； n is an integer from 0-4;

m為0-2的整數； m is an integer of 0-2;

m1為0-2的整數； m1 is an integer of 0-2;

y為0-4的整數；且 y is an integer from 0-4; and

p為0-2的整數。 p is an integer of 0-2.

一種製備如請求項22所述的通式(A-1)所示的化合物、其立體異構體或其藥學上可接受鹽的方法，其特徵在於包含如下步驟： A method for preparing the compound represented by the general formula (A-1), its stereoisomer or its pharmaceutically acceptable salt as described in claim 22, characterized by comprising the following steps:

其中： among them:

一種製備如請求項23所述的通式(A-2)所示的化合物、其立體異構體或其藥學上可接受鹽的方法，其特徵在於包含如下步驟： A method for preparing a compound represented by the general formula (A-2), its stereoisomers, or a pharmaceutically acceptable salt thereof as described in claim 23, characterized by comprising the following steps:

其中： among them:

一種製備如請求項6所述的通式(G-1)所示的化合物、其立體異構體或其藥學上可接受鹽的方法，其特徵在於包含如下步驟： A method for preparing the compound represented by general formula (G-1), its stereoisomers or pharmaceutically acceptable salts thereof as described in claim 6, characterized in that it comprises the following steps:

一種醫藥組成物，其包括治療有效劑量的如請求項1至20中所述的化合物及其立體異構體或其藥學上可接受的鹽以及一種或多種藥學上可接受的載體、稀釋劑或賦形劑。 A pharmaceutical composition comprising a therapeutically effective dose of the compound and its stereoisomers or pharmaceutically acceptable salts thereof as described in claims 1 to 20, and one or more pharmaceutically acceptable carriers, diluents or excipient.

一種如請求項1至20中任一項所述的化合物、及其立體異構體或其藥學上可接受的鹽或請求項27所述的醫藥組成物的用途，其用在製備MEK抑制劑、EGFR抑制劑和EGFR單抗及其聯用相關藥物。 A compound according to any one of claims 1 to 20, and its stereoisomers or pharmaceutically acceptable salts thereof, or use of the pharmaceutical composition according to claim 27, which are used in the preparation of MEK inhibitors , EGFR inhibitors, EGFR monoclonal antibodies and their associated drugs.

請求項如1至20中任一項所述的化合物及其立體異構體或其藥學上可接受的鹽或如請求項27所述的醫藥組成物在製備治癌症相關疾病中的應用；其中該癌症為肺癌。 The use of the compound according to any one of claims 1 to 20 and its stereoisomers or pharmaceutically acceptable salts thereof or the pharmaceutical composition according to claim 27 in the preparation and treatment of cancer-related diseases; wherein The cancer is lung cancer.

一種如請求項1至20中任一項所述的化合物及其立體異構體或其藥學上可接受的鹽或請求項27所述的醫藥組成物的用途，其用在製備治癌症相關疾病的藥物；其中該癌症選自乳腺癌、子宮頸癌、結腸癌、肺癌、胃癌、直腸癌、胰腺癌、腦癌、肝癌、實體瘤、神經膠質瘤、神經膠母細胞瘤、白血病、淋巴瘤或骨髓瘤；較佳非小細胞肺癌。 A use of the compound according to any one of claims 1 to 20 and its stereoisomers or pharmaceutically acceptable salts thereof or the pharmaceutical composition according to claim 27, which is used in the preparation and treatment of cancer-related diseases The drug; wherein the cancer is selected from breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumor, glioma, glioblastoma, leukemia, lymphoma Or myeloma; preferably non-small cell lung cancer.