TW202530214A - TRICYCLIC COMPOUNDS AS PI3Kα INHIBITORS - Google Patents

Abstract

The present application provides tricyclic compounds that modulate the activity of the PI3Kα, which are useful in the treatment of various diseases, including cancer.

Description

Translated fromChinese

作為PI3Kα抑制劑之三環化合物Tricyclic compounds as PI3Kα inhibitors

本揭示案提供調節PI3Kα活性且可用於治療與PI3Kα相關之各種疾病、包括癌症之三環化合物以及其醫藥組合物。The present disclosure provides tricyclic compounds and pharmaceutical compositions thereof that modulate PI3Kα activity and are useful for treating various diseases associated with PI3Kα, including cancer.

在過去的幾十年中，已對信號轉導事件進行研究，以證明其在調控生物反應之幾乎所有態樣中之關鍵作用。在許多人類癌症中常觀察到調控細胞存活及增殖之信號傳導路徑之異常活化。有記錄表明，磷酸肌醇3-激酶(PI3K)信號傳導路徑係人類癌症中之高度突變路徑之一(Vogelstein等人，Science, 2013, 339(6127), 1546-1558)。PI3K信號傳導路徑調控細胞存活及增殖。此路徑之活性增加與腫瘤進展及對癌症療法之抗性相關(Fusco等人，Front Oncol., 2021, 11, 644737)。Over the past few decades, signal transduction events have been studied to demonstrate their critical role in regulating nearly all aspects of biological responses. Aberrant activation of signaling pathways that regulate cell survival and proliferation is often observed in many human cancers. The phosphoinositide 3-kinase (PI3K) signaling pathway has been documented to be one of the most highly mutated pathways in human cancers (Vogelstein et al.,Science , 2013, 339(6127), 1546-1558). The PI3K signaling pathway regulates cell survival and proliferation. Increased activity of this pathway is associated with tumor progression and resistance to cancer therapies (Fusco et al.,Front Oncol. , 2021, 11, 644737).

PI3K屬於脂質激酶家族，其催化細胞膜中所含或與細胞膜締合之脂質之磷酸化。PI3K家族有15種具有不同受質、表現模式及調控模式之激酶。I類PI3K (p110α、p110β、p110δ及p110γ)通常由酪胺酸受體激酶或G蛋白偶合受體活化以生成PIP3，其使Akt、mTOR或Rho GTP酶之下游效應物活化(Fruman等人，Nat. Rev. Drug Discov.,2014, 13(2), 140-156)。PI3K belongs to the lipid kinase family, which catalyzes the phosphorylation of lipids contained in or associated with cell membranes. The PI3K family comprises 15 kinases with different substrates, expression patterns, and regulatory pathways. Class I PI3Ks (p110α, p110β, p110δ, and p110γ) are typically activated by tyrosine receptor kinases or G protein-coupled receptors to generate PIP3, which activates downstream effectors such as Akt, mTOR, or Rho GTPases (Fruman et al.,Nat. Rev. Drug Discov. ,2014 , 13(2), 140-156).

編碼PI3Kα之基因中之遺傳突變係螺旋及激酶結構域內之熱點點突變，諸如E542K、E545K及H1047R。已觀察到該等突變發生在許多癌症類型中，諸如肺癌、胃癌、子宮內膜癌、卵巢癌、膀胱癌、乳癌、結腸癌、腦癌、前列腺癌及皮膚癌。由於PI3Kα中之該等功能獲得型突變與腫瘤進展相關，故靶向此路徑可提供有價值之治療機會(Courtney等人，J. Clin. Oncol.,2010, 28 (6), 1075-1083)。儘管已開發出多種PI3K抑制劑(例如他賽里斯(taselisib)、阿派里斯(alpelisib)、布帕里斯(buparlisib)及其他抑制劑)，但該等分子抑制多種PI3K同種型。該等「泛PI3K」抑制劑在臨床開發中已遇到重大障礙，此乃因其無法在避免對癌症患者之毒性的同時達成所需之腫瘤靶向抑制水準(Fruman等人，Nat. Rev. Drug Discov.,2014, 13(2), 140-156)。PI3K抑制劑之毒性取決於其同種型選擇性概況。PI3Kα之抑制與高糖血症及皮疹相關，而PI3Kδ或PI3Kγ之抑制與腹瀉、骨髓抑制及轉胺酶升高相關(Hanker等人，Cancer Discov.,2019, 9(4), 482-491)。因此，PI3Kα之選擇性抑制劑可延長治療窗，使得能夠在腫瘤中實現足夠的靶向抑制，同時避免癌症患者中之劑量限制性毒性。然而，鑑於PI3Kα在調控葡萄糖穩態及其他關鍵生理過程中之中心作用，目前對野生型及突變型PI3Kα同等強效之PI3Kα選擇性抑制劑常引起高糖血症及/或高胰島素血症(Busaidy等人，J. Clin. Oncol.,2012, 30, 2919-2928)。總之，開發對突變型PI3Kα之選擇性強於對野生型PI3Kα之選擇性的抑制劑將能夠克服代償性胰島素產生及高糖血症之問題。Genetic mutations in the gene encoding PI3Kα are hotspot mutations within the helical and kinase domains, such as E542K, E545K, and H1047R. These mutations have been observed in many cancer types, including lung, gastric, endometrial, ovarian, bladder, breast, colon, brain, prostate, and skin cancers. Because these gain-of-function mutations in PI3Kα are associated with tumor progression, targeting this pathway may offer valuable therapeutic opportunities (Courtney et al.,J. Clin. Oncol .,2010 , 28(6), 1075-1083). Although a variety of PI3K inhibitors have been developed (e.g., taselisib, alpelisib, buparlisib, and others), these molecules inhibit multiple PI3K isoforms. These "pan-PI3K" inhibitors have encountered significant hurdles in clinical development due to their inability to achieve the desired level of tumor-targeted inhibition while avoiding toxicity in cancer patients (Fruman et al.,Nat. Rev. Drug Discov .,2014 , 13(2), 140-156). The toxicity of PI3K inhibitors depends on their isoform selectivity profile. Inhibition of PI3Kα is associated with hyperglycemia and rash, while inhibition of PI3Kδ or PI3Kγ is associated with diarrhea, bone marrow suppression, and elevated transaminases (Hanker et al.,Cancer Discov .,2019 , 9(4), 482-491). Therefore, selective inhibitors of PI3Kα may extend the therapeutic window, enabling sufficient targeted inhibition in tumors while avoiding dose-limiting toxicities in cancer patients. However, given the central role of PI3Kα in regulating glucose homeostasis and other critical physiological processes, current PI3Kα-selective inhibitors, which are equally potent against both wild-type and mutant PI3Kα, often cause hyperglycemia and/or hyperinsulinemia (Busaidy et al.,J. Clin. Oncol .,2012 , 30, 2919-2928). Therefore, developing inhibitors that are more selective for mutant PI3Kα than for wild-type PI3Kα would overcome the problems of compensatory insulin production and hyperglycemia.

本揭示案尤其提供式I化合物：I或其醫藥學上可接受之鹽，其中組成成員在本文中予以定義。This disclosure provides, inter alia, compounds of formula I:I or a pharmaceutically acceptable salt thereof, wherein the constituent members are defined herein.

本揭示案進一步提供醫藥組合物，該醫藥組合物包含本揭示案之化合物或其醫藥學上可接受之鹽以及醫藥學上可接受之載劑或賦形劑。The present disclosure further provides a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

本揭示案進一步提供抑制PI3Kα活性之方法，該方法包括使PI3Kα與本文所闡述之化合物或其醫藥學上可接受之鹽接觸。The present disclosure further provides methods for inhibiting PI3Kα activity, comprising contacting PI3Kα with a compound described herein or a pharmaceutically acceptable salt thereof.

本揭示案進一步提供治療患者之與PI3Kα相關之疾病或病症的方法，該方法係藉由向該患者投與治療有效量的本揭示案之化合物或其醫藥學上可接受之鹽來實施。The present disclosure further provides methods for treating a disease or condition associated with PI3Kα in a patient by administering to the patient a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

本揭示案進一步提供本文所闡述之化合物或其醫藥學上可接受之鹽，其用於本文所闡述之任一方法中。The disclosure further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

本揭示案進一步提供本文所闡述之化合物或其醫藥學上可接受之鹽之用途，其用於製備用於本文所闡述之任一方法中之藥劑。The present disclosure further provides the use of a compound described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein.

本揭示案提供式I化合物：I或其醫藥學上可接受之鹽，其中： n為0、1、2、3、4、5或6； 環A為C_3-14環烷基、C_6-10芳基、4-14員雜環烷基或5-10員雜芳基； L¹為C_1-4伸烷基，其中該C_1-4伸烷基視情況經1、2、3或4個獨立選擇之R^G取代基取代； L²係選自鍵、-O-及-N(R^L)-； R^L係選自H、C_1-6烷基及C_1-6鹵烷基； R¹係選自H、鹵基、C_1-4烷基、C_1-4鹵烷基、C_1-4烷氧基、C_1-4鹵烷氧基及-CN； R²係選自H、C_1-6烷基、C_1-6鹵烷基、C_3-7環烷基及C_3-7環烷基-C_1-4烷基，其中R²之該C_1-6烷基、該C_1-6鹵烷基、該C_3-7環烷基及該C_3-7環烷基-C_1-4烷基各自視情況經1、2、3或4個獨立選擇之R^G取代基取代； R³係選自H、鹵基、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6鹵烷基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基、(5-10員雜芳基)-C_1-4烷基、-CN、-OR^a3、-SR^a3、-NR^c3R^d3、-NO₂、-C(O)R^a3、-C(O)OR^a3、-C(O)NR^c3R^d3、-C(O)NR^c3(OR^a3)、-OC(O)R^a3、-OC(O)NR^c3R^d3、-OC(O)OR^a3、-OS(O)₂R^b3、-OS(O)₂NR^c3R^d3、-NR^c3C(O)R^a3、-NR^c3C(O)OR^a3、-NR^c3C(O)NR^c3R^d3、-NR^c3S(O)₂R^b3、-NR^c3S(O)₂NR^c3R^d3、-NR^c3OR^a3、-NR^c3S(O)R^b3、-NR^c3S(O)NR^c3R^d3、-S(O)R^b3、-S(O)₂R^b3、-S(O)NR^c3R^d3、-S(O)₂NR^c3R^d3、-C(=NR^e3)R^a3、-C(=NR^e3)NR^c3R^d3、-NR^c3C(=NR^e3)R^a3、-NR^c3C(=NR^e3)NR^c3R^d3、-NR^c3S(O)(=NR^e3)R^b3、-NR^c3S(O)(=NR^e3)NR^c3R^d3、-OS(O)(=NR^e3)R^b3、-S(O)(=NR^e3)R^b3、-S(O)(=NR^e3)NR^c3R^d3、-C(O)NR^c3S(O)₂R^b3、-C(O)NR^c3S(O)₂NR^c3R^d3、-S(O)₂NR^c3C(O)R^b3、-NR^c3S(O)NR^c3C(O)R^b3及-P(O)R^f3R^g3，其中R³之該C_1-6烷基、該C_2-6烯基、該C_2-6炔基、該C_1-6鹵烷基、該C_3-10環烷基、該C_6-10芳基、該4-10員雜環烷基、該5-10員雜芳基、該C_3-10環烷基-C_1-4烷基、該C_6-10芳基-C_1-4烷基、該(4-10員雜環烷基)-C_1-4烷基及該(5-10員雜芳基)-C_1-4烷基各自視情況經1、2、3、4、5或6個獨立選擇之R^3A取代基取代； 每一R^a3、R^c3及R^d3獨立地選自H、C_1-6烷基、C_1-6鹵烷基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基，其中R^a3、R^c3及R^d3之該C_1-6烷基、該C_2-6烯基、該C_2-6炔基、該C_1-6鹵烷基、該C_3-10環烷基、該C_6-10芳基、該4-10員雜環烷基、該5-10員雜芳基、該C_3-10環烷基-C_1-4烷基、該C_6-10芳基-C_1-4烷基、該(4-10員雜環烷基)-C_1-4烷基及該(5-10員雜芳基)-C_1-4烷基各自視情況經1、2、3、4、5或6個獨立選擇之R^3A取代基取代； 或連接至同一N原子之任何R^c3及R^d3與其所連接之該N原子一起形成4-10員雜環烷基，其中該4-10員雜環烷基視情況經1、2、3、4、5或6個獨立選擇之R^3A取代基取代； 每一R^b3獨立地選自C_1-6烷基、C_1-6鹵烷基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基，其中R^b3之該C_1-6烷基、該C_1-6鹵烷基、該C_2-6烯基、該C_2-6炔基、該C_3-10環烷基、該C_6-10芳基、該4-10員雜環烷基、該5-10員雜芳基、該C_3-10環烷基-C_1-4烷基、該C_6-10芳基-C_1-4烷基、該(4-10員雜環烷基)-C_1-4烷基及該(5-10員雜芳基)-C_1-4烷基各自視情況經1、2、3、4、5或6個獨立選擇之R^3A取代基取代； 每一R^e3獨立地選自H、OH、CN、C_1-6烷基、C_1-6烷氧基、C_1-6鹵烷基、C_1-6鹵烷氧基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基； 每一R^f3及R^g3獨立地選自H、C_1-6烷基、C_1-6烷氧基、C_1-6鹵烷基、C_1-6鹵烷氧基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基； 每一R^3A獨立地選自側氧基、H、鹵基、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6鹵烷基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基、(5-10員雜芳基)-C_1-4烷基、-CN、-OR^a3A、-SR^a3A、-NR^c3AR^d3A、-NO₂、-C(O)R^a3A、-C(O)OR^a3A、-C(O)NR^c3AR^d3A、-C(O)NR^c3A(OR^a3A)、-OC(O)R^a3A、-OC(O)NR^c3AR^d3A、-OC(O)OR^a3A、-OS(O)₂R^b3A、-OS(O)₂NR^c3AR^d3A、-NR^c3AC(O)R^a3A、-NR^c3AC(O)OR^a3A、-NR^c3AC(O)NR^c3AR^d3A、-NR^c3AS(O)₂R^b3A、-NR^c3AS(O)₂NR^c3AR^d3A、-NR^c3AOR^a3A、-NR^c3AS(O)R^b3A、-NR^c3AS(O)NR^c3AR^d3A、-S(O)R^b3A、-S(O)₂R^b3A、-S(O)NR^c3AR^d3A、-S(O)₂NR^c3AR^d3A、-C(=NR^e3A)R^a3A、-C(=NR^e3A)NR^c3AR^d3A、-NR^c3AC(=NR^e3A)R^a3A、-NR^c3AC(=NR^e3A)NR^c3AR^d3A、-NR^c3AS(O)(=NR^e3A)R^b3A、-NR^c3AS(O)(=NR^e3A)NR^c3AR^d3A、-OS(O)(=NR^e3A)R^b3A、-S(O)(=NR^e3A)R^b3A、-S(O)(=NR^e3A)NR^c3AR^d3A、-C(O)NR^c3AS(O)₂R^b3A、-C(O)NR^c3AS(O)₂NR^c3AR^d3A、-S(O)₂NR^c3AC(O)R^b3A、-NR^c3AS(O)NR^c3AC(O)R^b3A及-P(O)R^f3AR^g3A，其中R^3A之該C_1-6烷基、該C_2-6烯基、該C_2-6炔基、該C_1-6鹵烷基、該C_3-10環烷基、該C_6-10芳基、該4-10員雜環烷基、該5-10員雜芳基、該C_3-10環烷基-C_1-4烷基、該C_6-10芳基-C_1-4烷基、該(4-10員雜環烷基)-C_1-4烷基及該(5-10員雜芳基)-C_1-4烷基各自視情況經1、2、3、4、5或6個獨立選擇之R^G取代基取代； 每一R^a3A、R^c3A及R^d3A獨立地選自H、C_1-6烷基、C_1-6鹵烷基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基，其中R^a3A、R^c3A及R^d3A之該C_1-6烷基、該C_2-6烯基、該C_2-6炔基、該C_1-6鹵烷基、該C_3-10環烷基、該C_6-10芳基、該4-10員雜環烷基、該5-10員雜芳基、該C_3-10環烷基-C_1-4烷基、該C_6-10芳基-C_1-4烷基、該(4-10員雜環烷基)-C_1-4烷基及該(5-10員雜芳基)-C_1-4烷基各自視情況經1、2、3、4、5或6個獨立選擇之R^G取代基取代； 或連接至同一N原子之任何R^c3A及R^d3A與其所連接之該N原子一起形成4-10員雜環烷基，其中該4-10員雜環烷基視情況經1、2、3、4、5或6個獨立選擇之R^G取代基取代； 每一R^b3A獨立地選自C_1-6烷基、C_1-6鹵烷基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基，其中R^b3A之該C_1-6烷基、該C_1-6鹵烷基、該C_2-6烯基、該C_2-6炔基、該C_3-10環烷基、該C_6-10芳基、該4-10員雜環烷基、該5-10員雜芳基、該C_3-10環烷基-C_1-4烷基、該C_6-10芳基-C_1-4烷基、該(4-10員雜環烷基)-C_1-4烷基及該(5-10員雜芳基)-C_1-4烷基各自視情況經1、2、3、4、5或6個獨立選擇之R^G取代基取代； 每一R^e3A獨立地選自H、OH、CN、C_1-6烷基、C_1-6烷氧基、C_1-6鹵烷基、C_1-6鹵烷氧基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基； 每一R^f3A及R^g3A獨立地選自H、C_1-6烷基、C_1-6烷氧基、C_1-6鹵烷基、C_1-6鹵烷氧基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基； R⁴係選自側氧基、鹵基、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6鹵烷基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基、(5-10員雜芳基)-C_1-4烷基、-CN、-OR^a4、-SR^a4、-NR^c4R^d4、-NO₂、-C(O)R^a4、-C(O)OR^a4、-C(O)NR^c4R^d4、-C(O)NR^c4(OR^a4)、-OC(O)R^a4、-OC(O)NR^c4R^d4、-OC(O)OR^a4、-OS(O)₂R^b4、-OS(O)₂NR^c4R^d4、-NR^c4C(O)R^a4、-NR^c4C(O)OR^a4、-NR^c4C(O)NR^c4R^d4、-NR^c4S(O)₂R^b4、-NR^c4S(O)₂NR^c4R^d4、-NR^c4OR^a4、-NR^c4S(O)R^b4、-NR^c4S(O)NR^c4R^d4、-S(O)R^b4、-S(O)₂R^b4、-S(O)NR^c4R^d4、-S(O)₂NR^c4R^d4、-C(=NR^e4)R^a4、-C(=NR^e4)NR^c4R^d4、-NR^c4C(=NR^e4)R^a4、-NR^c4C(=NR^e4)NR^c4R^d4、-NR^c4S(O)(=NR^e4)R^b4、-NR^c4S(O)(=NR^e4)NR^c4R^d4、-OS(O)(=NR^e4)R^b4、-S(O)(=NR^e4)R^b4、-S(O)(=NR^e4)NR^c4R^d4、-C(O)NR^c4S(O)₂R^b4、-C(O)NR^c4S(O)₂NR^c4R^d4、-S(O)₂NR^c4C(O)R^b4、-NR^c4S(O)NR^c4C(O)R^b4及-P(O)R^f4R^g4，其中R⁴之該C_1-6烷基、該C_2-6烯基、該C_2-6炔基、該C_1-6鹵烷基、該C_3-10環烷基、該C_6-10芳基、該4-10員雜環烷基、該5-10員雜芳基、該C_3-10環烷基-C_1-4烷基、該C_6-10芳基-C_1-4烷基、該(4-10員雜環烷基)-C_1-4烷基及該(5-10員雜芳基)-C_1-4烷基各自視情況經1、2、3、4、5或6個獨立選擇之R^4A取代基取代； 每一R^a4、R^c4及R^d4獨立地選自H、C_1-6烷基、C_1-6鹵烷基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基，其中R^a4、R^c4及R^d4之該C_1-6烷基、該C_2-6烯基、該C_2-6炔基、該C_1-6鹵烷基、該C_3-10環烷基、該C_6-10芳基、該4-10員雜環烷基、該5-10員雜芳基、該C_3-10環烷基-C_1-4烷基、該C_6-10芳基-C_1-4烷基、該(4-10員雜環烷基)-C_1-4烷基及該(5-10員雜芳基)-C_1-4烷基各自視情況經1、2、3、4、5或6個獨立選擇之R^4A取代基取代； 或連接至同一N原子之任何R^c4及R^d4與其所連接之該N原子一起形成4-10員雜環烷基，其中該4-10員雜環烷基視情況經1、2、3、4、5或6個獨立選擇之R^4A取代基取代； 每一R^b4獨立地選自C_1-6烷基、C_1-6鹵烷基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基，其中R^b4之該C_1-6烷基、該C_1-6鹵烷基、該C_2-6烯基、該C_2-6炔基、該C_3-10環烷基、該C_6-10芳基、該4-10員雜環烷基、該5-10員雜芳基、該C_3-10環烷基-C_1-4烷基、該C_6-10芳基-C_1-4烷基、該(4-10員雜環烷基)-C_1-4烷基及該(5-10員雜芳基)-C_1-4烷基各自視情況經1、2、3、4、5或6個獨立選擇之R^4A取代基取代； 每一R^e4獨立地選自H、OH、CN、C_1-6烷基、C_1-6烷氧基、C_1-6鹵烷基、C_1-6鹵烷氧基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基； 每一R^f4及R^g4獨立地選自H、C_1-6烷基、C_1-6烷氧基、C_1-6鹵烷基、C_1-6鹵烷氧基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基； 每一R^4A獨立地選自側氧基、H、鹵基、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6鹵烷基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基、(5-10員雜芳基)-C_1-4烷基、-CN、-OR^a4A、-SR^a4A、-NR^c4AR^d4A、-NO₂、-C(O)R^a4A、-C(O)OR^a4A、-C(O)NR^c4AR^d4A、-C(O)NR^c4A(OR^a4A)、-OC(O)R^a4A、-OC(O)NR^c4AR^d4A、-OC(O)OR^a4A、-OS(O)₂R^b4A、-OS(O)₂NR^c4AR^d4A、-NR^c4AC(O)R^a4A、-NR^c4AC(O)OR^a4A、-NR^c4AC(O)NR^c4AR^d4A、-NR^c4AS(O)₂R^b4A、-NR^c4AS(O)₂NR^c4AR^d4A、-NR^c4AOR^a4A、-NR^c4AS(O)R^b4A、-NR^c4AS(O)NR^c4AR^d4A、-S(O)R^b4A、-S(O)₂R^b4A、-S(O)NR^c4AR^d4A、-S(O)₂NR^c4AR^d4A、-C(=NR^e4A)R^a4A、-C(=NR^e4A)NR^c4AR^d4A、-NR^c4AC(=NR^e4A)R^a4A、-NR^c4AC(=NR^e4A)NR^c4AR^d4A、-NR^c4AS(O)(=NR^e4A)R^b4A、-NR^c4AS(O)(=NR^e4A)NR^c4AR^d4A、-OS(O)(=NR^e4A)R^b4A、-S(O)(=NR^e4A)R^b4A、-S(O)(=NR^e4A)NR^c4AR^d4A、-C(O)NR^c4AS(O)₂R^b4A、-C(O)NR^c4AS(O)₂NR^c4AR^d4A、-S(O)₂NR^c4AC(O)R^b4A、-NR^c4AS(O)NR^c4AC(O)R^b4A及-P(O)R^f4AR^g4A，其中R^4A之該C_1-6烷基、該C_2-6烯基、該C_2-6炔基、該C_1-6鹵烷基、該C_3-10環烷基、該C_6-10芳基、該4-10員雜環烷基、該5-10員雜芳基、該C_3-10環烷基-C_1-4烷基、該C_6-10芳基-C_1-4烷基、該(4-10員雜環烷基)-C_1-4烷基及該(5-10員雜芳基)-C_1-4烷基各自視情況經1、2、3、4、5或6個獨立選擇之R^G取代基取代； 每一R^a4A、R^c4A及R^d4A獨立地選自H、C_1-6烷基、C_1-6鹵烷基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基，其中R^a4A、R^c4A及R^d4A之該C_1-6烷基、該C_2-6烯基、該C_2-6炔基、該C_1-6鹵烷基、該C_3-10環烷基、該C_6-10芳基、該4-10員雜環烷基、該5-10員雜芳基、該C_3-10環烷基-C_1-4烷基、該C_6-10芳基-C_1-4烷基、該(4-10員雜環烷基)-C_1-4烷基及該(5-10員雜芳基)-C_1-4烷基各自視情況經1、2、3、4、5或6個獨立選擇之R^G取代基取代； 或連接至同一N原子之任何R^c4A及R^d4A與其所連接之該N原子一起形成4-10員雜環烷基，其中該4-10員雜環烷基視情況經1、2、3、4、5或6個獨立選擇之R^G取代基取代； 每一R^b4A獨立地選自C_1-6烷基、C_1-6鹵烷基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基，其中R^b4A之該C_1-6烷基、該C_1-6鹵烷基、該C_2-6烯基、該C_2-6炔基、該C_3-10環烷基、該C_6-10芳基、該4-10員雜環烷基、該5-10員雜芳基、該C_3-10環烷基-C_1-4烷基、該C_6-10芳基-C_1-4烷基、該(4-10員雜環烷基)-C_1-4烷基及該(5-10員雜芳基)-C_1-4烷基各自視情況經1、2、3、4、5或6個獨立選擇之R^G取代基取代； 每一R^e4A獨立地選自H、OH、CN、C_1-6烷基、C_1-6烷氧基、C_1-6鹵烷基、C_1-6鹵烷氧基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基； 每一R^f4A及R^g4A獨立地選自H、C_1-6烷基、C_1-6烷氧基、C_1-6鹵烷基、C_1-6鹵烷氧基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基； 每一R^G獨立地選自H、D、OH、CN、鹵基、側氧基、C_1-4烷基、C_2-4烯基、C_2-4炔基、C_1-4鹵烷基、氰基-C_1-4烷基、HO-C_1-4烷基、C_1-4烷氧基-C_1-4烷基、C_3-7環烷基、4-7員雜環烷基、C_1-4烷氧基、C_1-4鹵烷氧基、胺基、C_1-3烷基胺基、二(C_1-3烷基)胺基、硫基、C_1-3烷基硫基、C_1-3烷基亞磺醯基、C_1-3烷基磺醯基、胺甲醯基、C_1-3烷基胺甲醯基、二(C_1-3烷基)胺甲醯基、羧基、C_1-3烷基羰基、C_1-3烷氧基羰基、C_1-3烷基羰基氧基、C_1-3烷基羰基胺基、C_1-3烷氧基羰基胺基、胺基羰基氧基、C_1-3烷基胺基羰基氧基、二(C_1-3烷基)胺基羰基氧基、C_1-3烷基磺醯基胺基、胺基磺醯基、C_1-3烷基胺基磺醯基、二(C_1-3烷基)胺基磺醯基、胺基磺醯基胺基、C_1-3烷基胺基磺醯基胺基、二(C_1-3烷基)胺基磺醯基胺基、胺基羰基胺基、C_1-3烷基胺基羰基胺基及二(C_1-3烷基)胺基羰基胺基。The present disclosure provides compounds of formula I:I or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, 2, 3, 4, 5 or 6; Ring A is C_3-14 cycloalkyl, C_6-10 aryl, 4-14 membered heterocycloalkyl or 5-10 membered heteroaryl; L¹ is C_1-4 alkylene, wherein the C_1-4 alkylene is optionally substituted with 1, 2, 3 or 4 independently selected^RG substituents; L² is selected from a bond, -O- and -N(^RL )-;^RL is selected from H, C_1-6 alkyl and C_1-6 haloalkyl; R¹ is selected from H, halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, C_1-4 haloalkoxy and -CN; R² is selected from H, C_1-6 alkyl, C_{C 1-6} haloalkyl, C_3-7 cycloalkyl and C_3-7 cycloalkyl-C_1-4 alkyl, wherein the C_1-6 alkyl, the C_1-6 haloalkyl, the C_3-7 cycloalkyl and the C_3-7 cycloalkyl-C_1-4 alkyl of R² are each optionally substituted with 1, 2, 3 or 4 independently selected R^G substituents; R³ is selected from H, haloalkyl, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C_3-10 cycloalkyl-C_1-4 alkyl, C_6-10 aryl-C_1-4 alkyl, (4-10 membered heterocycloalkyl)-C_1-4 alkyl, (5-10 membered heteroaryl)-C_1-4 alkyl, -CN, -OR^a3 , -SR^a3 , -NR^c3 R^d3 , -NO₂ , -C(O)R^a3 , -C(O)OR^a3 , -C(O)NR^c3 R^d3 , -C(O)NR^c3 (OR^a3 ), -OC(O)R^a3 , -OC(O)NR^c3 R^d3 , -OC(O)OR^a3 , -OS(O)₂ R^b3 , -OS(O)₂ NR^c3 R^d3 , -NR^c3 C(O)R^a3 , -NR^c3 C(O)OR^a3 , -NR^c3 C(O)NR^c3 R^d3 , -NR^c3 S(O)₂ R^b3 , -NR^c3 S(O)₂ NR^c3 R^d3 , -NR^c3 OR^a3 , -NR^c3 S(O)R^b3 , -NR^c3 S(O)NR^c3 R^d3 , -S(O)R^b3 , -S(O)₂ R^b3 , -S(O)NR^c3 R^d3 , -S(O)₂ NR^c3 R^d3 , -C(=NR^e3 )R^a3 , -C(=NR^e3 )NR^c3 R^d3 , -NR^c3 C(=NR^e3 )R^a3 , -NR^c3 C(=NR^e3 )NR^c3 R^d3 , -NR^c3 S(O)(=NR^e3 )R^b3 , -NR^c3 S(O)(=NR^e3 )NR^c3 R^d3 , -OS(O)(=NR^e3 )R^b3 , -S(O)(=NR^e3 )R^b3 , -S(O)(=NR^e3 )NR^c3 R^d3 , -C(O)NR^c3 S(O)₂ R^b3 , -C(O)NR^c3 S(O)₂ NR^c3 R^d3 , -S(O)₂ NR^c3 C(O)R^b3 , -NR^c3 S(O)NR^c3 C(O)R^b3 and -P(O)R^f3 R^g3 , wherein R³ is the C_1-6 alkyl, the C_2-6 alkenyl, the C_2-6 alkynyl, the C_1-6 haloalkyl, the C_3-10 cycloalkyl, the C_6-10 aryl, the 4-10 membered heterocycloalkyl, the 5-10 membered heteroaryl, the C_3-10 cycloalkyl-C_1-4 alkyl, the C the (_4-10 membered heterocycloalkyl)-C_1-4 alkyl and the (5-10 membered heteroaryl)-C_1-4 alkyl are each optionally substituted with 1,₂ , 3, 4, 5 or 6 independently selected R^3A substituents; each of^Ra3 ,^Rc3 and^Rd3 is independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C_3-10 cycloalkyl-C_1-4 alkyl, C_6-10 aryl-C_1-4 alkyl, (4-10 membered heterocycloalkyl)-C R^a3 , R^c3 and R^d3 are each_optionally substituted with_1,2,3,4,5or6 independently selected^R_{3Asubstituents;} or any R^c3 and R^d3 attached to the same N atom together with the N atom to which they are attached form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R^3A substituents; each R^b3 is independently selected from C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C_3-10 cycloalkyl-C_1-4 alkyl, C_6-10 aryl-C_1-4 alkyl, (4-10 membered heterocycloalkyl)-C_1-4 alkyl and (5-10 membered heteroaryl)-C 1-6 alkyl.^wherein the C_1-6 alkyl, the C_1-6 haloalkyl, the C_2-6 alkenyl, the C_2-6 alkynyl, the C_3-10 cycloalkyl, the C_6-10 aryl, the_4-10 membered heterocycloalkyl, the 5-10 membered heteroaryl, the C_3-10 cycloalkyl-C_1-4 alkyl, the C_6-10 aryl-C_1-4 alkyl, the (4-10 membered heterocycloalkyl)-C_1-4 alkyl and the (5-10 membered heteroaryl)-C 1-4 alkyl of R b3 are each optionally substituted with 1, 2, 3,₄ , 5 or 6 independently selected R^3A substituents; each R^e3 is independently selected from H, OH, CN, C_1-6 alkyl, C_1-6 alkoxy, C Rf3 and Rg3 are independently selected from H,_C1-6 alkyl,_C1-6 alkoxy,_C1-6 haloalkyl,_C1-6 haloalkoxy,_C2-6 alkenyl, C2-6 alkynyl,_C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,_C3-10 cycloalkyl-_C1-4 alkyl,_C6-10 aryl-_C1-4 alkyl, (4-10 membered heterocycloalkyl)_-C1-4 alkyl and (5-10 membered heteroaryl)_-C1-4 alkyl; each^Rf3 and^Rg3 are independently selected from H,_C1-6 alkyl, C1-6 alkoxy,_C1-6 haloalkyl, C1-6 haloalkoxy,_C2-6 alkenyl,_C2-6 alkynyl, C3-10 cycloalkyl,_C6-10 aryl, C1-4 alkyl, (_4-10 membered heterocycloalkyl)-C1-4 alkyl and_(5-10 membered heteroaryl)-C1-4 alkyl. C_6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C_3-10 cycloalkyl-C_1-4 alkyl, C_6-10 aryl-C_1-4 alkyl, (4-10 membered heterocycloalkyl)-C_1-4 alkyl and (5-10 membered heteroaryl)-C_1-4 alkyl; each R^3A is independently selected from a pendoxy group, H, a halogen group, a C 1-6 alkyl group, a C_2-6 alkenyl group, a C_2-6 alkynyl group, a C_1-6 halogen group, a C_3-10 cycloalkyl, a C_6-10 aryl, a 4-10 membered heterocycloalkyl, a 5-10 membered heteroaryl, a C 3-10 cycloalkyl-C_1-4 alkyl group, a C_6-10 aryl-C_1-4 alkyl group, a C 6-10 aryl-C_1-4 alkyl group_1-4 alkyl, (4-10 membered heterocycloalkyl)-C_1-4 alkyl, (5-10 membered heteroaryl)-C_1-4 alkyl, -CN, -OR^a3A , -SR^a3A , -NR^c3A R^d3A , -NO₂ , -C(O)R^a3A , -C(O)OR^a3A , -C(O)NR^c3A R^d3A , -C(O)NR^c3A (OR^a3A ), -OC(O)R^a3A , -OC(O)NR^c3A R^d3A , -OC(O)OR^a3A , -OS(O)₂ R^b3A , -OS(O)₂ NR^c3A R^d3A , -NR^c3A C(O)R^a3A , -NR^c3A C(O)OR^a3A , -NR^c3A C(O)NR^c3A R^d3A , -NR^c3A S(O)₂ R^b3A , -NR^c3A S(O)₂ NR^c3A R^d3A , -NR^c3A OR^a3A , -NR^c3A S(O)R^b3A , -NR^c3A S(O)NR^c3A R^d3A , -S(O)R^b3A , -S(O)₂ R^b3A , -S(O)NR^c3A R^d3A , -S(O)₂ NR^c3A R^d3A , -C(=NR^e3A )R^a3A , -C(=NR^e3A )NR^c3A R^d3A , -NR^c3A C(=NR^e3A )R^a3A , -NR^c3A C(=NR^e3A )NR^c3A R^d3A ,-NR^c3AS (O)(=^NRe3A )^Rb3A , -NRc3AS(O)(=^NRe3A )^NRc3ARd3A, -OS(O)(=^NRe3A )^Rb3A , -S(O)(=^NRe3A )^Rb3A_, -S(O)⁽ =^NRe3A )^NRc3ARd3A , -C^{(O)NRc3AS(O)2Rb3A, -C(O)NRc3AS(O)2NRc3ARd3A,}_-S^(O)_2NRc3AC^(O)Rb3A , -NRc3AS(O)^NRc3AC (O)^Rb3A and^-P (O)^Rf3ARg3A , wherein the^C1-6 alkyl, the_C2-6 alkenyl, the_C the C_2-6 alkynyl, the C_1-6 haloalkyl, the C_3-10 cycloalkyl, the C_6-10 aryl, the 4-10 membered heterocycloalkyl, the 5-10 membered heteroaryl, the C_3-10 cycloalkyl-C_1-4 alkyl, the C_6-10 aryl-C_1-4 alkyl, the (4-10 membered heterocycloalkyl)-C_1-4 alkyl and the (5-10 membered heteroaryl)-C_1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected^RG substituents; each R^a3A , R^c3A and R^d3A are independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C 2-6 alkenyl, C_2-6 alkynyl, C 3-10 cycloalkyl, C_1-4 alkyl, C_{6-10 aryl-C 1-4} alkyl, C_1-4 alkyl, (4-10 membered heterocycloalkyl)-C_1-4 alkyl and (5-10 membered heteroaryl)-C_1-4 alkyl, wherein the C_1-6 alkyl, the C_2-6 alkenyl, the C_2-6 alkynyl, the C_1-6 haloalkyl, the C 3-10 cycloalkyl, the C_6-10^aryl , the^4-10 membered heterocycloalkyl, the^5-10 membered heteroaryl, the C_3-10 cycloalkyl-C_1-4 alkyl, the C 6-10 aryl-C_1-4 alkyl, the C_6-10 aryl-C 1-4 alkyl, the C_6-10 aryl-C 1-4 alkyl, the C 6-10 aryl-C 1-4 alkyl, the C_6-10 aryl-C_1-4 alkyl, the C_6-10 aryl-C wherein the (4-10 membered heterocycloalkyl)-C_1-4 alkyl, the (4-10 membered heterocycloalkyl)-C_1-4 alkyl and the (5-10 membered heteroaryl)-C_1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected^RG substituents; or any R^c3A and R^d3A attached to the same N atom together with the N atom to which they are attached form a 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected^RG substituents; each R^b3A is independently selected from C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C R b3A is a C_1-6 alkyl, a C 1-6 halogenalkyl, a C_2-6 alkenyl, a C_2-6 alkynyl, a C 3-10 cycloalkyl, a C_6-10 aryl,_{a 4-10} membered heterocycloalkyl, a 5-10 membered heteroaryl, a C_3-10 cycloalkyl-C_1-4 alkyl, a C 6-10 aryl-C 1-4 alkyl, a (4-10 membered heterocycloalkyl)-C_1-4 alkyl and a (^5-10 membered heteroaryl)-C 1-4 alkyl, wherein the C_1-6 alkyl, the C_1-6 halogenalkyl, the C_2-6 alkenyl, the C_2-6 alkynyl, the C_3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocycloalkyl, the 5-10 membered heteroaryl, the C_3-10 cycloalkyl-C_1-4 alkyl, the C_6-10 aryl-C The (4-10 membered heterocycloalkyl)-C_1-4 alkyl, the (5-10 membered heteroaryl)-C_1-4 alkyl, and the (4-10 membered heterocycloalkyl)-C_1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected^R substituents; each R^e3A is independently selected from H, OH, CN, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 halogenalkyl, C_1-6 halogenalkoxy, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C_3-10 cycloalkyl-C_1-4 alkyl, C_6-10 aryl-C_1-4 alkyl, (4-10 membered heterocycloalkyl)-C each^Rf3A and^Rg3A is independently selected from H,_C1-6 alkyl,_C1-6 alkoxy, C1-6 halogenalkyl,_C1-6 halogenalkoxy, C2-6 alkenyl, C2-6 alkynyl,_C3-10 cycloalkyl, C6-10 aryl,_4-10 membered heterocycloalkyl,_5-10 membered heteroaryl, C3-10 cycloalkyl-_C1-4 alkyl,_C6-10 aryl-_C1-4 alkyl, (_4-10 membered heterocycloalkyl)-C1-4 alkyl and (5-10 membered heteroaryl)-C1-4 alkyl; R4 is selected from pendoxy, halogen,_C1-6 alkyl,_C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl,_4-10 membered heterocycloalkyl,_5-10 membered heteroaryl,^C3-10 cycloalkyl-_C1-4 alkyl, C6-10 aryl-_C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl and (_5-10 membered heteroaryl)-C1-4 alkyl; C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C_3-10 cycloalkyl-C_1-4 alkyl, C_6-10 aryl-C_1-4 alkyl, (4-10 membered heterocycloalkyl)-C_1-4 alkyl, (5-10 membered heteroaryl)-C_1-4 alkyl, -CN, -OR^a4 , -SR^a4 , -NR^c4 R^d4 , -NO₂ , -C(O)R^a4 , -C(O)OR^a4 , -C(O)NR^c4 R^d4 , -C(O)NR^c4 (OR^a4 ), -OC(O)R^a4 , -OC(O)NR^c4 R^d4 , -OC(O)OR^a4 , -OS(O)₂ R^b4 , -OS(O)₂ NR^c4 R^d4 , -NR^c4 C(O)R^a4 , -NR^c4 C(O)OR^a4 , -NR^c4 C(O)NR^c4 R^d4 , -NR^c4 S(O)₂ R^b4 , -NR^c4 S(O)₂ NR^c4 R^d4 , -NR^c4 OR^a4 , -NR^c4 S(O)R^b4 , -NR^c4 S(O)NR^c4 R^d4 , -S(O)R^b4 , -S(O)₂ R^b4 , -S(O)NR^c4 R^d4 , -S(O)₂ NR^c4 R^d4 , -C(=NR^e4 )R^a4 , -C(=NR^e4 )NR^c4 R^d4 , -NR^c4 C(=NR^e4 )R^a4 , -NR^c4 C(=NR^e4 )NR^c4 R^d4 , -NR^c4 S(O)(=NR^e4 )R^b4 , -NR^c4 S(O)(=NR^e4 )NR^c4 R^d4 , -OS(O)(=NR^e4 )R^b4 , -S(O)(=NR^e4 )R^b4 , -S(O)(=NR^e4 )NR^c4 R^d4 , -C(O)NR^c4 S(O)₂ R^b4 , -C(O)NR^c4 S(O)₂ NR^c4 R^d4 , -S(O)₂ NR^c4 C(O)R^b4 , -NR^c4 S(O)NR^c4 C(O)R^b4 and -P(O)R^f4 R^g4 , where R⁴ is the C_1-6 alkyl, the C The C_2-6 alkenyl, the C_2-6 alkynyl, the C_1-6 haloalkyl, the C_3-10 cycloalkyl, the C_6-10 aryl, the 4-10 membered heterocycloalkyl, the 5-10 membered heteroaryl, the C_3-10 cycloalkyl-C_1-4 alkyl, the C_6-10 aryl-C_1-4 alkyl, the (4-10 membered heterocycloalkyl)-C_1-4 alkyl and the (5-10 membered heteroaryl)-C_1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R^4A substituents; each R^a4 , R^c4 and R^d4 are independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C C_3-10 cycloalkyl, C_6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C_3-10 cycloalkyl-C_1-4 alkyl, C_6-10 aryl-C_1-4 alkyl, (4-10 membered heterocycloalkyl)-C_1-4 alkyl and (5-10 membered heteroaryl)-C_1-4 alkyl, wherein R^a4 , R^c4 and R^d4 are the C_1-6 alkyl, the C_2-6 alkenyl, the C_2-6 alkynyl, the C_1-6 haloalkyl, the C_3-10 cycloalkyl, the C_6-10 aryl, the 4-10 membered heterocycloalkyl, the 5-10 membered heteroaryl, the C_3-10 cycloalkyl-C_1-4 alkyl, the C_6-10 membered heterocycloalkyl-C_1-4 alkyl, the (4-10 membered heterocycloalkyl)-C_1-4 alkyl and the (5-10 membered heteroaryl)-C_1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R^4A substituents; or any R^c4 and R^d4 attached to the same N atom together with the N atom to which they are attached form a 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R^4A substituents; each R^b4 is independently selected from C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C R b4 is a C_1-6 alkyl, a C 1-6 halogen alkyl, a C_2-6 alkenyl, a C_2-6 alkynyl, a C 3-10 cycloalkyl, a C_6-10 aryl,_{a 4-10} membered heterocycloalkyl, a 5-10 membered heteroaryl, a C 3-10 cycloalkyl-C_1-4 alkyl, a C_6-10 aryl-C_1-4 alkyl, a (4-10 membered heterocycloalkyl)-C 1-4 alkyl and a (5-10 membered heteroaryl)-C_1-4 alkyl, wherein R^b4 is a C_1-6 alkyl, a C_1-6 halogen alkyl, a C 2-6 alkenyl, a C_2-6 alkynyl, a C_3-10 cycloalkyl, a C 6-10 aryl, a 4-10 membered heterocycloalkyl, a 5-10 membered heteroaryl, a C_3-10 cycloalkyl-C_1-4 alkyl, a C_6-10 aryl-C The (4-10 membered heterocycloalkyl)-C_1-4 alkyl, the (5-10 membered heteroaryl)-C_1-4 alkyl, and the (4-10 membered heterocycloalkyl)-C_1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R^4A substituents; each R^e4 is independently selected from H, OH, CN, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 halogenalkyl, C_1-6 halogenalkoxy, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C_3-10 cycloalkyl-C_1-4 alkyl, C_6-10 aryl-C_1-4 alkyl, (4-10 membered heterocycloalkyl)-C each^Rf4 and^Rg4 are independently selected from H,_C1-6 alkyl,_C1-6 alkoxy, C1-6 halogenalkyl,_C1-6 halogenalkoxy, C2-6 alkenyl, C2-6 alkynyl,_C3-10 cycloalkyl, C6-10 aryl,_4-10 membered heterocycloalkyl,_5-10 membered heteroaryl, C3-10 cycloalkyl-_C1-4 alkyl,_C6-10 aryl-C1-4 alkyl, (_4-10 membered heterocycloalkyl)-C1-4 alkyl and_(5-10 membered heteroaryl)-C1-4 alkyl; each R4A is independently selected from pendoxy, H, halogen, C1-6 alkyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl,_5-10 membered heteroaryl, C3-10 cycloalkyl-_C1-4 alkyl,_C6-10 aryl-_C1-4 alkyl, (4-10 membered heterocycloalkyl)_-C1-4 alkyl and (5-10 membered heteroaryl)-C1-4 alkyl; each^R4A is independently selected from pendoxy, H, halogen, C1-6 alkyl, C2-6 alkynyl, C2-6 alkynyl, C3-10 cycloalkyl,_C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl,_C6-10 aryl-C1-4 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C_3-10 cycloalkyl-C_1-4 alkyl, C_6-10 aryl-C_1-4 alkyl, (4-10 membered heterocycloalkyl)-C_1-4 alkyl, (5-10 membered heteroaryl)-C_1-4 alkyl, -CN, -OR^a4A , -SR^a4A , -NR^c4A R^d4A , -NO₂ , -C(O)R^a4A , -C(O)OR^a4A , -C(O)NR^c4A R^d4A , -C(O)NR^c4A (OR^a4A ), -OC(O)R^a4A , -OC(O)NR^c4A R^d4A , -OC(O)OR^a4A , -OS(O)₂ R^b4A , -OS(O)₂ NR^c4A R^d4A , -NR^c4A C(O)R^a4A , -NR^c4A C(O)OR^a4A , -NR^c4A C(O)NR^c4A R^d4A , -NR^c4A S(O)₂ R^b4A , -NR^c4A S(O)₂ NR^c4A R^d4A , -NR^c4A OR^a4A , -NR^c4A S(O)R^b4A , -NR^c4A S(O)NR^c4A R^d4A , -S(O)R^b4A , -S(O)₂ R^b4A , -S(O)NR^c4A R^d4A , -S(O)₂ NR^c4A R^d4A , -C(=NR^e4A )R^a4A , -C(=NR^e4A )NR^c4A R^d4A , -NR^c4A C(=NR^e4A )R^a4A , -NR^c4A C(=NR^e4A )NR^c4A R^d4A , -NR^c4A S(O)(=NR^e4A )R^b4A , -NR^c4A S(O)(=NR^e4A )NR^c4A R^d4A , -OS(O)(=NR^e4A )R^b4A , -S(O)(=NR^e4A )R^b4A , -S(O)(=NR^e4A )NR^c4A R^d4A , -C(O)NR^c4A S(O)₂ R^b4A , -C(O)NR^c4A S(O)₂ NR^c4A R^d4A , -S(O)₂ NR^c4A C(O)R^b4A , -NR^c4A S(O)NR^c4A C(O)R^b4A and -P(O)R^f4A R^g4A , wherein R^4A is the C_1-6 alkyl, the C_2-6 alkenyl, the C_2-6 alkynyl, the C_1-6 haloalkyl, the C_3-10 cycloalkyl, the C_6-10 aryl, the 4-10 membered heterocycloalkyl, the 5-10 membered heteroaryl, the C_3-10 cycloalkyl-C_1-4 alkyl, the C_6-10 aryl-C_1-4 alkyl, the (4-10 membered heterocycloalkyl)-C_1-4 alkyl and the (5-10 membered heteroaryl)-C wherein each of^Ra4A ,^Rc4A and Rd4A is optionally substituted with_1, 2, 3, 4, 5 or 6 independently selected^R substituents; each of Ra4A, Rc4A and^Rd4A is independently selected from H,_C1-6 alkyl,_C1-6 haloalkyl, C2-6 alkenyl,_C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl,_4-10 membered heterocycloalkyl,_5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-_C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl and_(5-10 membered heteroaryl)-C1-4 alkyl, wherein the C1-6 alkyl, C2-6 haloalkyl,_{C2-6 alkenyl, C2-6} alkynyl,_C3-10 cycloalkyl, C6-10 aryl,_4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-_C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl and (5-10 membered heteroaryl)_-C1-4 alkyl, wherein the C1-6^alkyl , C2-6 haloalkyl, C2-6^{alkenyl, C2-6 alkynyl} ,^C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl,_5-10 membered heteroaryl the C_2-6 alkenyl, the C_2-6 alkynyl, the C_1-6 haloalkyl, the C_3-10 cycloalkyl, the C_6-10 aryl, the 4-10 membered heterocycloalkyl, the 5-10 membered heteroaryl, the C_3-10 cycloalkyl-C_1-4 alkyl, the C_6-10 aryl-C_1-4 alkyl, the (4-10 membered heterocycloalkyl)-C_1-4 alkyl and the (5-10 membered heteroaryl)-C_1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R^G substituents; or any R^c4A and R c4A attached to the same N atom^d4A together with the N atom to which it is attached forms a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R^G substituents; each R^b4A is independently selected from C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C_3-10 cycloalkyl-C_1-4 alkyl, C_6-10 aryl-C_1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C_1-4 alkyl, wherein the C 1-6 alkyl group of R^b4A is C 6-10 aryl-C_1-4 alkyl, The C_1-6 alkyl, the C_1-6 halogenalkyl, the C_2-6 alkenyl, the C_2-6 alkynyl, the C_3-10 cycloalkyl, the C_6-10 aryl, the 4-10 membered heterocycloalkyl, the 5-10 membered heteroaryl, the C_3-10 cycloalkyl-C_1-4 alkyl, the C_6-10 aryl-C_1-4 alkyl, the (4-10 membered heterocycloalkyl)-C_1-4 alkyl and the (5-10 membered heteroaryl)-C_1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R^G substituents; each R^e4A is independently selected from H, OH, CN, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 halogenalkyl, C_1-6 halogenalkoxy, C Rf4A and Rg4A are independently selected from H,_C1-6 alkyl,_C1-6 alkoxy,_C1-6 halogenalkyl, C1-6 halogenalkoxy,_C2-6 alkenyl, C2-6 alkynyl,_C3-10 cycloalkyl, C6-10 aryl,_{4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl} , C3-10 cycloalkyl-_C1-4 alkyl, C6-10 aryl-_C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl and (5-10 membered heteroaryl)_-C1-4 alkyl; each^Rf4A and^Rg4A are independently selected from H,_C1-6 alkyl,_C1-6 alkoxy,_C1-6 halogenalkyl, C1-6 halogenalkoxy,_C2-6 alkenyl,_C2-6 alkynyl, C3-10 cycloalkyl,_C1-4 alkyl,_C6-10 aryl-C1-4 alkyl,_{C 6-10} membered heteroaryl, C 1-4 alkyl, C_6-10 membered heterocycloalkyl, C_1-4 alkyl, (_4-10 membered heterocycloalkyl)-C_1-4 alkyl and (5-10 membered heteroaryl)-C_1-4 alkyl_; each^RG is independently selected from H, D, OH, CN, halogen, pendoxy, C_1-4 alkyl, C 2-4 alkenyl, C_2-4 alkynyl, C_1-4 haloalkyl, cyano-C_1-4 alkyl, HO-C_{1-4 alkyl, C 1-4alkoxy} -_{C 1-4alkyl} , C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_1-4 alkoxy, C a_1-4 halogen alkoxy group, an amino group, a C_1-3 alkylamino group, a di(C_1-3 alkyl)amino group, a thio group,_{a C 1-3alkylthio} group, a C_1-3 alkylsulfinyl group, a C_1-3 alkylsulfonyl group, an aminoformyl group, a C 1-3 alkylaminoformyl group, a di(C_1-3 alkyl)aminoformyl group, a carboxyl group,_{a C 1-3alkylcarbonyl} group, a C_1-3 alkoxycarbonyl group, a C_1-3 alkylcarbonyloxy group, a C_1-3 alkylcarbonylamino group, a C 1-3 alkoxycarbonylamino group, an aminocarbonyloxy group, a C_1-3 alkylaminocarbonyloxy group, a di(C_1-3 alkyl)aminocarbonyloxy group, a C_1-3 alkylsulfonylamino group, an aminosulfonyl group, a C_1-3 alkylaminosulfonyl group, a di(C 1-3 alkyl) The present invention also comprises a_{C 1-3} alkyl)aminosulfonyl group, an aminosulfonylamino group, a C_1-3 alkylaminosulfonylamino group, a di(C_1-3 alkyl)aminosulfonylamino group, an aminocarbonylamino group, a C_1-3 alkylaminocarbonylamino group and a di(C_1-3 alkyl)aminocarbonylamino group.

在一些實施例中，L¹為伸乙基，其中該伸乙基視情況經一個R^G取代基取代。In some embodiments, L¹ is ethylene, wherein the ethylene is optionally substituted with one^RG substituent.

在一些實施例中，L¹為伸乙基，其中該伸乙基視情況經氘取代。In some embodiments, L¹ is ethylene, wherein the ethylene is optionally substituted with deuterium.

在一些實施例中，L²為-N(R^L)-。In some embodiments, L² is -N(^RL )-.

在一些實施例中，L²為-NH-。In some embodiments,^L2 is -NH-.

在一些實施例中，R¹係選自鹵基、C_1-3烷基及C_1-3鹵烷基。In some embodiments, R¹ is selected from halo, C_1-3 alkyl, and C_1-3 haloalkyl.

在一些實施例中，R¹係選自氯、甲基及三氟甲基。In some embodiments, R¹ is selected from chloro, methyl, and trifluoromethyl.

在一些實施例中，R¹為鹵基或C_1-3烷基。In some embodiments, R¹ is halogen or C_1-3 alkyl.

在一些實施例中，R¹為氯或甲基。In some embodiments, R¹ is chloro or methyl.

在一些實施例中，R¹為氯。In some embodiments, R¹ is chloro.

在一些實施例中，R¹為甲基。In some embodiments, R¹ is methyl.

在一些實施例中，R¹為三氟甲基。In some embodiments, R¹ is trifluoromethyl.

在一些實施例中，R²為C_1-3烷基。In some embodiments, R² is C_1-3 alkyl.

在一些實施例中，R²係選自甲基及三氘代甲基。In some embodiments, R² is selected from methyl and trideuterated methyl.

在一些實施例中，R²為甲基。In some embodiments, R² is methyl.

在一些實施例中，R²為三氘代甲基。In some embodiments, R² is trideuterated methyl.

在一些實施例中，R³係選自嘧啶基、氮雜環丁烷基甲基、吡唑基、吡啶基、六氫吡啶基、2H-吡唑并[3,4-b]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,5-a]吡啶基、咪唑基、噻唑基、6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪基及C(O)NR^c3R^d3，其中R³之該嘧啶基、該氮雜環丁烷基甲基、該吡唑基、該吡啶基、該六氫吡啶基、該2H-吡唑并[3,4-b]吡啶基、該吡唑并[1,5-a]吡啶基、該吡唑并[1,5-a]嘧啶基、該咪唑并[1,5-a]吡啶基、該咪唑基、該噻唑基及該6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪基各自視情況經1、2、3或4個獨立選擇之R^3A取代基取代。In some embodiments, R³ is selected from pyrimidinyl, azacyclobutanylmethyl, pyrazolyl, pyridinyl, hexahydropyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,5-a]pyridinyl, imidazolyl, thiazolyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, and C(O)NR^c3 R^d3 , wherein R³ , the pyrimidinyl, the azacyclobutanylmethyl, the pyrazolyl, the pyridinyl, the hexahydropyridinyl, the 2H-pyrazolo[3,4-b]pyridinyl, the pyrazolo[1,5-a]pyridinyl, the pyrazolo[1,5-a]pyrimidinyl, the imidazolyl, the thiazolyl and the 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl of each optionally substituted with 1, 2, 3 or 4 independently selected R^3A substituents.

在一些實施例中，R³係選自嘧啶基、氮雜環丁烷基甲基、吡唑基、吡啶基、六氫吡啶基、2H-吡唑并[3,4-b]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,5-a]吡啶基、咪唑基、噻唑基、6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪基及C(O)NR^c3R^d3，其中R³之該嘧啶基、該氮雜環丁烷基甲基、該吡唑基、該吡啶基、該六氫吡啶基、該2H-吡唑并[3,4-b]吡啶基、該吡唑并[1,5-a]吡啶基、該吡唑并[1,5-a]嘧啶基、該咪唑并[1,5-a]吡啶基、該咪唑基、該噻唑基及該6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪基各自視情況經1或2個獨立選擇之R^3A取代基取代。In some embodiments, R³ is selected from pyrimidinyl, azacyclobutanylmethyl, pyrazolyl, pyridinyl, hexahydropyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,5-a]pyridinyl, imidazolyl, thiazolyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, and C(O)NR^c3 R^d3 , wherein R³ , the pyrimidinyl, the azacyclobutanylmethyl, the pyrazolyl, the pyridinyl, the hexahydropyridinyl, the 2H-pyrazolo[3,4-b]pyridinyl, the pyrazolo[1,5-a]pyridinyl, the pyrazolo[1,5-a]pyrimidinyl, the imidazo[1,5-a]pyridinyl, the imidazolyl, the thiazolyl and the 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl are each optionally substituted with 1 or 2 independently selected R^3A substituents.

在一些實施例中，R³係選自吡唑基、嘧啶基、六氫吡啶基、氮雜環丁烷基甲基、吡啶基、2H-吡唑并[3,4-b]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,5-a]吡啶基及C(O)NR^c3R^d3，其中R³之該吡唑基、該嘧啶基、該六氫吡啶基、該氮雜環丁烷基甲基、該吡啶基、該2H-吡唑并[3,4-b]吡啶基、該吡唑并[1,5-a]吡啶基、該吡唑并[1,5-a]嘧啶基及該咪唑并[1,5-a]吡啶基各自視情況經1、2、3或4個獨立選擇之R^3A取代基取代。In some embodiments, R³ is selected from pyrazolyl, pyrimidinyl, hexahydropyridinyl, azacyclobutanylmethyl, pyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,5-a]pyridinyl and C(O)NR^c3 R^d3 , wherein the^pyrazolyl , pyrimidinyl, hexahydropyridinyl, azacyclobutanylmethyl, pyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl and imidazo[1,5-a]pyridinyl of R 3 are each optionally selected from 1, 2, 3 or 4 independently selected R^3A Substituent substitution.

在一些實施例中，R³係選自吡唑基、嘧啶基、六氫吡啶基及C(O)NR^c3R^d3，其中R³之該吡唑基、該吡啶基、該嘧啶基及該六氫吡啶基各自視情況經一個R^3A取代基取代。In some embodiments, R³ is selected from pyrazolyl, pyrimidinyl, hexahydropyridinyl, and C(O)NR^{c 3} R^{d 3} , wherein the pyrazolyl, pyridinyl, pyrimidinyl, and hexahydropyridinyl of R³ are each optionally substituted with one R^3A substituent.

在一些實施例中，每一R^3A獨立地選自鹵基、C_1-3烷基、C_1-3羥基烷基、C_1-3烷氧基、氧雜環丁烷基、胺基、C_1-3烷基胺基、二(C_1-3烷基)胺基、-C(O)C_1-3烷基、-C(O)C_1-3羥基烷基、-C(O)C_3-6環烷基及-S(O)₂C_1-3烷基；In some embodiments, each R^3A is independently selected from halo, C_1-3 alkyl, C_1-3 hydroxyalkyl, C_1-3 alkoxy, oxacyclobutane, amino, C_1-3 alkylamino, di(C_1-3 alkyl)amino, -C(O)C_1-3 alkyl, -C(O)C_1-3 hydroxyalkyl, -C(O)C_3-6 cycloalkyl, and -S(O)₂ C_1-3 alkyl;

在一些實施例中，R³係選自吡唑基、嘧啶基、六氫吡啶基及C(O)NR^c3R^d3，其中R³之該吡唑基、該吡啶基、該嘧啶基及該六氫吡啶基各自視情況經一個選自C_1-3烷基、胺基及-C(O)C_1-3烷基之R^3A取代基取代。In some embodiments, R³ is selected from pyrazolyl, pyrimidinyl, hexahydropyridinyl and C(O)NR^c3 R^d3 , wherein the pyrazolyl, pyridinyl, pyrimidinyl and hexahydropyridinyl of R³ are each optionally substituted with an R^3A substituent selected from C_1-3 alkyl, amino and -C(O)C_1-3 alkyl.

在一些實施例中，R³係選自吡唑基、嘧啶基及六氫吡啶基，其中R³之該吡唑基、該嘧啶基及該六氫吡啶基各自視情況經一個選自C_1-3烷基、胺基及-C(O)C_1-3烷基之R^3A取代基取代。In some embodiments, R³ is selected from pyrazolyl, pyrimidinyl, and hexahydropyridinyl, wherein the pyrazolyl, pyrimidinyl, and hexahydropyridinyl of R³ are each optionally substituted with an R^3A substituent selected from C_1-3 alkyl, amino, and -C(O)C_1-3 alkyl.

在一些實施例中，R³係選自吡唑基、吡啶基、嘧啶基及六氫吡啶基，其中R³之該吡唑基、該嘧啶基及該六氫吡啶基各自視情況經一個選自甲基、胺基及甲基羰基之R^3A取代基取代。In some embodiments, R³ is selected from pyrazolyl, pyridinyl, pyrimidinyl and hexahydropyridinyl, wherein the pyrazolyl, the pyrimidinyl and the hexahydropyridinyl of R³ are each optionally substituted with an R^3A substituent selected from methyl, amino and methylcarbonyl.

在一些實施例中，R³係選自甲基吡唑基、胺基嘧啶基及(甲基羰基)六氫吡啶基。In some embodiments, R³ is selected from methylpyrazolyl, aminopyrimidinyl, and (methylcarbonyl)hexahydropyridinyl.

在一些實施例中，R³係選自嘧啶基、氮雜環丁烷基甲基、吡唑基、吡啶基、六氫吡啶基、2H-吡唑并[3,4-b]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,5-a]吡啶基及C(O)NR^c3R^d3，其中R³之該嘧啶基、該氮雜環丁烷基甲基、該吡唑基、該吡啶基、該六氫吡啶基、該2H-吡唑并[3,4-b]吡啶基、該吡唑并[1,5-a]吡啶基、該吡唑并[1,5-a]嘧啶基及該咪唑并[1,5-a]吡啶基各自視情況經1或2個R^3A取代基取代。In some embodiments, R³ is selected from pyrimidinyl, azacyclobutanylmethyl, pyrazolyl, pyridinyl, hexahydropyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,5-a]pyridinyl, and C(O)NR^c3 R^d3 , wherein the^pyrimidinyl , the azacyclobutanylmethyl, the pyrazolyl, the pyridinyl, the hexahydropyridinyl, the 2H-pyrazolo[3,4-b]pyridinyl, the pyrazolo[1,5-a]pyridinyl, the pyrazolo[1,5-a]pyrimidinyl, and the imidazo[1,5-a]pyridinyl of R 3 are each optionally substituted with 1 or 2 R^3A substituents.

在一些實施例中，R³係選自嘧啶基、氮雜環丁烷基甲基、吡唑基、吡啶基、六氫吡啶基、2H-吡唑并[3,4-b]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基及咪唑并[1,5-a]吡啶基，其中R³之該嘧啶基、該氮雜環丁烷基甲基、該吡唑基、該吡啶基、該六氫吡啶基、該2H-吡唑并[3,4-b]吡啶基、該吡唑并[1,5-a]吡啶基、該吡唑并[1,5-a]嘧啶基及該咪唑并[1,5-a]吡啶基各自視情況經1或2個R^3A取代基取代。In some embodiments,^R is selected from pyrimidinyl, azacyclobutanylmethyl, pyrazolyl, pyridinyl, hexahydropyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, and imidazo[1,5-a]pyridinyl, wherein^each of the pyrimidinyl, azacyclobutanylmethyl, pyrazolyl, pyridinyl, hexahydropyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, and imidazo[1,5-a]pyridinyl groups of R is optionally substituted with 1 or 2^R substituents.

在一些實施例中，每一R^3A獨立地選自甲基、氟、氯、甲氧基、胺基、甲基胺基、二甲基胺基、羥基甲基、羥基乙基、氧雜環丁烷基、甲基羰基、異丙基羰基、羥基甲基羰基、環丙基羰基、甲基磺醯基、異丙基磺醯基及環丙基磺醯基。In some embodiments, each R^3A is independently selected from methyl, fluoro, chloro, methoxy, amino, methylamino, dimethylamino, hydroxymethyl, hydroxyethyl, oxacyclobutane, methylcarbonyl, isopropylcarbonyl, hydroxymethylcarbonyl, cyclopropylcarbonyl, methylsulfonyl, isopropylsulfonyl, and cyclopropylsulfonyl.

在一些實施例中，R³係選自(二氟氮雜環丁烷基)甲基、氧雜環丁烷基六氫吡啶基、(甲基羰基)六氫吡啶基、(異丙基羰基)六氫吡啶基、(羥基甲基羰基)六氫吡啶基、(環丙基羰基)六氫吡啶基、(甲基磺醯基)六氫吡啶基、(異丙基磺醯基)六氫吡啶基、(環丙基磺醯基)六氫吡啶基、吡唑基、甲基吡唑基、(羥基乙基)吡唑基、吡啶基、(羥基甲基)吡啶基、胺基吡啶基、(胺基)(氯)吡啶基、(甲基胺基)吡啶基、(二甲基胺基)吡啶基、胺基嘧啶基、(羥基甲基)嘧啶基、(胺基)(氟)嘧啶基、(胺基)(甲基)嘧啶基、(胺基)(甲氧基)嘧啶基、甲基-2H-吡唑并[3,4-b]吡啶、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,5-a]吡啶基、(胺基)(氟)吡啶基、甲基咪唑基、胺基噻唑基、(胺基)(甲基)噻唑基及6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪基。In some embodiments,^R is selected from (difluoroazolocyclobutane)methyl, oxadocyclobutane hexahydropyridinyl, (methylcarbonyl)hexahydropyridinyl, (isopropylcarbonyl)hexahydropyridinyl, (hydroxymethylcarbonyl)hexahydropyridinyl, (cyclopropylcarbonyl)hexahydropyridinyl, (methylsulfonyl)hexahydropyridinyl, (isopropylsulfonyl)hexahydropyridinyl, (cyclopropylsulfonyl)hexahydropyridinyl, pyrazolyl, methylpyrazolyl, (hydroxyethyl)pyrazolyl, pyridinyl, (hydroxymethyl)pyridinyl, aminopyridinyl, (amino)(chloro)pyridinyl, (methylamino)pyridinyl, (dichloropyridinyl) pyrimidinyl, (amino)(methyl)pyrimidinyl, (amino)(fluoro)pyrimidinyl, (amino)(methyl)pyrimidinyl, (amino)(methoxy)pyrimidinyl, methyl-2H-pyrazolo[3,4-b]pyridine, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,5-a]pyridinyl, (amino)(fluoro)pyridinyl, methylimidazolyl, aminothiazolyl, (amino)(methyl)thiazolyl, and 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl.

在一些實施例中，R³係選自(二氟氮雜環丁烷基)甲基、氧雜環丁烷基六氫吡啶基、(甲基羰基)六氫吡啶基、(異丙基羰基)六氫吡啶基、(羥基甲基羰基)六氫吡啶基、(環丙基羰基)六氫吡啶基、(甲基磺醯基)六氫吡啶基、(異丙基磺醯基)六氫吡啶基、(環丙基磺醯基)六氫吡啶基、吡唑基、甲基吡唑基、(羥基乙基)吡唑基、吡啶基、(羥基甲基)吡啶基、胺基吡啶基、(甲基胺基)吡啶基、(二甲基胺基)吡啶基、(胺基)(氯)吡啶基、胺基嘧啶基、(羥基甲基)嘧啶基、(胺基)(氟)嘧啶基、(胺基)(甲基)嘧啶基、(胺基)(甲氧基)嘧啶基、甲基-2H-吡唑并[3,4-b]吡啶、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基及咪唑并[1,5-a]吡啶基。In some embodiments,^R3 is selected from (difluoroazolocyclobutane)methyl, oxadocyclobutane hexahydropyridinyl, (methylcarbonyl)hexahydropyridinyl, (isopropylcarbonyl)hexahydropyridinyl, (hydroxymethylcarbonyl)hexahydropyridinyl, (cyclopropylcarbonyl)hexahydropyridinyl, (methylsulfonyl)hexahydropyridinyl, (isopropylsulfonyl)hexahydropyridinyl, (cyclopropylsulfonyl)hexahydropyridinyl, pyrazolyl, methylpyrazolyl, (hydroxyethyl)pyrazolyl, pyridinyl, (hydroxymethyl)pyrazolyl, pyridinyl, pyridinylamino ...

在一些實施例中，R³為C(O)NR^c3R^d3。In some embodiments, R³ is C(O)NR^c3 R^d3 .

在一些實施例中，R^c3及R^d3各自獨立地選自C_1-3烷基。In some embodiments, R^c3 and R^d3 are each independently selected from C_1-3 alkyl.

在一些實施例中，R^c3及R^d3各自獨立地選自甲基及三氘代甲基。In some embodiments, R^c3 and R^d3 are each independently selected from methyl and trideuterated methyl.

在一些實施例中，R^c3及R^d3各自為甲基。In some embodiments, R^c3 and R^d3 are each methyl.

在一些實施例中，R^c3及R^d3各自為三氘代甲基。In some embodiments, R^c3 and R^d3 are each trideuterated methyl.

在一些實施例中，環A係選自苯基及吡啶基。In some embodiments, Ring A is selected from phenyl and pyridyl.

在一些實施例中，環A為苯基。In some embodiments, Ring A is phenyl.

在一些實施例中，環A為吡啶基。In some embodiments, Ring A is pyridinyl.

在一些實施例中，n為1、2或3。In some embodiments, n is 1, 2, or 3.

在一些實施例中，n為1或2。In some embodiments, n is 1 or 2.

在一些實施例中，n為2。In some embodiments, n is 2.

在一些實施例中，每一R⁴獨立地選自H、鹵基、C_1-3烷基、C_1-3烷氧基、C(O)NR^c4R^d4及四唑基，其中R⁴之該四唑基視情況經一個R^4A取代基取代。In some embodiments, each R⁴ is independently selected from H, halogen, C_1-3 alkyl, C_1-3 alkoxy, C(O)NR^{c 4} R^{d 4} and tetrazolyl, wherein the tetrazolyl of R⁴ is optionally substituted with one R^4A substituent.

在一些實施例中，每一R^c4及R^d4獨立地選自H、C_1-3烷基及C_1-3鹵烷基。In some embodiments, each of R^c4 and R^d4 is independently selected from H, C_1-3 alkyl, and C_1-3 haloalkyl.

在一些實施例中，每一R^c4及R^d4為H。In some embodiments, each of R^c4 and R^d4 is H.

在一些實施例中，每一R⁴獨立地選自H、鹵基、C_1-3烷基、C_1-3烷氧基、C(O)NH₂及四唑基，其中R⁴之該四唑基視情況經一個R^4A取代基取代。In some embodiments, each R⁴ is independently selected from H, halogen, C_1-3 alkyl, C_1-3 alkoxy, C(O)NH₂ and tetrazolyl, wherein the tetrazolyl of R⁴ is optionally substituted with one R^4A substituent.

在一些實施例中，至少一個R⁴為C(O)NH₂。In some embodiments, at least one R⁴ is C(O)NH₂ .

在一些實施例中，至少一個R⁴為四唑基，其中R⁴之該四唑基視情況經一個R^4A取代基取代。In some embodiments, at least one R⁴ is tetrazolyl, wherein the tetrazolyl of R⁴ is optionally substituted with one R^4A substituent.

在一些實施例中，至少一個R⁴為C(O)NH₂；且每一額外R⁴獨立地選自H、鹵基、C_1-3烷基及C_1-3烷氧基。In some embodiments, at least one R⁴ is C(O)NH₂ ; and each additional R⁴ is independently selected from H, halogen, C_1-3 alkyl, and C_1-3 alkoxy.

在一些實施例中，至少一個R⁴為四唑基，其中R⁴之該四唑基視情況經一個R^4A取代基取代；且每一額外R⁴獨立地選自H、鹵基、C_1-3烷基及C_1-3烷氧基。In some embodiments, at least one R⁴ is tetrazolyl, wherein the tetrazolyl of R⁴ is optionally substituted with one R^4A substituent; and each additional R⁴ is independently selected from H, halo, C_1-3 alkyl, and C_1-3 alkoxy.

在一些實施例中，每一R⁴獨立地選自H、鹵基、C_1-3烷基及C_1-3烷氧基。In some embodiments, each R⁴ is independently selected from H, halogen, C_1-3 alkyl, and C_1-3 alkoxy.

在一些實施例中，每一R⁴獨立地選自H、氟、氯、甲基及甲氧基。In some embodiments, each R⁴ is independently selected from H, fluoro, chloro, methyl, and methoxy.

在一些實施例中，R⁴為鹵基。In some embodiments, R⁴ is halogen.

在一些實施例中，R⁴為氟或氯。In some embodiments, R⁴ is fluoro or chloro.

在一些實施例中，R⁴為氟。In some embodiments, R⁴ is fluoro.

在一些實施例中，R⁴為氯。In some embodiments, R⁴ is chloro.

在一些實施例中，R⁴為H。In some embodiments, R⁴ is H.

在一些實施例中，R⁴為甲基。In some embodiments, R⁴ is methyl.

在一些實施例中，R⁴為甲氧基。In some embodiments, R⁴ is methoxy.

在一些實施例中，每一R^4A獨立地選自C_1-3烷基、氮雜環丁烷基及六氫吡啶基，其中R⁴之該氮雜環丁烷基及該六氫吡啶基各自視情況經C_1-3烷基取代。In some embodiments, each R^4A is independently selected from C_1-3 alkyl, azacyclobutane and hexahydropyridinyl, wherein the azacyclobutane and hexahydropyridinyl of R⁴ are each optionally substituted with C_1-3 alkyl.

在一些實施例中，每一R^4A係選自C_1-3烷基、氮雜環丁烷基及六氫吡啶基，其中R⁴之該氮雜環丁烷基及該六氫吡啶基各自視情況經C_1-3烷基取代。In some embodiments, each R^4A is selected from C_1-3 alkyl, azacyclobutane and hexahydropyridinyl, wherein the azacyclobutane and hexahydropyridinyl of R⁴ are each optionally substituted with C_1-3 alkyl.

在一些實施例中，R^4A係選自甲基、三氘代甲基、乙基、氮雜環丁烷基及六氫吡啶基，其中R^4A之該氮雜環丁烷基及該六氫吡啶基各自視情況經甲基取代。In some embodiments, R^4A is selected from methyl, trideuterated methyl, ethyl, azacyclobutane and hexahydropyridinyl, wherein the azacyclobutane and hexahydropyridinyl of R^4A are each optionally substituted with methyl.

在一些實施例中，R^4A係選自甲基、三氘代甲基、乙基、甲基氮雜環丁烷基及甲基六氫吡啶基。In some embodiments, R^4A is selected from methyl, trideuterated methyl, ethyl, methylazacyclobutane, and methylhexahydropyridinyl.

在一些實施例中，R^4A為甲基。In some embodiments, R^4A is methyl.

在一些實施例中，R^4A為乙基。In some embodiments, R^4A is ethyl.

在一些實施例中，R^4A為三氘代甲基。In some embodiments, R^4A is trideuterated methyl.

在一些實施例中，R^4A為經選擇之甲基氮雜環丁烷基。In some embodiments, R^4A is selected methylazacyclobutane.

在一些實施例中，R^4A為甲基六氫吡啶基。In some embodiments, R^4A is methylhexahydropyridinyl.

在一些實施例中，R^G為H或D。In some embodiments,^RG is H or D.

在一些實施例中，R^G為H。In some embodiments,^RG is H.

在一些實施例中，R^G為D。In some embodiments,^RG is D.

在一些實施例中： R¹係選自氯、甲基及三氟甲基； R²係選自甲基及三氘代甲基； R³係選自吡唑基、吡啶基、嘧啶基、六氫吡啶基及C(O)NR^c3R^d3，其中R³之該吡唑基、該嘧啶基及該六氫吡啶基各自視情況經一個選自甲基、胺基及甲基羰基之R^3A取代基取代； R^c3及R^d3各自獨立地選自甲基及三氘代甲基； R⁴為氟或氯；且 R^G為H或D。In some embodiments: R¹ is selected from chloro, methyl and trifluoromethyl; R² is selected from methyl and trideuterated methyl; R³ is selected from pyrazolyl, pyridyl, pyrimidinyl, hexahydropyridinyl and C(O)NR^c3 R^d3 , wherein the pyrazolyl, the pyrimidinyl and the hexahydropyridinyl of R³ are each optionally substituted with an R^3A substituent selected from methyl, amino and methylcarbonyl; R^c3 and R^d3 are each independently selected from methyl and trideuterated methyl; R⁴ is fluoro or chloro; and^RG is H or D.

在一些實施例中： R¹為氯或甲基； R²為甲基或三氘代甲基； R³係選自嘧啶基、氮雜環丁烷基甲基、吡唑基、吡啶基、六氫吡啶基、2H-吡唑并[3,4-b]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,5-a]吡啶基、咪唑基、噻唑基、6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪基及C(O)NR^c3R^d3，其中R³之該嘧啶基、該氮雜環丁烷基甲基、該吡唑基、該吡啶基、該六氫吡啶基、該2H-吡唑并[3,4-b]吡啶基、該吡唑并[1,5-a]吡啶基、該吡唑并[1,5-a]嘧啶基、該咪唑并[1,5-a]吡啶基、該咪唑基、該噻唑基、該6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪基各自視情況經1或2個獨立選擇之R^3A取代基取代； 每一R^3A獨立地選自甲基、氟、氯、甲氧基、胺基、甲基胺基、二甲基胺基、羥基甲基、羥基乙基、氧雜環丁烷基、甲基羰基、異丙基羰基、羥基甲基羰基、環丙基羰基、甲基磺醯基、異丙基磺醯基及環丙基磺醯基； R^c3及R^d3各自獨立地選自甲基及三氘代甲基； R⁴係選自H、氟、氯、甲基及甲氧基； R^4A係選自甲基、三氘代甲基、乙基、氮雜環丁烷基及六氫吡啶基，其中R^4A之該氮雜環丁烷基及該六氫吡啶基各自視情況經甲基取代；且 R^G為H或D。In some embodiments: R¹ is chloro or methyl; R² is methyl or trideuterated methyl; R³ is selected from pyrimidinyl, azacyclobutanylmethyl, pyrazolyl, pyridinyl, hexahydropyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,5-a]pyridinyl, imidazolyl, thiazolyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl and C(O)NR^c3 R^d3 , wherein R³ , the pyrimidinyl, the azacyclobutanylmethyl, the pyrazolyl, the pyridinyl, the hexahydropyridinyl, the 2H-pyrazolo[3,4-b]pyridinyl, the pyrazolo[1,5-a]pyridinyl, the pyrazolo[1,5-a]pyrimidinyl, the imidazo[1,5-a]pyridinyl, the imidazolyl, the thiazolyl, the 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, each optionally substituted with 1 or 2 independently selected R^3A substituents; each R^{R 3A} is independently selected from methyl, fluoro, chloro, methoxy, amino, methylamino, dimethylamino, hydroxymethyl, hydroxyethyl, oxacyclobutane, methylcarbonyl, isopropylcarbonyl, hydroxymethylcarbonyl, cyclopropylcarbonyl, methylsulfonyl, isopropylsulfonyl, and cyclopropylsulfonyl; R^c3 and R^d3 are each independently selected from methyl and trideuteromethyl; R⁴ is selected from H, fluoro, chloro, methyl, and methoxy; R^4A is selected from methyl, trideuteromethyl, ethyl, azacyclobutane, and hexahydropyridinyl, wherein the azacyclobutane and the hexahydropyridinyl of R^4A are each optionally substituted with methyl; and^RG is H or D.

在一些實施例中： R¹為氯或甲基； R²為甲基或三氘代甲基； R³係選自嘧啶基、氮雜環丁烷基甲基、吡唑基、吡啶基、六氫吡啶基、2H-吡唑并[3,4-b]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,5-a]吡啶基及C(O)NR^c3R^d3，其中R³之該嘧啶基、該氮雜環丁烷基甲基、該吡唑基、該吡啶基、該六氫吡啶基、該2H-吡唑并[3,4-b]吡啶基、該吡唑并[1,5-a]吡啶基、該吡唑并[1,5-a]嘧啶基及該咪唑并[1,5-a]吡啶基各自視情況經1或2個R^3A取代基取代； 每一R^3A獨立地選自甲基、氟、氯、甲氧基、胺基、甲基胺基、二甲基胺基、羥基甲基、羥基乙基、氧雜環丁烷基、甲基羰基、異丙基羰基、羥基甲基羰基、環丙基羰基、甲基磺醯基、異丙基磺醯基及環丙基磺醯基； R^c3及R^d3各自獨立地選自甲基及三氘代甲基； R⁴係選自H、氟、氯、甲基及甲氧基； R^4A係選自甲基、三氘代甲基、乙基、氮雜環丁烷基及六氫吡啶基，其中R^4A之該氮雜環丁烷基及該六氫吡啶基各自視情況經甲基取代；且 R^G為H或D。In some embodiments: R¹ is chloro or methyl; R² is methyl or trideuterated methyl; R³ is selected from pyrimidinyl, azacyclobutanylmethyl, pyrazolyl, pyridinyl, hexahydropyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,5-a]pyridinyl and C(O)NR^c3 R^d3 , wherein R³ , the pyrimidinyl, the azacyclobutanylmethyl, the pyrazolyl, the pyridinyl, the hexahydropyridinyl, the 2H-pyrazolo[3,4-b]pyridinyl, the pyrazolo[1,5-a]pyridinyl, the pyrazolo[1,5-a]pyrimidinyl, and the imidazo[1,5-a]pyridinyl are each optionally substituted with 1 or 2 R^3A substituents; each R^3A is independently selected from methyl, fluoro, chloro, methoxy, amino, methylamino, dimethylamino, hydroxymethyl, hydroxyethyl, oxacyclobutanyl, methylcarbonyl, isopropylcarbonyl, hydroxymethylcarbonyl, cyclopropylcarbonyl, methylsulfonyl, isopropylsulfonyl, and cyclopropylsulfonyl; R^c3 and R^d3 is each independently selected from methyl and trideuterated methyl;^R4 is selected from H, fluorine, chlorine, methyl and methoxy;^R4A is selected from methyl, trideuterated methyl, ethyl, azacyclobutane and hexahydropyridinyl, wherein the azacyclobutane and hexahydropyridinyl of^R4A are each optionally substituted with methyl; and^RG is H or D.

在一些實施例中，式I化合物為式II化合物：II或其醫藥學上可接受之鹽。In some embodiments, the compound of formula I is a compound of formula II:II or its pharmaceutically acceptable salt.

在一些實施例中，式I化合物為式II化合物：II或其醫藥學上可接受之鹽，其中： R¹係選自鹵基、C_1-3烷基及C_1-3鹵烷基； R²為C_1-3烷基； R³係選自吡唑基、嘧啶基、六氫吡啶基及C(O)NR^c3R^d3，其中R³之該吡唑基、該吡啶基、該嘧啶基及該六氫吡啶基各自視情況經一個選自C_1-3烷基、胺基及-C(O)C_1-3烷基之R^3A取代基取代； 每一R^c3及R^d3獨立地選自C_1-3烷基及C_1-3鹵烷基； R⁴為鹵基；且 R^G為H或D。In some embodiments, the compound of formula I is a compound of formula II:II or a pharmaceutically acceptable salt thereof, wherein: R¹ is selected from halogen, C_1-3 alkyl and C_1-3 haloalkyl; R² is C_1-3 alkyl; R³ is selected from pyrazolyl, pyrimidinyl, hexahydropyridinyl and C(O)NR^c3 R^d3 , wherein the pyrazolyl, pyridinyl, pyrimidinyl and hexahydropyridinyl of R³ are each optionally substituted with an R^3A substituent selected from C_1-3 alkyl, amino and -C(O)C_1-3 alkyl; each R^c3 and R^d3 are independently selected from C_1-3 alkyl and C_1-3 haloalkyl; R⁴ is halo; and^RG is H or D.

在式II之一些實施例中，R¹係選自氯、甲基及三氟甲基。In some embodiments of Formula II, R¹ is selected from chloro, methyl, and trifluoromethyl.

在式II之一些實施例中，R¹為氯。In some embodiments of Formula II, R¹ is chloro.

在式II之一些實施例中，R¹為甲基。In some embodiments of Formula II, R¹ is methyl.

在式II之一些實施例中，R¹為三氟甲基。In some embodiments of Formula II, R¹ is trifluoromethyl.

在式II之一些實施例中，R²係選自甲基及三氘代甲基。In some embodiments of Formula II, R² is selected from methyl and trideuterated methyl.

在式II之一些實施例中，R²為甲基。In some embodiments of Formula II, R² is methyl.

在式II之一些實施例中，R²為三氘代甲基。In some embodiments of Formula II, R² is trideuterated methyl.

在式II之一些實施例中，R³為C(O)NR^c3R^d3。In some embodiments of Formula II, R³ is C(O)NR^{c 3} R^{d 3} .

在式II之一些實施例中，R^c3及R^d3各自獨立地選自甲基及三氘代甲基。In some embodiments of Formula II, R^c3 and R^d3 are each independently selected from methyl and trideuterated methyl.

在式II之一些實施例中，R^c3及R^d3各自為甲基。In some embodiments of Formula II, R^c3 and R^d3 are each methyl.

在式II之一些實施例中，R^c3及R^d3各自為三氘代甲基。In some embodiments of Formula II, R^c3 and R^d3 are each trideuterated methyl.

在式II之一些實施例中，R³係選自吡唑基、嘧啶基及六氫吡啶基，其中R³之該吡唑基、該嘧啶基及該六氫吡啶基各自視情況經一個選自C_1-3烷基、胺基及-C(O)C_1-3烷基之R^3A取代基取代。In some embodiments of Formula II, R³ is selected from pyrazolyl, pyrimidinyl, and hexahydropyridinyl, wherein the pyrazolyl, the pyrimidinyl, and the hexahydropyridinyl of R³ are each optionally substituted with an R^3A substituent selected from C_1-3 alkyl, amino, and -C(O)C_1-3 alkyl.

在式II之一些實施例中，R³係選自吡唑基、吡啶基、嘧啶基及六氫吡啶基，其中R³之該吡唑基、該嘧啶基及該六氫吡啶基各自視情況經一個選自甲基、胺基及甲基羰基之R^3A取代基取代。In some embodiments of Formula II, R³ is selected from pyrazolyl, pyridinyl, pyrimidinyl, and hexahydropyridinyl, wherein the pyrazolyl, pyrimidinyl, and hexahydropyridinyl of R³ are each optionally substituted with an R^3A substituent selected from methyl, amino, and methylcarbonyl.

在式II之一些實施例中，R³係選自甲基吡唑基、胺基嘧啶基及(甲基羰基)六氫吡啶基。In some embodiments of Formula II, R³ is selected from methylpyrazolyl, aminopyrimidinyl, and (methylcarbonyl)hexahydropyridinyl.

在式II之一些實施例中，R³為甲基吡唑基。In some embodiments of Formula II, R³ is methylpyrazolyl.

在式II之一些實施例中，R³為胺基嘧啶基。In some embodiments of Formula II, R³ is aminopyrimidinyl.

在式II之一些實施例中，R³為(甲基羰基)六氫吡啶基。In some embodiments of Formula II, R³ is (methylcarbonyl)hexahydropyridinyl.

在式II之一些實施例中，R⁴為氟或氯。In some embodiments of Formula II, R⁴ is fluoro or chloro.

在式II之一些實施例中，R⁴為氟。In some embodiments of Formula II, R⁴ is fluoro.

在式II之一些實施例中，R⁴為氯。In some embodiments of Formula II, R⁴ is chloro.

在式II之一些實施例中，R^G為H。In some embodiments of Formula II,^RG is H.

在式II之一些實施例中，R^G為D。In some embodiments of Formula II,^RG is D.

在式II之一些實施例中： R¹係選自氯、甲基及三氟甲基； R²係選自甲基及三氘代甲基； R³係選自吡唑基、吡啶基、嘧啶基、六氫吡啶基及C(O)NR^c3R^d3，其中R³之該吡唑基、該嘧啶基及該六氫吡啶基各自視情況經一個選自甲基、胺基及甲基羰基之R^3A取代基取代； R^c3及R^d3各自獨立地選自甲基及三氘代甲基； R⁴為氟或氯；且 R^G為H或D。In some embodiments of Formula II: R¹ is selected from chloro, methyl, and trifluoromethyl; R² is selected from methyl and trideuterated methyl; R³ is selected from pyrazolyl, pyridyl, pyrimidinyl, hexahydropyridinyl, and C(O)NR^c3 R^d3 , wherein the pyrazolyl, the pyrimidinyl, and the hexahydropyridinyl of R³ are each optionally substituted with an R^3A substituent selected from methyl, amino, and methylcarbonyl; R^c3 and R^d3 are each independently selected from methyl and trideuterated methyl; R⁴ is fluoro or chloro; and^RG is H or D.

在一些實施例中，式I或式II化合物為式IIa化合物：IIa或其醫藥學上可接受之鹽。In some embodiments, the compound of Formula I or Formula II is a compound of Formula IIa:IIa or its pharmaceutically acceptable salt.

在一些實施例中，式I或式II化合物為式IIb化合物：IIb或其醫藥學上可接受之鹽。In some embodiments, the compound of Formula I or Formula II is a compound of Formula IIb:IIb or its pharmaceutically acceptable salt.

在一些實施例中，式I化合物為式III化合物：III或其醫藥學上可接受之鹽。In some embodiments, the compound of formula I is a compound of formula III:III or its pharmaceutically acceptable salt.

在一些實施例中，式I化合物為式III化合物：III或其醫藥學上可接受之鹽，其中： R¹為鹵基或C_1-3烷基； R²為C_1-3烷基； R³係選自嘧啶基、氮雜環丁烷基甲基、吡唑基、吡啶基、六氫吡啶基、2H-吡唑并[3,4-b]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,5-a]吡啶基、咪唑基、噻唑基、6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪基及C(O)NR^c3R^d3，其中R³之該嘧啶基、該氮雜環丁烷基甲基、該吡唑基、該吡啶基、該六氫吡啶基、該2H-吡唑并[3,4-b]吡啶基、該吡唑并[1,5-a]吡啶基、該吡唑并[1,5-a]嘧啶基、該咪唑并[1,5-a]吡啶基、該咪唑基、該噻唑基及該6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪基各自視情況經1或2個R^3A取代基取代； 每一R^3A獨立地選自鹵基、C_1-3烷基、C_1-3羥基烷基、C_1-3烷氧基、氧雜環丁烷基、胺基、C_1-3烷基胺基、二(C_1-3烷基)胺基、-C(O)C_1-3烷基、-C(O)C_1-3羥基烷基、-C(O)C_3-6環烷基及-S(O)₂C_1-3烷基； R⁴係選自H、鹵基、C_1-3烷基及C_1-3烷氧基； R^4A係選自C_1-3烷基、氮雜環丁烷基及六氫吡啶基，其中R⁴之該氮雜環丁烷基及該六氫吡啶基各自視情況經C_1-3烷基取代；且 R^G為H或D。In some embodiments, the compound of formula I is a compound of formula III:III or a pharmaceutically acceptable salt thereof, wherein: R¹ is a halogen group or a C_1-3 alkyl group; R² is a C_1-3 alkyl group; R³ is selected from pyrimidinyl, azacyclobutanylmethyl, pyrazolyl, pyridinyl, hexahydropyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,5-a]pyridinyl, imidazolyl, thiazolyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl and C(O)NR^c3 R^d3 , wherein R³ , the pyrimidinyl, the azacyclobutanylmethyl, the pyrazolyl, the pyridinyl, the hexahydropyridinyl, the 2H-pyrazolo[3,4-b]pyridinyl, the pyrazolo[1,5-a]pyridinyl, the pyrazolo[1,5-a]pyrimidinyl, the imidazo[1,5-a]pyridinyl, the imidazolyl, the thiazolyl and the 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl are each optionally substituted with 1 or 2 R^3A substituents; each R^3A is independently selected from halogen, C_1-3 alkyl, C_1-3 hydroxyalkyl, C_1-3 alkoxy, oxacyclobutanyl, amino, C_1-3 alkylamino, di(C_1-3 alkyl)amino, -C(O)C_wherein the_{azacyclobutane} group and the_{hexahydropyridinyl} group of^{R4 are each}_optionally substituted^with a_{C1-3alkylgroup} ; and^RG is_H^or_D.

在一些實施例中，式I化合物為式III化合物：III或其醫藥學上可接受之鹽，其中： R¹為鹵基或C_1-3烷基； R²為C_1-3烷基； R³係選自嘧啶基、氮雜環丁烷基甲基、吡唑基、吡啶基、六氫吡啶基、2H-吡唑并[3,4-b]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,5-a]吡啶基及C(O)NR^c3R^d3，其中R³之該嘧啶基、該氮雜環丁烷基甲基、該吡唑基、該吡啶基、該六氫吡啶基、該2H-吡唑并[3,4-b]吡啶基、該吡唑并[1,5-a]吡啶基、該吡唑并[1,5-a]嘧啶基及該咪唑并[1,5-a]吡啶基各自視情況經1或2個R^3A取代基取代； 每一R^3A獨立地選自鹵基、C_1-3烷基、C_1-3羥基烷基、C_1-3烷氧基、氧雜環丁烷基、胺基、C_1-3烷基胺基、二(C_1-3烷基)胺基、-C(O)C_1-3烷基、-C(O)C_1-3羥基烷基、-C(O)C_3-6環烷基及-S(O)₂C_1-3烷基； R⁴係選自H、鹵基、C_1-3烷基及C_1-3烷氧基； R^4A係選自C_1-3烷基、氮雜環丁烷基及六氫吡啶基，其中R⁴之該氮雜環丁烷基及該六氫吡啶基各自視情況經C_1-3烷基取代；且 R^G為H或D。In some embodiments, the compound of formula I is a compound of formula III:III or a pharmaceutically acceptable salt thereof, wherein: R¹ is a halogen group or a C_1-3 alkyl group; R² is a C_1-3 alkyl group; R³ is selected from pyrimidinyl, azacyclobutanylmethyl, pyrazolyl, pyridinyl, hexahydropyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,5-a]pyridinyl and C(O)NR^c3 R^d3 , wherein R³ , the pyrimidinyl, the azacyclobutanylmethyl, the pyrazolyl, the pyridinyl, the hexahydropyridinyl, the 2H-pyrazolo[3,4-b]pyridinyl, the pyrazolo[1,5-a]pyridinyl, the pyrazolo[1,5-a]pyrimidinyl and the imidazo[1,5-a]pyridinyl are each optionally substituted with 1 or 2 R^3A substituents; each R^3A is independently selected from halogen, C_1-3 alkyl, C 1-3 hydroxyalkyl, C_1-3 alkoxy, oxacyclobutanyl, amino, C_1-3 alkylamino, di(C_1-3 alkyl)amino, -C(O)C_1-3 alkyl, -C(O)C_1-3 hydroxyalkyl, -C(O)_{C 3-6cycloalkyl} and -S(O)₂ C_1-3 alkyl; R⁴ is selected from H, halogen, C_1-3 alkyl and C_1-3 alkoxy; R^4A is selected from C_1-3 alkyl, azacyclobutane and hexahydropyridinyl, wherein the azacyclobutane and hexahydropyridinyl of R⁴ are each optionally substituted with C_1-3 alkyl; and^RG is H or D.

在式III之一些實施例中，R¹為氯或甲基。In some embodiments of Formula III, R¹ is chloro or methyl.

在式III之一些實施例中，R¹為氯。In some embodiments of Formula III, R¹ is chloro.

在式III之一些實施例中，R¹為甲基。In some embodiments of Formula III, R¹ is methyl.

在式III之一些實施例中，R²為甲基或三氘代甲基。In some embodiments of Formula III, R² is methyl or trideuterated methyl.

在式III之一些實施例中，R²為甲基。In some embodiments of Formula III, R² is methyl.

在式III之一些實施例中，R²為三氘代甲基。In some embodiments of Formula III, R² is trideuterated methyl.

在式III之一些實施例中，R³係選自嘧啶基、氮雜環丁烷基甲基、吡唑基、吡啶基、六氫吡啶基、2H-吡唑并[3,4-b]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,5-a]吡啶基及C(O)NR^c3R^d3，其中R³之該嘧啶基、該氮雜環丁烷基甲基、該吡唑基、該吡啶基、該六氫吡啶基、該2H-吡唑并[3,4-b]吡啶基、該吡唑并[1,5-a]吡啶基、該吡唑并[1,5-a]嘧啶基及該咪唑并[1,5-a]吡啶基各自視情況經1或2個R^3A取代基取代。In some embodiments of Formula III, R³ is selected from pyrimidinyl, azacyclobutanylmethyl, pyrazolyl, pyridinyl, hexahydropyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,5-a]pyridinyl, and C(O)NR^c3 R^d3 , wherein^each of the pyrimidinyl, the azacyclobutanylmethyl, the pyrazolyl, the pyridinyl, the hexahydropyridinyl, the 2H-pyrazolo[3,4-b]pyridinyl, the pyrazolo[1,5-a]pyridinyl, the pyrazolo[1,5-a]pyrimidinyl, and the imidazo[1,5-a]pyridinyl of R 3 is optionally substituted with 1 or 2 R^3A substituents.

在式III之一些實施例中，R³係選自嘧啶基、氮雜環丁烷基甲基、吡唑基、吡啶基、六氫吡啶基、2H-吡唑并[3,4-b]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基及咪唑并[1,5-a]吡啶基，其中R³之該嘧啶基、該氮雜環丁烷基甲基、該吡唑基、該吡啶基、該六氫吡啶基、該2H-吡唑并[3,4-b]吡啶基、該吡唑并[1,5-a]吡啶基、該吡唑并[1,5-a]嘧啶基及該咪唑并[1,5-a]吡啶基各自視情況經1或2個R^3A取代基取代。In some embodiments of Formula III,^R is selected from pyrimidinyl, azacyclobutanylmethyl, pyrazolyl, pyridinyl, hexahydropyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, and imidazo[1,5-a]pyridinyl, wherein^each of the pyrimidinyl, azacyclobutanylmethyl, pyrazolyl, pyridinyl, hexahydropyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, and imidazo[1,5-a]pyridinyl groups of R is optionally substituted with 1 or 2^R substituents.

在式III之一些實施例中，每一R^3A獨立地選自甲基、氟、氯、甲氧基、胺基、甲基胺基、二甲基胺基、羥基甲基、羥基乙基、氧雜環丁烷基、甲基羰基、異丙基羰基、羥基甲基羰基、環丙基羰基、甲基磺醯基、異丙基磺醯基及環丙基磺醯基。In some embodiments of Formula III, each R^3A is independently selected from methyl, fluoro, chloro, methoxy, amino, methylamino, dimethylamino, hydroxymethyl, hydroxyethyl, oxacyclobutane, methylcarbonyl, isopropylcarbonyl, hydroxymethylcarbonyl, cyclopropylcarbonyl, methylsulfonyl, isopropylsulfonyl, and cyclopropylsulfonyl.

在式III之一些實施例中，R³係選自(二氟氮雜環丁烷基)甲基、氧雜環丁烷基六氫吡啶基、(甲基羰基)六氫吡啶基、(異丙基羰基)六氫吡啶基、(羥基甲基羰基)六氫吡啶基、(環丙基羰基)六氫吡啶基、(甲基磺醯基)六氫吡啶基、(異丙基磺醯基)六氫吡啶基、(環丙基磺醯基)六氫吡啶基、吡唑基、甲基吡唑基、(羥基乙基)吡唑基、吡啶基、(羥基甲基)吡啶基、胺基吡啶基、(胺基)(氯)吡啶基、(甲基胺基)吡啶基、(二甲基胺基)吡啶基、胺基嘧啶基、(羥基甲基)嘧啶基、(胺基)(氟)嘧啶基、(胺基)(甲基)嘧啶基、(胺基)(甲氧基)嘧啶基、甲基-2H-吡唑并[3,4-b]吡啶、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,5-a]吡啶基、(胺基)(氟)吡啶基、甲基咪唑基、胺基噻唑基、(胺基)(甲基)噻唑基及6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪基。In some embodiments of Formula III,^R is selected from (difluoroazidocyclobutanyl)methyl, oxacyclobutanylhexahydropyridinyl, (methylcarbonyl)hexahydropyridinyl, (isopropylcarbonyl)hexahydropyridinyl, (hydroxymethylcarbonyl)hexahydropyridinyl, (cyclopropylcarbonyl)hexahydropyridinyl, (methylsulfonyl)hexahydropyridinyl, (isopropylsulfonyl)hexahydropyridinyl, (cyclopropylsulfonyl)hexahydropyridinyl, pyrazolyl, methylpyrazolyl, (hydroxyethyl)pyrazolyl, pyridinyl, (hydroxymethyl)pyridinyl, aminopyridinyl, (amino)(chloro)pyridinyl, (methylamino)pyridinyl, (difluoroazido)pyridinyl, pyrimidinyl, (amino)(methyl)pyrimidinyl, (amino)(fluoro)pyrimidinyl, (amino)(methyl)pyrimidinyl, (amino)(methoxy)pyrimidinyl, methyl-2H-pyrazolo[3,4-b]pyridine, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,5-a]pyridinyl, (amino)(fluoro)pyridinyl, methylimidazolyl, aminothiazolyl, (amino)(methyl)thiazolyl, and 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl.

在式III之一些實施例中，R³係選自(二氟氮雜環丁烷基)甲基、氧雜環丁烷基六氫吡啶基、(甲基羰基)六氫吡啶基、(異丙基羰基)六氫吡啶基、(羥基甲基羰基)六氫吡啶基、(環丙基羰基)六氫吡啶基、(甲基磺醯基)六氫吡啶基、(異丙基磺醯基)六氫吡啶基、(環丙基磺醯基)六氫吡啶基、吡唑基、甲基吡唑基、(羥基乙基)吡唑基、吡啶基、(羥基甲基)吡啶基、胺基吡啶基、(胺基)(氯)吡啶基、(甲基胺基)吡啶基、(二甲基胺基)吡啶基、胺基嘧啶基、(羥基甲基)嘧啶基、(胺基)(氟)嘧啶基、(胺基)(甲基)嘧啶基、(胺基)(甲氧基)嘧啶基、甲基-2H-吡唑并[3,4-b]吡啶、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基及咪唑并[1,5-a]吡啶基。In some embodiments of Formula III,^R is selected from (difluoroazacyclobutanyl)methyl, oxacyclobutanylhexahydropyridinyl, (methylcarbonyl)hexahydropyridinyl, (isopropylcarbonyl)hexahydropyridinyl, (hydroxymethylcarbonyl)hexahydropyridinyl, (cyclopropylcarbonyl)hexahydropyridinyl, (methylsulfonyl)hexahydropyridinyl, (isopropylsulfonyl)hexahydropyridinyl, (cyclopropylsulfonyl)hexahydropyridinyl, pyrazolyl, methylpyrazolyl, (hydroxyethyl)pyrazolyl, pyridinyl, (hydroxymethyl)pyrazolyl, pyridinyl, pyridinyl, aminopyridinyl, (amino)(chloro)pyridinyl, (methylamino)pyridinyl, (dimethylamino)pyridinyl, aminopyrimidinyl, (hydroxymethyl)pyrimidinyl, (amino)(fluoro)pyrimidinyl, (amino)(methyl)pyrimidinyl, (amino)(methoxy)pyrimidinyl, methyl-2H-pyrazolo[3,4-b]pyridine, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, and imidazo[1,5-a]pyridinyl.

在式III之一些實施例中，R³為(二氟氮雜環丁烷基)甲基。In some embodiments of Formula III, R³ is (difluoroazacyclobutane)methyl.

在式III之一些實施例中，R³係選自氧雜環丁烷基六氫吡啶基。In some embodiments of Formula III, R³ is selected from oxacyclobutane hexahydropyridinyl.

在式III之一些實施例中，R³為(甲基羰基)六氫吡啶基。In some embodiments of Formula III, R³ is (methylcarbonyl)hexahydropyridinyl.

在式III之一些實施例中，R³為(異丙基羰基)六氫吡啶基。In some embodiments of Formula III, R³ is (isopropylcarbonyl)hexahydropyridinyl.

在式III之一些實施例中，R³為(羥基甲基羰基)六氫吡啶基。In some embodiments of Formula III, R³ is (hydroxymethylcarbonyl)hexahydropyridinyl.

在式III之一些實施例中，R³為(環丙基羰基)六氫吡啶基。In some embodiments of Formula III, R³ is (cyclopropylcarbonyl)hexahydropyridinyl.

在式III之一些實施例中，R³為(甲基磺醯基)六氫吡啶基。In some embodiments of Formula III, R³ is (methylsulfonyl)hexahydropyridinyl.

在式III之一些實施例中，R³為(異丙基磺醯基)六氫吡啶基。In some embodiments of Formula III, R³ is (isopropylsulfonyl)hexahydropyridinyl.

在式III之一些實施例中，R³為(環丙基磺醯基)六氫吡啶基。In some embodiments of Formula III, R³ is (cyclopropylsulfonyl)hexahydropyridinyl.

在式III之一些實施例中，R³為吡唑基。In some embodiments of Formula III, R³ is pyrazolyl.

在式III之一些實施例中，R³為甲基吡唑基。In some embodiments of Formula III, R³ is methylpyrazolyl.

在式III之一些實施例中，R³為(羥基乙基)吡唑基。In some embodiments of Formula III, R³ is (hydroxyethyl)pyrazolyl.

在式III之一些實施例中，R³為吡啶基。In some embodiments of Formula III, R³ is pyridinyl.

在式III之一些實施例中，R³為(羥基甲基)吡啶基。In some embodiments of Formula III, R³ is (hydroxymethyl)pyridinyl.

在式III之一些實施例中，R³為胺基吡啶基。In some embodiments of Formula III, R³ is aminopyridinyl.

在式III之一些實施例中，R³為(胺基)(氯)吡啶基。In some embodiments of Formula III, R³ is (amino)(chloro)pyridinyl.

在式III之一些實施例中，R³為(甲基胺基)吡啶基。In some embodiments of Formula III, R³ is (methylamino)pyridinyl.

在式III之一些實施例中，R³為(二甲基胺基)吡啶基。In some embodiments of Formula III, R³ is (dimethylamino)pyridinyl.

在式III之一些實施例中，R³為胺基嘧啶基。In some embodiments of Formula III, R³ is aminopyrimidinyl.

在式III之一些實施例中，R³為(羥基甲基)嘧啶基。In some embodiments of Formula III, R³ is (hydroxymethyl)pyrimidinyl.

在式III之一些實施例中，R³為(胺基)(氟)嘧啶基。In some embodiments of Formula III, R³ is (amino)(fluoro)pyrimidinyl.

在式III之一些實施例中，R³為(胺基)(甲基)嘧啶基。In some embodiments of Formula III, R³ is (amino)(methyl)pyrimidinyl.

在式III之一些實施例中，R³為(胺基)(甲氧基)嘧啶基。In some embodiments of Formula III, R³ is (amino)(methoxy)pyrimidinyl.

在式III之一些實施例中，R³為甲基-2H-吡唑并[3,4-b]吡啶。In some embodiments of Formula III, R³ is methyl-2H-pyrazolo[3,4-b]pyridine.

在式III之一些實施例中，R³為吡唑并[1,5-a]吡啶基。In some embodiments of Formula III, R³ is pyrazolo[1,5-a]pyridinyl.

在式III之一些實施例中，R³為吡唑并[1,5-a]嘧啶基。In some embodiments of Formula III, R³ is pyrazolo[1,5-a]pyrimidinyl.

在式III之一些實施例中，R³為咪唑并[1,5-a]吡啶基。In some embodiments of Formula III, R³ is imidazo[1,5-a]pyridinyl.

在式III之一些實施例中，R³為(胺基)(氟)吡啶基。In some embodiments of Formula III, R³ is (amino)(fluoro)pyridinyl.

在式III之一些實施例中，R³為甲基咪唑基。In some embodiments of Formula III, R³ is methylimidazolyl.

在式III之一些實施例中，R³為胺基噻唑基。In some embodiments of Formula III, R³ is aminothiazolyl.

在式III之一些實施例中，R³為(胺基)(甲基)噻唑基。In some embodiments of Formula III, R³ is (amino)(methyl)thiazolyl.

在式III之一些實施例中，R³為6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪基。In some embodiments of Formula III, R³ is 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl.

在式III之一些實施例中，R³為C(O)NR^c3R^d3。In some embodiments of Formula III, R³ is C(O)NR^{c 3} R^{d 3} .

在式III之一些實施例中，R^c3及R^d3各自獨立地選自甲基及三氘代甲基。In some embodiments of Formula III, R^c3 and R^d3 are each independently selected from methyl and trideuterated methyl.

在式III之一些實施例中，R^c3及R^d3各自為甲基。In some embodiments of Formula III, R^c3 and R^d3 are each methyl.

在式III之一些實施例中，R^c3及R^d3各自為三氘代甲基。In some embodiments of Formula III, R^c3 and R^d3 are each trideuterated methyl.

在式III之一些實施例中，R⁴係選自H、氟、氯、甲基及甲氧基。In some embodiments of Formula III, R⁴ is selected from H, fluoro, chloro, methyl, and methoxy.

在式III之一些實施例中，R⁴為H。In some embodiments of Formula III, R⁴ is H.

在式III之一些實施例中，R⁴為氟。In some embodiments of Formula III, R⁴ is fluoro.

在式III之一些實施例中，R⁴為氯。In some embodiments of Formula III, R⁴ is chloro.

在式III之一些實施例中，R⁴為甲基。In some embodiments of Formula III, R⁴ is methyl.

在式III之一些實施例中，R⁴為甲氧基。In some embodiments of Formula III, R⁴ is methoxy.

在式III之一些實施例中，R^4A係選自甲基、三氘代甲基、乙基、氮雜環丁烷基及六氫吡啶基，其中R^4A之該氮雜環丁烷基及該六氫吡啶基各自視情況經甲基取代。In some embodiments of Formula III, R^4A is selected from methyl, trideuterated methyl, ethyl, azacyclobutanyl, and hexahydropyridinyl, wherein the azacyclobutanyl and the hexahydropyridinyl of R^4A are each optionally substituted with methyl.

在式III之一些實施例中，R^4A係選自甲基、三氘代甲基、乙基、甲基氮雜環丁烷基及甲基六氫吡啶基。In some embodiments of Formula III, R^4A is selected from methyl, trideuterated methyl, ethyl, methylazacyclobutane, and methylhexahydropyridinyl.

在式III之一些實施例中，R^4A為甲基。In some embodiments of Formula III, R^4A is methyl.

在式III之一些實施例中，R^4A為三氘代甲基。In some embodiments of Formula III, R^4A is trideuterated methyl.

在式III之一些實施例中，R^4A為乙基。In some embodiments of Formula III, R^4A is ethyl.

在式III之一些實施例中，R^4A為甲基氮雜環丁烷基。In some embodiments of Formula III, R^4A is methylazetidine.

在式III之一些實施例中，R^4A為甲基六氫吡啶基。In some embodiments of Formula III, R^4A is methylhexahydropyridinyl.

在式III之一些實施例中，R^G為H。In some embodiments of Formula III,^RG is H.

在式III之一些實施例中，R^G為D。In some embodiments of Formula III,^RG is D.

在式III之一些實施例中： R¹為氯或甲基； R²為甲基或三氘代甲基； R³係選自嘧啶基、氮雜環丁烷基甲基、吡唑基、吡啶基、六氫吡啶基、2H-吡唑并[3,4-b]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,5-a]吡啶基、咪唑基、噻唑基、6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪基及C(O)NR^c3R^d3，其中R³之該嘧啶基、該氮雜環丁烷基甲基、該吡唑基、該吡啶基、該六氫吡啶基、該2H-吡唑并[3,4-b]吡啶基、該吡唑并[1,5-a]吡啶基、該吡唑并[1,5-a]嘧啶基、該咪唑并[1,5-a]吡啶基、該咪唑基、該噻唑基及該6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪基各自視情況經1或2個R^3A取代基取代； 每一R^3A獨立地選自甲基、氟、氯、甲氧基、胺基、甲基胺基、二甲基胺基、羥基甲基、羥基乙基、氧雜環丁烷基、甲基羰基、異丙基羰基、羥基甲基羰基、環丙基羰基、甲基磺醯基、異丙基磺醯基及環丙基磺醯基； R^c3及R^d3各自獨立地選自甲基及三氘代甲基； R⁴係選自H、氟、氯、甲基及甲氧基； R^4A係選自甲基、三氘代甲基、乙基、氮雜環丁烷基及六氫吡啶基，其中R^4A之該氮雜環丁烷基及該六氫吡啶基各自視情況經甲基取代；且 R^G為H或D。In some embodiments of Formula III: R¹ is chloro or methyl; R² is methyl or trideuterated methyl; R³ is selected from pyrimidinyl, azacyclobutanylmethyl, pyrazolyl, pyridinyl, hexahydropyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,5-a]pyridinyl, imidazolyl, thiazolyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl and C(O)NR^c3 R^d3 , wherein R³ , the pyrimidinyl, the azacyclobutanylmethyl, the pyrazolyl, the pyridinyl, the hexahydropyridinyl, the 2H-pyrazolo[3,4-b]pyridinyl, the pyrazolo[1,5-a]pyridinyl, the pyrazolo[1,5-a]pyrimidinyl, the imidazo[1,5-a]pyridinyl, the imidazolyl, the thiazolyl and the 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl are each optionally substituted with 1 or 2 R^3A substituents; each R^{R 3A} is independently selected from methyl, fluoro, chloro, methoxy, amino, methylamino, dimethylamino, hydroxymethyl, hydroxyethyl, oxacyclobutane, methylcarbonyl, isopropylcarbonyl, hydroxymethylcarbonyl, cyclopropylcarbonyl, methylsulfonyl, isopropylsulfonyl, and cyclopropylsulfonyl; R^c3 and R^d3 are each independently selected from methyl and trideuteromethyl; R⁴ is selected from H, fluoro, chloro, methyl, and methoxy; R^4A is selected from methyl, trideuteromethyl, ethyl, azacyclobutane, and hexahydropyridinyl, wherein the azacyclobutane and the hexahydropyridinyl of R^4A are each optionally substituted with methyl; and^RG is H or D.

在式III之一些實施例中： R¹為氯或甲基； R²為甲基或三氘代甲基； R³係選自嘧啶基、氮雜環丁烷基甲基、吡唑基、吡啶基、六氫吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,5-a]吡啶基及C(O)NR^c3R^d3，其中R³之該嘧啶基、該氮雜環丁烷基甲基、該吡唑基、該吡啶基、該六氫吡啶基、該2H-吡唑并[3,4-b]吡啶基、該吡唑并[1,5-a]吡啶基、該吡唑并[1,5-a]嘧啶基及該咪唑并[1,5-a]吡啶基各自視情況經1或2個R^3A取代基取代； 每一R^3A獨立地選自甲基、氟、氯、甲氧基、胺基、甲基胺基、二甲基胺基、羥基甲基、羥基乙基、氧雜環丁烷基、甲基羰基、異丙基羰基、羥基甲基羰基、環丙基羰基、甲基磺醯基、異丙基磺醯基及環丙基磺醯基； R^c3及R^d3各自獨立地選自甲基及三氘代甲基； R⁴係選自H、氟、氯、甲基及甲氧基； R^4A係選自甲基、三氘代甲基、乙基、氮雜環丁烷基及六氫吡啶基，其中R^4A之該氮雜環丁烷基及該六氫吡啶基各自視情況經甲基取代；且 R^G為H或D。In some embodiments of Formula III: R¹ is chloro or methyl; R² is methyl or trideuterated methyl; R³ is selected from pyrimidinyl, azacyclobutanylmethyl, pyrazolyl, pyridinyl, hexahydropyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,5-a]pyridinyl and C(O)NR^c3 R^d3 , wherein the^pyrimidinyl , the azacyclobutanylmethyl, the pyrazolyl, the pyridinyl, the hexahydropyridinyl, the 2H-pyrazolo[3,4-b]pyridinyl, the pyrazolo[1,5-a]pyridinyl, the pyrazolo[1,5-a]pyrimidinyl and the imidazo[1,5-a]pyridinyl of R 3 are each optionally substituted with 1 or 2 R^3A substituents; each R^{R 3A} is independently selected from methyl, fluoro, chloro, methoxy, amino, methylamino, dimethylamino, hydroxymethyl, hydroxyethyl, oxacyclobutane, methylcarbonyl, isopropylcarbonyl, hydroxymethylcarbonyl, cyclopropylcarbonyl, methylsulfonyl, isopropylsulfonyl, and cyclopropylsulfonyl; R^c3 and R^d3 are each independently selected from methyl and trideuteromethyl; R⁴ is selected from H, fluoro, chloro, methyl, and methoxy; R^4A is selected from methyl, trideuteromethyl, ethyl, azacyclobutane, and hexahydropyridinyl, wherein the azacyclobutane and the hexahydropyridinyl of R^4A are each optionally substituted with methyl; and^RG is H or D.

在一些實施例中，式III化合物為式IIIa化合物：IIIa或其醫藥學上可接受之鹽。In some embodiments, the compound of formula III is a compound of formula IIIa:IIIa or its pharmaceutically acceptable salt.

在一些實施例中，式III化合物為式IIIb化合物：IIIb或其醫藥學上可接受之鹽。In some embodiments, the compound of formula III is a compound of formula IIIb:IIIb or its pharmaceutically acceptable salt.

在一些實施例中，本文所提供之化合物係選自： 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-N,N-雙(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-7-甲基-N,N,4-參(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-N,N,7-三甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基-1-d)-4,7-二甲基-N,N-雙(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基-1-d)-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(吡啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)-3-(吡啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 2-((1-(3-(1-乙醯基六氫吡啶-4-基)-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)-5-氟苯甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-7-氯-4-甲基-N,N-雙(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基-1-d)-7-氯-4-甲基-N,N-雙(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-N,N-雙(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,7-三甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基-1-d)-4-甲基-N,N-雙(甲基-d₃)-5-側氧基-7-(三氟甲基)-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(吡啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(6-(羥基甲基)吡啶-3-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-3-(6-(羥基甲基)吡啶-3-基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(2-(羥基甲基)嘧啶-5-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-3-(2-(羥基甲基)嘧啶-5-基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(2-(羥基甲基)吡啶-3-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(6-(甲基胺基)吡啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(6-(二甲基胺基)吡啶-3-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(1-(2-羥基乙基)-1H-吡唑-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(1-甲基-1H-吡唑-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(1H-吡唑-4-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(吡唑并[1,5-a]嘧啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基-4-甲基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基-5-氟吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(咪唑并[1,5-a]吡啶-6-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((2-胺甲醯基-6-氯吡啶-3-基)胺基)乙基-1-d)-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-6-氯吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氯苯基)胺基)乙基-1-d)-7-甲基-N,N,4-參(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(1-環丙基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-N,N,4-參(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； (3-((1-(3-(雙(甲基-d3)胺甲醯基)-7-甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)-6-氯吡啶-2-基)胺基甲酸甲酯； 9-(1-((2-胺甲醯基-4-氯苯基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((4-氟-2-(1-甲基-1H-四唑-5-基)苯基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(1-環丙基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((4-氟-2-(1-甲基-1H-1,2,3-三唑-4-基)苯基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； (6-氯-3-((1-(3-(二甲基胺甲醯基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)吡啶-2-基)胺基甲酸甲酯； 9-(1-((4-氟-2-胺磺醯基苯基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((5-氯喹啉-8-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； N,N,4,7-四甲基-9-(1-((6-甲基-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 2-((1-(3-(1-乙醯基六氫吡啶-4-基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-5-氟苯甲醯胺； 2-((1-(3-(2-胺基嘧啶-5-基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-5-氟苯甲醯胺； 2-((1-(3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)-5-氟苯甲醯胺； 2-((1-(4,7-二甲基-3-(1-甲基-1H-吡唑-5-基)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-5-氟苯甲醯胺； 5-氟-2-((1-(7-甲基-4-(甲基-d3)-3-(1-甲基-1H-吡唑-5-基)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)苯甲醯胺； 2-((1-(3-(2-胺基嘧啶-5-基)-7-氯-4-甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-5-氟苯甲醯胺； 2-((1-(3-(2-胺基嘧啶-5-基)-7-氯-4-甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)-5-氟苯甲醯胺； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(1-(氧雜環丁-3-基)六氫吡啶-4-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(1-乙醯基六氫吡啶-4-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(1-(2-羥基乙醯基)六氫吡啶-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(1-乙醯基六氫吡啶-4-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(1-異丁醯基六氫吡啶-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(1-(環丙烷羰基)六氫吡啶-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(1-(甲基磺醯基)六氫吡啶-4-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(1-(異丙基磺醯基)六氫吡啶-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(1-(環丙基磺醯基)六氫吡啶-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-甲氧基-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d3)-9-(1-((6-甲基-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d3)-9-(1-((2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-甲氧基-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((4-氟-2-(1-(甲基-d3)-1H-四唑-5-基)苯基)胺基)乙基)-4,7-二甲基-3-(吡啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((4-氟-2-(1-甲基-1H-1,2,4-三唑-3-基)苯基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((4-氟-2-(1-甲基-1H-1,2,4-三唑-3-基)苯基)胺基)乙基)-4,7-二甲基-3-(1-甲基-1H-吡唑-5-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((4-氟-2-(1-甲基-1H-1,2,3-三唑-4-基)苯基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基-3-吡啶基)-9-[1-[4-氟-2-(1-甲基三唑-4-基)苯胺基]乙基]-4,7-二甲基-咪唑并[1,5-a]喹唑啉-5-酮； 3-(1-乙醯基六氫吡啶-4-基)-9-(1-(6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-(6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)乙基)-3-(1-(2-羥基乙醯基)六氫吡啶-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基吡啶-3-基)-9-((6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)甲基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-((6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)甲基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-((6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)甲基)-4,7-二甲基-3-(1-甲基-1H-吡唑-5-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-((6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)甲基)-3-(2-(羥基甲基)嘧啶-5-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-((3-氟氮雜環丁-1-基)甲基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-((3-氟氮雜環丁-1-基)甲基)吡啶-3-基)胺基)乙基)-N-(2-羥基乙基)-N,4,7-三甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； ((6-氯-3-((1-(3-(二甲基胺甲醯基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)吡啶-2-基)甲基)胺基甲酸甲酯； (6-氯-3-(((3-(二甲基胺甲醯基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)甲基)胺基)吡啶-2-基)胺基甲酸甲酯； 9-[(6-氯-2,3-二氫吡啶并[2,3-b][1,4]噁嗪-1-基)甲基]-N,N,4,7-四甲基-5-側氧基-咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-[(6-氯-2,3-二氫吡啶并[2,3-b][1,4]噁嗪-1-基)甲基]-4,7-二甲基-5-側氧基-N,N-雙(三氘代甲基)咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-(1-甲基氮雜環丁-3-基)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-(1-甲基六氫吡啶-4-基)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-(1-甲基氮雜環丁-3-基)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-(1-甲基六氫吡啶-4-基)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 3-(2-胺基嘧啶-5-基)-9-((6-氯-3,4-二氫-1,5-萘啶-1(2H)-基)甲基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-((3,3-二氟氮雜環丁-1-基)甲基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-(6-氯-3,4-二氫-1,5-萘啶-1(2H)-基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-(6-氯-3,4-二氫-1,5-萘啶-1(2H)-基)乙基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-乙基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (3-((1-(3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-6-氯吡啶-2-基)胺基甲酸甲酯； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1-甲基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氟-2-(1-甲基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1-環丙基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1-(氧雜環丁-3-基)-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(嘧啶-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(4-羥基六氫吡啶-1-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-嗎啉基吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1,3-二甲基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1,5-二甲基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(5-甲基-1,3,4-噁二唑-2-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1,3,4-噁二唑-2-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(3-((1-(3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-6-氯吡啶-2-基)-1,2,4-噁二唑-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1-甲基-5-側氧基-4,5-二氫-1H-1,2,4-三唑-3-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (3-(((3-(2-胺基嘧啶-5-基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)甲基)胺基)-6-氯吡啶-2-基)胺基甲酸甲酯； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(1H-吡唑-5-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基-5-氯吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基-5-甲基吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基-5-甲氧基吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基-4-甲氧基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(2-甲基-2H-吡唑并[3,4-b]吡啶-5-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(吡唑并[1,5-a]吡啶-6-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-乙基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基-5-氟吡啶-3-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； (R)-3-(6-胺基-5-氟吡啶-3-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； (S)-3-(6-胺基-5-氟吡啶-3-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基-4-甲基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(1-甲基-1H-咪唑-5-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪-3-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基噻唑-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮；及 3-(2-胺基-4-甲基噻唑-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 或其醫藥學上可接受之鹽。In some embodiments, the compound provided herein is selected from: 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-N,N,7-trimethyl-4-(methyl-_d3 )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl-1-d)-4,7-dimethyl-N,N-bis(methyl-_d3) )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d 3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(pyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )-3-(pyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 2-((1-(3-(1-acetylhexahydropyridin-4-yl)-7-methyl-4-(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-5-fluorobenzamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-7-chloro-4-methyl-N,N-bis(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl-1-d)-7-chloro-4-methyl-N,N-bis(methyl-_{d 3} )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,7-trimethyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-(methyl-d 3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl-1-d)-4-methyl-N,N-bis(methyl-d₃ )-5-oxo-7-(trifluoromethyl)-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-(methyl-d₃ 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(6-(hydroxymethyl)pyridin-3-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-3-(6-(hydroxymethyl)pyridin-3-yl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(2-(hydroxymethyl)pyrimidin-5-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-3-(2-(hydroxymethyl)pyrimidin-5-yl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(2-(hydroxymethyl)pyridin-3-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-aminopyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-aminopyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(6-(methylamino)pyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(6-(dimethylamino)pyridin-3-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methyl-1H-pyrazol-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1H-pyrazol-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(pyrazolo[1,5-a]pyrimidin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one); 3-(2-amino-4-methylpyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-amino-5-fluoropyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(imidazo[1,5-a]pyridin-6-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((2-aminoformyl-6-chloropyridin-3-yl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-_d3) )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-6-chloropyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-4-chlorophenyl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; methyl (3-((1-(3-(bis(methyl-d3)aminocarboxyl)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-6-chloropyridin-2-yl)carbamate; 9-(1-((2-aminoformyl-4-chlorophenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((4-fluoro-2-(1-methyl-1H-tetrazol-5-yl)phenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((4-fluoro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; Methyl (6-chloro-3-((1-(3-(dimethylaminoformyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)pyridin-2-yl)carbamate; 9-(1-((4-fluoro-2-sulfaminylphenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((5-chloroquinolin-8-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; N,N,4,7-Tetramethyl-9-(1-((6-methyl-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 2-((1-(3-(1-acetylhexahydropyridin-4-yl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-5-fluorobenzamide; 2-((1-(3-(2-aminopyrimidin-5-yl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-5-fluorobenzamide; 2-((1-(3-(2-aminopyrimidin-5-yl)-7-methyl-4-(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-5-fluorobenzamide; 2-((1-(4,7-dimethyl-3-(1-methyl-1H-pyrazol-5-yl)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-5-fluorobenzamide; 5-Fluoro-2-((1-(7-methyl-4-(methyl-d3)-3-(1-methyl-1H-pyrazol-5-yl)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)benzamide; 2-((1-(3-(2-aminopyrimidin-5-yl)-7-chloro-4-methyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-5-fluorobenzamide; 2-((1-(3-(2-aminopyrimidin-5-yl)-7-chloro-4-methyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-5-fluorobenzamide; 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-(oxocyclobutan-3-yl)hexahydropyridin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(1-acetylhexahydropyridin-4-yl)-9-(1-((6-chloro-2-(2-(methyl-d_{3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d 3} )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)_-one )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2-hydroxyacetyl)hexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(1-acetylhexahydropyridin-4-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-_d3) )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-isobutyrylhexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-(cyclopropanecarbonyl)hexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one_; )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-(methylsulfonyl)hexahydropyridin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-(isopropylsulfonyl)hexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d 3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-(isopropylsulfonyl)hexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)_-one )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-(cyclopropylsulfonyl)hexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-methoxy-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-7-methyl-4-(methyl-d3)-9-(1-((6-methyl-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-7-methyl-4-(methyl-d3)-9-(1-((2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-methoxy-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((4-fluoro-2-(1-(methyl-d3)-1H-tetrazol-5-yl)phenyl)amino)ethyl)-4,7-dimethyl-3-(pyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((4-fluoro-2-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((4-fluoro-2-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)ethyl)-4,7-dimethyl-3-(1-methyl-1H-pyrazol-5-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((4-fluoro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-amino-3-pyridinyl)-9-[1-[4-fluoro-2-(1-methyltriazol-4-yl)anilino]ethyl]-4,7-dimethylimidazo[1,5-a]quinazolin-5-one; 3-(1-acetylhexahydropyridin-4-yl)-9-(1-(6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-(6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethyl)-3-(1-(2-hydroxyacetyl)hexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-aminopyridin-3-yl)-9-((6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-((6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-((6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-4,7-dimethyl-3-(1-methyl-1H-pyrazol-5-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-((6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-3-(2-(hydroxymethyl)pyrimidin-5-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-((3-fluoroazidocyclobutan-1-yl)methyl)pyridin-3-yl)amino)ethyl)-N,N ,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-((3-fluoroazidocyclobutan-1-yl)methyl)pyridin-3-yl)amino)ethyl)-N-(2-hydroxyethyl)-N,4,7-trimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; methyl ((6-chloro-3-((1-(3-(dimethylaminocarbonyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)pyridin-2-yl)methyl)carbamate; Methyl (6-chloro-3-(((3-(dimethylaminocarbonyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)methyl)amino)pyridin-2-yl)carbamate; 9-[(6-chloro-2,3-dihydropyrido[2,3-b][1,4]oxazin-1-yl)methyl]-N ,N ,4,7-tetramethyl-5-oxo-imidazo[1,5-a]quinazoline-3-carboxamide; 9-[(6-chloro-2,3-dihydropyrido[2,3-b][1,4]oxazin-1-yl)methyl]-4,7-dimethyl-5-oxo-N ,N -Bis(trideuteriomethyl)imidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-(1-methylazinocyclobutan-3-yl)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-(1-methylhexahydropyridin-4-yl)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-(1-methylhexahydropyridin-4-yl)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-N,N,4-tris(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-(1-methylhexahydropyridin-4-yl)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-N,N,4-tris(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 3-(2-aminopyrimidin-5-yl)-9-((6-chloro-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)methyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-((3,3-difluoroazolobutyl-1-yl)methyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-(6-chloro-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-(6-chloro-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethyl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-ethyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; methyl (3-((1-(3-(2-aminopyrimidin-5-yl)-7-methyl-4-(methyl-_d3 )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-6-chloropyridin-2-yl)carbamate; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-fluoro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1-(oxacyclobutan-3-yl)-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(pyrimidin-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(4-hydroxyhexahydropyridin-1-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(4-hydroxyhexahydropyridin-1-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1,3,4-oxadiazol-2-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(3-((1-(3-(2-aminopyrimidin-5-yl)-7-methyl-4-(methyl-d₃ )-5-(1-((6-chloro-2-(1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one); (3-(((3-(2-aminopyrimidin-5-yl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)methyl)amino)-6-chloropyridin-2-yl)carbamate; 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1H-pyrazol-5-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-amino-5-chloropyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d 3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1H-pyrazol-5-yl)imidazo[1,5-a]quinazolin-5(4H)_-one )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-amino-5-methylpyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-amino-5-methoxypyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d 3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)_-one )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-amino-4-methoxypyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(pyrazolo[1,5-a]pyridin-6-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-ethyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-amino-5-fluoropyridin-3-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; (R )-3-(6-amino-5-fluoropyridin-3-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; (S )-3-(6-amino-5-fluoropyridin-3-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-amino-4-methylpyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methyl-1H-imidazol-5-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminothiazol-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; and 3-(2-Amino-4-methylthiazol-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; or pharmaceutically acceptable salts thereof.

在一些實施例中，本文所提供之化合物係選自： 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； (R)-9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-N,N-雙(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； (S)-9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-N,N-雙(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-7-甲基-N,N,4-參(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-N,N,7-三甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基-1-d)-4,7-二甲基-N,N-雙(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基-1-d)-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (R)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； (S)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(吡啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)-3-(吡啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 2-((1-(3-(1-乙醯基六氫吡啶-4-基)-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)-5-氟苯甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-7-氯-4-甲基-N,N-雙(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基-1-d)-7-氯-4-甲基-N,N-雙(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-N,N-雙(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,7-三甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基-1-d)-4-甲基-N,N-雙(甲基-d₃)-5-側氧基-7-(三氟甲基)-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(吡啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(6-(羥基甲基)吡啶-3-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-3-(6-(羥基甲基)吡啶-3-基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(2-(羥基甲基)嘧啶-5-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-3-(2-(羥基甲基)嘧啶-5-基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(2-(羥基甲基)吡啶-3-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(6-(甲基胺基)吡啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(6-(二甲基胺基)吡啶-3-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(1-(2-羥基乙基)-1H-吡唑-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(1-甲基-1H-吡唑-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(1H-吡唑-4-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(吡唑并[1,5-a]嘧啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基-4-甲基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基-5-氟吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(咪唑并[1,5-a]吡啶-6-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((2-胺甲醯基-6-氯吡啶-3-基)胺基)乙基-1-d)-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-6-氯吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氯苯基)胺基)乙基-1-d)-7-甲基-N,N,4-參(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(1-環丙基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-N,N,4-參(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； (3-((1-(3-(雙(甲基-d3)胺甲醯基)-7-甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)-6-氯吡啶-2-基)胺基甲酸甲酯； 9-(1-((2-胺甲醯基-4-氯苯基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((4-氟-2-(1-甲基-1H-四唑-5-基)苯基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(1-環丙基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((4-氟-2-(1-甲基-1H-1,2,3-三唑-4-基)苯基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； (6-氯-3-((1-(3-(二甲基胺甲醯基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)吡啶-2-基)胺基甲酸甲酯； 9-(1-((4-氟-2-胺磺醯基苯基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((5-氯喹啉-8-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； N,N,4,7-四甲基-9-(1-((6-甲基-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 2-((1-(3-(1-乙醯基六氫吡啶-4-基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-5-氟苯甲醯胺； 2-((1-(3-(2-胺基嘧啶-5-基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-5-氟苯甲醯胺； 2-((1-(3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)-5-氟苯甲醯胺； 2-((1-(4,7-二甲基-3-(1-甲基-1H-吡唑-5-基)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-5-氟苯甲醯胺； 5-氟-2-((1-(7-甲基-4-(甲基-d3)-3-(1-甲基-1H-吡唑-5-基)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)苯甲醯胺； 2-((1-(3-(2-胺基嘧啶-5-基)-7-氯-4-甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-5-氟苯甲醯胺；In some embodiments, the compound provided herein is selected from: 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; (R )-9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; (S )-9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-N,N,7-trimethyl-4-(methyl-_d3) )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl-1-d)-4,7-dimethyl-N,N-bis(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d_{3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2} -Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d 3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)_-one )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; (R )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; (S )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)_-one )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-1-d)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(pyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )-3-(pyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 2-((1-(3-(1-acetylhexahydropyridin-4-yl)-7-methyl-4-(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-5-fluorobenzamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-7-chloro-4-methyl-N,N-bis(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl-1-d)-7-chloro-4-methyl-N,N-bis(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,7-trimethyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-(methyl-d 3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl-1-d)-4-methyl-N,N-bis(methyl-d₃ )-5-oxo-7-(trifluoromethyl)-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-(methyl-d₃ 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(6-(hydroxymethyl)pyridin-3-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-3-(6-(hydroxymethyl)pyridin-3-yl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(2-(hydroxymethyl)pyrimidin-5-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-3-(2-(hydroxymethyl)pyrimidin-5-yl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(2-(hydroxymethyl)pyridin-3-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-aminopyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-aminopyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(6-(methylamino)pyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(6-(dimethylamino)pyridin-3-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methyl-1H-pyrazol-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1H-pyrazol-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(pyrazolo[1,5-a]pyrimidin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one); 3-(2-amino-4-methylpyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-amino-5-fluoropyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(imidazo[1,5-a]pyridin-6-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((2-aminoformyl-6-chloropyridin-3-yl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-_d3) )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-6-chloropyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-4-chlorophenyl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; methyl (3-((1-(3-(bis(methyl-d3)aminocarboxyl)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-6-chloropyridin-2-yl)carbamate; 9-(1-((2-aminoformyl-4-chlorophenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((4-fluoro-2-(1-methyl-1H-tetrazol-5-yl)phenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((4-fluoro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; Methyl (6-chloro-3-((1-(3-(dimethylaminoformyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)pyridin-2-yl)carbamate; 9-(1-((4-fluoro-2-sulfaminylphenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((5-chloroquinolin-8-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; N,N,4,7-Tetramethyl-9-(1-((6-methyl-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 2-((1-(3-(1-acetylhexahydropyridin-4-yl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-5-fluorobenzamide; 2-((1-(3-(2-aminopyrimidin-5-yl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-5-fluorobenzamide; 2-((1-(3-(2-aminopyrimidin-5-yl)-7-methyl-4-(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-5-fluorobenzamide; 2-((1-(4,7-dimethyl-3-(1-methyl-1H-pyrazol-5-yl)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-5-fluorobenzamide; 5-Fluoro-2-((1-(7-methyl-4-(methyl-d3)-3-(1-methyl-1H-pyrazol-5-yl)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)benzamide; 2-((1-(3-(2-aminopyrimidin-5-yl)-7-chloro-4-methyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-5-fluorobenzamide;

2-((1-(3-(2-胺基嘧啶-5-基)-7-氯-4-甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)-5-氟苯甲醯胺； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(1-(氧雜環丁-3-基)六氫吡啶-4-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(1-乙醯基六氫吡啶-4-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(1-(2-羥基乙醯基)六氫吡啶-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮；2-((1-(3-(2-aminopyrimidin-5-yl)-7-chloro-4-methyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-5-fluorobenzamide; 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-(oxocyclobutan-3-yl)hexahydropyridin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(1-acetylhexahydropyridin-4-yl)-9-(1-((6-chloro-2-(2-(methyl-d 3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-(oxocyclobutan-3-yl)hexahydropyridin-4-yl)imidazo[1,5-a]quinazolin-5(4H)_-one 9-(1-((6-chloro-2-(2-(methyl-d 3 )-2H-tetrazol-5-yl)pyridin-₃ -yl)amino)ethyl)-3-(1-(2-hydroxyacetyl)hexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one);

3-(1-乙醯基六氫吡啶-4-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(1-異丁醯基六氫吡啶-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(1-(環丙烷羰基)六氫吡啶-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(1-(甲基磺醯基)六氫吡啶-4-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(1-(異丙基磺醯基)六氫吡啶-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(1-(環丙基磺醯基)六氫吡啶-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-甲氧基-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d3)-9-(1-((6-甲基-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d3)-9-(1-((2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-甲氧基-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((4-氟-2-(1-(甲基-d3)-1H-四唑-5-基)苯基)胺基)乙基)-4,7-二甲基-3-(吡啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((4-氟-2-(1-甲基-1H-1,2,4-三唑-3-基)苯基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((4-氟-2-(1-甲基-1H-1,2,4-三唑-3-基)苯基)胺基)乙基)-4,7-二甲基-3-(1-甲基-1H-吡唑-5-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((4-氟-2-(1-甲基-1H-1,2,3-三唑-4-基)苯基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基-3-吡啶基)-9-[1-[4-氟-2-(1-甲基三唑-4-基)苯胺基]乙基]-4,7-二甲基-咪唑并[1,5-a]喹唑啉-5-酮； 3-(1-乙醯基六氫吡啶-4-基)-9-(1-(6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-(6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)乙基)-3-(1-(2-羥基乙醯基)六氫吡啶-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基吡啶-3-基)-9-((6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)甲基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-((6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)甲基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-((6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)甲基)-4,7-二甲基-3-(1-甲基-1H-吡唑-5-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-((6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)甲基)-3-(2-(羥基甲基)嘧啶-5-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-((3-氟氮雜環丁-1-基)甲基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-((3-氟氮雜環丁-1-基)甲基)吡啶-3-基)胺基)乙基)-N-(2-羥基乙基)-N,4,7-三甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； ((6-氯-3-((1-(3-(二甲基胺甲醯基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)吡啶-2-基)甲基)胺基甲酸甲酯； (6-氯-3-(((3-(二甲基胺甲醯基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)甲基)胺基)吡啶-2-基)胺基甲酸甲酯； 9-[(6-氯-2,3-二氫吡啶并[2,3-b][1,4]噁嗪-1-基)甲基]-N,N,4,7-四甲基-5-側氧基-咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-[(6-氯-2,3-二氫吡啶并[2,3-b][1,4]噁嗪-1-基)甲基]-4,7-二甲基-5-側氧基-N,N-雙(三氘代甲基)咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-(1-甲基氮雜環丁-3-基)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-(1-甲基六氫吡啶-4-基)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-(1-甲基氮雜環丁-3-基)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-(1-甲基六氫吡啶-4-基)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 3-(2-胺基嘧啶-5-基)-9-((6-氯-3,4-二氫-1,5-萘啶-1(2H)-基)甲基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-((3,3-二氟氮雜環丁-1-基)甲基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-(6-氯-3,4-二氫-1,5-萘啶-1(2H)-基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； (S)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； (R)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； (S)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； (R)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； (S)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； (R)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； (S)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (R)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (S)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (R)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (S)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (R)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (S)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (R)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (S)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-N,N-雙(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； (R)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-N,N-雙(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； (S)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(2-(羥基甲基)嘧啶-5-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； (R)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(2-(羥基甲基)嘧啶-5-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； (S)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-3-(2-(羥基甲基)嘧啶-5-基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (R)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-3-(2-(羥基甲基)嘧啶-5-基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (S)-2-((1-(3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)-5-氟苯甲醯胺； (R)-2-((1-(3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)-5-氟苯甲醯胺； 3-(2-胺基嘧啶-5-基)-9-(1-(6-氯-3,4-二氫-1,5-萘啶-1(2H)-基)乙基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-乙基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (3-((1-(3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-6-氯吡啶-2-基)胺基甲酸甲酯； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1-甲基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氟-2-(1-甲基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1-環丙基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1-(氧雜環丁-3-基)-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(嘧啶-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(4-羥基六氫吡啶-1-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-嗎啉基吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1,3-二甲基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1,5-二甲基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(5-甲基-1,3,4-噁二唑-2-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1,3,4-噁二唑-2-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(3-((1-(3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-6-氯吡啶-2-基)-1,2,4-噁二唑-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1-甲基-5-側氧基-4,5-二氫-1H-1,2,4-三唑-3-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (3-(((3-(2-胺基嘧啶-5-基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)甲基)胺基)-6-氯吡啶-2-基)胺基甲酸甲酯； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(1H-吡唑-5-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基-5-氯吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基-5-甲基吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基-5-甲氧基吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基-4-甲氧基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(2-甲基-2H-吡唑并[3,4-b]吡啶-5-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(吡唑并[1,5-a]吡啶-6-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-乙基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基-5-氟吡啶-3-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基-4-甲基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(1-甲基-1H-咪唑-5-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪-3-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基噻唑-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮；及 3-(2-胺基-4-甲基噻唑-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 或其醫藥學上可接受之鹽。3-(1-acetylhexahydropyridin-4-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-_d3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-isobutyrylhexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-isobutyrylhexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)_-one )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-(cyclopropanecarbonyl)hexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-(methylsulfonyl)hexahydropyridin-4-_yl) imidazo[1,5-a]quinazolin-5(4H)-one; )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-(isopropylsulfonyl)hexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-(cyclopropylsulfonyl)hexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-methoxy-2-(2-(methyl-d_{3 )} - )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-7-methyl-4-(methyl-d 3 )-9-(1-((6-methyl-2-(2-(methyl-d 3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-7-methyl-4-(methyl-d3)-9-(1-((2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-methoxy-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((4-fluoro-2-(1-(methyl-d3)-1H-tetrazol-5-yl)phenyl)amino)ethyl)-4,7-dimethyl-3-(pyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((4-fluoro-2-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((4-fluoro-2-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)ethyl)-4,7-dimethyl-3-(1-methyl-1H-pyrazol-5-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((4-fluoro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-amino-3-pyridyl)-9-[1-[4-fluoro-2-(1-methyltriazol-4-yl)anilino]ethyl]-4,7-dimethylimidazo[1,5-a]quinazolin-5-one; 3-(1-acetylhexahydropyridin-4-yl)-9-(1-(6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-(6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethyl)-3-(1-(2-hydroxyacetyl)hexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-aminopyridin-3-yl)-9-((6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-((6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-((6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-4,7-dimethyl-3-(1-methyl-1H-pyrazol-5-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-((6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-3-(2-(hydroxymethyl)pyrimidin-5-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-((3-fluoroazolobutyl-1-yl)methyl)pyridin-3-yl)amino)ethyl)-N,N 9-(1-((6-chloro-2-((3-fluoroazolobutyl-1-yl)methyl)pyridin-3-yl)amino)ethyl)-N-(2-hydroxyethyl)-N,4,7-trimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide); methyl ((6-chloro-3-((1-(3-(dimethylaminocarbonyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)pyridin-2-yl)methyl)carbamate; Methyl (6-chloro-3-(((3-(dimethylaminocarbonyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)methyl)amino)pyridin-2-yl)carbamate; 9-[(6-chloro-2,3-dihydropyrido[2,3-b][1,4]oxazin-1-yl)methyl]-N ,N ,4,7-tetramethyl-5-oxo-imidazo[1,5-a]quinazoline-3-carboxamide; 9-[(6-chloro-2,3-dihydropyrido[2,3-b][1,4]oxazin-1-yl)methyl]-4,7-dimethyl-5-oxo-N ,N -Bis(trideuteriomethyl)imidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-(1-methylazinocyclobutan-3-yl)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-(1-methylhexahydropyridin-4-yl)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-(1-methylhexahydropyridin-4-yl)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-N,N,4-tris(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-(1-methylhexahydropyridin-4-yl)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-N,N,4-tris(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 3-(2-aminopyrimidin-5-yl)-9-((6-chloro-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)methyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-((3,3-difluoroazolobutyl-1-yl)methyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-(6-chloro-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; (S )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; (R )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; (S )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-1-d)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; (R )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; (S )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; (R )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; (S )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; (R )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; (S )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; (R )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; (S )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; (R )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; (S )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; (R )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; (S )-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; (R )-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; (S )-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(2-(hydroxymethyl)pyrimidin-5-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; (R )-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(2-(hydroxymethyl)pyrimidin-5-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; (S )-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-3-(2-(hydroxymethyl)pyrimidin-5-yl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; (R )-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-3-(2-(hydroxymethyl)pyrimidin-5-yl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; (S )-2-((1-(3-(2-aminopyrimidin-5-yl)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-5-fluorobenzamide; (R )-2-((1-(3-(2-aminopyrimidin-5-yl)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-5-fluorobenzamide; 3-(2-aminopyrimidin-5-yl)-9-(1-(6-chloro-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethyl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-ethyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; methyl (3-((1-(3-(2-aminopyrimidin-5-yl)-7-methyl-4-(methyl-_d3 )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-6-chloropyridin-2-yl)carbamate; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-fluoro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1-(oxacyclobutan-3-yl)-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(pyrimidin-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(4-hydroxyhexahydropyridin-1-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(4-hydroxyhexahydropyridin-1-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1,3,4-oxadiazol-2-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(3-((1-(3-(2-aminopyrimidin-5-yl)-7-methyl-4-(methyl-d₃ )-5-(1-((6-chloro-2-(1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one); (3-(((3-(2-aminopyrimidin-5-yl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)methyl)amino)-6-chloropyridin-2-yl)carbamate; 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1H-pyrazol-5-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-amino-5-chloropyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d 3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1H-pyrazol-5-yl)imidazo[1,5-a]quinazolin-5(4H)_-one )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-amino-5-methylpyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-amino-5-methoxypyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d 3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)_-one )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-amino-4-methoxypyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(pyrazolo[1,5-a]pyridin-6-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-ethyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-amino-5-fluoropyridin-3-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-amino-4-methylpyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methyl-1H-imidazol-5-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminothiazol-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; and 3-(2-Amino-4-methylthiazol-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; or pharmaceutically acceptable salts thereof.

在一些實施例中，本文所提供之化合物係選自： 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-N,N-雙(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-7-甲基-N,N,4-參(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-N,N,7-三甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基-1-d)-4,7-二甲基-N,N-雙(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺；及 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基-1-d)-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 或其醫藥學上可接受之鹽。In some embodiments, the compound provided herein is selected from: 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-N,N,7-trimethyl-4-(methyl-_d3 )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl-1-d)-4,7-dimethyl-N,N-bis(methyl-_d3) )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; and 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; or pharmaceutically acceptable salts thereof.

在一些實施例中，本文所提供之化合物係選自： 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮；及 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 或其醫藥學上可接受之鹽。In some embodiments, the compound provided herein is selected from: 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)_-one ; )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(₂ -methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d 3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; and 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; or pharmaceutically acceptable salts thereof.

在一些實施例中，本文所提供之化合物為9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-N,N-雙(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺或其醫藥學上可接受之鹽。In some embodiments, the compound provided herein is 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide or a pharmaceutically acceptable salt thereof.

在一些實施例中，本文所提供之化合物為(R)-9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-N,N-雙(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺或其醫藥學上可接受之鹽。In some embodiments, the compound provided herein is (R )-9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide or a pharmaceutically acceptable salt thereof.

在一些實施例中，本文所提供之化合物為(S)-9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-N,N-雙(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺或其醫藥學上可接受之鹽。In some embodiments, the compound provided herein is (S )-9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide or a pharmaceutically acceptable salt thereof.

在一些實施例中，本文所提供之化合物為3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮或其醫藥學上可接受之鹽。In some embodiments, the compound provided herein is 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one or a pharmaceutically acceptable salt thereof.

應進一步瞭解，本發明為清晰起見而闡述於單獨實施例之上下文中之某些特徵亦可在單一實施例中組合提供。相反，本發明為簡便起見而闡述於單一實施例之上下文中之各種特徵亦可單獨地或以任何適宜子組合提供。It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

在本說明書中之不同地方，闡述二價連接取代基。每一二價連接取代基明確地意欲包括該連接取代基之正向及反向形式二者。舉例而言，-NR(CR'R'')_n-包括-NR(CR'R'')_n-及-(CR'R'')_nNR-二者。倘若結構明顯需要連接基團，則應理解針對該基團所列示之馬庫什變數(Markush variable)為連接基團。At various points in this specification, divalent linking substituents are described. Each divalent linking substituent is expressly intended to include both the forward and reverse forms of the linking substituent. For example, -NR(CR'R")_n- includes both -NR(CR'R")_n- and -(CR'R")_nNR- . Where a linking group is clearly required by the structure, the Markush variable listed for that group is understood to be the linking group.

術語「n員」(其中n為整數)通常闡述部分中成環原子之數目，其中成環原子之數目為n。舉例而言，六氫吡啶基為6員雜環烷基環之實例，吡唑基為5員雜芳基環之實例，吡啶基為6員雜芳基環之實例，且1,2,3,4-四氫-萘為10員環烷基之實例。The term "n-membered" (where n is an integer) generally describes the number of ring atoms in a moiety, where the number of ring atoms is n. For example, hexahydropyridinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl ring.

如本文所用，片語「視情況經取代」意指未經取代或經取代。取代基經獨立選擇，且取代可在任何化學可及之位置處。如本文所用，術語「經取代」意味著氫原子去除且由取代基置換。單一二價取代基(例如側氧基)可置換兩個氫原子。應理解，給定原子處之取代受化合價限制。As used herein, the phrase "optionally substituted" means unsubstituted or substituted. Substituents are independently selected, and substitution may occur at any chemically accessible position. As used herein, the term "substituted" means the removal of a hydrogen atom and its replacement by a substituent. A single divalent substituent (e.g., a pendoxy group) may replace two hydrogen atoms. It is understood that substitution at a given atom is limited by valency.

如本文所用，片語「每一『變數』獨立地選自」意指與其中「『變數』在每次出現時係選自」實質上相同。As used herein, the phrase "each 'variable' is independently selected from" means substantially the same as "the 'variable' is selected from each time it occurs therein."

在整個定義中，術語「C_n-m」及「C_m-n」指示包括端點之範圍，其中n及m為整數且指示碳數目。實例包括C_1-3、C_1-4、C_1-6及諸如此類。Throughout the definitions, the terms "C_nm " and "C_mn " indicate inclusive ranges, where n and m are integers and indicate the number of carbons. Examples include C_1-3 , C_1-4 , C_1-6 , and the like.

如本文所用，單獨或與其他術語組合使用之術語「C_n-m烷基」係指具有n至m個碳之可為直鏈或具支鏈之飽和烴基。烷基部分之實例包括(但不限於)諸如以下等化學基團：甲基(Me)、乙基(Et)、正丙基(n-Pr)、異丙基(iPr)、正丁基、第三丁基、異丁基、第二丁基；高碳數同系物，諸如2-甲基-1-丁基、正戊基、3-戊基、正己基、1,2,2-三甲基丙基及諸如此類。術語「C_n-m烷基」應理解為包括如本文所定義之飽和烴基之氘化類似物，包括(但不限於)諸如三氘代甲基(CD₃)、五氘代乙基(CD₂CD₃)及諸如此類之基團。在一些實施例中，烷基含有1至6個碳原子、1至4個碳原子、1至3個碳原子、2至6個碳原子、2至4個碳原子、2至3個碳原子或1至2個碳原子。As used herein, the term "C_nm alkyl," alone or in combination with other terms, refers to a saturated alkyl group having n to m carbon atoms, which may be linear or branched. Examples of alkyl moieties include, but are not limited to, groups such as methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), n-butyl, t-butyl, isobutyl, sec-butyl; and higher carbon number homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. The term "C_nm alkyl" should be understood to include deuterated analogs of saturated alkyl groups as defined herein, including but not limited to trideuterated methyl (CD₃ ), pentadeuterated ethyl (CD₂ CD₃ ), and the like. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, or 1 to 2 carbon atoms.

如本文所用，「C_n-m烯基」係指具有一或多個碳-碳雙鍵且具有n至m個碳之烷基。實例烯基包括(但不限於)乙烯基、正丙烯基、異丙烯基、正丁烯基、第二丁烯基及諸如此類。在一些實施例中，烯基部分含有2至6個、2至4個或2至3個碳原子。As used herein, "C_nm alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds and having n to m carbon atoms. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

如本文所用，「C_n-m炔基」係指具有一或多個碳-碳三鍵且具有n至m個碳之烷基。實例炔基包括(但不限於)乙炔基、丙炔-1-基、丙炔-2-基及諸如此類。在一些實施例中，炔基部分含有2至6個、2至4個或2至3個碳原子。As used herein, "C_nM alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds and having n to m carbon atoms. Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

如本文所用，單獨或與其他術語組合使用之術語「C_n-m烷氧基」係指式-O-烷基之基團，其中該烷基具有n至m個碳。實例烷氧基包括(但不限於)甲氧基、乙氧基、丙氧基(例如正丙氧基及異丙氧基)、丁氧基(例如正丁氧基及第三丁氧基)及諸如此類。在一些實施例中，烷基具有1至6個、1至4個或1至3個碳原子。As used herein, the term "C_nM alkoxy," alone or in combination with other terms, refers to a radical of the formula -O-alkyl, wherein the alkyl group has n to m carbon atoms. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

如本文所用，單獨或與其他術語組合使用之術語「芳基」係指芳香族烴基，其可為單環或多環的(例如具有2、3或4個稠合環)。術語「C_n-m芳基」係指具有n至m個環碳原子之芳基。芳基包括(例如)苯基、萘基、蒽基、菲基及諸如此類。在一些實施例中，芳基具有5至10個碳原子。在一些實施例中，芳基為苯基或萘基。在一些實施例中，芳基為苯基。As used herein, the term "aryl," alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings). The term "C_nM aryl" refers to an aryl group having n to m ring carbon atoms. Aryl groups include, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, an aryl group has 5 to 10 carbon atoms. In some embodiments, an aryl group is phenyl or naphthyl. In some embodiments, an aryl group is phenyl.

如本文所用，「鹵基」係指F、Cl、Br或I。在一些實施例中，鹵基為F、Cl或Br。在一些實施例中，鹵基為F或Cl。在一些實施例中，鹵基為F。在一些實施例中，鹵基為Cl。As used herein, "halogen" refers to F, Cl, Br, or I. In some embodiments, the halogen group is F, Cl, or Br. In some embodiments, the halogen group is F or Cl. In some embodiments, the halogen group is F. In some embodiments, the halogen group is Cl.

如本文所用，「C_n-m鹵烷氧基」係指式-O-鹵烷基之基團，其具有n至m個碳原子。實例鹵烷氧基包括OCF₃及OCHF₂。在一些實施例中，鹵烷氧基僅經氟化。在一些實施例中，烷基具有1至6個、1至4個或1至3個碳原子。As used herein, "C_{n m} haloalkoxy" refers to a radical of the formula -O-haloalkyl having n to m carbon atoms. Example haloalkoxy radicals include OCF₃ and OCHF₂ . In some embodiments, the haloalkoxy radical is only fluorinated. In some embodiments, the alkyl radical has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

如本文所用，單獨或與其他術語組合使用之術語「C_n-m鹵烷基」係指具有1個鹵素原子至2s+1個可能相同或不同鹵素原子之烷基，其中「s」為該烷基中之碳原子數目，其中該烷基具有n至m個碳原子。在一些實施例中，鹵烷基僅經氟化。在一些實施例中，烷基具有1至6個、1至4個或1至3個碳原子。實例鹵烷基包括CF₃、C₂F₅、CHF₂、CH₂F、CCl₃、CHCl₂、C₂Cl₅及諸如此類。As used herein, the term "C_{n m} haloalkyl," alone or in combination with other terms, refers to an alkyl group having from 1 to 2s + 1 halogen atoms, which may be the same or different, where "s" is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is only fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Example haloalkyl groups include CF₃ , C₂ F₅ , CHF₂ , CH₂ F, CCl₃ , CHCl₂ , C₂ Cl₅ , and the like.

如本文所用，「環烷基」係指非芳香族環烴，包括環化烷基及烯基。環烷基可包括單環或多環(例如具有2個稠合環)基團、螺環及橋接環(例如橋接雙環烷基)。環烷基之成環碳原子可視情況經側氧基或硫橋基(例如C(O)或C(S))取代。環烷基之定義中亦包括具有一或多個與環烷基環稠合(亦即具有共同鍵)之芳香族環的部分，例如環戊烷、環己烷及諸如此類之苯并或噻吩基衍生物。含有稠合芳香族環之環烷基可經由任何成環原子連接，包括稠合芳香族環之成環原子。環烷基可具有3、4、5、6、7、8、9或10個成環碳(亦即C_3-10)。在一些實施例中，環烷基為C_3-10單環或雙環環烷基。在一些實施例中，環烷基為C_3-7單環環烷基。在一些實施例中，環烷基為C_4-7單環環烷基。在一些實施例中，環烷基為C_4-10螺環或橋接環烷基(例如橋接雙環烷基)。實例環烷基包括環丙基、環丁基、環戊基、環己基、環庚基、環戊烯基、環己烯基、環己二烯基、環庚三烯基、降莰基、降菔基(norpinyl)、降蒈基(norcarnyl)、立方烷、金剛烷、雙環[1.1.1]戊基、雙環[2.1.1]己基、雙環[2.2.1]庚烷基、雙環[3.1.1]庚烷基、雙環[2.2.2]辛烷基、螺[3.3]庚烷基及諸如此類。在一些實施例中，環烷基為環丙基、環丁基、環戊基或環己基。As used herein, "cycloalkyl" refers to non-aromatic cyclic hydrocarbons, including cyclized alkyl and alkenyl groups. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having two fused rings) groups, spirocyclic rings, and bridged rings (e.g., bridged bicyclic alkyl groups). The ring carbon atoms of a cycloalkyl group may be substituted with pendant oxy groups or sulfide bridge groups (e.g., C(O) or C(S)), as appropriate. The definition of cycloalkyl also includes moieties having one or more aromatic rings fused to (i.e., having a common bond with) a cycloalkyl ring, such as cyclopentane, cyclohexane, and such benzo- or thienyl derivatives. Cycloalkyl groups containing fused aromatic rings may be attached via any ring atom, including ring atoms of the fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring carbon atoms (i.e.,_C3-10 ). In some embodiments, cycloalkyl groups are_C3-10 monocyclic or bicyclic cycloalkyl groups. In some embodiments, cycloalkyl groups are_C3-7 monocyclic cycloalkyl groups. In some embodiments, cycloalkyl groups are_C4-7 monocyclic cycloalkyl groups. In some embodiments, cycloalkyl groups are_C4-10 spirocyclic or bridged cycloalkyl groups (e.g., bridged bicyclic cycloalkyl groups). Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, cubane, adamantane, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, spiro[3.3]heptyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

如本文所用，「雜芳基」係指具有至少一個選自N、O、S及B之雜原子環成員之單環或多環(例如具有2個稠合環)芳香族雜環。在一些實施例中，雜芳基環具有1、2、3或4個獨立地選自N、O、S及B之雜原子環成員。在一些實施例中，雜芳基部分中之任何成環N可為N-氧化物。在一些實施例中，雜芳基為具有1、2、3或4個獨立地選自N、O、S及B之雜原子環成員之5-10員單環或雙環雜芳基。在一些實施例中，雜芳基為具有1、2、3或4個獨立地選自N、O、S及B之雜原子環成員之5員、7員、8員、9員或10員單環或雙環雜芳基。在一些實施例中，雜芳基為具有1、2、3或4個獨立地選自N、O及S之雜原子環成員之5-10員單環或雙環雜芳基。在一些實施例中，雜芳基為具有1、2、3或4個獨立地選自N、O及S之雜原子環成員之5員、7員、8員、9員或10員單環或雙環雜芳基。在一些實施例中，雜芳基為具有1或2個獨立地選自N、O、S及B之雜原子環成員之5-6員單環雜芳基。在一些實施例中，雜芳基為具有1或2個獨立地選自N、O、S及B之雜原子環成員之5員單環雜芳基。在一些實施例中，雜芳基為具有1或2個獨立地選自N、O及S之雜原子環成員之5員單環雜芳基。在一些實施例中，雜芳基含有5至10個、5至7個、3至7個或5至6個成環原子。在一些實施例中，雜芳基具有1至4個成環雜原子、1至3個成環雜原子、1至2個成環雜原子或1個成環雜原子。當雜芳基含有一個以上之雜原子環成員時，雜原子可相同或不同。實例雜芳基包括(但不限於)噻吩基(thienyl或thiophenyl)、呋喃基(furyl或furanyl)、吡咯基、咪唑基、噻唑基、噁唑基、吡唑基、異噻唑基、異噁唑基、1,2,3-三唑基、四唑基、1,2,3-噻二唑基、1,2,3-噁二唑基、1,2,4-三唑基、1,2,4-噻二唑基、1,2,4-噁二唑基、1,3,4-三唑基、1,3,4-噻二唑基、1,3,4-噁二唑基及1,2-二氫-1,2-氮雜硼烷、吡啶基、嘧啶基、吡嗪基、嗒嗪基、吖唑基(azolyl)、三唑基、噻二唑基、喹啉基、異喹啉基、吲哚基、苯并噻吩基、苯并呋喃基、苯并異噁唑基、咪唑并[1,2-b]噻唑基、嘌呤基、三嗪基、噻吩并[3,2-b]吡啶基、咪唑并[1,2-a]吡啶基、1,5-萘啶基、1H-吡唑并[4,3-b]吡啶基、三唑并[4,3-a]吡啶基、1H-吡咯并[3,2-b]吡啶基、1H-吡咯并[2,3-b]吡啶基、吡唑并[1,5-a]吡啶基、吲唑基及諸如此類。As used herein, "heteroaryl" refers to a monocyclic or polycyclic (e.g., having two fused rings) aromatic heterocycle having at least one heteroatom ring member selected from N, O, S, and B. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, any ring-forming N in the heteroaryl moiety may be an N-oxide. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl group is a 5-, 7-, 8-, 9-, or 10-membered monocyclic or bicyclic heteroaryl group having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl group is a 5-10-membered monocyclic or bicyclic heteroaryl group having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl group is a 5-, 7-, 8-, 9-, or 10-membered monocyclic or bicyclic heteroaryl group having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl group is a 5-6 membered monocyclic heteroaryl group having 1 or 2 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl group is a 5 membered monocyclic heteroaryl group having 1 or 2 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl group is a 5 membered monocyclic heteroaryl group having 1 or 2 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl group contains 5 to 10, 5 to 7, 3 to 7, or 5 to 6 ring atoms. In some embodiments, the heteroaryl group has 1 to 4 ring-forming heteroatoms, 1 to 3 ring-forming heteroatoms, 1 to 2 ring-forming heteroatoms, or 1 ring-forming heteroatom. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. Examples of heteroaryl groups include, but are not limited to, thienyl (thiophenyl), furyl (furyl), pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, and 1,2-dihydro-1,2-azaborane, pyridyl, pyrimidine 1,5-naphthyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, triazolo[4,3-a]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, indazolyl, and the like.

如本文所用，「雜環烷基」係指具有至少一個非芳香族環(飽和或部分不飽和環)之單環或多環雜環，其中雜環烷基之一或多個成環碳原子經選自N、O、S及B之雜原子置換，且其中雜環烷基之成環碳原子及雜原子可視情況經一或多個側氧基或硫橋基(例如C(O)、S(O)、C(S)或S(O)₂等)取代。當雜環烷基之成環碳原子或雜原子視情況經一或多個側氧基或硫橋基取代時，該基團之O或S係本文所指定之成環原子數目以外的(例如，1-甲基-6-側氧基-1,6-二氫嗒嗪-3-基為6員雜環烷基，其中一個成環碳原子經側氧基取代，且其中該6員雜環烷基進一步經甲基取代)。雜環烷基包括單環及多環(例如具有2個稠合環)系統。雜環烷基包括3至10員、4至10員、5至10員、4至7員、5至7員或5至6員單環及多環雜環烷基。雜環烷基亦可包括螺環及橋接環(例如5至10員橋接雙雜環烷基環，其一或多個成環碳原子經獨立地選自N、O、S及B之雜原子置換)。雜環烷基可經由成環碳原子或成環雜原子連接。在一些實施例中，雜環烷基含有0至3個雙鍵。在一些實施例中，雜環烷基含有0至2個雙鍵。As used herein, "heterocycloalkyl" refers to a monocyclic or polycyclic heterocycle having at least one non-aromatic ring (saturated or partially unsaturated ring), wherein one or more ring-constituting carbon atoms of the heterocycloalkyl group are replaced by a heteroatom selected from N, O, S and B, and wherein the ring-constituting carbon atoms and heteroatoms of the heterocycloalkyl group may be substituted with one or more pendant oxy groups or sulfide bridge groups (e.g., C(O), S(O), C(S) or S(O)₂ , etc.). When the ring-forming carbon atoms or heteroatoms of the heterocycloalkyl group are optionally substituted with one or more oxo groups or sulfhydryl groups, the O or S group of the group is in addition to the number of ring atoms specified herein (e.g., 1-methyl-6-oxo-1,6-dihydropyridazin-3-yl is a 6-membered heterocycloalkyl group in which one ring-forming carbon atom is substituted with an oxo group, and wherein the 6-membered heterocycloalkyl group is further substituted with a methyl group). Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having two fused rings) systems. Heterocycloalkyl groups include 3-10, 4-10, 5-10, 4-7, 5-7, or 5-6 membered monocyclic and polycyclic heterocycloalkyl groups. Heterocycloalkyl groups may also include spiro rings and bridged rings (e.g., 5-10 membered bridged biheterocycloalkyl rings in which one or more ring carbon atoms are replaced by heteroatoms independently selected from N, O, S, and B). Heterocycloalkyl groups may be linked via ring carbon atoms or ring heteroatoms. In some embodiments, heterocycloalkyl groups contain 0 to 3 double bonds. In some embodiments, heterocycloalkyl groups contain 0 to 2 double bonds.

雜環烷基之定義中亦包括具有一或多個與非芳香族雜環稠合(亦即具有共同鍵)之芳香族環的部分，例如六氫吡啶、嗎啉、氮呯等之苯并或噻吩基衍生物。含有稠合芳香族環之雜環烷基可經由任何成環原子連接，包括稠合芳香族環之成環原子。The definition of heterocycloalkyl also includes moieties containing one or more aromatic rings fused to (i.e., sharing a common bond with) a non-aromatic heterocyclic ring, such as benzo- or thienyl derivatives of hexahydropyridine, morpholine, azophenone, etc. Heterocycloalkyl groups containing fused aromatic rings may be attached via any ring atom, including a ring atom of the fused aromatic ring.

在一些實施例中，雜環烷基含有3至10個成環原子、4至10個成環原子、4至8個成環原子、3至7個成環原子或5至6個成環原子。在一些實施例中，雜環烷基具有1至4個雜原子、1至3個雜原子、1至2個雜原子或1個雜原子。在一些實施例中，雜環烷基為4-6員單環雜環烷基，其具有1或2個獨立地選自N、O、S及B之雜原子且具有一或多個經氧化之環成員。在一些實施例中，雜環烷基為5-10員單環或雙環雜環烷基，其具有1、2、3或4個獨立地選自N、O、S及B之雜原子且具有一或多個經氧化之環成員。在一些實施例中，雜環烷基為5至10員單環或雙環雜環烷基，其具有1、2、3或4個獨立地選自N、O及S之雜原子且具有一或多個經氧化之環成員。在一些實施例中，雜環烷基為5至6員單環雜環烷基，其具有1、2、3或4個獨立地選自N、O及S之雜原子且具有一或多個經氧化之環成員。In some embodiments, the heterocycloalkyl group contains 3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, 4 to 8 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. In some embodiments, the heterocycloalkyl group is a 4-6 membered monocyclic heterocycloalkyl group having 1 or 2 heteroatoms independently selected from N, O, S, and B and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl group is a 5-10 membered monocyclic or bicyclic heterocycloalkyl group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, and B, and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl group is a 5-10 membered monocyclic or bicyclic heterocycloalkyl group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl group is a 5-6 membered monocyclic heterocycloalkyl group having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, and having one or more oxidized ring members.

實例雜環烷基包括吡咯啶-2-酮(或2-側氧基吡咯啶基)、1,3-異噁唑啶-2-酮、哌喃基、四氫哌喃、氧雜環丁烷基、氮雜環丁烷基、嗎啉基、硫嗎啉基、六氫吡嗪基、四氫呋喃基、四氫噻吩基、六氫吡啶基、吡咯啶基、異噁唑啶基、異噻唑啶基、吡唑啶基、噁唑啶基、噻唑啶基、咪唑啶基、氮雜環庚烷基、1,2,3,4-四氫異喹啉、四氫噻吩基、四氫噻吩基1,1-二氧化物、苯并氮雜環庚三烯(benzazapene)、氮雜雙環[3.1.0]己烷基、二氮雜雙環[3.1.0]己烷基、側氧基雙環[2.1.1]己烷基、氮雜雙環[2.2.1]庚烷基、二氮雜雙環[2.2.1]庚烷基、氮雜雙環[3.1.1]庚烷基、二氮雜雙環[3.1.1]庚烷基、氮雜雙環[3.2.1]辛烷基、二氮雜雙環[3.2.1]辛烷基、側氧基雙環[2.2.2]辛烷基、氮雜雙環[2.2.2]辛烷基、氮雜金剛烷基、二氮雜金剛烷基、側氧基-金剛烷基、氮雜螺[3.3]庚烷基、2-氮雜螺[3.3]庚烷基、二氮雜螺[3.3]庚烷基、氮雜螺[3.5]壬烷基、7-氮雜螺[3.5]壬烷基、側氧基-氮雜螺[3.3]庚烷基、氮雜螺[3.4]辛烷基、二氮雜螺[3.4]辛烷基、側氧基-氮雜螺[3.4]辛烷基、氮雜螺[2.5]辛烷基、二氮雜螺[2.5]辛烷基、氮雜螺[4.4]壬烷基、二氮雜螺[4.4]壬烷基、側氧基-氮雜螺[4.4]壬烷基、氮雜螺[4.5]癸烷基、二氮雜螺[4.5]癸烷基、二氮雜螺[4.4]壬烷基、側氧基-二氮雜螺[4.4]壬烷基、側氧基-二氫嗒嗪基、側氧基-2,6-二氮雜螺[3.4]辛烷基、側氧基六氫吡咯并[1,2-a]吡嗪基、3-側氧基六氫吡嗪基、側氧基-吡咯啶基、側氧基-吡啶基及諸如此類。Examples of heterocycloalkyl groups include pyrrolidin-2-one (or 2-oxopyrrolidinyl), 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyranyl, oxacyclobutanyl, azacyclobutanyl, oxolinyl, thiooxolinyl, hexahydropyrazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, hexahydropyridinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azacycloheptanyl, 1,2,3,4-tetrahydroisoquinoline, tetrahydrothiophenyl, tetrahydrothiophenyl 1,1-dioxide, benzazepine, benzazapene, azabicyclo[3.1.0]hexyl, diazabicyclo[3.1.0]hexyl, pentooxybicyclo[2.1.1]hexyl, azabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, azabicyclo[3.1.1]heptyl, diazabicyclo[3.1.1]heptyl, azabicyclo[3.2.1]octyl, diazabicyclo[3.2.1]octyl, pentooxybicyclo[2.2.2]octyl, azabicyclo[2 .2.2]octyl, azaadamantanyl, diazaadamantanyl, oxo-adamantanyl, azaspiro[3.3]heptyl, 2-azaspiro[3.3]heptyl, diazaspiro[3.3]heptyl, azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, oxo-azaspiro[3.3]heptyl, azaspiro[3.4]octyl, diazaspiro[3.4]octyl, oxo-azaspiro[3.4]octyl, azaspiro[2.5]octyl, diazaspiro[2.5]octyl , azaspiro[4.4]nonyl, diazaspiro[4.4]nonyl, oxo-azaspiro[4.4]nonyl, azaspiro[4.5]decyl, diazaspiro[4.5]decyl, diazaspiro[4.4]nonyl, oxo-diazaspiro[4.4]nonyl, oxo-dihydropyrazinyl, oxo-2,6-diazaspiro[3.4]octanyl, oxo-hexahydropyrrolo[1,2-a]pyrazinyl, 3-oxo-hexahydropyrazinyl, oxo-pyrrolidinyl, oxo-pyridinyl and the like.

如本文所用，「C_o-p環烷基-C_n-m烷基-」係指式環烷基-伸烷基-之基團，其中該環烷基具有o至p個碳原子且該伸烷基連接基團具有n至m個碳原子。As used herein, "C_{0 p} cycloalkyl-_{C n m} alkyl-" refers to a radical of the formula cycloalkyl-alkylene-, wherein the cycloalkyl group has o to p carbon atoms and the alkylene linking group has n to m carbon atoms.

如本文所用，「C_o-p芳基-C_n-m烷基-」係指式芳基-伸烷基-之基團，其中該芳基具有o至p個碳原子且該伸烷基連接基團具有n至m個碳原子。As used herein, "C_{0 p} aryl-_{C n m} alkyl-" refers to a radical of the formula aryl-alkylene-, wherein the aryl group has o to p carbon atoms and the alkylene linking group has n to m carbon atoms.

如本文所用，「雜芳基-C_n-m烷基-」係指式雜芳基-伸烷基-之基團，其中伸烷基連接基團具有n至m個碳原子。As used herein, "heteroaryl-C_{n m} alkyl-" refers to a radical of the formula heteroaryl-alkylene-, wherein the alkylene linking group has n to m carbon atoms.

如本文所用，「雜環烷基-C_n-m烷基-」係指式雜環烷基-伸烷基-之基團，其中伸烷基連接基團具有n至m個碳原子。As used herein, "heterocycloalkyl-_{C n m} alkyl-" refers to a radical of the formula heterocycloalkyl-alkylene-, wherein the alkylene linking group has n to m carbon atoms.

如本文所用，「烷基連接基團」或「伸烷基連接基團」為二價直鏈或具支鏈烷基連接基團(「伸烷基」)。舉例而言，「C_o-p環烷基-C_n-m烷基-」、「C_o-p芳基-C_n-m烷基-」、「苯基-C_n-m烷基-」、「雜芳基-C_n-m烷基-」及「雜環烷基-C_n-m烷基-」含有烷基連接基團。「烷基連接基團」或「伸烷基」之實例包括亞甲基、乙-1,1-二基、乙-1,2-二基、丙-1,3-二基、丙-1,2-二基、丙-1,1-二基及諸如此類。As used herein, an "alkyl linking group" or "alkylene linking group" is a divalent linear or branched alkyl linking group ("alkylene"). For example, "C_₁ ₇ alkyl-,""C ₁_₇ alkyl-,""C_₁ ₇ alkyl-,""phenyl-C_₇ alkyl-,""heteroaryl-_{C ₇alkyl-} ," and "heterocycloalkyl-C_₇ alkyl-" contain an alkyl linking group. Examples of "alkyl linking groups" or "alkylene" include methylene, ethane-1,1-diyl, ethane-1,2-diyl, propan-1,3-diyl, propan-1,2-diyl, propan-1,1-diyl, and the like.

如本文所用，「鹵烷基連接基團」或「伸鹵烷基連接基團」為二價直鏈或具支鏈鹵烷基連接基團(「伸鹵烷基」)。實例伸鹵烷基包括-CF₂-、-C₂F₄-、-CHF-、-CCl₂-、-CHCl-、-C₂Cl₄-及諸如此類。As used herein, a "haloalkyl linking group" or "haloalkylene linking group" is a divalent linear or branched haloalkyl linking group ("haloalkylene"). Example haloalkylene groups include_-CF2- ,_-C2F4- , -CHF-,_-CCl2- , -CHCl-,_-C2Cl4-, and_the like.

如本文所用，「環烷基連接基團」或「伸環烷基連接基團」為二價直鏈或具支鏈環烷基連接基團(「伸環烷基」)。「環烷基連接基團」或「伸環烷基」之實例包括環丙-1,1,-二基、環丙-1,2-二基、環丁-1,3,-二基、環戊-1,3,-二基、環戊-1,4,-二基、環己-1,2,-二基、環己-1,3,-二基、環己-1,4,-二基及諸如此類。As used herein, a "cycloalkyl linking group" or "cycloalkylene linking group" is a divalent linear or branched cycloalkyl linking group ("cycloalkylene"). Examples of "cycloalkyl linking groups" or "cycloalkylene" include cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane-1,3-diyl, cyclopentane-1,3-diyl, cyclopentane-1,4-diyl, cyclohexane-1,2-diyl, cyclohexane-1,3-diyl, cyclohexane-1,4-diyl, and the like.

如本文所用，「雜環烷基連接基團」或「伸雜環烷基連接基團」為二價直鏈或具支鏈雜環烷基連接基團(「伸雜環烷基」)。「雜環烷基連接基團」或「伸雜環烷基」之實例包括氮雜環丁-1,2-二基、氮雜環丁-1,3-二基、吡咯啶-1,2-二基、吡咯啶-1,3-二基、吡咯啶-2,3-二基、六氫吡啶-1,2-二基、六氫吡啶-1,3-二基、六氫吡啶-1,4-二基、六氫吡啶-2,3-二基、六氫吡啶-2,4-二基及諸如此類。As used herein, a "heterocycloalkyl linking group" or "heterocycloalkylene linking group" is a divalent linear or branched heterocycloalkyl linking group ("heterocycloalkylene"). Examples of "heterocycloalkyl linking groups" or "heterocycloalkylene" include azacyclobutane-1,2-diyl, azacyclobutane-1,3-diyl, pyrrolidine-1,2-diyl, pyrrolidine-1,3-diyl, pyrrolidine-2,3-diyl, hexahydropyridine-1,2-diyl, hexahydropyridine-1,3-diyl, hexahydropyridine-1,4-diyl, hexahydropyridine-2,3-diyl, hexahydropyridine-2,4-diyl, and the like.

如本文所用，「雜芳基連接基團」或「伸雜芳基連接基團」為二價直鏈或具支鏈雜芳基連接基團(「伸雜芳基」)。「雜芳基連接基團」或「伸雜芳基」之實例包括吡唑-1,3-二基、咪唑-1,2,-二基、吡啶-2,3-二基、吡啶-2,4-二基、吡啶-3,4-二基及諸如此類。As used herein, a "heteroaryl linking group" or "heteroaryl-extended linking group" is a divalent linear or branched heteroaryl linking group ("heteroaryl-extended"). Examples of "heteroaryl linking groups" or "heteroaryl-extended" groups include pyrazole-1,3-diyl, imidazole-1,2-diyl, pyridine-2,3-diyl, pyridine-2,4-diyl, pyridine-3,4-diyl, and the like.

在某些地方，定義或實施例係指具體環(例如氮雜環丁烷環、吡啶環等)。除非另有指示，否則該等環可連接至任何環成員，前提條件為不超過原子之化合價。舉例而言，氮雜環丁烷環可連接在環之任何位置，而吡啶-3-基環則連接在3位。In some places, definitions or examples refer to specific rings (e.g., azacyclobutane ring, pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member, provided that the valence of the atom is not exceeded. For example, the azacyclobutane ring can be attached at any position of the ring, while the pyridin-3-yl ring is attached at the 3-position.

如本文所用，術語「側氧基」係指作為二價取代基之氧原子(亦即=O)，其在連接至碳時形成羰基(例如C=O或C(O))，或連接至氮或硫雜原子形成亞硝基、亞磺醯基或磺醯基。As used herein, the term "oxy" refers to an oxygen atom (i.e., =O) as a divalent substituent that forms a carbonyl group (e.g., C=O or C(O)) when attached to a carbon atom, or forms a nitroso, sulfinyl, or sulfonyl group when attached to a nitrogen or sulfur atom.

如本文所用，術語「獨立地選自」意味著每次出現之變數或取代基(例如每一R^G)在每次出現時獨立地選自適用清單。As used herein, the term "independently selected from" means that each occurrence of the variable or substituent (eg, each R^G ) is independently selected from the applicable list at each occurrence.

本文所闡述之化合物可不對稱(例如具有一或多個立體中心)。除非另有指示，否則預期所有立體異構物，諸如鏡像異構物及非鏡像異構物。含有不對稱取代之碳原子的本揭示案之化合物可以光學活性形式或外消旋形式分離。此項技術中已知由光學無活性起始材料製備光學活性形式之方法，諸如藉由拆分外消旋混合物或藉由立體選擇性合成來製備。烯烴、C=N雙鍵及諸如此類之許多幾何異構物亦可存在於本文所描述之化合物中，且本發明中考慮所有此等穩定異構物。本揭示案之化合物之順式及反式幾何異構物已有闡述，且可以異構物混合物形式或以分開的異構形式分離。在一些實施例中，化合物具有(R)-構形。在一些實施例中，化合物具有(S)-構形。本文所提供之各式(例如式I、式II等)包括化合物之立體異構物。The compounds described herein may not be symmetric (e.g., have one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as mirror and non-mirror isomers, are contemplated. Compounds of the present disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials are known in the art, such as by resolving racemic mixtures or by stereoselective synthesis. Numerous geometric isomers of alkenes, C=N double bonds, and the like may also exist in the compounds described herein, and all such stable isomers are contemplated in the present invention. The compounds of the present disclosure have been described as cis and trans geometric isomers and can be isolated as mixtures of isomers or as separated isomers. In some embodiments, the compounds have an (R)-configuration. In some embodiments, the compounds have an (S)-configuration. The formulae provided herein (e.g., Formula I, Formula II, etc.) include stereoisomers of the compounds.

化合物之外消旋混合物之拆分可藉由此項技術中已知之眾多方法中之任一者實施。實例方法包括使用手性拆分酸之分段再結晶，該手性拆分酸為光學活性成鹽有機酸。用於分段再結晶方法之適宜拆分劑為(例如)光學活性酸，諸如D及L形式之酒石酸、二乙醯基酒石酸、二苯甲醯基酒石酸、苦杏仁酸、蘋果酸、乳酸或各種光學活性樟腦磺酸，諸如β-樟腦磺酸。適用於分段結晶方法之其他拆分劑包括α-甲基苄胺之立體異構純形式(例如S及R形式或非鏡像異構純形式)、2-苯基甘胺醇、去甲麻黃鹼、麻黃鹼、N-甲基麻黃鹼、環己基乙胺、1,2-二胺基環己烷及諸如此類。Resolution of a racemic mixture of compounds can be achieved by any of a variety of methods known in the art. An example method includes fractional recrystallization using a chiral resolving acid that is an optically active, salt-forming organic acid. Suitable resolving agents for the fractional recrystallization method are, for example, optically active acids such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Other resolving agents suitable for use in the fractional crystallization method include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms or non-mirrorally pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

亦可藉由在填充有光學活性拆分劑(例如二硝基苯甲醯基苯基甘胺酸)之管柱上溶析來拆分外消旋混合物。適宜溶析溶劑組成可由熟習此項技術者確定。The racemic mixture can also be resolved by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). The composition of the appropriate elution solvent can be determined by one skilled in the art.

本文所提供之化合物亦包括互變異構形式。互變異構形式源自單鍵與毗鄰雙鍵之調換以及質子之伴隨遷移。互變異構形式包括質子移變互變異構物，其為具有相同經驗式及總電荷之異構質子化狀態。實例質子移變互變異構物包括酮-烯醇對、醯胺-亞胺酸對、內醯胺-內醯亞胺對、烯胺-亞胺對及其中質子可佔據雜環系統之兩個或更多個位置之環形形式，例如1H-及3H-咪唑、1H-、2H-及4H-1,2,4-三唑、1H-及2H-異吲哚、2-羥基吡啶及2-吡啶酮以及1H-及2H-吡唑。互變異構形式可呈平衡狀態或藉由適當取代在空間上鎖定成一種形式。The compounds provided herein also include tautomeric forms. Tautomeric forms arise from the swapping of single bonds for adjacent double bonds and the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include keto-enol pairs, amide-imidic acid pairs, lactamide-lactimide pairs, enamine-imine pairs, and cyclic forms in which a proton can occupy two or more positions in a heterocyclic system, such as 1H- and 3H-imidazoles, 1H-, 2H-, and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, 2-hydroxypyridines and 2-pyridones, and 1H- and 2H-pyrazoles. Tautomeric forms can exist in equilibrium or be sterically locked into one form by appropriate substitution.

所有化合物及其醫藥學上可接受之鹽可與其他物質(諸如水及溶劑)一起發現(例如水合物及溶劑合物)，或可分離。All compounds and their pharmaceutically acceptable salts may be found together with other substances, such as water and solvents (e.g., hydrates and solvates), or may be isolated.

在一些實施例中，化合物之製備可涉及添加酸或鹼以影響例如期望反應之催化或鹽形式(諸如酸加成鹽)之形成。In some embodiments, preparation of the compounds may involve the addition of an acid or base to effect, for example, catalysis of a desired reaction or the formation of a salt form (such as an acid addition salt).

在一些實施例中，本文所提供之化合物或其鹽實質上經分離。「實質上經分離」意指化合物與形成或偵測到該化合物之環境至少部分地或實質上分離。部分分離可包括(例如)富含本文所提供之化合物之組合物。實質上分離可包括含有至少約50重量%、至少約60重量%、至少約70重量%、至少約80重量%、至少約90重量%、至少約95重量%、至少約97重量%或至少約99重量%之本文所提供之化合物或其鹽之組合物。In some embodiments, the compounds provided herein, or salts thereof, are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial isolation can include, for example, a composition enriched with a compound provided herein. Substantially isolated can include a composition containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of a compound provided herein, or salt thereof.

如本文所用之術語「化合物」意欲包括所繪示結構之所有立體異構物、幾何異構物、互變異構物及同位素。除非另有指定，否則本文藉由名稱或結構鑑別為一種特定互變異構形式之化合物意欲包括其他互變異構形式。As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of a depicted structure. Unless otherwise specified, a compound identified herein as a particular tautomeric form by name or structure is intended to include the other tautomeric forms.

片語「醫藥學上可接受」在本文中用以指在合理醫學判斷範圍內適用於與人類及動物之組織接觸而無過度毒性、刺激、過敏反應或其他問題或併發症且與合理益處/風險比相稱之彼等化合物、材料、組合物及/或劑型。The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and/or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response or other problems or complications and are commensurate with a reasonable benefit/risk ratio.

本申請案亦包括本文所闡述化合物之醫藥學上可接受之鹽。如本文所用，「醫藥學上可接受之鹽」係指所揭示化合物之衍生物，其中母體化合物藉由將現有酸或鹼部分轉化成其鹽形式而經修飾。醫藥學上可接受之鹽之實例包括(但不限於)鹼性殘基(諸如胺)之礦物酸鹽或有機酸鹽；酸性殘基(諸如羧酸)之鹼性鹽或有機鹽；及諸如此類。本揭示案之醫藥學上可接受之鹽包括由例如無毒無機酸或有機酸形成的母體化合物之習用無毒鹽。本揭示案之醫藥學上可接受之鹽可藉由習用化學方法由含有鹼性或酸性部分之母體化合物來合成。通常，此等鹽可藉由使該等化合物之游離酸或鹼形式與化學計算量之適當鹼或酸在水中或在有機溶劑中或在兩者之混合物中反應來製備；通常，非水性介質如乙醚、乙酸乙酯、醇(例如甲醇、乙醇、異丙醇或丁醇)或乙腈(ACN)較佳。適宜鹽之清單參見Remington's Pharmaceutical Sciences，第17版，Mack Publishing Company, Easton, Pa., 1985，第1418頁及Journal of Pharmaceutical Science, 66, 2 (1977)，其各自係以全文引用的方式併入本文中。合成This application also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound has been modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; basic or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts of the present disclosure include customary nontoxic salts of the parent compound formed, for example, from nontoxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of the compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (ACN) are preferred. For lists of suitable salts, see Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.Synthesis

本發明之化合物(包括其鹽)可使用已知之有機合成技術且根據各種可能的合成途徑來製備。下文方案中提供用於製備本發明化合物之實例合成方法。The compounds of the present invention (including their salts) can be prepared using known organic synthesis techniques and according to various possible synthetic routes. The following schemes provide exemplary synthetic methods for preparing the compounds of the present invention.

式I-12化合物可例如使用方案I中所示之製程來合成。利用適宜試劑(例如N-溴琥珀醯亞胺)使I-1鹵化可得到I-2。化合物I-2可經由醯胺偶合轉化成I-3，在用適宜試劑(例如三光氣)處理I-3後，其接著轉化成I-4。可藉由用適宜試劑(例如POCl₃)處理I-4製備中間體I-5。可藉由包括使中間體I-5與試劑I-6接觸之製程來製備化合物I-7。可自I-7經由適宜反應(例如過渡金屬催化之交叉偶合反應)、之後還原反應來製備化合物I-8。可藉由用適宜試劑(例如PBr₃)處理I-8來製備中間體I-9。可經由使I-9與適宜親核劑反應、之後去保護來獲得I-11。最後，I-11可經由醯胺偶合反應轉化成I-12。方案I.Compounds of formulaI-12 can be synthesized, for example, using the process shown inScheme 1. Halogenationof I-1 using a suitable reagent (e.g., N-bromosuccinimide) can provideI-2 . CompoundI-2 can be converted toI-3 via amide coupling, which, after treatment with a suitable reagent (e.g., triphosgene), is then converted toI-4 . IntermediateI-5 can be prepared by treatingI-4 with a suitable reagent (e.g., POCl₃ ). CompoundI-7 can be prepared by a process comprising contacting intermediateI-5 with reagentI-6 . CompoundI-8 can be prepared fromI-7 via a suitable reaction (e.g., a transition metal-catalyzed cross-coupling reaction) followed by reduction. IntermediateI-9 can be prepared by treatingI-8 with a suitable reagent (e.g., PBr₃ ).I-11 can be obtained by reactingI-9 with a suitable nucleophile followed by deprotection. Finally,I-11 can be converted toI-12 via an amide coupling reaction.Scheme I.

式II-3化合物可例如使用方案II中所示之製程來合成。可在鹼性條件下在適宜試劑(例如N-碘琥珀醯亞胺)存在下經由使II-1去羧鹵化來製備化合物II-2。II-2可經由適宜條件(例如金屬催化之交叉偶合反應)轉化成II-3。方案II.Compounds of formulaII-3 can be synthesized, for example, using the process shown inScheme II . CompoundII-2 can be prepared by decarboxylationof II-1 in the presence of a suitable reagent (e.g., N-iodosuccinimide) under alkaline conditions.II-2 can be converted toII-3 under suitable conditions (e.g., a metal-catalyzed cross-coupling reaction).Scheme II.

用於製備本發明化合物之反應可在適宜溶劑中進行，該等溶劑可由熟習有機合成技術者容易地選擇。適宜溶劑在進行反應之溫度(例如，範圍可為溶劑之冷凍溫度至溶劑之沸騰溫度之溫度)下可實質上不與起始材料(反應物)、中間體或產物反應。給定反應可在一種溶劑或一種以上溶劑之混合物中進行。端視於特定反應步驟而定，熟習此項技術者可選擇用於特定反應步驟之適宜溶劑。Reactions used to prepare the compounds of the present invention can be carried out in suitable solvents, which can be readily selected by those skilled in the art of organic synthesis. Suitable solvents are substantially unreactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out (e.g., temperatures ranging from the solvent's freezing temperature to the solvent's boiling temperature). A given reaction can be carried out in a single solvent or a mixture of more than one solvent. Depending on the particular reaction step, one skilled in the art can select a suitable solvent for a particular reaction step.

本發明化合物之製備可涉及各種化學基團之保護及去保護。熟習此項技術者可容易地確定保護及去保護之需要以及適當保護基團之選擇。保護基團之化學可參見(例如) T.W. Greene及P.G.M. Wuts，Protective Groups in Organic Synthesis，第3版，Wiley & Sons, Inc., New York (1999)，其係以全文引用的方式併入本文中。The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. Those skilled in the art can readily determine the need for protection and deprotection and the selection of appropriate protecting groups. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts,Protective Groups in Organic Synthesis , 3rd ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

可根據此項技術中已知之任何適宜方法來監測反應。舉例而言，產物形成可藉由光譜學手段(諸如核磁共振光譜法(例如¹H或¹³C)、紅外光譜法、分光光度法(例如UV-可見)或質譜法)或藉由層析(諸如高效液相層析(HPLC)或薄層層析)來監測。The reaction can be monitored by any suitable method known in the art. For example, product formation can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g.,¹ H or¹³ C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

如本文所用，表述「環境溫度」、「室溫」及「r.t.」為此項技術中所理解，且通常係指約為實施反應之房間溫度之溫度(例如反應溫度)，例如約20℃至約30℃之溫度。使用方法As used herein, the expressions "ambient temperature,""roomtemperature," and "rt" are understood in the art and typically refer to a temperature about the temperature of the room in which the reaction is conducted (e.g., reaction temperature), forexample , a temperature of about 20°C to about 30°C.

本揭示案提供本文所闡述之化合物及組合物之用途。本文所闡述之化合物可抑制PI3Kα激酶之活性。在一些實施例中，所提供之化合物及組合物用於醫學(例如作為療法)。在一些實施例中，所提供之化合物及組合物可用於治療疾病、病症或疾患，其中潛在病理完全或部分地由PI3Kα介導。在一些實施例中，所提供之化合物及組合物在研究中可用作(例如)生物分析中之分析工具及/或對照化合物。This disclosure provides uses of the compounds and compositions described herein. The compounds described herein can inhibit the activity of PI3Kα kinase. In some embodiments, the provided compounds and compositions are used in medicine (e.g., as a therapy). In some embodiments, the provided compounds and compositions can be used to treat a disease, condition, or disorder in which the underlying pathology is mediated, in whole or in part, by PI3Kα. In some embodiments, the provided compounds and compositions can be used in research, for example, as analytical tools and/or control compounds in biological assays.

在一些實施例中，本揭示案提供向有需要之個體投與所提供化合物或組合物之方法。在一些實施例中，本揭示案提供向患有或易患與PI3Kα相關之疾病、病症或疾患之個體投與所提供化合物或組合物之方法。在一些實施例中，本揭示案提供向患有或易患疾病、病症或疾患之個體投與所提供化合物或組合物之方法，其中潛在病理完全或部分地由PI3Kα介導。In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject in need thereof. In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject suffering from or susceptible to a disease, disorder, or condition associated with PI3Kα. In some embodiments, the present disclosure provides methods of administering provided compounds or compositions to a subject suffering from or susceptible to a disease, disorder, or condition in which the underlying pathology is mediated in whole or in part by PI3Kα.

在一些實施例中，本文所提供之化合物可用作PI3Kα抑制劑。在一些實施例中，本揭示案提供抑制個體體內之PI3Kα之方法，其包括投與所提供之化合物或組合物。在一些實施例中，本揭示案提供抑制生物樣品中之PI3Kα之方法，其包括使該樣品與所提供之化合物或組合物接觸。In some embodiments, the compounds provided herein can be used as PI3Kα inhibitors. In some embodiments, the present disclosure provides methods for inhibiting PI3Kα in a subject, comprising administering a provided compound or composition. In some embodiments, the present disclosure provides methods for inhibiting PI3Kα in a biological sample, comprising contacting the sample with a provided compound or composition.

在一些實施例中，本揭示案提供治療有需要之個體的與PI3Kα相關之疾病、病症或疾患之方法，其包括向該個體投與本揭示案之化合物、鹽或組合物。在一些實施例中，疾病、病症或疾患與PI3Kα之突變相關。在一些實施例中，本揭示案提供治療有需要之個體的疾病、病症或疾患之方法，其中潛在病理完全或部分地由PI3Kα介導，該等方法包括向該個體投與所提供之化合物或組合物。In some embodiments, the present disclosure provides methods for treating a disease, disorder, or condition associated with PI3Kα in a subject in need thereof, comprising administering to the subject a compound, salt, or composition of the present disclosure. In some embodiments, the disease, disorder, or condition is associated with a mutation in PI3Kα. In some embodiments, the present disclosure provides methods for treating a disease, disorder, or condition in a subject in need thereof, wherein the underlying pathology is mediated in whole or in part by PI3Kα, comprising administering to the subject a provided compound or composition.

在一些實施例中，本揭示案提供治療多種PI3Kα依賴性疾病及病症之方法。在一些實施例中，疾病或病症為癌症(例如乳癌、腦癌、前列腺癌、子宮內膜癌、胃癌、白血病、淋巴瘤、肉瘤、結腸直腸癌、肺癌、卵巢癌、皮膚癌及頭頸癌)。在一些實施例中，與PI3Kα相關之疾病或病症包括(但不限於) CLOVES症候群(先天性脂肪瘤過度生長、血管畸形、表皮痣、脊柱側彎/骨骼及脊柱症候群)、PIK3CA相關之過度生長症候群(PROS)、子宮內膜癌、乳癌、食管鱗狀細胞癌、子宮頸鱗狀細胞癌、子宮頸腺癌、結腸直腸腺癌、膀胱尿路上皮癌、神經膠母細胞瘤、卵巢癌、非小細胞肺癌、食管胃癌、神經鞘瘤、頭頸部鱗狀細胞癌、黑色素瘤、食管胃腺癌、軟組織肉瘤、前列腺癌、纖維板層癌、肝細胞癌、瀰漫性神經膠質瘤、結腸直腸癌、胰臟癌、膽道癌、B細胞淋巴瘤、間皮瘤、腎上腺皮質癌、腎非透明細胞癌、腎透明細胞癌、生殖細胞癌、胸腺腫瘤、嗜鉻細胞瘤、混雜性神經上皮瘤、甲狀腺癌、白血病及包裹性神經膠質瘤。在一些實施例中，癌症為乳癌。In some embodiments, the present disclosure provides methods for treating a variety of PI3Kα-dependent diseases and conditions. In some embodiments, the disease or condition is cancer (e.g., breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, and head and neck cancer). In some embodiments, diseases or conditions associated with PI3Kα include (but are not limited to) CLOVES syndrome (congenital lipomatous hyperplasia, vascular malformations, epidermal nevus, scoliosis/skeletal and spinal syndrome), PIK3CA-related hyperplasia syndrome (PROS), endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, neuroglioblastoma, ovarian cancer, non-small cell lung cancer, esophageal and gastric cancer, and neurotheliomas , head and neck squamous cell carcinoma, melanoma, esophageal and gastric adenocarcinoma, soft tissue sarcoma, prostate cancer, lamina fibrosa, hepatocellular carcinoma, diffuse neuroglioma, colorectal cancer, pancreatic cancer, gallbladder cancer, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, renal non-clear cell carcinoma, renal clear cell carcinoma, germ cell carcinoma, thymic tumor, pheochromocytoma, mixed neuroepithelioma, thyroid cancer, leukemia, and encapsulated neuroglioma. In some embodiments, the cancer is breast cancer.

在一些實施例中，本文提供延長患者之存活期或無進展存活期之方法，其包括向該患者投與本文所提供之化合物。在一些實施例中，患者患有癌症。在一些實施例中，患者患有本文所闡述之疾病或病症。如本文所用，無進展存活期係指在實體腫瘤治療期間及之後，患者與疾病共存但該疾病未惡化之時間長度。無進展存活期可指自首次投與化合物直至死亡或疾病進展中較早者之時間長度。疾病進展可由RECIST 1.1版(實體腫瘤中之反應評估準則)定義，如由獨立的集中放射學審議委員會所評價。在一些實施例中，投與化合物產生大於約1個月、約2個月、約3個月、約4個月、約5個月、約6個月、約8個月、約9個月、約12個月、約16個月或約24個月之無進展存活期。在一些實施例中，投與化合物產生至少約1個月、約2個月、約3個月、約4個月、約5個月、約6個月、約8個月、約9個月或約12個月；且少於約24個月、約16個月、約12個月、約9個月、約8個月、約6個月、約5個月、約4個月、約3個月或約2個月之無進展存活期。在一些實施例中，投與化合物使得無進展存活期延長至少約1個月、約2個月、約3個月、約4個月、約5個月、約6個月、約8個月、約9個月或約12個月；且少於約24個月、約16個月、約12個月、約9個月、約8個月、約6個月、約5個月、約4個月、約3個月或約2個月。In some embodiments, provided herein are methods for extending a patient's survival or progression-free survival, comprising administering to the patient a compound provided herein. In some embodiments, the patient suffers from cancer. In some embodiments, the patient suffers from a disease or condition as described herein. As used herein, progression-free survival refers to the length of time during and after treatment of a solid tumor that the patient coexists with the disease but the disease does not worsen. Progression-free survival may refer to the length of time from the first administration of a compound until death or disease progression, whichever is earlier. Disease progression may be defined by RECIST version 1.1 (Response Evaluation Criteria in Solid Tumors), as assessed by an independent centralized radiology review committee. In some embodiments, administration of the compound results in a progression-free survival of greater than about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, about 12 months, about 16 months, or about 24 months. In some embodiments, administration of the compound results in a progression-free survival of at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, or about 12 months; and less than about 24 months, about 16 months, about 12 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, or about 2 months. In some embodiments, administration of the compound prolongs progression-free survival by at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, or about 12 months; and less than about 24 months, about 16 months, about 12 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, or about 2 months.

本揭示案進一步提供本文所闡述之化合物或其醫藥學上可接受之鹽，其用於本文所闡述之任一方法中。The disclosure further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

本揭示案進一步提供本文所闡述之化合物或其醫藥學上可接受之鹽之用途，其用於製備用於本文所闡述之任一方法中之藥劑。The present disclosure further provides the use of a compound described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein.

如本文所用，術語「細胞」意欲指活體外、離體或活體內細胞。在一些實施例中，離體細胞可為自生物體(諸如哺乳動物)切除之組織樣品之一部分。在一些實施例中，活體外細胞可為細胞培養物中之細胞。在一些實施例中，活體內細胞為生活在生物體(諸如哺乳動物)中之細胞。As used herein, the term "cell" is intended to refer to cells in vitro, in vitro, or in vivo. In some embodiments, an in vitro cell may be part of a tissue sample removed from an organism (such as a mammal). In some embodiments, an in vitro cell may be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism (such as a mammal).

如本文所用，術語「接觸」係指使活體外系統或活體內系統中之指示部分置於一起。舉例而言，使PI3Kα激酶與本文所闡述之化合物「接觸」包括向具有PI3Kα激酶之個體或患者(諸如人類)投與本文所闡述之化合物，以及例如將本文所闡述之化合物引入至含有含PI3Kα激酶之細胞或經純化製劑之樣品中。As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro or in vivo system. For example, "contacting" a PI3Kα kinase with a compound described herein includes administering a compound described herein to an individual or patient (e.g., a human) possessing a PI3Kα kinase, as well as, for example, introducing a compound described herein into a sample containing cells or purified preparations containing a PI3Kα kinase.

如本文所用，術語「個體」或「患者」可互換使用，其係指任何動物，包括哺乳動物，較佳小鼠、大鼠、其他齧齒類動物、兔、狗、貓、豬、牛、綿羊、馬或靈長類動物，且最佳為人類。As used herein, the terms "subject" or "patient" are used interchangeably and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

如本文所用，片語「治療有效量」係指引發研究者、獸醫師、醫師或其他臨床醫師所尋求之組織、系統、動物、個體或人類之生物或醫學反應的活性化合物或醫藥劑之量，諸如如本文所揭示之任一固體形式或其鹽之量。可使用熟習此項技術者已知之技術確定任何個別病例中之適當「有效」量。As used herein, the phrase "therapeutically effective amount" refers to the amount of an active compound or pharmaceutical agent, such as any solid form or salt thereof disclosed herein, that elicits the biological or medical response of a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, physician, or other clinician. The appropriate "effective" amount in any individual case can be determined using techniques known to those skilled in the art.

片語「醫藥學上可接受」在本文中用於指在合理醫學判斷範圍內適用於與人類及動物之組織接觸而無過度毒性、刺激、過敏反應、免疫原性或其他問題或併發症且與合理益處/風險比相稱之彼等化合物、材料、組合物及/或劑型。The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and/or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications, and are commensurate with a reasonable benefit/risk ratio.

如本文所用，片語「醫藥學上可接受之載劑或賦形劑」係指醫藥學上可接受之材料、組合物或媒劑，諸如液體或固體填充劑、稀釋劑、溶劑或囊封材料。賦形劑或載劑通常安全、無毒且既不在生物學上亦不在其他方面不合意，且包括對於獸醫學用途以及人類醫藥用途可接受之賦形劑或載劑。在一個實施例中，每一組分為如本文所定義之「醫藥學上可接受」的。例如，參見Remington: The Science and Practice ofPharmacy，第21版; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005；Handbook of Pharmaceutical Excipients，第6版;Rowe等人編輯; The Pharmaceutical Press and the American Pharmaceutical Association: 2009；Handbook of Pharmaceutical Additives，第3版;Ash及Ash編輯; Gower Publishing Company: 2007；Pharmaceutical Preformulation and Formulation，第2版;Gibson編輯; CRC Press LLC: Boca Raton, Fla., 2009。As used herein, the phrase "pharmaceutically acceptable carrier or excipient" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients or carriers are generally safe, non-toxic, and neither biologically nor otherwise undesirable, and include excipients or carriers that are acceptable for veterinary as well as human pharmaceutical use. In one embodiment, each component is "pharmaceutically acceptable" as defined herein. See, e.g.,Remington: The Science and Practice ofPharmacy , 21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005;Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009;Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash, eds.; Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson, ed.; CRC Press LLC: Boca Raton, Fla., 2009.

如本文所用，術語「治療(treating或treatment)」係指抑制疾病；例如，抑制正在經歷或展示疾病、疾患或病症之病狀或症狀之個體的疾病、疾患或病症(亦即，阻止病狀及/或症狀之進一步發展)，或改善疾病；例如，改善正在經歷或展示疾病、疾患或病症之病狀或症狀之個體的疾病、疾患或病症(亦即，逆轉病狀及/或症狀)，諸如減輕疾病之嚴重程度。As used herein, the terms "treating" or "treatment" refer to inhibiting the disease; e.g., inhibiting the disease, disorder or condition in a subject who is experiencing or exhibiting signs or symptoms of the disease, disorder or condition (i.e., arresting further development of the signs and/or symptoms), or ameliorating the disease; e.g., ameliorating the disease, disorder or condition in a subject who is experiencing or exhibiting signs or symptoms of the disease, disorder or condition (i.e., reversing the signs and/or symptoms), such as reducing the severity of the disease.

在一些實施例中，本發明之化合物可用於預防或降低發生本文所提及之任何疾病之風險；例如，預防或降低可能易患疾病、疾患或病症、但尚未經歷或展示疾病之病狀或症狀之個體發生該疾病、疾患或病症之風險。In some embodiments, the compounds of the invention can be used to prevent or reduce the risk of developing any of the diseases mentioned herein; for example, to prevent or reduce the risk of developing a disease, disorder or condition in an individual who may be susceptible to the disease, disorder or condition but has not yet experienced or displayed signs or symptoms of the disease.

應瞭解，本揭示案為清晰起見在單獨實施例之上下文中闡述之某些特徵亦可在單一實施例中組合提供(而該等實施例意欲如同以多重依賴形式書寫一般來組合)。相反，本揭示案為簡便起見在單一實施例之上下文中闡述之各種特徵亦可單獨地或以任何適宜子組合提供。組合療法It will be appreciated that certain features of this disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment (and such embodiments are intended to be combined as if written in multiple dependency form). Conversely, various features of this disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.Combination Therapy

一或多種額外治療劑諸如化學治療劑或其他抗癌劑、抗炎劑、類固醇、免疫抑制劑、麻醉劑(例如用於與手術程序組合使用)或可用於治療與PI3Kα相關之疾病之其他劑可與本文所提供之化合物及鹽組合使用。該等劑可與本發明化合物組合於單一劑型中，或該等劑可作為單獨劑型同時或依序投與。One or more additional therapeutic agents, such as chemotherapeutics or other anticancer agents, anti-inflammatory agents, steroids, immunosuppressants, anesthetics (e.g., for use in conjunction with surgical procedures), or other agents useful for treating diseases associated with PI3Kα, can be used in combination with the compounds and salts provided herein. These agents can be combined with the compounds of the present invention in a single dosage form, or these agents can be administered simultaneously or sequentially as separate dosage forms.

本文所闡述之化合物可與一或多種其他激酶抑制劑組合使用，以供治療受多種信號傳導路徑影響之疾病，諸如癌症。舉例而言，組合可包括以下激酶之一或多種抑制劑以供治療癌症：Akt1、Akt2、Akt3、TGF-βR、Pim、PKA、PKG、PKC、CaM激酶、磷酸化酶激酶、CDK4/6、MEKK、ERK、MAPK、mTOR、EGFR、HER2、HER3、HER4、INS-R、IGF-1R、IR-R、PDGFαR、PDGFβR、CSFIR、KIT、FLK-II、KDR/FLK-1、FLK-4、flt-1、FGFR1、FGFR2、FGFR3、FGFR4、c-Met、Ron、Sea、TRKA、TRKB、TRKC、FLT3、VEGFR/Flt2、Flt4、EphA1、EphA2、EphA3、EphB2、EphB4、Tie2、Src、Fyn、Lck、Fgr、Btk、Fak、SYK、FRK、JAK、ABL、ALK及B-Raf。另外，如本文所闡述抑制劑之固體形式可與同PIK3/Akt/mTOR信號傳導路徑相關之激酶(諸如PI3K、Akt (包括Akt1、Akt2及Akt3)及mTOR激酶)之抑制劑組合。The compounds described herein can be used in combination with one or more other kinase inhibitors for the treatment of diseases affected by various signaling pathways, such as cancer. For example, a combination can include one or more inhibitors of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, TGF-βR, Pim, PKA, PKG, PKC, CaM kinase, phosphorylase kinase, CDK4/6, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT, FLK-II, KDR /FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf. In addition, the solid forms of the inhibitors described herein can be combined with inhibitors of kinases associated with the PIK3/Akt/mTOR signaling pathway, such as PI3K, Akt (including Akt1, Akt2 and Akt3) and mTOR kinase.

為治療癌症及其他增殖性疾病，本文所闡述之化合物可與靶向療法組合使用，該等靶向療法包括JAK激酶抑制劑(魯索替尼(ruxolitinib)、其他JAK1/2及JAK1選擇性抑制劑、巴瑞替尼(baricitinib)或伊他替尼(itacitinib))、Pim激酶抑制劑(例如LGH447、INCB053914及SGI-1776)、PI3激酶抑制劑(包括PI3K-δ選擇性及廣譜PI3K抑制劑(例如帕沙利昔(parsaclisib)及INCB50797))、PI3K-γ抑制劑(諸如PI3K-γ選擇性抑制劑)、MEK抑制劑、CSF1R抑制劑(例如PLX3397及LY3022855)、TAM受體酪胺酸激酶抑制劑(Tyro-3、Axl及Mer；例如INCB81776)、血管生成抑制劑、介白素受體抑制劑、週期蛋白依賴性激酶抑制劑(例如帕博西尼(palbociclib)、瑞博西尼(ribociclib)及阿貝西尼(abemaciclib))、BRAF抑制劑、mTOR抑制劑、蛋白酶體抑制劑(硼替佐米(Bortezomib)、卡非佐米(Carfilzomib))、HDAC-抑制劑(帕比司他(panobinostat)、伏立諾他(vorinostat))、DNA甲基轉移酶抑制劑、地塞米松(dexamethasone)、溴及額外末端家族成員抑制劑(例如溴結構域抑制劑或BET抑制劑，諸如OTX015、CPI-0610、INCB54329或INCB57643)、LSD1抑制劑(例如GSK2979552、INCB59872及INCB60003)、雌激素受體調節劑(例如氟維司群(fulvestrant))、雄激素受體調節劑(例如恩雜魯胺(enzalutamide))、BCL2抑制劑(例如維奈托克(venetoclax))、低氧誘導因子-2α抑制劑(例如貝株替凡(belzutifan))、輸出蛋白-1 (XPO-1)抑制劑(例如塞利尼索(selinexor))、KRAS抑制劑(例如索拉昔布(sotorasib))、精胺酸酶抑制劑(例如INCB1158)、吲哚胺2,3-雙加氧酶抑制劑(例如愛帕司他(epacadostat)、NLG919或BMS-986205)、PARP抑制劑(例如奧拉帕尼(olaparib)或盧卡帕尼(rucaparib))及BTK抑制劑(諸如依魯替尼(ibrutinib))。For the treatment of cancer and other proliferative diseases, the compounds described herein can be used in combination with targeted therapies, including JAK kinase inhibitors (ruxolitinib, other JAK1/2 and JAK1 selective inhibitors, baricitinib or itacitinib), Pim kinase inhibitors (such as LGH447, INCB053914 and SGI-1776), PI3 kinase inhibitors (including PI3K-δ selective and broad-spectrum PI3K inhibitors (such as pasadini), and PI3K inhibitors. parsaclisib and INCB50797), PI3K-γ inhibitors (such as PI3K-γ selective inhibitors), MEK inhibitors, CSF1R inhibitors (such as PLX3397 and LY3022855), TAM receptor tyrosine kinase inhibitors (Tyro-3, Axl, and Mer; such as INCB81776), angiogenesis inhibitors, interleukin receptor inhibitors, cyclin-dependent kinase inhibitors (such as palbociclib, ribociclib), and abemaciclib), BRAF inhibitors, mTOR inhibitors, proteasome inhibitors (bortezomib, carfilzomib), HDAC-inhibitors (panobinostat, vorinostat), DNA methyltransferase inhibitors, dexamethasone, bromodomain and extra-terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors, such as OTX015, C PI-0610, INCB54329 or INCB57643), LSD1 inhibitors (e.g., GSK2979552, INCB59872 and INCB60003), estrogen receptor modulators (e.g., fulvestrant), androgen receptor modulators (e.g., enzalutamide), BCL2 inhibitors (e.g., venetoclax), hypoxia-inducing factor-2α inhibitors (e.g., belzutifan), exportin-1 (XPO-1) inhibitors (e.g., selinexor), KRAS inhibitors (e.g., sotorasib), arginine kinase inhibitors (e.g., INCB1158), indoleamine 2,3-dioxygenase inhibitors (e.g., epacadostat, NLG919, or BMS-986205), PARP inhibitors (e.g., olaparib or rucaparib), and BTK inhibitors (e.g., ibrutinib).

為治療癌症及其他增殖性疾病，本文所闡述之化合物可與化學治療劑、核受體促效劑或拮抗劑或其他抗增殖劑組合使用。本文所闡述之化合物亦可與醫學療法(諸如手術或放射療法，例如γ-輻射、中子束放射療法、電子束放射療法、質子療法、近程療法及全身性放射性同位素)組合使用。For the treatment of cancer and other proliferative diseases, the compounds described herein can be used in combination with chemotherapeutic agents, nuclear receptor agonists or antagonists, or other anti-proliferative agents. The compounds described herein can also be used in combination with medical treatments such as surgery or radiation therapy, such as gamma irradiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes.

適宜化學治療劑之實例包括以下中之任一者：阿巴瑞克(abarelix)、阿比特龍(abiraterone)、阿法替尼(afatinib)、阿柏西普(aflibercept)、阿地介白素(aldesleukin)、阿倫單抗(alemtuzumab)、阿曲諾英(alitretinoin)、別嘌呤醇、六甲蜜胺、阿米多(amidox)、安吖啶(amsacrine)、阿那曲唑(anastrozole)、阿菲迪隆(aphidicolon)、三氧化二砷、天冬醯胺酶、阿西替尼(axitinib)、阿扎胞苷(azacitidine)、貝伐珠單抗(bevacizumab)、貝沙羅汀(bexarotene)、巴瑞替尼、苯達莫司汀(bendamustine)、比卡魯胺(bicalutamide)、博來黴素(bleomycin)、硼替佐必(bortezombi)、硼替佐米、布立尼布(brivanib)、布帕里斯、靜脈內白消安(busulfan intravenous)、口服白消安、卡普睪酮(calusterone)、抗癌妥(camptosar)、卡培他濱(capecitabine)、卡鉑(carboplatin)、卡莫司汀(carmustine)、西地尼布(cediranib)、西妥昔單抗(cetuximab)、苯丁酸氮芥(chlorambucil)、順鉑(cisplatin)、克拉屈濱(cladribine)、氯法拉濱(clofarabine)、克唑替尼(crizotinib)、環磷醯胺、阿糖胞苷(cytarabine)、達卡巴嗪(dacarbazine)、達克替尼(dacomitinib)、放線菌素D (dactinomycin)、達肝素鈉(dalteparin sodium)、達沙替尼(dasatinib)、放線菌素D、道諾黴素(daunorubicin)、地西他濱(decitabine)、地加瑞克(degarelix)、地尼白介素(denileukin)、地尼白介素2 (denileukin diftitox)、去氧助間型黴素(deoxycoformycin)、右雷佐生(dexrazoxane)、地多西(didox)、多西他賽(docetaxel)、多柔比星(doxorubicin)、卓洛昔芬(droloxafine)、丙酸屈他雄酮(dromostanolone propionate)、依庫珠單抗(eculizumab)、恩雜魯胺、表鬼臼毒素、表柔比星(epirubicin)、埃博黴素(epothilone)、厄洛替尼(erlotinib)、雌莫司汀(estramustine)、磷酸依託泊苷(etoposide phosphate)、依託泊苷、依西美坦(exemestane)、檸檬酸芬太尼(fentanyl citrate)、非格司亭(filgrastim)、氟尿苷、氟達拉濱(fludarabine)、氟尿嘧啶、氟他胺(flutamide)、氟維司群、吉非替尼(gefitinib)、吉西他濱(gemcitabine)、吉妥珠單抗奧唑米星(gemtuzumab ozogamicin)、乙酸戈舍瑞林(goserelin acetate)、乙酸組胺瑞林(histrelin acetate)、替伊莫單抗(ibritumomab tiuxetan)、伊達比星(idarubicin)、艾代拉里斯(idelalisib)、異環磷醯胺、甲磺酸伊馬替尼(imatinib mesylate)、干擾素α2a、伊立替康(irinotecan)、二甲苯磺酸拉帕替尼(lapatinib ditosylate)、雷利竇邁(lenalidomide)、來曲唑(letrozole)、甲醯四氫葉酸、乙酸柳培林(leuprolide acetate)、左旋咪唑(levamisole)、洛那法尼(lonafarnib)、洛莫司汀(lomustine)、二氯甲基二乙胺(meclorethamine)、乙酸甲地孕酮(megestrol acetate)、美法侖(melphalan)、巰嘌呤、胺甲喋呤、甲氧沙林(methoxsalen)、光輝黴素(mithramycin)、絲裂黴素C、米托坦(mitotane)、米托蒽醌(mitoxantrone)、苯丙酸諾龍(nandrolone phenpropionate)、諾維本(navelbene)、奈昔木單抗(necitumumab)、奈拉濱(nelarabine)、來那替尼(neratinib)、尼羅替尼(nilotinib)、尼鲁米特(nilutamide)、尼拉帕尼(niraparib)、諾非單抗(nofetumomab)、奧舍瑞林(oserelin)、奧沙利鉑(oxaliplatin)、太平洋紫杉醇(paclitaxel)、帕米膦酸((pamidronate))、帕尼單抗(panitumumab)、帕比司他、帕唑帕尼(pazopanib)、培門冬酶(pegaspargase)、聚乙二醇非格司亭(pegfilgrastim)、培美曲塞二鈉(pemetrexed disodium)、噴司他汀(pentostatin)、匹拉里斯(pilaralisib)、哌泊溴烷(pipobroman)、普卡黴素(plicamycin)、普納替尼(ponatinib)、卟吩姆(porfimer)、普賴松(prednisone)、丙卡巴肼(procarbazine)、奎納克林(quinacrine)、蘭尼單抗(ranibizumab)、拉布立酶(rasburicase)、瑞格菲尼(regorafenib)、雷洛薩芬(reloxafine)、瑞複美(revlimid)、利妥昔單抗(rituximab)、盧卡帕尼、魯索替尼、索拉菲尼(sorafenib)、鏈脲黴素(streptozocin)、舒尼替尼(sunitinib)、馬來酸舒尼替尼、他莫昔芬(tamoxifen)、替加氟(tegafur)、替莫唑胺(temozolomide)、替尼泊苷(teniposide)、睪內酯、替扎他濱(tezacitabine)、沙利竇邁(thalidomide)、硫鳥嘌呤、噻替派(thiotepa)、替吡法尼(tipifarnib)、托泊替康(topotecan)、托瑞米芬(toremifene)、托西莫單抗(tositumomab)、曲妥珠單抗(trastuzumab)、維A酸(tretinoin)、曲阿平(triapine)、曲米多西(trimidox)、曲普瑞林(triptorelin)、尿嘧啶氮芥、戊柔比星(valrubicin)、凡德他尼(vandetanib)、長春鹼(vinblastine)、長春新鹼(vincristine)、長春地辛(vindesine)、長春瑞濱(vinorelbine)、伏立諾他、維利帕尼((veliparib))、塔拉帕尼(talazoparib)及唑來膦酸(zoledronate)。Examples of suitable chemotherapy agents include any of the following: abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol, hexamethylmelamine, amidox, amsacrine, anastrozole, aphidilone, dapoxetine ... dicolon), arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab, bexarotene, baricitinib, bendamustine, bicalutamide, bleomycin, bortezombi, bortezomib, brivanib, buparis, intravenous busulfan intravenous), oral busulfan, calusterone, camptosar, capecitabine, carboplatin, carmustine, cediranib, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin, dalteparin sodium), dasatinib, actinomycin D, daunorubicin, decitabine, degarelix, denileukin, denileukin diftitox, deoxycoformycin, dexrazoxane, didox, docetaxel, doxorubicin, droloxafine, dromostanolone propionate propionate, eculizumab, enzaluamide, epipodophyllotoxin, epirubicin, epothilone, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan), idarubicin, idelalisib, isocyclophosphamide, imatinib mesylate, interferon alpha 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, folinic acid, leuprolide acetate, levamisole, lonafarnib, lomustine, meclorethamine, megestrol acetate acetate), melphalan, purine, methotrexate, methoxsalen, mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolone phenylpropionate phenpropionate), navelbene, necitumumab, nelarabine, neratinib, nilotinib, nilutamide, niraparib, nofetumomab, oserelin, oxaliplatin, paclitaxel, pamidronate, panitumumab, panobinostat, pazopanib, pegaspargase, pegfilgrastim, pemetrexed disodium disodium), pentostatin, pilaralisib, pipobroman, plicamycin, ponatinib, porfimer, prednisone, procarbazine, quinacrine, ranibizumab, rasburicase se), regorafenib, reloxafine, revlimid, rituximab, rucaparib, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, tegafur, temozolomide, teniposide niposide), testolactone, tezacitabine, thalidomide, thioguanine, thiotepa, tipifarnib, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, triapine, tramidoxime, imidox), triptorelin, uracil mustard, valrubicin, vandetanib, vinblastine, vincristine, vindesine, vinorelbine, vorinostat, veliparib, talazoparib, and zoledronic acid.

安全且有效投與大多數該等化學治療劑之方法為熟習此項技術者所已知。另外，其投與闡述於標準文獻中。舉例而言，許多化學治療劑之投與闡述於「Physicians' Desk Reference」(PDR，例如1996年版，Medical Economics Company, Montvale, NJ)中，其揭示內容如同以全文陳述一般以引用的方式併入本文中。Methods for safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. Furthermore, their administration is described in standard literature. For example, the administration of many chemotherapeutic agents is described in the Physicians' Desk Reference (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if fully set forth.

實例抗炎劑包括(但不限於)阿斯匹林(aspirin)、柳酸膽鹼、塞來昔布(celecoxib)、雙氯芬酸鉀(diclofenac potassium)、雙氯芬酸鈉、雙氯芬酸鈉聯合米索前列醇(misoprostol)、二氟尼柳(diflunisal)、依託度酸(etodolac)、非諾洛芬(fenoprofen)、氟比洛芬(flurbiprofen)、布洛芬(ibuprofen)、酮洛芬(ketoprofen)、甲芬那酸鈉(meclofenamate sodium)、甲芬那酸、萘丁美酮(nabumetone)、萘普生(naproxen)、萘普生鈉、奧沙普秦(oxaprozin)、吡羅昔康(piroxican)、羅非昔布(rofecoxib)、雙柳酸酯、柳酸鈉、舒林酸(sulindac)、妥美汀鈉(tolmetin sodium)及伐地昔布(valdecoxib)。Examples of anti-inflammatory agents include, but are not limited to, aspirin, cholestylate, celecoxib, diclofenac potassium, diclofenac sodium, diclofenac sodium combined with misoprostol, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, meclofenamate sodium, and fenapyr. sodium), mefenamic acid, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam, rofecoxib, disalate, sodium salicylate, sulindac, tolmetin sodium, and valdecoxib.

實例類固醇包括(但不限於)皮質類固醇，諸如可體松(cortisone)、地塞米松、氫化可體松(hydrocortisone)、甲基普賴蘇濃(methylprednisolone)、普賴蘇濃及普賴松。Example steroids include, but are not limited to, corticosteroids such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone.

實例免疫抑制劑包括(但不限於)硫唑嘌呤(azathioprine)、苯丁酸氮芥、環磷醯胺、環孢素、達克珠單抗(daclizumab)、英利昔單抗(infliximab)、胺甲喋呤及他克莫司(tacrolimus)。Example immunosuppressants include, but are not limited to, azathioprine, chlorambucil, cyclophosphamide, cyclosporine, daclizumab, infliximab, methotrexate, and tacrolimus.

實例麻醉劑包括(但不限於)局部麻醉劑(例如利多卡因(lidocaine)、普魯卡因(procain)、羅哌卡因(ropivacaine))及全身麻醉劑(例如地氟醚(desflurane)、安氟醚(enflurane)、鹵神(halothane)、異氟醚(isoflurane)、甲氧基氟醚、氧化亞氮、七氟醚(sevoflurane)、異戊巴比妥(mmobarbital)、美索比妥(methohexital)、硫阿米妥(thiamylal)、硫噴妥(thiopental)、二氮平(diazepam)、氯羥去甲安定(lorazepam)、咪達唑侖(midazolam)、依託咪酯(etomidate)、氯胺酮(ketamine)、丙泊酚(propofol)、阿華吩坦尼(alfentanil)、芬太尼、瑞芬太尼(remifentanil)、丁基原啡因(buprenorphine)、布托啡諾(butorphanol)、氫嗎啡酮(hydromorphone)、左嗎南(levorphanol)、得美樂(meperidine)、美沙酮(methadone)、嗎啡(morphine)、納布啡(nalbuphine)、羥嗎啡酮(oxymorphone)、戊唑辛(pentazocine))。Example anesthetics include, but are not limited to, local anesthetics (e.g., lidocaine, procain, ropivacaine) and general anesthetics (e.g., desflurane, enflurane, halothane, isoflurane, methoxyflurane, nitrous oxide, sevoflurane, mmobarbital, methohexital, thiamylal, thiopental, diazepam, lorazepam, midazolam, chlorpromazine, chlorpromazine, dapoxet ... midazolam, etomidate, ketamine, propofol, alfentanil, fentanyl, remifentanil, buprenorphine, butorphanol, hydromorphone, levorphanol, meperidine, methadone, morphine, nalbuphine, oxymorphone, pentazocine).

在一些實施例中，額外治療劑係與本文所提供之化合物或鹽同時投與。在一些實施例中，額外治療劑係在投與本文所提供之化合物或鹽之後投與。在一些實施例中，額外治療劑係在投與本文所提供之化合物或鹽之前投與。在一些實施例中，本文所提供之化合物或鹽係在手術程序期間投與。在一些實施例中，本文所提供之化合物或鹽係在手術程序期間與額外治療劑組合投與。In some embodiments, the additional therapeutic agent is administered concurrently with a compound or salt provided herein. In some embodiments, the additional therapeutic agent is administered after administration of a compound or salt provided herein. In some embodiments, the additional therapeutic agent is administered before administration of a compound or salt provided herein. In some embodiments, the additional therapeutic agent is administered during a surgical procedure. In some embodiments, the compound or salt provided herein is administered in combination with an additional therapeutic agent during a surgical procedure.

如本文所提供，可將額外化合物、抑制劑、劑等與本文所提供之化合物組合於單一或連續劑型中，或其可作為單獨劑型同時或依序投與。醫藥調配物及劑型As provided herein, additional compounds, inhibitors, agents, etc. can be combined with the compounds provided herein in a single or sequential dosage form, or they can be administered simultaneously or sequentially as separate dosage forms.Pharmaceutical Formulations and Dosage Formulations

當用作醫藥時，本發明之化合物可以醫藥組合物之形式投與，該醫藥組合物係指本發明之化合物或其醫藥學上可接受之鹽與至少一種醫藥學上可接受之載劑的組合。該等組合物可以醫藥技術中所熟知之方式製備，且可藉由多種途徑投與，此取決於期望局部還是全身性治療以及欲治療之區域。投與可為外用(包括經眼及投與至黏膜，包括鼻內、經陰道及直腸遞送)、經肺(例如藉由吸入或吹入粉末或氣溶膠，包括藉由霧化器；氣管內、鼻內、表皮及經皮)、經眼、經口或非經腸。經眼遞送之方法可包括外用投與(滴眼劑)、結膜下、眼周或玻璃體內注射或藉由以手術方式置入結膜囊中之氣囊導管或眼部插入件引入。非經腸投與包括靜脈內、動脈內、皮下、腹膜內或肌內注射或輸注；或顱內(例如鞘內或室內)投與。非經腸投與可呈單一濃注劑量之形式，或可例如藉由連續灌注幫浦來實施。用於外用投與之醫藥組合物及調配物可包括經皮貼劑、軟膏劑、洗劑、乳霜、凝膠、滴劑、栓劑、噴霧、液體及粉末。習用醫藥載劑、水性、粉末或油性基質、增稠劑及諸如此類可能為必需或期望的。When used as a medicine, the compounds of the present invention can be administered in the form of a pharmaceutical composition, which refers to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. Such compositions can be prepared in a manner well known in the pharmaceutical art and can be administered by a variety of routes, depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including ocular and administration to mucous membranes, including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of a powder or aerosol, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral. Methods of ocular delivery may include topical administration (eye drops), subconjunctival, periocular, or intravitreal injection, or introduction via a balloon catheter or ocular insert surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial (e.g., intrathecal or intraventricular) administration. Parenteral administration may be in the form of a single bolus or may be administered, for example, by continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. The use of customary pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

本發明亦包括醫藥組合物，其含有上文中本發明之一或多種化合物作為活性成分與一或多種醫藥學上可接受之載劑的組合。在製備本發明之組合物時，通常將活性成分與賦形劑混合，經賦形劑稀釋或包封在呈(例如)膠囊、小藥囊、紙或其他容器形式之此一載體內。當賦形劑用作稀釋劑時，其可為固體、半固體或液體材料，該材料對活性成分起媒劑、載劑或介質作用。因此，組合物可呈以下形式：錠劑、丸劑、粉末、菱形錠劑、小藥囊、扁囊劑、酏劑、懸浮液、乳液、溶液、糖漿、氣溶膠(呈固體形式或於液體介質中)、含有(例如)高達10重量%活性化合物之軟膏劑、軟質及硬質明膠膠囊、栓劑、無菌可注射溶液及無菌包裝粉末。The present invention also includes pharmaceutical compositions containing one or more compounds of the present invention as active ingredients in combination with one or more pharmaceutically acceptable carriers. When preparing the compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted with the excipient, or encapsulated within such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semisolid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (either in solid form or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

在製備調配物時，在與其他成分組合之前，可將活性化合物碾磨以提供適當粒徑。若活性化合物實質上不可溶，則可將其碾磨至小於200目之粒徑。若活性化合物實質上可溶於水，則可藉由碾磨調整粒徑以在調配物中提供實質上均勻之分佈，例如約40目。In preparing the formulation, the active compound may be milled to provide an appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it may be milled to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size may be adjusted by milling to provide a substantially uniform distribution in the formulation, for example, about 40 mesh.

活性化合物可在寬劑量範圍內有效，且通常係以在醫藥學上有效之量投與。然而，應理解，實際上投與之化合物之量通常將由醫師根據相關情況確定，該等相關情況包括欲治療之疾患、所選投與途徑、所投與之實際化合物、個別患者之年齡、體重及反應、患者症狀之嚴重程度及諸如此類。The active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. However, it will be understood that the actual amount of compound administered will generally be determined by a physician based on relevant circumstances, including the condition to be treated, the route of administration selected, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

為了製備固體組合物(諸如錠劑)，將主要活性成分與醫藥賦形劑混合以形成含有本發明化合物之均質混合物的固體預調配組合物。在將該等預調配組合物稱為均質時，活性成分通常均勻分散於整個組合物中，使得可易於將組合物細分成同等有效之單位劑型，諸如錠劑、丸劑及膠囊。接著，將此固體預調配物細分成上文所闡述類型之單位劑型。To prepare solid compositions (such as tablets), the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When such preformulation compositions are referred to as homogeneous, the active ingredient is typically dispersed evenly throughout the composition, making it readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above.

本發明之錠劑或丸劑可經包衣或以其他方式複合，以提供具有持久作用優點之劑型。舉例而言，錠劑或丸劑可包含內部劑量組分及外部劑量組分，後者呈包被於前者上之形式。該兩種組分可由腸溶層隔開，該腸溶層用於抵抗胃中之崩解且允許內部組分完整通過進入十二指腸中或延遲釋放。The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form with the advantage of sustained action. For example, a tablet or pill may comprise an inner dosage component and an outer dosage component, the outer dosage component being coated on the inner dosage component. These two components may be separated by an enteric layer, which serves to resist disintegration in the stomach and allows the inner component to pass intact into the duodenum or to be released later.

可併入本發明之化合物及組合物中以供經口或藉由注射投與之液體形式包括水溶液、適宜矯味之糖漿、水性或油性懸浮液以及用可食用油矯味之乳液。Liquid forms in which the compounds and compositions of the present invention can be incorporated for oral or injection administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils.

用於吸入或吹入之組合物包括於醫藥學上可接受之水性或有機溶劑或其混合物中之溶液及懸浮液，以及粉末。液體或固體組合物可含有如上文所闡述之適宜的醫藥學上可接受之賦形劑。在一些實施例中，組合物藉由經口或經鼻呼吸途徑投與，以獲得局部或全身性效應。組合物可藉由使用惰性氣體來霧化。霧化溶液可直接自霧化器件呼吸或霧化器件可連接至面罩、帷罩或間歇式正壓呼吸機。溶液、懸浮液或粉末組合物可自以適當方式遞送調配物之器件經口或經鼻投與。Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. The liquid or solid composition may contain a suitable pharmaceutically acceptable excipient as described above. In some embodiments, the composition is administered by the oral or nasal respiratory route to obtain a local or systemic effect. The composition can be aerosolized by using an inert gas. The aerosolized solution can be breathed directly from the aerosolizing device or the aerosolizing device can be connected to a mask, tent or intermittent positive pressure ventilator. The solution, suspension or powder composition can be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

投與給患者之化合物或組合物之量將端視於所投與藥物、投與目的(諸如預防或治療)、患者狀態、投與方式及諸如此類而變化。在治療應用中，可將組合物以足以治癒或至少部分地阻止疾病及其併發症之症狀之量投與給已患該疾病之患者。有效劑量將取決於所治療之疾病狀況以及臨床主治醫師端視諸如疾病之嚴重程度、患者之年齡、體重及一般狀況及諸如此類等因素所作出之判斷。The amount of compound or composition administered to a patient will vary depending on the agent being administered, the purpose of administration (e.g., prevention or treatment), the patient's condition, the route of administration, and the like. In therapeutic applications, the composition can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the disease condition being treated and the judgment of the attending clinician, depending on factors such as the severity of the disease, the patient's age, weight, and general condition, and the like.

投與給患者之組合物可呈上文所闡述之醫藥組合物形式。該等組合物可藉由習用滅菌技術來滅菌，或可經無菌過濾。水溶液可按原樣包裝使用，或凍亁，將凍亁製劑在投與之前與無菌水性載劑合併。化合物製劑之pH通常將介於3與11之間，更佳為5至9且最佳為7至8。應理解，使用某些上述賦形劑、載劑或穩定劑將形成醫藥鹽。The compositions administered to the patient may be in the form of pharmaceutical compositions as described above. Such compositions may be sterilized by customary sterilization techniques or may be aseptically filtered. Aqueous solutions may be packaged for use as is or frozen, the frozen preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound formulation will generally be between 3 and 11, more preferably between 5 and 9, and most preferably between 7 and 8. It will be appreciated that the use of certain of the above-mentioned excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

本發明化合物之治療劑量可根據例如所進行治療之特定用途、化合物之投與方式、患者之健康及狀況以及開處醫師之判斷而變化。本發明化合物在醫藥組合物中之比例或濃度可端視諸多因素(包括劑量、化學特性(例如疏水性)及投與途徑)而有所變化。劑量有可能取決於諸如以下等變數：疾病或病症之類型及進展程度、特定患者之總體健康狀態、所選化合物之相對生物學功效、賦形劑之調配物及其投與途徑。有效劑量可根據自活體外或動物模型測試系統獲得之劑量反應曲線外推獲得。The therapeutic dosage of the compounds of the invention may vary depending on, for example, the specific treatment being administered, the route of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compounds of the invention in a pharmaceutical composition may vary depending on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. The dosage may depend on variables such as the type and progression of the disease or condition, the general health of the particular patient, the relative biological efficacy of the selected compound, the formulation of the dosage form, and its route of administration. The effective dose may be extrapolated from dose-response curves obtained in in vitro or animal model test systems.

本揭示案之組合物可進一步包括一或多種額外醫藥劑，諸如化學治療劑、類固醇、抗發炎性化合物或免疫抑制劑，其實例在本文中提供。經標記化合物及分析方法The compositions of the present disclosure may further include one or more additional pharmaceutical agents, such as chemotherapeutic agents, steroids, anti-inflammatory compounds, or immunosuppressive agents, examples of which are provided herein.Labeled Compounds and Analytical Methods

本發明之另一態樣係關於經螢光染料、自旋標記、重金屬或放射性標記之本發明化合物，其不僅將可用於成像且亦可用於活體外及活體內分析中，以供定位且量化組織樣品(包括人類)中之PI3Kα酶，且藉由抑制經標記化合物之結合來鑑別PI3Kα酶配位體。因此，本發明包括含有此等經標記化合物之PI3Kα酶分析。Another aspect of the present invention relates to compounds of the present invention labeled with fluorescent dyes, spin labels, heavy metals, or radioactive species. These compounds can be used not only for imaging but also for in vitro and in vivo assays to localize and quantify PI3Kα enzymes in tissue samples (including humans) and to identify PI3Kα enzyme ligands by inhibiting the binding of the labeled compounds. Therefore, the present invention includes PI3Kα enzyme assays containing these labeled compounds.

本發明進一步包括經同位素標記之本發明化合物。「經同位素標記」或「經放射性標記」化合物係其中一或多個原子經原子質量或質量數不同於自然界中通常發現(亦即天然)之原子質量或質量數之原子置換或取代之本發明化合物。可併入在本發明化合物中之適宜放射性核種包括(但不限於)²H (氘亦寫作D )、³H (氚亦寫作T)、¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、¹⁸F、³⁵S、³⁶Cl、⁸²Br、⁷⁵Br、⁷⁶Br、⁷⁷Br、¹²³I、¹²⁴I、¹²⁵I及¹³¹I。併入在本發明經放射性標記之化合物中之放射性核種將取決於該經放射性標記之化合物之具體應用。舉例而言，對於活體外FGFR酶標記及競爭分析而言，併有³H、¹⁴C、⁸²Br、¹²⁵I、¹³¹I或³⁵S之化合物通常將最有用。對於放射性成像應用而言，¹¹C、¹⁸F、¹²⁵I、¹²³I、¹²⁴I、¹³¹I、⁷⁵Br、⁷⁶Br或⁷⁷Br通常將最有用。The present invention further includes isotopically labeled compounds of the present invention. "Isotopically labeled" or "radiolabeled" compounds are compounds of the present invention in which one or more atoms are replaced or substituted with an atomic mass or mass number different from the atomic mass or mass number usually found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated into the compounds of the present invention include, but are not limited to,^2H (deuterium, also abbreviated as D),^3H (tritium, also abbreviated as T),^11C ,^13C ,^14C ,^13N ,^15N ,^15O ,^17O ,^18O ,^18F ,^35S ,^36Cl ,^82Br ,^75Br ,^76Br ,^77Br ,^123I ,^124I ,^125I , and^131I . The radionuclide incorporated into the radiolabeled compounds of the present invention will depend on the specific application of the radiolabeled compound. For example, for in vitro FGFR enzyme labeling and competition assays, compounds incorporating³ H,¹⁴ C,⁸² Br,¹²⁵ I,¹³¹ I, or³⁵ S will generally be most useful. For radioimaging applications,¹¹ C,¹⁸ F,¹²⁵ I,¹²³ I,¹²⁴ I,¹³¹ I,⁷⁵ Br,⁷⁶ Br, or⁷⁷ Br will generally be most useful.

本文所呈現化合物之一或多個組成原子可經該等原子之同位素以天然或非天然豐度置換或取代。在一些實施例中，一或多個原子經氘置換或取代。舉例而言，本揭示案化合物中之一或多個氫原子可經氘原子置換(例如，式I之C_1-6烷基之一或多個氫原子可視情況經氘原子取代，諸如-CD₃取代-CH₃)。在一些實施例中，所揭示式(例如式I-式VIIa中之任一者之化合物)之烷基可經全氘化。One or more constituent atoms of the compounds presented herein may be replaced or substituted with isotopes of such atoms in natural or unnatural abundance. In some embodiments, one or more atoms are replaced or substituted with deuterium. For example, one or more hydrogen atoms in the compounds of the present disclosure may be replaced with deuterium atoms (e.g., one or more hydrogen atoms of a C_1-6 alkyl group of Formula I may be replaced with deuterium atoms, such as -CD₃ replacing -CH₃ , as appropriate). In some embodiments, the alkyl groups of the disclosed formulae (e.g., compounds of any of Formulas I to VIIa) may be perdeuterated.

在一些實施例中，本文所提供之化合物(例如式I-式IIIb中之任一者之化合物)或其醫藥學上可接受之鹽包含至少一個氘原子。In some embodiments, the compounds provided herein (e.g., compounds of any one of Formula I-Formula IIIb) or pharmaceutically acceptable salts thereof contain at least one deuterium atom.

在一些實施例中，本文所提供之化合物(例如式I-式IIIb中之任一者之化合物)或其醫藥學上可接受之鹽包含兩個或更多個氘原子。In some embodiments, the compounds provided herein (e.g., compounds of any one of Formula I-Formula IIIb) or pharmaceutically acceptable salts thereof contain two or more deuterium atoms.

在一些實施例中，本文所提供之化合物(例如式I-式IIIb中之任一者之化合物)或其醫藥學上可接受之鹽包含三個或更多個氘原子。In some embodiments, the compounds provided herein (e.g., compounds of any one of Formula I-Formula IIIb) or pharmaceutically acceptable salts thereof contain three or more deuterium atoms.

在一些實施例中，對於本文所提供之化合物(例如式I-式IIIb中之任一者之化合物)或其醫藥學上可接受之鹽，所有氫原子均經氘原子置換(亦即化合物為「全氘化」的)。In some embodiments, for a compound provided herein (e.g., a compound of any one of Formula I-IIIb) or a pharmaceutically acceptable salt thereof, all hydrogen atoms are replaced with deuterium atoms (i.e., the compound is "perdeuterated").

應理解，「經放射性標記」或「經標記化合物」係併有至少一種放射性核種之化合物。在一些實施例中，放射性核種選自由以下組成之群：³H、¹⁴C、¹²⁵I、³⁵S及⁸²Br。It is understood that "radiolabeled" or "labeled compound" is a compound that incorporates at least one radionuclide. In some embodiments, the radionuclide is selected from the group consisting of³ H,¹⁴ C,¹²⁵ I,³⁵ S, and⁸² Br.

將同位素納入有機化合物中之合成方法為此項技術中所已知(Deuterium Labeling in Organic Chemistry，Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts, 1971；The Renaissance of H/D Exchange，Jens Atzrodt、Volker Derdau、Thorsten Fey及Jochen Zimmermann，Angew. Chem. Int. Ed. 2007, 7744-7765；The Organic Chemistry of Isotopic Labelling, James R. Hanson, Royal Society of Chemistry, 2011)。經同位素標記之化合物可用於各種研究中，諸如NMR光譜法、代謝實驗及/或分析。Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry, Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts, 1971); The Renaissance of H/D Exchange, Jens Atzrodt, Volker Derdau, Thorsten Fey, and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling, James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in a variety of studies, such as NMR spectroscopy, metabolic experiments, and/or analysis.

經較重同位素(諸如氘)取代可因具有更強之代謝穩定性而提供某些治療優勢，例如活體內半衰期延長或劑量需求降低，且因此在一些情況中可能較佳。(例如，參見A. Kerekes等人，J. Med. Chem.2011, 54, 201-210；R. Xu等人，J. Label Compd. Radiopharm.2015, 58, 308-312)。特定而言，在一或多個代謝位點處取代可提供一或多種治療優勢。Substitution with heavier isotopes, such as deuterium, may offer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some circumstances. (See, for example, A. Kerekes et al., J.Med. Chem. 2011, 54, 201-210; R. Xu et al.,J. Label Compd. Radiopharm. 2015, 58, 308-312.) In particular, substitution at one or more metabolic sites may provide one or more therapeutic advantages.

本發明之經放射性標記之化合物可用於篩選分析中以鑑別/評估化合物。一般而言，可評估新合成或鑑別之化合物(亦即測試化合物)降低本發明之放射性標記化合物與PI3Kα酶之結合的能力。因此，測試化合物與放射性標記化合物競爭結合至PI3Kα酶之能力直接與其結合親和力相關。套組The radiolabeled compounds of the present invention can be used in screening assays to identify/evaluate compounds. Generally, a newly synthesized or identified compound (i.e., a test compound) can be evaluated for its ability to reduce the binding of a radiolabeled compound of the present invention to the PI3Kα enzyme. Thus, the ability of a test compound to compete with the radiolabeled compound for binding to the PI3Kα enzyme is directly related to its bindingaffinity .

本發明亦包括可用於例如治療或預防本文所提及之PI3Kα相關之疾病或病症之醫藥套組，其包括一或多個含有醫藥組合物之容器，該醫藥組合物包含治療有效量之本發明化合物。如熟習此項技術者將易於明瞭，若期望，此類套組可進一步包括各種習用醫藥套組組件中之一或多者，諸如含有一或多種醫藥學上可接受之載劑之容器、額外容器等。套組中亦可包括指示欲投與組分之量之說明書(作為插頁或作為標籤)、投與指南及/或混合組分之指南。The present invention also includes pharmaceutical kits useful, for example, for treating or preventing the PI3Kα-related diseases or conditions mentioned herein, comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention. As will be readily apparent to one skilled in the art, such kits may further include one or more of the various conventional pharmaceutical kit components, such as a container containing one or more pharmaceutically acceptable carriers, additional containers, and the like, if desired. The kits may also include instructions (as an insert or as a label) indicating the amounts of the components to be administered, instructions for administration, and/or instructions for mixing the components.

將藉助具體實例更詳細地闡述本發明。以下實例係出於說明性目的而提供，且不意欲以任何方式限制本發明。熟習此項技術者將容易地識別多個非關鍵參數，該等參數可進行改變或修改以產生基本上相同之結果。如下文所闡述，發現實例化合物為PI3Kα抑制劑。實例The present invention will be described in more detail with the aid of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way. Those skilled in the art will readily recognize a number of non-critical parameters that can be changed or modified to produce essentially the same results. As described below, the example compounds were found to be PI3Kα inhibitors.Examples

下文提供本發明化合物之實驗程序。所製備之一些化合物之製備型LC-MS純化係在Waters質量定向分餾系統上實施。用於操作該等系統之基本設備設置、方案及控制軟體已詳細地闡述於文獻中。例如，參見「Two-Pump At Column Dilution Configuration for Preparative LC-MS」, K. Blom,J. Combi. Chem., 4, 295 (2002)；「Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification」, K. Blom、R. Sparks、J. Doughty、G. Everlof、T. Haque、A. Combs,J. Combi. Chem., 5, 670 (2003)；及「Preparative LC-MS Purification: Improved Compound Specific Method Optimization」, K. Blom、B. Glass、R. Sparks、A. Combs,J. Combi. Chem., 6, 874-883 (2004)。所分離之化合物通常經受分析型液相層析質譜法(LCMS)，以進行純度檢查。The following experimental procedures for the compounds of the present invention are provided. Preparative LC-MS purification of some of the prepared compounds was performed on a Waters mass fractionation system. The basic equipment setup, protocols, and control software used to operate these systems are described in detail in the literature. See, for example, "Two-Pump At Column Dilution Configuration for Preparative LC-MS", K. Blom,J. Combi. Chem ., 4, 295 (2002); "Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification", K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs,J. Combi. Chem ., 5, 670 (2003); and "Preparative LC-MS Purification: Improved Compound Specific Method Optimization," K. Blom, B. Glass, R. Sparks, A. Combs,J. Combi. Chem ., 6, 874-883 (2004). The isolated compounds were typically subjected to analytical liquid chromatography-mass spectrometry (LCMS) to check their purity.

亦如實例中所指示，藉由具有MS偵測器之反相高效液相層析(RP-HPLC)或急速層析(矽膠)以製備規模分離一些所製備之化合物。中間體1. 6-甲基-2-(2-甲基-2H-四唑-5-基)吡啶-3-胺Some of the prepared compounds were also separated on a preparative scale by reverse phase high performance liquid chromatography (RP-HPLC) with MS detection or flash chromatography (silica gel), as indicated in the examples.Intermediate 1. 6-Methyl-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-amine

使6-氯-2-(2-甲基四唑-5-基)吡啶-3-胺(實例8，步驟4) (55.0 mg, 0.26 mmol)、四(三苯基膦)鈀(0) (60.4 mg, 0.05 mmol)、K₃PO₄(166.3 mg, 0.78 mmol)及甲基硼酸(31.3 mg, 0.52 mmol)於3 mL二噁烷/H₂O (5:1)中之溶液用N₂鼓泡1 min。將所得反應混合物在100℃下攪拌2 h。LCMS分析指示反應完成。用水稀釋混合物且用EtOAc萃取。將合併的有機物用飽和NaCl洗滌，經無水硫酸鈉乾燥，過濾並在減壓下濃縮。藉由矽膠管柱層析，用DCM及EtOAc (0至100%)溶析純化殘餘物，提供呈白色固體之期望產物。LCMS C₈H₁₁N₆(M+H)⁺m/z計算值= 191.1；實驗值191.1。中間體2至3. 4-氟-2-(1-(甲基-d3)-1H-四唑-5-基)苯胺(中間體2)及4-氟-2-(2-(甲基-d3)-2H-四唑-5-基)苯胺(中間體3)步驟1：2-(4-氟-2-(1H-四唑-5-基)苯基)異吲哚啉-1,3-二酮A solution of 6-chloro-2-(2-methyltetrazol-5-yl)pyridin-3-amine (Example 8, Step 4) (55.0 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium(0) (60.4 mg, 0.05 mmol), K₃ PO₄ (166.3 mg, 0.78 mmol) and methylboronic acid (31.3 mg, 0.52 mmol) in 3 mL of dioxane/H₂ O (5:1) was bubbled with N₂ for 1 min. The resulting reaction mixture was stirred at 100 ° C for 2 h. LCMS analysis indicated that the reaction was complete. The mixture was diluted with water and extracted with EtOAc. The combined organics were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure._The residue was purified by_silica gel column chromatography eluting with DCM and EtOAc (0-100%) to provide the desired product as a white solid. LCMS_C8H11N6 (M+H)⁺ m/z calculated = 191.1; found 191.1.Intermediates 2 to 3. 4-Fluoro-2-(1-(methyl-d3)-1H-tetrazol-5-yl)aniline (Intermediate 2) and 4-Fluoro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)aniline (Intermediate 3)Step1:2-(4-fluoro-2-(1H-tetrazol-5-yl)phenyl)isoindole-1,3-dione

使用與針對實例8所闡述類似之程序，在步驟1中用2-胺基-5-氟苯甲腈替代3-胺基-6-氯-吡啶-2-甲腈來製備標題中間體。用水稀釋反應混合物，且藉由添加10% HCl將pH調整至2。藉由過濾收集沈澱物，得到呈棕色固體之產物。LCMS C₁₅H₉FN₅O₂(M+H)⁺m/z計算值= 310.1；實驗值310.1。步驟2：2-(4-氟-2-(1-(甲基-d3)-1H-四唑-5-基)苯基)異吲哚啉-1,3-二酮及2-(4-氟-2-(2-(甲基-d3)-2H-四唑-5-基)苯基)異吲哚啉-1,3-二酮The title intermediate was prepared using a procedure similar to that described forExample 8 , substituting 2-amino-5-fluorobenzonitrile for 3-amino-6-chloro-pyridine-2-carbonitrile in Step 1. The reaction mixture was diluted with water and the pH was adjusted to 2 by adding 10% HCl_. The precipitate was collected by filtration to give the product as_a brown solid. LCMS m/z Calcd. for_Ci5H9FN5O2 (M+H)₊⁼ 310.1; Found 310.1.Step2:2-(4-fluoro-2-(1-(methyl-d3)-1H-tetrazol-5-yl)phenyl)isoindoleline-1,3-dione and2-(4-fluoro-2-(2-(methyl-d3)-2H -tetrazol-5-yl)phenyl)isoindoleline-1,3-dione

向2-(4-氟-2-(1H-四唑-5-基)苯基)異吲哚啉-1,3-二酮(2.49 g, 8.05 mmol)於10 mL DMF中之溶液中添加CD₃I (0.70 mL, 11.27 mmol)及K₂CO₃(3.34 g, 24.15 mmol)。在室溫下攪拌2 h後，用水稀釋混合物且用EtOAc萃取。將合併的有機物用鹽水洗滌且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。藉由矽膠管柱層析，用DCM及乙酸乙酯溶析純化所得混合物，提供2種產物異構物1及異構物2。LCMS C₁₆H₈D₃FN₅O₂(M+H)⁺m/z計算值= 327.1；實驗值327.1步驟3：4-氟-2-(1-(甲基-d₃)-1H-四唑-5-基)苯胺To a solution of 2-(4-fluoro-2-(1H-tetrazol-5-yl)phenyl)isoindoline-1,3-dione (2.49 g, 8.05 mmol) in 10 mL of DMF were added CD₃ I (0.70 mL, 11.27 mmol) and K₂ CO₃ (3.34 g, 24.15 mmol). After stirring at room temperature for 2 h, the mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography eluting with DCM and ethyl acetate to provide two products, isomer 1 and isomer 2. LCMS Calcd for C₁₆ H₈ D₃ FN₅ O₂ (M+H)⁺ m/z = 327.1; Found 327.1Step 3: 4-Fluoro-2-(1-(methyl-d₃ )-1H-tetrazol-5-yl)aniline

將2-(4-氟-2-(1-(甲基-d3)-1H-四唑-5-基)苯基)異吲哚啉-1,3-二酮(0.13 g, 0.40 mmol)於1 mL一水合肼中之混合物在45℃下攪拌2 h，接著冷卻至室溫並用水稀釋。藉由過濾收集沈澱物且用水洗滌，得到呈白色固體之產物。LCMS C₈H₆D₃FN₅(M+H)⁺m/z計算值= 197.1；實驗值197.1。步驟4：4-氟-2-(2-(甲基-d3)-2H-四唑-5-基)苯胺A mixture of 2-(4-fluoro-2-(1-(methyl-d3)-1H-tetrazol-5-yl)phenyl)isoindolin-1,3-dione (0.13 g, 0.40 mmol) in 1 mL of hydrazine monohydrate was stirred at 45°C for 2 h, then cooled to room temperature and diluted with water._The precipitate was collected by filtration and washed with water to give the product as_a white solid. LCMS_C8H6D3FN5 (M+H)⁺ m/_z Calcd = 197.1; Found 197.1.Step 4: 4-Fluoro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)aniline

使用與步驟3中所闡述類似之程序，用2-(4-氟-2-(2-(甲基-d₃)-2H-四唑-5-基)苯基)異吲哚啉-1,3-二酮替代2-(4-氟-2-(1-(甲基-d₃)-1H-四唑-5-基)苯基)異吲哚啉-1,3-二酮來製備標題中間體。LCMS C₈H₆D₃FN₅(M+H)⁺m/z計算值= 197.1；實驗值197.1。中間體4. 4-氟-2-(1-甲基-1,2,4-三唑-3-基)苯胺The title intermediate was prepared using a procedure similar to that described in step 3, substituting 2-(4-fluoro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)phenyl)isoindoline-1,3-dione for 2-(4-fluoro-2-(1-(methyl-d₃ )-1H-tetrazol-5-yl)phenyl)isoindoline-1,3-dione. LCMS Calcd. for C₈ H₆ D₃ FN₅ (M+H)⁺ m/z = 197.1; Found 197.1.Intermediate 4. 4-Fluoro-2-(1-methyl-1,2,4-triazol-3-yl)aniline

將4-氟-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯胺(1.0 g, 4.22 mmol)、3-溴-1-甲基-1,2,4-三唑(683.3 mg, 4.22 mmol)、K₃PO₄(2686 mg, 12.65 mmol)及[2-(2-胺基苯基)苯基]-氯-鈀;二環己基-[2-(2,4,6-三異丙基苯基)苯基]磷烷(663.8 mg, 0.84 mmol)於15 mL二噁烷/H₂O (5:1)中之溶液用N₂鼓泡1 min。將所得反應混合物在90℃下攪拌2 h。LCMS分析指示反應完成。用水稀釋混合物且用EtOAc萃取。將合併的有機物用飽和NaCl洗滌，經無水硫酸鈉乾燥，過濾並在減壓下濃縮。藉由矽膠管柱層析，用DCM及EtOAc (0至100%)溶析純化殘餘物，提供呈白色固體之期望產物。LCMS C₉H₁₀FN₄(M+H)⁺m/z計算值= 193.1；實驗值193.1。中間體5. (3-胺基-6-氯吡啶-2-基)胺基甲酸甲酯步驟1. (6-氯-3-硝基吡啶-2-基)胺基甲酸甲酯A solution of 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatolan-2-yl)aniline (1.0 g, 4.22 mmol), 3-bromo-1-methyl-1,2,4_- triazole (683.3 mg, 4.22 mmol),_K₃PO₄ (2686 mg, 12.65 mmol), and [2-(2-aminophenyl)phenyl]-chloro-palladium; dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (663.8 mg, 0.84 mmol) in 15 mL of dioxane/_H₂O (5:1) was bubbled with_N₂ for 1 minute. The resulting reaction mixture was stirred at 90°C for 2 hours. LCMS analysis indicated the reaction was complete. The mixture was diluted with water and extracted with EtOAc. The combined organics were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM and EtOAc (0 to₁₀₀ %₎ to provide the desired product as a white solid. LCMS_C9H10FN4 (M+H)⁺ m/z calculated = 193.1; found 193.1.Intermediate5. Methyl (3-amino-6-chloropyridin-2-yl)carbamateStep 1. Methyl (6-chloro-3-nitropyridin-2-yl)carbamate

向6-氯-3-硝基吡啶-2-胺(5.00 g, 28.81 mmol)於DCM中之懸浮液中添加N,N-二異丙基乙胺(24 mL, 172.85 mmol)，之後逐滴添加氯甲酸甲酯(26.8 mL, 345.71 mmol)。將所得混合物在45℃下加熱1小時。使反應物冷卻至室溫。在真空下濃縮反應混合物，且裝載至矽膠(20 g)上，用含0-50%乙酸乙酯之己烷溶析，得到呈黃色固體之期望產物(1.14 g, 17.1%)。LCMS C₇H₇ClN₃O₄(M+H)⁺m/z計算值= 232.0；實驗值232.0。步驟2. (3-胺基-6-氯吡啶-2-基)胺基甲酸甲酯To a suspension of 6-chloro-3-nitropyridin-2-amine (5.00 g, 28.81 mmol) in DCM was addedN, N-diisopropylethylamine (24 mL, 172.85 mmol), followed by the dropwise addition of methyl chloroformate (26.8 mL, 345.71 mmol). The resulting mixture was heated at 45°C for 1 hour. The reaction was allowed to cool to room temperature. The reaction mixture was concentrated under vacuum and loaded onto silica gel (20 g). Elution with_0-50% ethyl acetate in hexanes afforded the desired product (1.14 g, 17.1%) as a yellow solid. LCMS m/z Calcd._{forCₐHₐClN₃O₄} (M+H)⁺ = 232.0; Found 232.0.Step 2. Methyl (3-amino-6-chloropyridin-2-yl)carbamate

在室溫下向N-(6-氯-3-硝基-2-吡啶基)胺基甲酸甲酯(1.11 g, 4.79 mmol)於乙醇與水之5:1混合物中之溶液中添加鐵(0.94 g, 16.78 mmol)及氯化銨(0.90 g, 16.78 mmol)。將所得混合物在60℃下加熱1小時。反應完成後，使混合物冷卻至室溫，經由矽藻土墊過濾並濃縮。利用矽膠層析，用含0-100%乙酸乙酯之二氯甲烷溶析純化殘餘物，得到呈黃色固體之期望產物(0.33 g, 34.2%)。LCMS C₇H₉ClN₃O₂(M+H)⁺m/z計算值= 202.0；實驗值202.0。中間體6. N,N,4,7-四甲基-5-側氧基-9-乙烯基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺步驟1. 9-溴-4,7-二甲基-5-側氧基-咪唑并[1,5-a]喹唑啉-3-甲酸To a solution of methyl N-(6-chloro-3-nitro-2-pyridyl)carbamate (1.11 g, 4.79 mmol) in a 5:1 mixture of ethanol and water was added iron (0.94 g, 16.78 mmol) and ammonium chloride (0.90 g, 16.78 mmol) at room temperature. The resulting mixture was heated at 60°C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, filtered through a pad of celite, and concentrated. The residue was purified by silica gel chromatography using 0-100% ethyl acetate in dichloromethane to give the desired product (0.33 g, 34.2%) as a yellow solid. LCMS C₇ H₉ ClN₃ O₂ (M+H)⁺ m/z calcd = 202.0; found 202.0.Intermediate 6. N,N,4,7-Tetramethyl-5-oxo-9-vinyl-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamideStep 1. 9-Bromo-4,7-dimethyl-5 -oxo-imidazo[1,5-a]quinazoline-3-carboxylic acid

在室溫下用TFA (20 mL)處理9-溴-4,7-二甲基-5-側氧基-咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯之固體(實例1，步驟6) (4.00 g, 10.20 mmol)。將所得混合物在室溫下攪拌2 h。完成後，在減壓下去除溶劑。使殘餘物與甲苯(20 mL)共沸3次，得到粗產物，其直接用於下一步驟中。LCMS C₁₃H₁₁BrN₃O₃(M+H)⁺m/z計算值= 336.0；實驗值336.0。步驟2. 9-溴-N,N,4,7-四甲基-5-側氧基-咪唑并[1,5-a]喹唑啉-3-甲醯胺A solid of tert-butyl 9-bromo-4,7-dimethyl-5-oxo-imidazo[1,5-a]quinazoline-3-carboxylate (Example 1, Step 6) (4.00 g, 10.20 mmol) was treated with TFA (20 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. Upon completion, the solvent was removed under_reduced pressure_. The residue was azeotroped three times with toluene (20 mL) to afford the crude product, which was used directly in the next step. LCMS m/z calculated_{forCi3H11BrN3O3} (M+H)⁺ = 336.0; found 336.0.Step 2. 9-Bromo-N,N,4,7-tetramethyl-5-oxo-imidazo[1,5-a]quinazoline-3-carboxamide

在室溫下向9-溴-4,7-二甲基-5-側氧基-咪唑并[1,5-a]喹唑啉-3-甲酸(3.43 g, 10.20 mmol)於DMF (20 mL)中之溶液中添加[二甲基胺基(三唑并[4,5-b]吡啶-3-基氧基)亞甲基]-二甲基-銨;六氟磷酸鹽(5.82 g, 15.31 mmol)、N-乙基-N-異丙基-丙-2-胺(17.8 mL, 102.04 mmol)及二甲胺(2 M THF, 6.1 mL, 12.24 mmol)。將所得混合物在室溫下攪拌1 h。完成後，用水(50 mL)稀釋混合物，用乙酸乙酯(100 mL)萃取，用水(50 mL × 3)洗滌有機層。使合併的有機層經硫酸鈉乾燥，在減壓下濃縮。利用矽膠層析純化殘餘物，得到呈淺黃色固體之期望產物(2.54 g, 68.5%)。LCMS C₁₅H₁₆BrN₄O₂(M+H)+ m/z計算值= 363.0；實驗值363.0。步驟3. N,N,4,7-四甲基-5-側氧基-9-乙烯基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺To a solution of 9-bromo-4,7-dimethyl-5-oxoimidazo[1,5-a]quinazoline-3-carboxylic acid (3.43 g, 10.20 mmol) in DMF (20 mL) at room temperature were added [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium hexafluorophosphate (5.82 g, 15.31 mmol), N-ethyl-N-isopropyl-propan-2-amine (17.8 mL, 102.04 mmol), and dimethylamine (2 M THF, 6.1 mL, 12.24 mmol). The resulting mixture was stirred at room temperature for 1 h. Upon completion, the mixture was diluted with water (50 mL), extracted with ethyl acetate (100 mL), and the organic layer was washed with water (50 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product (2.54 g, 68.5%) as_alightyellow solid. LCMS_C15H16BrN4O2 (M+H)+ m/z calcd = 363.0; found 363.0.Step 3. N,N,4,7-Tetramethyl-5-oxo-9-vinyl-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide

在室溫下向THF與水之5:1混合物(25 mL)中添加9-溴-N,N,4,7-四甲基-5-側氧基-咪唑并[1,5-a]喹唑啉-3-甲醯胺(0.94 g, 2.59 mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之錯合物(211 mg , 0.26 mmol)、三氟(乙烯基)硼酸鉀(1.04 g, 7.76 mmol)及K₂CO₃(1.07 g, 7.76 mmol)。將所得混合物在70℃下加熱4 h。冷卻至室溫後，用DCM (50 mL)稀釋反應混合物，用水(20 mL)洗滌。使合併的有機層經硫酸鈉乾燥，濃縮，且利用矽膠層析進行純化，得到呈黃色固體之期望產物(0.50 g, 62.3%)。LCMS C₁₇H₁₉N₄O₂(M+H)⁺m/z計算值= 311.2；實驗值311.2。中間體7. 4-(5-(3-胺基-6-氯吡啶-2-基)-2H-四唑-2-基)六氫吡啶-1-甲酸第三丁酯步驟1. 4-(5-(6-氯-3-(1,3-二側氧基異吲哚啉-2-基)吡啶-2-基)-2H-四唑-2-基)六氫吡啶-1-甲酸第三丁酯To a 5:1 mixture of THF and water (25 mL) at room temperature were added 9-bromo-N,N,4,7-tetramethyl-5-oxo-imidazo[1,5-a]quinazoline-3-carboxamide (0.94 g, 2.59 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (211 mg, 0.26 mmol), potassium trifluoro(vinyl)borate (1.04 g, 7.76 mmol), and_K₂CO₃ (1.07_g , 7.76 mmol). The resulting mixture was heated at 70°C for 4 h. After cooling to room temperature, the reaction mixture was diluted with DCM (50 mL) and washed with water (20 mL). The combined organic layers_were dried over sodium sulfate, concentrated, and purified by silica gel chromatography to provide the desired product as_a yellow solid (0.50 g, 62.3%). LCMS m/z calculated for_Ci7H19N4O2 (M+H)⁺ = 311.2; found 311.2. Intermediate 7. tert-Butyl 4-(5-(3-amino-6_-chloropyridin-2-yl)-2H-tetrazol-2-yl)hexahydropyridine-1-carboxylateStep1. 4-(5-(6-chloro-3-(1,3-dioxoisoindolin-2-yl)pyridin-2-yl)-2H-tetrazol-2-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester

向2-(6-氯-2-(2H-四唑-5-基)吡啶-3-基)異吲哚啉-1,3-二酮(實例8，步驟1) (100 mg, 0.31 mmol)於DMF中之懸浮液中添加K₂CO₃(63 mg, 0.46 mmol) 及4-((甲基磺醯基)氧基)六氫吡啶-1-甲酸第三丁酯(171 mg, 0.61 mmol)。將所得混合物在80℃下加熱隔夜。使反應物冷卻至室溫。在真空下濃縮反應混合物，利用矽膠層析進行純化，得到期望產物。LCMS C₂₄H₂₅ClN₇O₄(M+H)⁺m/z計算值= 510.2；實驗值510.2。步驟2. 4-(5-(3-胺基-6-氯吡啶-2-基)-2H-四唑-2-基)六氫吡啶-1-甲酸第三丁酯To a suspension of 2-(6-chloro-2-(2H-tetrazol-5-yl)pyridin-3-yl)_isoindoline -1,3-dione (Example 8, Step 1) (100 mg, 0.31 mmol) in DMF were added_K₂CO₃ (63 mg, 0.46 mmol) and tert-butyl 4-((methylsulfonyl)oxy)hexahydropyridine-1-carboxylate (171 mg, 0.61 mmol). The resulting mixture was heated at 80°C overnight. The reaction was allowed to cool to room temperature. The reaction mixture was concentrated under vacuum and purified by silica gel chromatography to provide the desired product. LCMS C₂₄ H₂₅ ClN₇ O₄ (M+H)⁺ m/z calcd = 510.2; found 510.2.Step 2. tert-Butyl 4-(5-(3-amino-6-chloropyridin-2-yl)-2H-tetrazol-2-yl)hexahydropyridine-1-carboxylate

將4-(5-(6-氯-3-(1,3-二側氧基異吲哚啉-2-基)吡啶-2-基)-2H-四唑-2-基)六氫吡啶-1-甲酸第三丁酯(30 mg, 0.06 mmol)於0.5 mL一水合肼中之混合物在45℃下攪拌2 h，接著冷卻至室溫且在真空下濃縮。利用矽膠層析純化殘餘物，得到期望產物。LCMS C₁₆H₂₃ClN₇O₂(M+H)⁺m/z計算值= 380.2；實驗值380.2。中間體8. 3-(5-(3-胺基-6-氯吡啶-2-基)-2H-四唑-2-基)氮雜環丁烷-1-甲酸第三丁酯A mixture of tert-butyl 4-(5-(6-chloro-3-(1,3-dioxoisoindolin-2-yl)pyridin-2-yl)-2H-tetrazol-2-yl)hexahydropyridine-1-carboxylate (30 mg, 0.06 mmol) in 0.5 mL of hydrazine monohydrate was stirred at 45°C for 2 h, then cooled to room temperature and concentrated under vacuum. The residue was purified by silica_gel chromatography to provide the desired product. LCMS m/z calculated_{forCi6H23ClN7O2} (M+H)₊⁼ 380.2; found 380.2.Intermediate 8. 3-(5-(3-amino-6-chloropyridin-2-yl)-2H-tetrazol-2-yl)azinecyclobutane-1-carboxylic acid tert-butyl ester

使用與中間體7中所闡述類似之程序，在步驟1中用3-((甲基磺醯基)氧基)氮雜環丁烷-1-甲酸第三丁酯替代4-((甲基磺醯基)氧基)六氫吡啶-1-甲酸第三丁酯來製備標題中間體。LCMS C₁₄H₁₉ClN₇O₂(M+H)⁺m/z計算值= 352.1；實驗值352.1。中間體9. 4-氟-2-(1-甲基-1H-1,2,3-三唑-4-基)苯胺The title intermediate was prepared using a procedure analogous to that described for Intermediate 7, substituting tert-butyl 3-((methylsulfonyl)oxy)azepanecyclobutane-1-carboxylate for tert-butyl 4-((methylsulfonyl)oxy)_{hexahydropyridine} -1-carboxylate in Step 1. LCMS_Calcd ._{forCi4H19ClN7O2} (M+H)⁺ m/z = 352.1; Found 352.1.Intermediate 9. 4-Fluoro-2-(1-methyl-1H-1,2,3-triazol-4-yl)aniline

使用與針對中間體4所闡述類似之程序，用4-溴-1-甲基-1H-1,2,3-三唑替代3-溴-1-甲基-1,2,4-三唑來製備標題化合物。藉由矽膠管柱層析，用DCM及EtOAc (0至100%)溶析純化殘餘物，提供呈白色固體之期望產物。LCMS C₉H₁₀FN₄(M+H)⁺m/z計算值= 193.1；實驗值193.1。中間體10. 6-氯-1,2,3,4-四氫-1,5-萘啶步驟1. (E)-3-(3-胺基-6-氯-2-吡啶基)丙-2-烯酸甲酯The title compound was prepared using a procedure similar to that described for Intermediate 4, substituting 4-bromo-1-methyl-1H-_1,2,3 -triazole for 3-bromo-1-methyl-1,2,4-triazole. The residue was purified by silica gel column chromatography eluting with_DCM and EtOAc (0 to 100%) to provide the desired product as a white solid. LCMS_C9H10FN4 (M+H)⁺ m/z calcd = 193.1; found 193.1.Intermediate 10. 6-Chloro-1,2,3,4-tetrahydro-1,5-naphthyridineStep 1. Methyl (E)-3-(3-amino-6-chloro-2-pyridinyl)prop-2-enoate

在室溫下向6-氯-2-碘-吡啶-3-胺(1.00 g, 3.93 mmol)於無水DMF (3.33 mL)中之溶液中添加Pd(OAc)₂(88 mg, 0.39 mmol)、參-鄰甲苯基磷烷(84 mg, 0.28 mmol)、丙-2-烯酸甲酯(605.43 uL, 6.68 mmol)及N-乙基-N-異丙基-丙-2-胺(2.05 mL, 11.79 mmol)。藉由三次真空-氮氣循環使混合物去氧。將所得混合物在100℃下加熱16 h。反應完成後，使反應混合物冷卻至室溫，用水(20 mL)稀釋，用乙酸乙酯(20 mL × 3)萃取。使合併的有機層經硫酸鈉乾燥。在減壓下去除溶劑。利用矽膠層析，用含0-100% EA之DCM溶析純化殘餘物，得到呈黃色固體之期望產物(740 mg, 88.6%)。LCMS C₉H₁₀ClN₂O₂(M+H)⁺m/z計算值= 213.0；實驗值213.0。步驟2. 3-(3-胺基-6-氯-2-吡啶基)丙酸甲酯To a solution of 6-chloro-2-iodo-pyridin-3-amine (1.00 g, 3.93 mmol) in anhydrous DMF (3.33 mL) at room temperature were added Pd(OAc)₂ (88 mg, 0.39 mmol), tris-o-tolylphosphane (84 mg, 0.28 mmol), methyl prop-2-enoate (605.43 μL, 6.68 mmol), and N-ethyl-N-isopropyl-propan-2-amine (2.05 mL, 11.79 mmol). The mixture was deoxygenated by three vacuum-nitrogen cycles. The resulting mixture was heated at 100°C for 16 h. After the reaction was complete, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography using 0-100% EA in DCM to give the desired product (740 mg, 88.6%) as a yellow solid. LCMS C₉ H₁₀ ClN₂ O₂ (M+H)⁺ m/z calculated = 213.0; experimental value 213.0.Step 2. Methyl 3-(3-amino-6-chloro-2-pyridinyl)propanoate

向乾燥小瓶中裝填於2-甲基丙-2-醇( 857 uL, 9.03 mmol) 及無水甲苯(2.0 mL)中之二乙醯氧基銅(55 mg, 0.30 mmol) 及(2-二苯基磷烷基苯基)-二苯基-磷烷(13 mg, 0.03 mmol)，將所得混合物在氮氣下在室溫下攪拌20 min，之後經由注射器添加聚甲基氫矽氧烷(557 uL)，溶液在約5 min內自藍色變成深黃色；接著一次性添加(E)-3-(3-胺基-6-氯-2-吡啶基)丙-2-烯酸甲酯(640 mg, 3.01 mmol)。將所得混合物在室溫下攪拌2天，之後用DCM稀釋，接著用水洗滌，分離有機層，經Na₂SO₄乾燥，接著在減壓下去除溶劑。向殘餘物中加入DCM，藉由過濾收集沈澱物，將濾液裝載至矽膠上，利用矽膠進行純化，用0-100% DCM/EA、之後0-30% MeOH/EA溶析，得到呈白色固體之期望產物(362 mg, 56.1%)。LCMS C₉H₁₂ClN₂O₂(M+H)⁺m/z計算值= 215.1；實驗值215.1。步驟3. 6-氯-3,4-二氫-1H-1,5-萘啶-2-酮A dry vial was charged with copper diacetyloxide (55 mg, 0.30 mmol) and (2-diphenylphosphanylphenyl)-diphenyl-phosphane (13 mg, 0.03 mmol) in 2-methylpropan-2-ol (857 uL, 9.03 mmol) and anhydrous toluene (2.0 mL). The resulting mixture was stirred at room temperature under nitrogen for 20 min. Polymethylsiloxane (557 uL) was then added via syringe, and the solution turned from blue to dark yellow in approximately 5 min. Methyl (E)-3-(3-amino-6-chloro-2-pyridinyl)prop-2-enoate (640 mg, 3.01 mmol) was then added in one portion. The resulting mixture was stirred at room temperature for 2 days, then diluted with DCM and washed with water. The organic layer was separated, dried_{overNa₂SO₄} , and the solvent removed under reduced pressure. DCM was added to the residue,_and the precipitate was collected by filtration. The filtrate was loaded onto silica gel and purified on silica gel using 0-100% DCM/EA followed by 0-30% MeOH/EA to give the desired product (362 mg, 56.1%) as a white_solid . LCMS m/z calculated for_{C₆H₁₂ClN₂O₂} (M+H)₊⁼ 215.1; found 215.1.Step 3. 6-Chloro-3,4-dihydro-1H-1,5-naphthyridin-2-one

在室溫下向3-(3-胺基-6-氯-2-吡啶基)丙酸甲酯(362 mg, 1.69 mmol)中添加 乙醇與乙酸之10:1混合物(10 mL)。將所得混合物在70℃下加熱隔夜。在減壓下去除溶劑。使殘餘物與EA/DCM共沸2次，得到呈黃色固體之期望粗製材料，其直接用於下一步驟中。LCMS C₈H₈ClN₂O (M+H)⁺m/z計算值= 183.0；實驗值183.0。步驟4. 6-氯-1,2,3,4-四氫-1,5-萘啶To methyl 3-(3-amino-6-chloro-2-pyridinyl)propanoate (362 mg, 1.69 mmol) was added a 10:1 mixture of ethanol and acetic acid (10 mL) at room temperature. The resulting mixture was heated at₇₀ °C overnight. The solvent was removed under reduced pressure. The residue was azeotroped twice with EA/DCM to give the desired crude material as a yellow solid, which was used directly in the next step. LCMS_C8H8ClN2O (M+H)⁺ m/_z calculated = 183.0; found 183.0.Step 4. 6-Chloro-1,2,3,4-tetrahydro-1,5-naphthyridine

在0℃下向6-氯-3,4-二氫-1H-1,5-萘啶-2-酮(512 mg, 2.80 mmol)於無水THF (5.6 mL)中之溶液中添加LAH (THF溶液，5.61 mL, 5.61 mmol)。將所得混合物在60℃下加熱14小時。用冰水淬滅反應物，用EA萃取兩次。接著使有機層經硫酸鈉乾燥，在減壓下濃縮。利用矽膠層析純化殘餘物，得到呈白色固體之期望產物(296 mg，62.6%，2步)。LCMS C₈H₁₀ClN₂(M+H)⁺m/z計算值= 169.1；實驗值169.1。中間體11. 6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-胺To a solution of 6-chloro-3,4-dihydro-1H-1,5-naphthyridin-2-one (512 mg, 2.80 mmol) in anhydrous THF (5.6 mL) at 0°C was added LAH (THF solution, 5.61 mL, 5.61 mmol). The resulting mixture was heated at 60°C for 14 hours. The reaction was quenched with ice water and extracted twice with EA. The organic layer was then dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel_{chromatography to give the desired product as a white solid (296 mg, 62.6% over 2 steps). LCMS m/z calculated for C8H10ClN2(M} +H)⁺ = 169.1; found 169.1.Intermediate 11. 6-Chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-amine

使用與針對實例8所闡述類似之程序，在步驟3中用碘甲烷-d₃替代碘甲烷來製備標題化合物。LCMS C₇H₅D₃ClN₆(M+H)⁺m/z計算值= 214.1；實驗值214.1。中間體12. 9-(1-溴乙基-1-d)-7-甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯The title compound was prepared using a procedure similar to that described forExample 8 , substituting iodomethane-_d3for iodomethane in step 3. LCMS_Calcd ._{forC7H5D3ClN6} (M+H)⁺ m/z = 214.1; Found 214.1.Intermediate 12. tert-Butyl 9-(1-bromoethyl-1-d)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate

使用與針對實例1所闡述類似之程序，在步驟4中用2-胺基-3-溴-5-甲基-N-(甲基-d₃)苯甲醯胺(實例4，步驟1)替代2-胺基-3-溴-N,5-二甲基苯甲醯胺，且在步驟8中用NaBD₄替代NaBH₄來製備標題化合物。LCMS C₁₉H₁₉D₄BrN₃O₃(M+H)⁺m/z計算值= 424.1；實驗值424.1。中間體13. 9-甲醯基-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯步驟1：4,7-二甲基-5-側氧基-9-乙烯基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯The title compound was prepared using a procedure similar to that described for Example1 , substituting 2-amino-3-bromo-5-methyl-N-(methyl-d₃ )benzamide (Example 4, Step 1) for 2-amino-3-bromo-N,5-dimethylbenzamide in Step 4 and substituting NaBD₄ for NaBH₄ in Step 8. LCMS Calcd. for C₁₉ H₁₉ D₄ BrN₃ O₃ (M+H)⁺ m/z = 424.1; Found 424.1.Intermediate 13. 9-Formyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid tert-butyl esterStep 1: 4,7-Dimethyl-5-oxo-9-vinyl-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid tert-butyl ester

在室溫下向9-溴-4,7-二甲基-5-側氧基-咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯(實例1，步驟6) (2.00 g, 5.10 mmol)於THF與水之5:1混合物(75 mL)中之混合物中添加[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之錯合物(416.4 mg, 0.51 mmol)、碳酸鉀(2.11 g, 15.30 mmol)及乙烯基三氟硼酸鉀(2.05 g, 15.30 mmol)。將所得混合物用氮氣脫氣1分鐘。將混合物在70℃下加熱4小時，接著冷卻至室溫且用DCM (250 mL)稀釋，用水(100 mL)洗滌。接著分離有機層，經硫酸鈉乾燥。在減壓下去除溶劑。利用矽膠層析純化殘餘物，得到呈黃色固體之期望產物(1.21 g, 69.9%)。LCMS C₁₉H₂₂N₃O₃(M+H)+ m/z計算值= 340.2；實驗值340.2。步驟2：9-甲醯基-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯To a mixture of tert-butyl 9-bromo-4,7-dimethyl-5-oxo-imidazo[1,5-a]quinazoline-3-carboxylate (Example 1, Step 6) (2.00 g, 5.10 mmol) in a 5:1 mixture of THF and water (75 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (416.4 mg, 0.51 mmol), potassium carbonate (2.11 g, 15.30 mmol), and potassium vinyl trifluoroborate (2.05 g, 15.30 mmol) at room temperature. The resulting mixture was degassed with nitrogen for 1 minute. The mixture was heated at 70°C for 4 hours, then cooled to room temperature and diluted with DCM (250 mL) and washed with water (100 mL). The organic layer was then separated and dried over sodium sulfate. The solvent was removed under_{reducedpressure} . The residue was purified by silica gel chromatography to give the desired product (1.21 g, 69.9%) as_a yellow solid. LCMS_C19H22N3O3 (M+H)+ m/z calculated = 340.2; experimental value 340.2.Step 2: 9-Formyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid tert-butyl ester

向THF與水之5:1混合物中相繼加入4,7-二甲基-5-側氧基-9-乙烯基-咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯(1.21 g, 3.57 mmol)、OsO₄(4%水溶液，679 uL , 0.11 mmol)、2,6-二甲基吡啶(826 uL, 7.13 mmol)及 過碘酸鈉(3.05 g, 14.26 mmol)。將所得混合物在45℃下加熱2小時。使反應混合物冷卻至室溫，用DCM (15 mL)稀釋，用水(10 mL × 2)洗滌。接著分離有機層，經硫酸鈉乾燥。接著在減壓下去除溶劑，殘餘物直接用於下一步驟中。LCMS C₁₈H₂₀N₃O₄(M+H)⁺m/z計算值= 342.1；實驗值342.1。中間體14.9-甲醯基-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺To a 5:1 mixture of THF and water were added tert-butyl 4,7-dimethyl-5-oxo-9-vinyl-imidazo[1,5-a]quinazoline-3-carboxylate (1.21 g, 3.57 mmol),_OsO₄ (4% aqueous solution, 679 μL, 0.11 mmol), 2,6-lutidine (826 μL, 7.13 mmol), and sodium periodate (3.05 g, 14.26 mmol) in sequence. The resulting mixture was heated at 45°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with DCM (15 mL), and washed with water (10 mL × 2). The organic layer was then separated and dried over sodium sulfate. The solvent was then removed under reduced pressure, and the residue was used directly in the next step. LCMS C₁₈ H₂₀ N₃ O₄ (M+H)⁺ m/z Calcd = 342.1; Found 342.1.Intermediate 14.9-Formyl-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide

使用與針對中間體13所闡述類似之程序，在步驟2中用N,N,4,7-四甲基-5-側氧基-9-乙烯基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺(中間體6)替代4,7-二甲基-5-側氧基-9-乙烯基-咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯來製備標題化合物。LCMS C₁₆H₁₇N₄O₃(M+H)⁺m/z計算值= 313.1；實驗值313.1。中間體15. 6-氯-2-(1-環丙基-1H-吡唑-4-基)吡啶-3-胺The title compound was prepared using a procedure similar to that described for Intermediate 13, substituting N,N,4,7-tetramethyl-5-oxo-9-vinyl-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid tert-butyl ester for N,N,4,7-tetramethyl-5-oxo-9-vinyl-4,5-dihydroimidazo[1,5-a]_quinazoline -3-_carboxylate in step 2. LCMS_Calcd . for_Ci6H17N4O3 (M+H)⁺ m/z = 313.1; Found 313.1.Intermediate 15. 6-Chloro-2-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-amine

在氮氣下向2-溴-6-氯吡啶-3-胺(300 mg, 1.5 mmol)於2.5 mL二噁烷及0.5 mL水中之溶液中添加1-環丙基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1H-吡唑(230 mg, 1.8 mmol)、碳酸鉀(400 mg, 2.9 mmol)及四(三苯基膦)鈀(220 mg, 0.2 mmol)。在85℃下攪拌1 h後，用水稀釋混合物且用EtOAc萃取。將合併的有機物用鹽水洗滌且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。藉由矽膠管柱層析，用DCM及乙酸乙酯溶析純化殘餘物，提供呈黃色固體之期望產物。LCMS C₁₁H₁₂ClN₄(M+H)⁺m/z計算值= 235.1；實驗值235.1。中間體16至21.To a solution of 2-bromo-6-chloropyridin-3-amine (300 mg, 1.5 mmol) in 2.5 mL of dioxane and 0.5 mL of water was added 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)-1H-pyrazole (230 mg, 1.8 mmol), potassium carbonate (400 mg, 2.9 mmol), and tetrakis(triphenylphosphine)palladium (220 mg, 0.2 mmol) under nitrogen. After stirring at 85°C for 1 h, the mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM and ethyl acetate to provide the desired product as a yellow solid. LCMS C₁₁ H₁₂ ClN₄ (M+H)⁺ m/z calcd = 235.1; found 235.1.Intermediates 16 to 21.

表I-1中之以下中間體係根據針對中間體15所闡述之程序類似地製備。表I-1.中間體編號化學名稱結構LCMSm/z (M+H)⁺166-氯-2-(1-甲基-1H-吡唑-4-基)吡啶-3-胺209.1176-氟-2-(1-甲基-1H-吡唑-4-基)吡啶-3-胺193.1186-氯-2-(1-(氧雜環丁-3-基)-1H-吡唑-4-基)吡啶-3-胺251.1196-氯-2-(嘧啶-5-基)吡啶-3-胺207.1206-氯-2-(1,3-二甲基-1H-吡唑-4-基)吡啶-3-胺223.1216-氯-2-(1,5-二甲基-1H-吡唑-4-基)吡啶-3-胺223.1中間體22. 1-(3-胺基-6-氯吡啶-2-基)六氫吡啶-4-醇The following intermediates in Table I-1 were prepared similarly to the procedures described for Intermediate 15.Table I-1.Intermediate numberChemical namestructureLCMSm/z (M+H)⁺16 6-Chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-amine 209.117 6-Fluoro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-amine 193.118 6-Chloro-2-(1-(oxacyclobutan-3-yl)-1H-pyrazol-4-yl)pyridin-3-amine 251.119 6-Chloro-2-(pyrimidin-5-yl)pyridin-3-amine 207.120 6-Chloro-2-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-amine 223.1twenty one 6-Chloro-2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-amine 223.1Intermediate 22. 1-(3-amino-6-chloropyridin-2-yl)hexahydropyridin-4-ol

向6-氯-2-氟-3-硝基-吡啶(100 mg, 0.57 mmol)於3 mL EtOH中之溶液中添加六氫吡啶-4-醇(57.3 mg, 0.57 mmol)。將反應混合物在45℃下攪拌1 h。向此混合物中添加第三丁醇鉀(127 mg, 1.13 mmol)及4,4,4',4',5,5,5',5'-八甲基-2,2'-雙(1,3,2-二氧雜硼雜環戊烷) (432 mg, 1.70 mmol)。在80℃下攪拌隔夜後，使混合物冷卻至室溫，用水稀釋且用EtOAc萃取。將合併的有機物用鹽水洗滌且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。藉由矽膠管柱層析，用DCM及乙酸乙酯溶析純化殘餘物，提供呈黃色固體之期望產物(90 mg, 70%)。LCMS C₁₀H₁₅ClN₃O (M+H)⁺m/z計算值= 228.1；實驗值228.1。中間體23. 6-氯-2-嗎啉基吡啶-3-胺To a solution of 6-chloro-2-fluoro-3-nitro-pyridine (100 mg, 0.57 mmol) in 3 mL of EtOH was added hexahydropyridin-4-ol (57.3 mg, 0.57 mmol). The reaction mixture was stirred at 45°C for 1 h. To this mixture were added potassium tert-butoxide (127 mg, 1.13 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (432 mg, 1.70 mmol). After stirring at 80°C overnight, the mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organics were washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by_silica gel_column chromatography eluting with DCM and ethyl acetate to provide the desired product (90 mg, 70%) as a yellow solid. LCMS_C10H15ClN3O (M+H)⁺ m/z calculated = 228.1; found 228.1.Intermediate 23. 6-Chloro-2-morpholinylpyridin-3-amine

使用與針對中間體22所闡述類似之程序，用嗎啉替代六氫吡啶-4-醇來製備標題化合物。LCMS C₉H₁₃ClN₃O (M+H)⁺m/z計算值= 214.1；實驗值214.1。中間體24：3-(3-胺基-6-氯吡啶-2-基)-1,2,4-噁二唑-5(4H)-酮步驟1：3-胺基-6-氯-N-羥基吡啶甲脒The title compound was prepared using a procedure similar to that described for Intermediate 22, substituting morpholine for hexahydropyridin-4-ol. LCMS C₉ H₁₃ ClN₃ O (M+H)⁺ m/z calcd = 214.1; found 214.1.Intermediate 24: 3-(3-amino-6-chloropyridin-2-yl)-1,2,4-oxadiazol-5(4H)-oneStep 1: 3-amino-6-chloro-N-hydroxypyridinecarboxamidine

將3-胺基-6-氯吡啶甲腈(5.0 g, 32.5 mmol)及50%羥胺水溶液(2 mL, 32.5 mmol)於MeOH (100 mL)中之混合物在室溫下攪拌1 h。接著將混合物傾倒至水(500 mL)中。經由過濾收集所得固體，用水(100 mL)洗滌並乾燥，得到呈棕色固體之期望產物(5.1 g，84%產率)。LCMS C₆H₈ClN₄O (M+H)⁺m/z計算值= 187.0；實驗值187.0。步驟2：3-(3-胺基-6-氯吡啶-2-基)-1,2,4-噁二唑-5(4H)-酮A mixture of 3-amino-6-chloropicolinonitrile (5.0 g, 32.5 mmol) and 50% aqueous hydroxylamine solution (2 mL, 32.5 mmol) in MeOH (100 mL) was stirred at room temperature for 1 h. The mixture was then poured into water (500 mL). The resulting solid was collected by filtration, washed with water (100 mL) and dried to give the desired product (5.1 g, 84% yield) as a brown solid. LCMS C₆ H₈ ClN₄ O (M+H)⁺ m/z calculated = 187.0; found 187.0.Step 2: 3-(3-amino-6-chloropyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one

在0℃下向3-胺基-6-氯-N-羥基吡啶甲脒(5.1 g, 27.3 mmol)於THF (100 mL)中之溶液中添加1,1'-羰基二咪唑(4.87 g, 30 mmol)及1,8-二氮雜雙環[5.4.0]十一-7-烯(16.6 mL, 109 mmol)。在室溫下攪拌4 h後，用500 mL水稀釋混合物。將水相用50 mL乙酸乙酯洗滌3次，接著用3 N HCl將pH調整至7。經由過濾收集所得固體，用水(100 mL)洗滌並乾燥，得到呈棕色固體之期望產物(4.9 g，84%產率)。LCMS C₇H₆ClN₄O₂(M+H)⁺m/z計算值= 213.0；實驗值213.0。中間體25. 6-氯-2-(1,3,4-噁二唑-2-基)吡啶-3-胺To a solution of 3-amino-6-chloro-N-hydroxypyridinecarboximidamide (5.1 g, 27.3 mmol) in THF (100 mL) at 0°C were added 1,1'-carbonyldiimidazole (4.87 g, 30 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (16.6 mL, 109 mmol). After stirring at room temperature for 4 h, the mixture was diluted with 500 mL of water. The aqueous phase was washed three times with 50 mL of ethyl acetate, followed by adjusting the pH to 7 with 3 N HCl. The resulting solid was collected by filtration, washed with water (100 mL), and dried to give the desired product as a brown solid (4.9 g, 84% yield). LCMS_C7H6ClN4O2 (M+H)⁺ m/_z calcd = 213.0; found 213.0. Intermediate 25. 6_- Chloro-_2-(1,3,4-oxadiazol-2-yl)pyridin-3-amine

向3-胺基-6-氯吡啶甲酸(100 mg, 0.58 mmol)於2 mL DCM中之溶液中添加(N-異氰基亞胺基)三苯基磷烷(175 mg, 0.58 mmol)。在室溫下攪拌隔夜後，用水稀釋混合物且用DCM萃取。將合併的有機物用鹽水洗滌且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。藉由矽膠管柱層析，用DCM及乙酸乙酯溶析純化殘餘物，提供呈黃色固體之期望產物(84 mg, 74%)。LCMS C₇H₆ClN₄O (M+H)⁺m/z計算值= 197.0；實驗值197.0。中間體26. 6-氯-2-(5-甲基-1,3,4-噁二唑-2-基)吡啶-3-胺To a solution of 3-amino-6-chloropicolinic acid (100 mg, 0.58 mmol) in 2 mL of DCM was added (N-isocyanimido)triphenylphosphane (175 mg, 0.58 mmol). After stirring overnight at room temperature, the mixture was diluted with water and extracted with DCM. The combined organics were washed with brine and dried over anhydrous sodium sulfate, filtered, and_{concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM and ethyl acetate to provide the desired product (84 mg, 74%) as a yellow solid. LCMS m/z calculated for C7H6ClN4O(M} +H)⁺ = 197.0; found 197.0.Intermediate 26. 6-Chloro-2-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-amine

將6-氯-2-(1H-四唑-5-基)吡啶-3-胺(實例8，步驟1) (500 mg, 2.55 mmol)於2 mL乙酸酐中之溶液在110℃下攪拌隔夜，在減壓下濃縮混合物。藉由矽膠管柱層析，用DCM及乙酸乙酯溶析純化殘餘物，提供呈棕色固體之期望產物(187 mg, 35%)。LCMS C₈H₈ClN₄O (M+H)⁺m/z計算值= 211.0；實驗值211.0。中間體27. 6-氯-2-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-3-胺步驟1：3-胺基-6-氯-N'-甲基吡啶醯亞胺醯肼A solution of 6-chloro-2-(1H-tetrazol-5-yl)pyridin-3-amine (Example 8, Step 1) (500 mg, 2.55 mmol) in 2 mL of acetic anhydride was stirred at 110°C overnight,_and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM and ethyl acetate to provide the desired product (187 mg, 35%) as a brown solid. LCMS_C8H8ClN4O (M+H)⁺ m/z Calcd = 211.0; Found 211.0. Intermediate 27. 6-Chloro-2-(1-methyl-1H-1,2,4_-triazol-3-yl)pyridin-3-amineStep 1: 3-amino-6-chloro-N'-methylpyridinium imide hydrazide

在室溫下向3-胺基-6-氯-吡啶-2-甲腈(500 mg, 3.26 mmol)於10 mL EtOH中之溶液中添加甲基肼(1.03 mL, 19.54 mml)。在100℃下攪拌24 h後，在真空下去除溶劑，提供呈黃色固體之期望產物(600 mg, 92%)。LCMS C₇H₁₁ClN₅(M+H)⁺m/z計算值= 200.1；實驗值200.1。步驟2：6-氯-2-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-3-胺To a solution of 3-amino-6-chloro-pyridine-2-carbonitrile (500 mg, 3.26 mmol) in 10 mL of EtOH was added methylhydrazine (1.03 mL, 19.54 mmol) at room temperature. After stirring at 100 °C for 24 h, the solvent was removed under vacuum to provide the desired product as a yellow solid (600 mg, 92%)_. LCMS_C7H11ClN5 (M+H)⁺ m/zcalcd = 200.1; found 200.1. Step 2: 6-Chloro-_2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-amine

將3-胺基-6-氯-N'-甲基吡啶醯亞胺醯肼(600 mg, 3 mmol)於5 mL甲酸中之溶液在105℃下攪拌隔夜。冷卻至室溫後，在真空下去除溶劑。接著向殘餘物中添加5 mL氫氧化銨於水及EtOH中之溶液，將混合物在100℃下攪拌隔夜。用水稀釋混合物且用EtOAc萃取。將合併的有機物用鹽水洗滌且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。將殘餘物與乙醚一起研磨，過濾且用乙醚洗滌，提供呈黃色固體之期望產物(420 mg, 67%)。LCMS C₈H₉ClN₅(M+H)⁺m/z計算值= 210.1；實驗值210.1。中間體28. 5-(3-胺基-6-氯吡啶-2-基)-2-甲基-2,4-二氫-3H-1,2,4-三唑-3-酮A solution of 3-amino-6-chloro-N'-methylpyridinium imide hydrazide (600 mg, 3 mmol) in 5 mL of formic acid was stirred at 105°C overnight. After cooling to room temperature, the solvent was removed under vacuum. 5 mL of a solution of ammonium hydroxide in water and EtOH was then added to the residue, and the mixture was stirred at 100°C overnight. The mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether, filtered, and washed with diethyl ether to provide the desired product (420 mg, 67%) as a yellow solid. LCMS C₈ H₉ ClN₅ (M+H)⁺ m/z calcd = 210.1; found 210.1.Intermediate 28. 5-(3-amino-6-chloropyridin-2-yl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

向3-胺基-6-氯-N'-甲基吡啶醯亞胺醯肼(中間體27，步驟1) (200 mg, 1.3 mmol)於2 mL THF中之溶液中添加CDI (230 mg, 1.43 mmol)，之後緩慢添加DBU (0.58 mL, 3.9 mmol)。在室溫下攪拌所得混合物。接著用水稀釋混合物且用EtOAc萃取。將合併的有機物用鹽水洗滌且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。藉由矽膠管柱層析，用DCM及乙酸乙酯溶析純化殘餘物，提供呈棕色固體之期望產物。LCMS C₈H₉ClN₅O (M+H)⁺m/z計算值= 226.0；實驗值226.0。實例1.9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺步驟1：2-胺基-3-溴-5-甲基苯甲酸To a solution of 3-amino-6-chloro-N'-methylpyridinium imide hydrazide (Intermediate 27, Step 1) (200 mg, 1.3 mmol) in 2 mL of THF was added CDI (230 mg, 1.43 mmol) followed by the slow addition of DBU (0.58 mL, 3.9 mmol). The resulting mixture was stirred at room temperature. The mixture was then diluted with water and extracted with EtOAc. The combined organics were washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM and ethyl acetate to provide the desired product as a brown solid. LCMS C₈ H₉ ClN₅ O (M+H)⁺ m/z calcd = 226.0; found 226.0.Example 1.9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamideStep 1: 2-amino-3-bromo-5-methylbenzoic acid

在0℃下在氮氣氣氛下向2-胺基-5-甲基苯甲酸(100 g, 660 mmol)於DMF (300 mL)中之混合物中添加NBS (117 g, 660 mmol)。接著使反應混合物緩慢升溫至室溫並攪拌1 h。完成後，用冰水稀釋反應物，同時攪拌。收集所得固體，得到呈淺棕色固體之期望產物(127 g, 85%)，其不經進一步純化即用於下一步驟中。LCMS C₈H₉BrNO₂(M+H)⁺m/z計算值= 230.0；實驗值230.1。步驟2：8-溴-6-甲基-2H-苯并[d][1,3]噁嗪-2,4(1H)-二酮To a mixture of 2-amino-5-methylbenzoic acid (100 g, 660 mmol) in DMF (300 mL) at 0°C under nitrogen atmosphere was added NBS (117 g, 660 mmol). The reaction mixture was then slowly warmed to room temperature and stirred for 1 h. Upon completion, the reaction was diluted with ice water while stirring. The resulting solid was collected to_give the desired product as_a light brown solid (127 g, 85%), which was used in the next step without further purification. LCMS_C8H9BrNO2 (M+H)⁺ m/z calculated = 230.0; found 230.1.Step 2: 8-Bromo-6-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione

在0℃下向2-胺基-3-溴-5-甲基苯甲酸(110 g, 480 mmol)於二噁烷(1000 mL)中之混合物中添加三光氣(57 g, 192 mmol)。將所得混合物在100℃下攪拌2 h。冷卻至室溫後，收集所得固體，得到呈白色固體之期望產物，其不經進一步純化即用於下一步驟中。步驟3：2-胺基-3-溴-N,5-二甲基苯甲醯胺To a mixture of 2-amino-3-bromo-5-methylbenzoic acid (110 g, 480 mmol) in dioxane (1000 mL) was added triphosgene (57 g, 192 mmol) at 0°C. The resulting mixture was stirred at 100°C for 2 h. After cooling to room temperature, the resulting solid was collected to give the desired product as a white solid, which was used in the next step without further purification.Step 3: 2-amino-3-bromo-N,5-dimethylbenzamide

在0℃下向8-溴-6-甲基-2H-苯并[d][1,3]噁嗪-2,4(1H)-二酮(90 g, 354 mmol)於THF (900 mL)中之混合物中添加甲胺(175 mL，於THF中之2 M溶液)。使所得混合物升溫至室溫，且接著攪拌1 h。去除溶劑，且粗產物不經進一步純化即用於下一步驟中。步驟4：8-溴-2-羥基-3,6-二甲基喹唑啉-4(3H)-酮To a mixture of 8-bromo-6-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (90 g, 354 mmol) in THF (900 mL) was added methylamine (175 mL, 2 M solution in THF) at 0°C. The resulting mixture was allowed to warm to room temperature and then stirred for 1 h. The solvent was removed and the crude product was used in the next step without further purification.Step 4: 8-Bromo-2-hydroxy-3,6-dimethylquinazolin-4(3H)-one

在室溫下向來自步驟3之固體添加THF (700 mL)及三光氣(70 g, 237 mmol)。將所得混合物在70℃下加熱2 h，冷卻至室溫後，在真空下去除一半溶劑，收集所得固體。接著用4:1之己烷與乙酸乙酯洗滌固體產物，接著在真空下乾燥隔夜，得到呈白色固體之純產物，其不經進一步純化即用於下一步驟中。步驟5：8-溴-2-氯-3,6-二甲基喹唑啉-4(3H)-酮To the solid fromstep 3 was added THF (700 mL) and triphosgene (70 g, 237 mmol) at room temperature. The resulting mixture was heated at 70°C for 2 h, cooled to room temperature, and half of the solvent was removed under vacuum to collect the resulting solid. The solid product was then washed with 4:1 hexane and ethyl acetate, and then dried under vacuum overnight to obtain the pure product as a white solid, which was used in the next step without further purification.Step5:8-Bromo-2-chloro-3,6-dimethylquinazolin-4(3H)-one

在0℃下向8-溴-2-羥基-3,6-二甲基喹唑啉-4(3H)-酮(72 g, 269 mmol)於POCl₃(374 mL)中之混合物中添加DIEA (182 mL, 1.1 mmol)。於壓力容器中將所得混合物在120℃下攪拌12 h。冷卻至室溫後，將混合物小心地緩慢傾倒至4000 mL冰上。2 h後，收集所得固體，得到淺棕色固體，用水、飽和NaHCO₃、接著水洗滌該固體。使固體在真空下乾燥，得到呈淺棕色固體之期望產物(62.5 g, 82%)。步驟6：9-溴-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯To a mixture of 8-bromo-2-hydroxy-3,6-dimethylquinazolin-4(3H)-one (72 g, 269 mmol) in_POCl₃ (374 mL) at 0°C was added DIEA (182 mL, 1.1 mmol). The resulting mixture was stirred at 120°C in a pressure vessel for 12 h. After cooling to room temperature, the mixture was carefully poured slowly onto 4000 mL of ice. After 2 h, the resulting solid was collected to give a light brown solid, which was washed with water, saturated_NaHCO₃ , and then water. The solid was dried under vacuum to give the desired product (62.5 g, 82%) as a light brown solid.Step 6: 9-Bromo-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid tert-butyl ester

在0℃下在氮氣下向KO^tBu (29 g, 260 mmol)於無水DMF (700 mL)中之混合物中逐滴添加2-異氰基乙酸第三丁酯(27 mL, 191.3 mmol)。將所得混合物在0℃下攪拌10 min，接著一次性添加8-溴-2-氯-3,6-二甲基喹唑啉-4(3H)-酮(50 g, 173 mmol)。使所得混合物升溫至室溫並攪拌2 h。完成後，將反應混合物傾倒至1000 mL飽和NH₄Cl溶液中，接著用800 mL水稀釋。藉由過濾收集所得固體，用水洗滌，接著在真空下乾燥，提供呈米色固體之期望產物(59 g, 90%)。LCMS C₁₇H₁₉BrN₃O₃(M+H)⁺m/z計算值= 392.1；實驗值392.1。步驟7：9-乙醯基-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯To a mixture of KO^t Bu (29 g, 260 mmol) in anhydrous DMF (700 mL) at 0°C under nitrogen was added tert-butyl 2-isocyanoacetate (27 mL, 191.3 mmol) dropwise. The resulting mixture was stirred at 0°C for 10 min, followed by the addition of 8-bromo-2-chloro-3,6-dimethylquinazolin-4(3H)-one (50 g, 173 mmol) in one portion. The resulting mixture was allowed to warm to room temperature and stirred for 2 h. Upon completion, the reaction mixture was poured into 1000 mL of saturated NH₄ Cl solution and then diluted with 800 mL of water. The resulting solid was collected by filtration, washed with water, and then dried under vacuum to provide the desired product (59 g, 90%) as a beige solid. LCMS C₁₇ H₁₉ BrN₃ O₃ (M+H)⁺ m/z calcd = 392.1; found 392.1.Step 7: tert-butyl 9-acetyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate

在氮氣氣氛下將9-溴-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯(22.8 g, 58.1 mmol)、PdCl₂(PPh₃)₂(4.1 g, 5.8 mmol)及三丁基(1-乙氧基乙烯基)錫烷(25 g, 69.9 mmol)於二噁烷(750 mL)中之混合物在100℃下加熱8 h。冷卻至室溫後，向反應混合物中添加2 N HCl，接著攪拌4 h。用水稀釋混合物且用EtOAc萃取。將合併的有機物用飽和NaCl洗滌，經無水硫酸鈉乾燥，過濾並在減壓下濃縮。在去除大部分溶劑後，添加己烷與EtOAc之4:1混合物。將混合物攪拌2 h，經由過濾收集沈澱固體，用4:1己烷與EtOAc之混合物洗滌，提供呈棕色固體之期望產物(17 g, 84%)。LCMS C₁₉H₂₂N₃O₄(M+H)⁺m/z計算值= 356.2；實驗值356.2。步驟8：9-(1-羥基乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯A mixture of tert-butyl 9-bromo-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate (22.8 g, 58.1 mmol), PdCl₂ (PPh₃ )₂ (4.1 g, 5.8 mmol), and tributyl(1-ethoxyvinyl)tinane (25 g, 69.9 mmol) in dioxane (750 mL) was heated at 100°C for 8 h under a nitrogen atmosphere. After cooling to room temperature, 2 N HCl was added to the reaction mixture, followed by stirring for 4 h. The mixture was diluted with water and extracted with EtOAc. The combined organics were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After most of the solvent was removed, a 4:1 mixture of hexanes and EtOAc was added. The mixture was stirred for 2 h, and the precipitated solid was collected by filtration and washed with a 4:1 mixture of hexanes and EtOAc to provide the desired product (17 g, 84%) as a brown solid. LCMS C₁₉ H₂₂ N₃ O₄ (M+H)⁺ m/z calcd = 356.2; found 356.2.Step 8: tert-butyl 9-(1-hydroxyethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate

將9-乙醯基-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯(7 g, 19.6 mmol)溶解於MeOH (200 mL)及DCM (200 mL)中，接著在氮氣下在0℃下分三次添加NaBH₄(771.4 mg, 20.4 mmol)。將所得混合物在相同溫度下攪拌10 min，之後用飽和NH₄Cl淬滅。用水稀釋混合物且用DCM萃取。將合併的有機物用飽和NaCl洗滌，且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。藉由矽膠管柱層析，用DCM及MeOH (0至4%)溶析純化殘餘物，提供呈淺黃色固體之期望產物(5.3 g 75%)。LCMS C₁₉H₂₄N₃O₄(M+H)⁺m/z計算值= 358.2；實驗值358.2。步驟9：9-(1-溴乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯tert-Butyl 9-acetyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate (7 g, 19.6 mmol) was dissolved in MeOH (200 mL) and DCM (200 mL), followed by the addition of_NaBH₄ (771.4 mg, 20.4 mmol) in three portions at 0°C under nitrogen. The resulting mixture was stirred at the same temperature for 10 min, then quenched with saturated_NH₄Cl . The mixture was diluted with water and extracted with DCM. The combined organics were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM and MeOH (_0-4 %) to provide the desired product (5.3 g, 75%) as_a pale yellow solid. LCMS_C19H24N3O4 (M+H)⁺ m/z calculated = 358.2; found 358.2. Step 9: tert_-butyl 9-(1-bromoethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate

在0℃下向9-(1-羥基乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯(4.0 g, 11.2 mmol)於THF (300 mL)中之混合物中添加吡啶(1.7 g, 22 mmol)及 PBr₃(1.26 mL, 13.3 mmol)。使所得混合物升溫至室溫並攪拌2 h。接著用飽和NaHCO₃淬滅混合物且用DCM (2×)萃取。將合併的有機物用飽和NaCl洗滌，且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。殘餘物不經進一步純化即直接用於下一步驟中。步驟10：9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯To a mixture of tert-butyl 9-(1-hydroxyethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate (4.0 g, 11.2 mmol) in THF (300 mL) at 0°C was added pyridine (1.7 g, 22 mmol) and PBr₃ (1.26 mL, 13.3 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was then quenched with saturated NaHCO₃ and extracted with DCM (2×). The combined organics were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used directly in the next step without further purification.Step 10: tert-butyl 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate

向9-(1-溴乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯(1.6 g, 3.8 mmol)於DMF (50 mL)中之溶液中添加2-胺基-5-氟苯甲醯胺(770 mg, 5 mmol)。將混合物加熱至80℃持續2 h。冷卻至室溫後，用水稀釋混合物且用乙酸乙酯(3×)萃取。將合併的有機物用水、飽和NaCl洗滌，且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。藉由矽膠管柱層析，用己烷及EtOAc (0至100%)溶析純化殘餘物，提供呈淺黃色固體之期望產物(1.5 g, 80%)。LCMS C₂₆H₂₉FN₅O₄(M+H)⁺m/z計算值= 494.2；實驗值494.2。步驟11：9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸To a solution of tert-butyl 9-(1-bromoethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate (1.6 g, 3.8 mmol) in DMF (50 mL) was added 2-amino-5-fluorobenzamide (770 mg, 5 mmol). The mixture was heated to 80°C for 2 h. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate (3×). The combined organics were washed with water, saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexanes_and EtOAc (0 to 100%) to provide the desired product (1.5 g, 80%) as_a pale yellow_solid . LCMS_C26H29FN5O4 (M+H)⁺ m/z Calcd = 494.2; Found 494.2.Step 11: 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid

將9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯(1.5 g, 3.0 mmol)溶解於TFA (20 mL)中。將混合物在室溫下攪拌3 h。完成後，在真空下去除TFA。向反應殘餘物中添加EtOAc (100 mL)及己烷(100 mL)，同時攪拌。攪拌20 min後，收集所得固體，得到白色固體，用己烷/EtOAc (1:1)洗滌。使固體在真空下乾燥，提供純產物(1.1 g, 83%)。LCMS C₂₂H₂₁FN₅O₄(M+H)⁺m/z計算值= 438.2；實驗值438.2。步驟12：9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺tert-Butyl 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate (1.5 g, 3.0 mmol) was dissolved in TFA (20 mL). The mixture was stirred at room temperature for 3 h. Upon completion, the TFA was removed under vacuum. EtOAc (100 mL) and hexane (100 mL) were added to the reaction residue while stirring. After stirring for 20 min, the resulting solid was collected to give a white solid, which was washed with hexane/EtOAc (1:1). The solid was dried under vacuum to provide the pure product (1.1 g, 83%). LCMS C₂₂ H₂₁ FN₅ O₄ (M+H)⁺ m/z calcd = 438.2; found 438.2.Step 12: 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide

向9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸(20 mg, 0.045 mmol)於DMF (0.5 mL)中之混合物中添加HATU (22 mg, 0.06 mmol)、二甲胺(30 uL，2 M THF溶液)及DIEA (10 uL, 0.06 mmol)。攪拌1 h後，用MeOH稀釋反應物且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₄H₂₆FN₆O₃(M+H)⁺m/z計算值= 465.2；實驗值465.2。¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (s, 1H), 8.37 (s, 1H), 8.09-7.97 (bs, 2H), 7.78 (s, 1H), 7.53 (dd, J = 10.1, 3.0 Hz, 1H), 7.44 (s, 1H), 7.03 (td, J = 8.6, 3.0 Hz, 1H), 6.36 (dd, J = 9.2, 4.6 Hz, 1H), 5.27 (q, J = 6.5 Hz, 1H), 3.48 (s, 3H), 3.06 (s, 3H), 3.03 (s, 3H), 2.36 (s, 3H), 1.60 (d, J = 6.3 Hz, 3H)。實例2.9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-N,N-雙(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺(峰1)步驟1：9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯To a mixture of 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid (20 mg, 0.045 mmol) in DMF (0.5 mL) were added HATU (22 mg, 0.06 mmol), dimethylamine (30 uL, 2 M THF solution) and DIEA (10 uL, 0.06 mmol). After stirring for 1 hour, the reaction was diluted with MeOH and purified by preparative HPLC (Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The eluted fractions were collected and lyophilized to provide the desired product as a_whitesolid as its TFA salt. LCMS m/z calculated_{forC₂₄H₂₆FN₆O₃} (M+H)^⁺ = 465.2; found 465.2.¹ H NMR (400 MHz, DMSO-d₆ ) δ 8.64 (s, 1H), 8.37 (s, 1H), 8.09-7.97 (bs, 2H), 7.78 (s, 1H), 7.53 (dd, J = 10.1, 3.0 Hz, 1H), 7.44 (s, 1H), 7.03 (td, J = 8.6, 3.0 Hz, 1H), 6.36 (dd, J = 9.2, 4.6 Hz, 1H), 5.27 (q, J = 6.5 Hz, 1H), 3.48 (s, 3H), 3.06 (s, 3H), 3.03 (s, 3H), 2.36 (s, 3H), 1.60 (d, J = 6.3 Hz, 3H).Example 2.9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide (Peak 1)Step 1: 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid tert-butyl ester

藉由手性HPLC分離標題外消旋化合物(實例1，步驟10)，得到2種鏡像異構物，峰1用於下一步驟中。步驟2：9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸(峰1)The title racemic compound (Example 1, Step 10) was separated by chiral HPLC to obtain two mirror isomers. Peak 1 was used in the next step.Step 2: 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid (Peak 1)

將上述9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯之峰1 (60 mg, 0.12 mmol)添加於2打蘭反應小瓶中。向反應小瓶中添加0.5 mL純TFA，將反應物在室溫下攪拌1 h。完成後，在真空下去除TFA。向反應小瓶中添加1 mL EtOAc及1 mL己烷，同時攪拌。攪拌20 min後，收集所得固體，得到白色固體，用己烷/EtOAc (1:1)洗滌。使固體在真空下乾燥，提供純產物(48 mg, 91%)。LCMS C₂₂H₂₁FN₅O₄(M+H)⁺m/z計算值= 438.2；實驗值438.2。步驟3：9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-N,N-雙(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺(峰1)Peak 1 (60 mg, 0.12 mmol) of the above tert-butyl 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate was added to a 2-dram reaction vial. 0.5 mL of neat TFA was added to the reaction vial, and the reaction was stirred at room temperature for 1 hour. Upon completion, the TFA was removed under vacuum. 1 mL of EtOAc and 1 mL of hexane were added to the reaction vial while stirring. After stirring for 20 minutes, the resulting solid was collected to give a white solid, which was washed with hexane/EtOAc (1:1). The solid was dried under vacuum to provide the pure product (48 mg, 91%). LCMS C₂₂ H₂₁ FN₅ O₄ (M+H)⁺ m/z calcd = 438.2; found 438.2.Step 3: 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide (peak 1)

向9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸(峰1) (20 mg, 0.045 mmol)於DMF (0.5 mL)中之混合物中添加HATU (22 mg, 0.06 mmol)、雙(甲基-d₃)胺HCl鹽(5 mg, 0.06 mmol)及DIEA (20 uL, 0.12 mmol)。攪拌1 h後，用MeOH稀釋反應物且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₄H₂₀D₆FN₆O₃(M+H)⁺m/z計算值= 471.2；實驗值471.2。實例3.9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-N,N-雙(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺(峰2)To a mixture of 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid (peak 1) (20 mg, 0.045 mmol) in DMF (0.5 mL) were added HATU (22 mg, 0.06 mmol), bis(methyl-_d3 )amine HCl salt (5 mg, 0.06 mmol) and DIEA (20 uL, 0.12 mmol). After stirring for 1 hour, the reaction was diluted with MeOH and purified by preparative HPLC (Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The eluted fractions were collected and lyophilized to provide the desired product as_{awhitesolidas} its TFA salt. LCMS m/z calculated for_{C₂₄H₂O₀FN₆O₃} (M+H)^⁺ = 471.2; found 471.2.Example 3.9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide (Peak 2)

使用與針對實例2所闡述類似之程序，在步驟2中用9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯(實例2，步驟1，峰2)替代9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯(峰1) 來製備標題化合物。用MeOH稀釋粗產物，且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₄H₂₀D₆FN₆O₃(M+H)⁺m/z計算值= 471.2；實驗值471.2。實例4.9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-7-甲基-N,N,4-參(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺步驟1：2-胺基-3-溴-5-甲基-N-(甲基-d3)苯甲醯胺The title compound was prepared using a procedure similar to that described for Example2 , substituting tert-butyl 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate (Example 2, Step 1, Peak 2) for tert-butyl 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate (Peak 1) in Step 2. The crude product was diluted with MeOH and purified by preparative HPLC (Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate:₆₀ mL/min). The eluted fractions were collected and lyophilized to provide the desired product as_a white solid as its TFA salt._{LCMSC₂₄H₂O₀FN₆O₃} (M+H)^⁺ m/z Calcd =_471.2 ; Found 471.2.Example 4.9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-7-methyl-N,N,4-tris(methyl-d₃)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamideStep 1: 2-amino-3-bromo-5-methyl-N-(methyl-d3)benzamide

在0℃下向2-胺基-3-溴-5-甲基苯甲酸(6.90 g, 30 mmol)於DMF (80 mL)中之混合物中添加HATU (14.83 g, 39 mmol)、甲-d₃-胺HCl鹽(2.33 g, 33 mmol)及DIEA (20.96 mL, 120 mmol)。在室溫下攪拌3 h後，將混合物傾倒在1000 mL冰水中。收集所得固體，得到淺棕色固體，用水洗滌且在真空下乾燥，得到呈淺棕色固體之期望產物。LCMS C₉H₉D₃BrN₂O (M+H)⁺m/z計算值= 246.0；實驗值246.0。步驟2：9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-7-甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸To a mixture of 2-amino-3-bromo-5-methylbenzoic acid (6.90 g, 30 mmol) in DMF (80 mL) at 0°C was added HATU (14.83 g, 39 mmol), methyl-d₃ -amine HCl salt (2.33 g, 33 mmol), and DIEA (20.96 mL, 120 mmol). After stirring at room temperature for 3 h, the mixture was poured into 1000 mL of ice-cold water. The resulting solid was collected to give a light brown solid, which was washed with water and dried under vacuum to give the desired product as a light brown solid. LCMS m/z calculated for C₉ H₉ D₃ BrN₂ O (M+H)⁺ = 246.0; found 246.0.Step 2: 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid

使用與針對實例1所闡述類似之程序，在步驟4中用2-胺基-3-溴-5-甲基-N-(甲基-d3)苯甲醯胺替代2-胺基-3-溴-N,5-二甲基苯甲醯胺來製備標題化合物。LCMS C₂₂H₁₈D₃FN₅O₄(M+H)⁺m/z計算值= 441.2；實驗值441.2。步驟3：9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-7-甲基-N,N,4-參(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺The title compound was prepared using a procedure similar to that described forExample 1 , substituting 2-amino-3-bromo-5-methyl-N-(methyl-d3)benzamide for 2-amino-3-bromo-N,5-_{dimethylbenzamide} in Step_4. LCMS_Calcd ._{forC22H18D3FN5O4} (M+H)⁺ m/z = 441.2; Found 441.2.Step 3: 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide

向9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-7-甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸(20 mg, 0.045 mmol)於DMF (0.5 mL)中之混合物中添加HATU (22 mg, 0.06 mmol)、雙(甲基-d₃)胺HCl鹽(10 mg, 0.25 mmol)及DIEA (100 uL, 0.6 mmol)。攪拌1 h後，用MeOH稀釋反應物且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₄H₁₇D₉FN₆O₃(M+H)⁺m/z計算值= 474.3；實驗值474.3。實例5至7.To a mixture of 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid (20 mg, 0.045 mmol) in DMF (0.5 mL) were added HATU (22 mg, 0.06 mmol), bis(methyl-_d3 )amine HCl salt (10 mg, 0.25 mmol) and DIEA (100 uL, 0.6 mmol). After stirring for 1 hour, the reaction was diluted with MeOH and purified by preparative HPLC (Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The eluted fractions were collected and lyophilized_to provide the desired product as_{a white solid as its TFA salt. LCMS calculated for C₂₄H₁₁₇D₆FN₆O₃(M+} H)^⁺ m/z = 474.3; found 474.3.Examples 5 to 7.

表1中之以下化合物係根據針對實例1所闡述之程序，使用適當中間體類似地製備。表1.實例編號化學名稱結構LCMSm/z (M+H)⁺59-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-N,N,7-三甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺468.269-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基-1-d)-4,7-二甲基-N,N-雙(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺472.279-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基-1-d)-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺475.3實例8.3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮步驟1：6-氯-2-(1H-四唑-5-基)吡啶-3-胺The following compounds in Table 1 were similarly prepared according to the procedures described for Example 1 using appropriate intermediates.Table 1.Instance NumberChemical namestructureLCMSm/z (M+H)⁺5 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-N,N,7-trimethyl-4-(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide 468.26 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl-1-d)-4,7-dimethyl-N,N-bis(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide 472.27 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide 475.3Example 8.3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-oneStep 1: 6-chloro-2-(1H-tetrazol-5-yl)pyridin-3-amine

向3-胺基-6-氯-吡啶-2-甲腈(1.54 g, 10.00 mmol)於20 mL DMF中之溶液中一次性添加疊氮化鈉(1.3 g, 20.00 mmol)及氨鹽酸鹽(1.7 g, 20.00 mmol)。在120℃下攪拌12 h後，在真空下去除溶劑。將殘餘物溶解於水中，且藉由添加10% HCl將pH調整至2。藉由過濾收集沈澱物，得到呈白色固體之產物(1.8 g, 92%)。LCMS C₆H₆ClN₆(M+H)⁺m/z計算值= 197.0；實驗值197.0。步驟2：2-(6-氯-2-(1H-四唑-5-基)吡啶-3-基)異吲哚啉-1,3-二酮To a solution of 3-amino-6-chloro-pyridine-2-carbonitrile (1.54 g, 10.00 mmol) in 20 mL of DMF, sodium azide (1.3 g, 20.00 mmol) and ammonium hydrochloride (1.7 g, 20.00 mmol) were added in one portion. After stirring at 120°C for 12 h, the solvent was removed under vacuum. The residue was dissolved in water, and the pH was adjusted to 2 by adding 10% HCl. The precipitate was collected by filtration to give the product as a_{whitesolid (1.8 g, 92%). LCMS m/z calculated for C₆H₆ClN₆(} M+H)^⁺ = 197.0; found 197.0.Step2:2-(6-chloro-2-(1H-tetrazol-5-yl)pyridin-3-yl)isoindole-1,3-dione

在室溫下向6-氯-2-(1H-四唑-5-基)吡啶-3-胺(1.8 g, 9.16 mmol)於10 mL乙酸中之溶液中添加異苯并呋喃-1,3-二酮(3.4 g, 22.89 mmol)。在120℃下攪拌隔夜後，在真空下去除溶劑，提供呈黃色固體之期望產物(2.9 g, 97%)。LCMS C₁₄H₈ClN₆O₂(M+H)⁺m/z計算值= 327.0；實驗值327.0。步驟3：2-(6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)異吲哚啉-1,3-二酮To a solution of 6-chloro-2-(1H-tetrazol-5-yl)pyridin-3-amine (1.8 g, 9.16 mmol) in 10 mL of acetic acid was added isobenzofuran-1,3-dione (3.4 g, 22.89 mmol) at_{room temperature. After stirring overnight at 120°C, the solvent was removed under vacuum to provide the desired product (2.9 g, 97%) as a yellow solid. LCMS C14H8ClN6O2(M+} H)⁺ m/z Calcd = 327.0; Found 327.0.Step3:2-(6-Chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)isoindoline-1,3-dione

向2-[6-氯-2-(1H-四唑-5-基)-3-吡啶基]異吲哚啉-1,3-二酮(3.00 g, 9.18 mmol)於10 mL DMF中之溶液中添加碘甲烷(0.86 mL, 1.96 g, 13.77 mmol)及碳酸鉀(3.81 g, 27.55 mmol)。將反應混合物在室溫下攪拌2 h，接著用水稀釋且用EtOAc萃取。將合併的有機物用鹽水洗滌且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。藉由矽膠管柱層析，用己烷及乙酸乙酯溶析純化所得混合物，提供呈黃色固體之期望產物(540 mg, 17%)及呈黃色固體之另一區域異構物(570 mg, 18%)。LCMS C₁₅H₁₀ClN₆O₂(M+H)⁺m/z計算值= 341.1；實驗值341.1。步驟4：6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-胺To a solution of 2-[6-chloro-2-(1H -tetrazol-5-yl)-3-pyridyl]isoindoline-1,3-dione (3.00 g, 9.18 mmol) in 10 mL of DMF was added iodomethane (0.86 mL, 1.96 g, 13.77 mmol) and potassium carbonate (3.81 g, 27.55 mmol). The reaction mixture was stirred at room temperature for 2 h, then diluted with water and extracted with EtOAc. The combined organics were washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography using hexanes and ethyl acetate to provide the desired product (540 mg, 17%) and another regioisomer (570 mg, 18%) as_a yellow solid. LCMS_{C₁₅H₁₀ClN₆O₂} (M+H)^⁺ m/_z calcd = 341.1; found 341.1. Step 4:₆-Chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-amine

將2-(6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)異吲哚啉-1,3-二酮(540 mg, 1.58 mmol)於10 mL一水合肼中之混合物在45℃下攪拌2 h，接著冷卻至室溫，且藉由過濾收集所得沈澱物並用水洗滌，得到呈白色固體之產物(330 mg, 100%)。LCMS C₇H₈ClN₆(M+H)⁺m/z計算值= 211.0；實驗值211.0。步驟5：9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯A mixture of 2-(6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)isoindoline-1,3-dione (540 mg, 1.58 mmol) in 10 mL of hydrazine monohydrate was stirred at₄₅ °C for 2 h, then cooled to room temperature. The resulting precipitate was collected by filtration and washed with water to give the product as a white_solid (330 mg, 100%). LCMS calculated for_{CₐH₈ClN₆} (M+H)^⁺ m/z = 211.0; found 211.0.Step 5: tert-butyl 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate

向9-(1-溴乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯(實例1，步驟9) (3.2 g, 7.6 mmol)於DMF (70 mL)中之溶液中添加6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-胺(1.8 g, 8.5 mmol)。將混合物加熱至70℃持續3 h。冷卻至室溫後，用水稀釋混合物且用乙酸乙酯(3×)萃取。將合併的有機物用水、飽和NaCl洗滌，且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。藉由矽膠管柱層析純化殘餘物，提供呈淺黃色固體之期望產物(1.25 g, 30%)。LCMS C₂₆H₂₉ClN₉O₃(M+H)⁺m/z計算值= 550.2；實驗值550.2。步驟6：9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸To a solution of tert-butyl 9-(1-bromoethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate (Example 1, Step 9) (3.2 g, 7.6 mmol) in DMF (70 mL) was added 6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-amine (1.8 g, 8.5 mmol). The mixture was heated to 70°C for 3 h. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate (3×). The combined organics were washed with water, saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to provide the desired product (1.25 g, 30%) as a pale yellow solid. LCMS C₂₆ H₂₉ ClN₉ O₃ (M+H)⁺ m/z calcd = 550.2; found 550.2.Step 6: 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid

將9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯(1.25 g, 2.27 mmol)溶解於TFA (10 mL)中。將混合物在室溫下攪拌3 h。完成後，在真空下去除TFA。向反應殘餘物中添加EtOAc (20 mL)及己烷(20 mL)，同時攪拌。攪拌20 min後，收集所得固體，得到白色固體，用己烷/EtOAc (1:1)洗滌。使固體在真空下乾燥，提供純產物(1.0 g, 90%)。LCMS C₂₂H₂₁ClN₉O₃(M+H)⁺m/z計算值= 494.1；實驗值494.2。步驟7：9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-碘-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮tert-Butyl 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate (1.25 g, 2.27 mmol) was dissolved in TFA (10 mL). The mixture was stirred at room temperature for 3 h. Upon completion, the TFA was removed under vacuum. EtOAc (20 mL) and hexane (20 mL) were added to the reaction residue while stirring. After stirring for 20 min, the resulting solid was collected to give a white solid, which was washed with hexane/EtOAc (1:1). The solid was dried under vacuum to provide the pure product (1.0 g, 90%). LCMS C₂₂ H₂₁ ClN₉ O₃ (M+H)⁺ m/z calcd = 494.1; found 494.2.Step 7: 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-iodo-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one

在0℃下在氮氣下向9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸(1.0 g, 1.05 mmol)於DMF (10 mL)中之混合物中添加NaHCO₃(336 mg, 4 mmol)，攪拌5 min後，一次性添加NIS (234 mg, 1.05 mmol)。使所得混合物升溫至室溫且在真空下攪拌2 h。完成後，用飽和Na₂S₂O₃淬滅反應混合物，且用水稀釋。藉由過濾收集呈棕色固體之所得固體，藉由矽膠管柱層析，用DCM及EtOAc溶析進行純化，提供呈白色固體之期望產物(470 mg, 78%)。LCMS C₂₁H₂₀ClIN₉O (M+H)⁺m/z計算值= 576.1；實驗值576.1。步驟8：3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮To a mixture of 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid (1.0 g, 1.05 mmol) in DMF (10 mL) at 0°C under nitrogen was added_NaHCO₃ (336 mg, 4 mmol) and stirred for 5 min before adding NIS (234 mg, 1.05 mmol) in_one portion. The resulting mixture was allowed to warm to room temperature and stirred under vacuum for 2 h. Upon completion, the reaction mixture was quenched with saturated_{Na₂S₂O₃} and_diluted with water. The resulting brown solid was collected by filtration and purified by_silica gel column chromatography eluting with DCM and EtOAc to provide the desired product as a white solid (470 mg,₇₈ %). LCMS_C21H20C1N9O (M+H)⁺ m/z calculated = 576.1; found 576.1.Step 8: 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one

將9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-碘-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮(47 mg, 0.08 mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)嘧啶-2-胺(27 mg, 0.12 moml)、K₃PO₄(52 mg, 0.24 mmol)及Pd(PPh₃)₄(19 mg, 0.02 mmol)於二噁烷(3.0 mL)及水(0.6 mL)中之混合物在氮氣氣氛下在80℃下加熱8 h。在真空下去除溶劑，且藉由矽膠管柱層析(含0-95% EA之DCM，接著含0-20% MeOH之DCM)純化殘餘物，提供粗產物。用MeOH稀釋產物，且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈淺黃色固體之期望產物TFA鹽。LCMS C₂₅H₂₄ClN₁₂O (M+H)⁺m/z計算值= 543.2；實驗值543.2。實例9至14.A mixture of 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-iodo-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (47 mg, 0.08 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolacyclopentan-2-yl)pyrimidin-2-amine (27 mg, 0.12 mmol), K₃ PO₄ (52 mg, 0.24 mmol) and Pd(PPh₃ )₄ (19 mg, 0.02 mmol) in dioxane (3.0 mL) and water (0.6 mL) was heated at 80° C. for 8 h under nitrogen atmosphere. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (0-95% EA in DCM, followed by 0-20% MeOH in DCM) to provide the crude product. The product was diluted with MeOH and purified by preparative HPLC (column: Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The eluted fractions were collected and lyophilized to provide the desired product as a_light yellow solid_as its TFA salt. LCMS_{C₂₅H₂₄ClN₁₂O} (M+H)⁺ m/z calculated = 543.2; found 543.2.Examples 9 to 14.

表2中之以下化合物係根據針對實例8所闡述之程序，使用適當中間體類似地製備。表2.實例編號化學名稱結構LCMSm/z (M+H)⁺93-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮546.2103-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮547.2113-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮544.2123-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮547.2133-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮546.2143-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮549.2實例15.3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮(峰1)步驟1：9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-碘-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮The following compounds in Table 2 were similarly prepared according to the procedures described for Example 8 using appropriate intermediates.Table 2.Instance NumberChemical namestructureLCMSm/z (M+H)⁺9 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one 546.210 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one 547.211 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one 544.212 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one 547.213 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one 546.214 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one 549.2Example 15.3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (Peak 1)Step 1: 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-iodo-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one

使用與針對實例8所闡述類似之程序，在步驟5中用6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-胺(中間體11)替代6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-胺來製備標題化合物。LCMS C₂₁H₁₇D₃ClIN₉O (M+H)⁺m/z計算值= 579.1；實驗值579.1。The title compound was prepared using a procedure analogous to that described for Example8 , substituting 6-chloro-2-(2-(methyl-_d3 )-2H-tetrazol-5-yl)pyridin-3-amine (Intermediate 11) for 6-chloro-2-(2-methyl-_2H -tetrazol-5-yl)pyridin-3-amine in step 5. LCMS_Calcd ._{forC21H17D3C1N9O} (M+H)⁺ m/z = 579.1; Found 579.1.

藉由手性HPLC分離外消旋化合物，得到2種鏡像異構物，峰1用於下一步驟中。步驟2：3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮(峰1)The racemic compound was separated by chiral HPLC to obtain two mirror isomers. Peak 1 was used in the next step.Step 2: 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (Peak 1)

將9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-碘-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮(峰1) (47 mg, 0.08 mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)嘧啶-2-胺(27 mg, 0.12 moml)、K₃PO₄(52 mg, 0.24 mmol)及Pd(PPh₃)₄(19 mg, 0.02 mmol)於二噁烷(3.0 mL)及水(0.6 mL)中之混合物在氮氣氣氛下在80℃下加熱8 h。在減壓真空下去除溶劑，且藉由矽膠管柱層析(含0-95% EA之DCM，接著含0-20% MeOH之DCM)純化殘餘物，提供粗產物。用MeOH稀釋粗產物，且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈淺黃色之期望產物TFA鹽。LCMS C₂₅H₂₁D₃ClN₁₂O (M+H)⁺m/z計算值= 546.2；實驗值546.2。實例16.3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮(峰2)A mixture of 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-iodo-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (peak 1) (47 mg, 0.08 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolacyclopentan-2-yl)pyrimidin-2-amine (27 mg, 0.12 mmol), K₃ PO₄ (52 mg, 0.24 mmol) and Pd(PPh₃ )₄ (19 mg, 0.02 mmol) in dioxane (3.0 mL) and water (0.6 mL) was heated at 80° C. for 8 h under nitrogen atmosphere. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (0-95% EA in DCM, followed by 0-20% MeOH in DCM) to provide the crude product. The crude product was diluted with MeOH and purified by preparative HPLC (Sunfire Prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The eluted fractions were collected_and lyophilized to_{provide the desired product as a light yellow TFA salt. LCMS m/z calculated for C₂₅H₂₁D₃ClN₁₂O(} M+H)₊⁼ 546.2; found 546.2.Example 16.3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (Peak 2)

使用與針對實例15所闡述類似之程序，在步驟2中用9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-碘-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮(實例15，步驟1，峰2)替代9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-碘-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮(峰1) 來製備標題化合物。用MeOH稀釋粗產物，且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈淺黃色固體之期望產物TFA鹽。LCMS C₂₅H₂₁D₃ClN₁₂O (M+H)⁺m/z計算值= 546.2；實驗值546.2。實例17.3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮步驟1：9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-3-碘-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮The title compound was prepared using a procedure similar to that described forExample 15 , substituting 9-(1-((6-chloro-2-(2-(methyl-_d3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-iodo-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (Example 15, step 1, peak 2) for 9-(1-((6-chloro-2-(2-(methyl-_d3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-iodo-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (peak 1) in step 2. The crude product was diluted with MeOH and purified by preparative HPLC (Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate:₆₀ mL/min). The eluted fractions were collected and lyophilized to provide the desired product as_a light yellow solid as its TFA salt. LCMS m/z calculated for_{C₂₅H₂₁D₃ClN₁₂O} (M+H)_⁺⁼ 546.2; found 546.2.Example 17.3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-oneStep 1: 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-3-iodo-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one

使用與針對實例8所闡述類似之程序，在步驟5中用9-(1-溴乙基-1-d)-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯(中間體12)替代9-(1-溴乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯且用6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-胺(中間體11) 替代6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-胺來製備標題化合物。LCMS C₂₁H₁₃D₇ClIN₉O (M+H)⁺m/z計算值= 583.1；實驗值583.1。步驟2：3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮The title compound was prepared using procedures similar to those described for Example8 , substituting tert-butyl 9-(1-bromoethyl-1-d)-7-methyl-4-(methyl-_d3 )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate (Intermediate 12) for tert-butyl 9-(1-bromoethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate and 6-chloro-2-(2-(methyl-_d3 )-2H-tetrazol-5-yl)pyridin-3-amine (Intermediate 11) for 6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-amine in step 5. LCMS C₂₁ H₁₃ D₇ ClIN₉ O (M+H)⁺ m/z calcd = 583.1; found 583.1.Step 2: 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one

將9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-3-碘-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮(200 mg, 0.34 mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)嘧啶-2-胺(62.0 mg, 0.45 mmol)、K₃PO₄(218.5 mg, 1.03 mmol)及Pd(PPh₃)₄(39.7 mg, 0.03 mmol)於二噁烷(6.0 mL)及水(1.2 mL)中之混合物在氮氣氣氛下在80℃下加熱8 h。在真空下去除溶劑，且藉由矽膠管柱層析(含0-95% EA之DCM，接著含0-20% MeOH之DCM)純化殘餘物，提供粗產物。用MeOH稀釋粗產物，且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈淺黃色之期望產物TFA鹽。LCMS C₂₅H₁₇D₇ClN₁₂O (M+H)⁺m/z計算值= 550.2；實驗值550.2。實例18.9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(吡啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-3-iodo-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one (200 mg, 0.34 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)pyrimidin-2-amine (62.0 mg, 0.45 mmol), K₃ PO₄ (218.5 mg, 1.03 mmol) and Pd(PPh₃ )₄ (39.7 mg, 0.03 mmol) were dissolved in dioxane (6.0 mL) and water (1.2 The mixture (50 mL) was heated at 80°C under a nitrogen atmosphere for 8 h. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (0-95% EA in DCM, followed by 0-20% MeOH in DCM) to provide the crude product. The crude product was diluted with MeOH and purified by preparative HPLC (column: Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate:₆₀ mL/min). The eluted fractions were collected and lyophilized to provide the desired product as_alight yellow TFA salt. LCMS_{C₂₅H₁₇D₁₇O} (M+H)⁺ m/z calculated = 550.2; found 550.2.Example 18.9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(pyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one

將9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-碘-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮(實例8，步驟7) (10 mg, 0.02 mmol)、吡啶-3-基硼酸(5 mg, 0.04 moml)、K₃PO₄(10 mg, 0.05 mmol)及Pd(PPh₃)₄(2 mg, 0.002 mmol)於二噁烷(0.5 mL)及水(0.1 mL)中之混合物在氮氣氣氛下在100℃下加熱20 min。冷卻至室溫後，用MeOH稀釋混合物且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₆H₂₄ClN₁₀O (M+H)⁺m/z計算值= 527.2；實驗值527.2。實例19.9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)-3-(吡啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮A mixture of 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-iodo-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (Example 8, Step 7) (10 mg, 0.02 mmol), pyridin-3-ylboronic acid (5 mg, 0.04 mmol), K₃ PO₄ (10 mg, 0.05 mmol) and Pd(PPh₃ )₄ (2 mg, 0.002 mmol) in dioxane (0.5 mL) and water (0.1 mL) was heated at 100° C. for 20 min under nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with MeOH and purified by preparative HPLC (column: Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate:_{60 mL/min). The eluted fractions were collected and lyophilized to provide the desired product as a white solid as its TFA salt. LCMS m/z calculated for C₂₆H₂₄ClN₁₀O(M} +H)^⁺ = 527.2; found 527.2.Example 19.9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )-3-(pyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one

使用與針對實例18所闡述類似之程序來製備標題化合物。用MeOH稀釋粗產物，且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₆H₁₈D₆ClN₁₀O (M+H)⁺m/z計算值= 533.2；實驗值533.2。實例20. 2-((1-(3-(1-乙醯基六氫吡啶-4-基)-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)-5-氟苯甲醯胺步驟1：9-乙醯基-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯The title compound was prepared using a procedure similar to that described forExample 18. The crude product was diluted with MeOH and purified by preparative HPLC (column: Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min)._{Theeluted fractions were collected and lyophilized to provide the desired product as a white solid as its TFA salt. LCMS m/z calculated for C₂₆H₁₈D₆ClN₁₀O(} M+H)_⁺⁼ 533.2; found 533.2.Example 20. 2-((1-(3-(1-acetylhexahydropyridin-4-yl)-7-methyl-4-(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-5-fluorobenzamideStep 1: 9-Acetyl-7-methyl-4-(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid tert-butyl ester

使用與針對實例1所闡述類似之程序，在步驟4中用2-胺基-3-溴-5-甲基-N-(甲基-d₃)苯甲醯胺(實例4，步驟1)替代2-胺基-3-溴-N,5-二甲基苯甲醯胺來製備標題化合物。LCMS C₁₉H₁₉D₃N₃O₄(M+H)⁺m/z計算值= 359.2；實驗值359.2。步驟2：9-乙醯基-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸The title compound was prepared using a procedure similar to that described for Example1 , substituting 2-amino-3-bromo-5-methyl-N-(methyl-d₃ )benzamide (Example 4, Step 1) for 2-amino-3-bromo-N,5-dimethylbenzamide in Step 4. LCMS Calcd. for C₁₉ H₁₉ D₃ N₃ O₄ (M+H)⁺ m/z = 359.2; Found 359.2.Step 2: 9-Acetyl-7-methyl-4-(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid

將9-乙醯基-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯(2.0 g, 5.5 mmol)溶解於TFA (20 mL)中。將混合物在室溫下攪拌3 h。完成後，在真空下去除TFA。向反應殘餘物中添加EtOAc (50 mL)及己烷(50 mL)，同時攪拌。攪拌20 min後，收集所得固體，得到白色固體，用己烷/EtOAc (1:1)洗滌。使固體在真空下乾燥，提供純產物(1.5 g, 90%)。LCMS C₁₅H₁₁D₃N₃O₄(M+H)⁺m/z計算值= 303.1；實驗值303.1。步驟3：9-乙醯基-3-碘-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮Dissolve tert-butyl 9-acetyl-7-methyl-4-(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate (2.0 g, 5.5 mmol) in TFA (20 mL). The mixture was stirred at room temperature for 3 h. Upon completion, the TFA was removed under vacuum. EtOAc (50 mL) and hexane (50 mL) were added to the reaction residue while stirring. After stirring for 20 min, the resulting solid was collected to give a white solid, which was washed with hexane/EtOAc (1:1). The solid was dried under vacuum to provide the pure product (1.5 g, 90%). LCMS C₁₅ H₁₁ D₃ N₃ O₄ (M+H)⁺ m/z calcd = 303.1; found 303.1.Step 3: 9-Acetyl-3-iodo-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one

在氮氣下在0℃下向9-乙醯基-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸(1.5 g, 4.9 mmol)於DMF (20 mL)中之混合物中添加NaHCO₃(1.68 g, 20 mmol)，攪拌5 min後，一次性添加NIS (1.1 g, 5 mmol)。使所得混合物升溫至室溫且在真空下攪拌2 h。完成後，用飽和Na₂S₂O₃淬滅反應混合物，且用水稀釋。藉由過濾收集呈棕色固體之粗產物，藉由矽膠管柱層析，用DCM及EtOAc溶析純化該粗產物，提供呈白色固體之期望產物(1.5 g, 84%)。LCMS C₁₄H₁₀D₃IN₃O₂(M+H)⁺m/z計算值= 385.0；實驗值385.0。步驟4：4-(9-乙醯基-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-基)-3,6-二氫吡啶-1(2H)-甲酸第三丁酯To a mixture of 9-acetyl-7-methyl-4-(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid (1.5 g, 4.9 mmol) in DMF (20 mL) at 0° C. under nitrogen was added NaHCO₃ (1.68 g, 20 mmol). After stirring for 5 min, NIS (1.1 g, 5 mmol) was added in one portion. The resulting mixture was allowed to warm to room temperature and stirred under vacuum for 2 h. Upon completion, the reaction mixture was quenched with saturated Na₂ S₂ O₃ and diluted with water. The crude product was collected by filtration as a brown solid and purified by silica_gel column chromatography eluting with DCM and EtOAc to provide the desired product (1.5 g, 84%) as_awhite solid. LCMS_{C14H10D3IN3O2} (M+H)⁺ m/z Calcd = 385.0; Found 385.0. Step 4: tert_-butyl 4-(9-acetyl-7-methyl-4-(methyl-_d3 )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate

將9-乙醯基-3-碘-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮(1.5 g, 3.91 mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,6-二氫吡啶-1(2H)-甲酸第三丁酯(1.29 g, 4.2 moml)、K₃PO₄(1.5 g, 7 mmol)及Xphos-PdG2 (306 mg, 0.39 mmol)於二噁烷(50 mL)及水(5 mL)中之混合物在氮氣氣氛下在100℃下加熱1 h。用水稀釋混合物，且用乙酸乙酯(3×)萃取。將合併的有機物用水、飽和NaCl洗滌，且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。藉由矽膠管柱層析純化殘餘物，提供呈淺黃色固體之期望產物(1.2 g, 70%)。LCMS C₂₄H₂₆D₃N₄O₄(M+H)⁺m/z計算值= 440.2；實驗值440.2。步驟5：9-乙醯基-7-甲基-4-(甲基-d₃)-3-(1,2,3,6-四氫吡啶-4-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮A mixture of 9-acetyl-3-iodo-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one (1.5 g, 3.91 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.29 g, 4.2 mmol), K₃ PO₄ (1.5 g, 7 mmol), and Xphos-PdG2 (306 mg, 0.39 mmol) in dioxane (50 mL) and water (5 mL) was heated at 100° C. for 1 h under a nitrogen atmosphere. The mixture was diluted with water and extracted with ethyl acetate (3×). The combined organics were washed with water, saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue_was purified by silica gel column chromatography to provide the desired product (1.2 g, 70%) as_alight yellow solid. LCMS_C24H26D3N4O4 (M+H)⁺ m/z Calcd = 440.2; Found 440.2. Step 5:₉-Acetyl-7-methyl-4-(methyl-_d3 )-3-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one

將4-(9-乙醯基-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-基)-3,6-二氫吡啶-1(2H)-甲酸第三丁酯(1.2 g, 2.7 mmol)溶解於TFA (10 mL)中。將混合物在室溫下攪拌3 h。完成後，在真空下去除TFA。用飽和NaHCO₃淬滅殘餘物，用DCM/IPA (3:1)萃取混合物。將合併的有機物用水、飽和NaCl洗滌，且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。殘餘物不經進一步純化即直接用於下一步驟中。LCMS C₁₉H₁₈D₃N₄O₂(M+H)⁺m/z計算值= 340.2；實驗值340.2。步驟6：9-乙醯基-3-(1-乙醯基-1,2,3,6-四氫吡啶-4-基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮4-(9-Acetyl-7-methyl-4-(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.2 g, 2.7 mmol) was dissolved in TFA (10 mL). The mixture was stirred at room temperature for 3 h. Upon completion, the TFA was removed under vacuum. The residue was quenched with saturated NaHCO₃ and the mixture was extracted with DCM/IPA (3:1). The combined organics were washed with water, saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used directly in the next step without further purification. LCMS C₁₉ H₁₈ D₃ N₄ O₂ (M+H)⁺ m/z calcd = 340.2; found 340.2.Step 6: 9-Acetyl-3-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one

將9-乙醯基-7-甲基-4-(甲基-d₃)-3-(1,2,3,6-四氫吡啶-4-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮(920 mg, 2.4 mmol)溶解於DCM (50 mL)中，接著在0℃下添加乙醯氯(218 mg, 2.8 mmol)，之後添加DIEA (619 mg, 4.8 mmol)。將所得混合物在相同溫度下攪拌20 min，之後用飽和NaHCO₃稀釋。用水稀釋混合物且用DCM萃取。將合併的有機物用飽和NaCl洗滌，且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。殘餘物不經進一步純化即直接用於下一步驟中。LCMS C₂₁H₂₀D₃N₄O₃(M+H)⁺m/z計算值= 382.2；實驗值382.2。步驟7：3-(1-乙醯基-1,2,3,6-四氫吡啶-4-基)-9-(1-羥基乙基-1-d)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮9-Acetyl-7-methyl-4-(methyl-d₃ )-3-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one (920 mg, 2.4 mmol) was dissolved in DCM (50 mL), followed by the addition of acetyl chloride (218 mg, 2.8 mmol) at 0°C, followed by the addition of DIEA (619 mg, 4.8 mmol). The resulting mixture was stirred at the same temperature for 20 min, then diluted with saturated NaHCO₃ . The mixture was diluted with water and extracted with DCM. The combined organics were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used directly in the next step without further purification. LCMS C₂₁ H₂₀ D₃ N₄ O₃ (M+H)⁺ m/z calcd = 382.2; found 382.2.Step 7: 3-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-9-(1-hydroxyethyl-1-d)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one

將9-乙醯基-3-(1-乙醯基-1,2,3,6-四氫吡啶-4-基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮(910 mg, 2.34 mmol)溶解於MeOH (30 mL)及DCM (30 mL)中，接著在氮氣下在0℃下分三次添加NaBD₄(107 mg, 2.5 mmol)。將所得混合物在相同溫度下攪拌10 min，之後用飽和NH₄Cl淬滅。用水稀釋混合物且用DCM萃取。將合併的有機物用飽和NaCl洗滌，且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。藉由矽膠管柱層析，用DCM及MeOH (0至4%)溶析純化殘餘物，提供呈淺棕色固體之期望產物(781 mg 87%)。LCMS C₂₁H₂₁D₄N₄O₃(M+H)⁺m/z計算值= 385.2；實驗值385.3。步驟8：3-(1-乙醯基六氫吡啶-4-基)-9-(1-羥基乙基-1-d)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮9-Acetyl-3-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one (910 mg, 2.34 mmol) was dissolved in MeOH (30 mL) and DCM (30 mL), followed by the addition of NaBD₄ (107 mg, 2.5 mmol) in three portions at 0° C. under nitrogen. The resulting mixture was stirred at the same temperature for 10 min, then quenched with saturated NH₄ Cl. The mixture was diluted with water and extracted with DCM. The combined organics were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure._The residue_was purified by silica gel column chromatography eluting with DCM_and MeOH (0-4%) to provide the desired product (781 mg, 87%) as_a light brown solid. LCMS_C21H21D4N4O3 (M+H)⁺ m/z calculated = 385.2; found 385.3.Step 8: 3-(1-acetylhexahydropyridin-4-yl)-9-(1-hydroxyethyl-1-d)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one

將3-(1-乙醯基-1,2,3,6-四氫吡啶-4-基)-9-(1-羥基乙基-1-d)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮(781 mg, 2.03 mmol)、Pd/C (212 mg, 10 wt%, 0.2 mmol)及甲酸銨(1.2 g, 20 mmol) 溶解於MeOH (30 mL)及0.5 mL AcOH中。用氮氣吹掃反應小瓶，且將混合物在60℃下攪拌隔夜。完成後，過濾反應混合物，且在減壓下去除溶劑。藉由矽膠管柱層析，用DCM及MeOH (0至8%)溶析純化殘餘物，提供呈淺色固體之期望產物(631 mg 81%)。LCMS C₂₁H₂₃D₄N₄O₃(M+H)⁺m/z計算值= 387.2；實驗值387.3。步驟9：3-(1-乙醯基六氫吡啶-4-基)-9-(1-溴乙基-1-d)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮3-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)-9-(1-hydroxyethyl-1-d)-7-methyl-4-(methyl-_d3 )imidazo[1,5-a]quinazolin-5(4H)-one (781 mg, 2.03 mmol), Pd/C (212 mg, 10 wt%, 0.2 mmol), and ammonium formate (1.2 g, 20 mmol) were dissolved in MeOH (30 mL) and 0.5 mL of AcOH. The reaction vial was purged with nitrogen and the mixture was stirred at 60°C overnight. Upon completion, the reaction mixture was filtered and the solvent removed under reduced pressure. The residue_was purified by silica gel column chromatography eluting with DCM_{and MeOH (0-8%) to provide the desired product (631 mg, 81%) as a pale solid. LCMS C₂₁H₂₃D₄N₄O₃(M} +_H )^⁺ m/z calcd = 387.2; found 387.3.Step 9: 3-(1-acetylhexahydropyridin-4-yl)-9-(1-bromoethyl-1-d₃)-7-methyl-4-(methyl-_d₃ )imidazo[1,5-a]quinazolin-5(4H)-one

在0℃下向3-(1-乙醯基六氫吡啶-4-基)-9-(1-羥基乙基-1-d)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮(631 mg, 1.63 mmol)於DCM (100 mL)中之混合物中添加PBr₃(0.33 mL, 3.2 mmol)。使所得混合物升溫至室溫並攪拌2 h。接著用飽和NaHCO₃淬滅混合物且用DCM (2×)萃取。將合併的有機物用飽和NaCl洗滌，且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。殘餘物不經進一步純化即直接用於下一步驟中。步驟10：2-((1-(3-(1-乙醯基六氫吡啶-4-基)-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)-5-氟苯甲醯胺To a mixture of 3-(1-acetylhexahydropyridin-4-yl)-9-(1-hydroxyethyl-1-d)-7-methyl-4-(methyl-_d )imidazo[1,5-a]quinazolin-5(4H)-one (631 mg, 1.63 mmol) in DCM (100 mL) at 0°C was added_PBr (0.33 mL, 3.2 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was then_quenched with saturated NaHCO and extracted with DCM (2×). The combined organics were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used directly in the next step without further purification.Step 10: 2-((1-(3-(1-acetylhexahydropyridin-4-yl)-7-methyl-4-(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-5-fluorobenzamide

向3-(1-乙醯基六氫吡啶-4-基)-9-(1-溴乙基-1-d)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮(20 mg, 0.04 mmol)於DMF (0.5 mL)中之溶液中添加2-胺基-5-氟苯甲醯胺(20 mg, 0.13 mmol)。將混合物加熱至80℃持續2 h。冷卻至室溫後，用MeOH稀釋混合物且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₈H₂₈D₄FN₆O₃(M+H)⁺m/z計算值= 523.3；實驗值523.3。實例21.9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-7-氯-4-甲基-N,N-雙(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺To a solution of 3-(1-acetylhexahydropyridin-4-yl)-9-(1-bromoethyl-1-d)-7-methyl-4-(methyl-_d3 )imidazo[1,5-a]quinazolin-5(4H)-one (20 mg, 0.04 mmol) in DMF (0.5 mL) was added 2-amino-5-fluorobenzamide (20 mg, 0.13 mmol). The mixture was heated to 80°C for 2 h. After cooling to room temperature, the mixture was diluted with MeOH and purified by preparative HPLC (column: Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The eluted fractions were collected and lyophilized to provide the desired product as a_{whitesolidas its TFA salt. LCMS m/z calculated for C₂₈H₂₈D₄FN₆O₃(} M+H)_⁺⁼ 523.3; found 523.3.Example 21.9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-7-chloro-4-methyl-N,N-bis(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide

使用與針對實例1所闡述類似之程序，在步驟1中用2-胺基-5-氯苯甲酸替代2-胺基-5-甲基苯甲酸，且在步驟12中用雙(甲基-d₃)胺HCl鹽替代二甲胺來製備標題化合物。用MeOH稀釋粗產物，且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₃H₁₇D₆ClFN₆O₃(M+H)⁺m/z計算值= 491.2；實驗值491.2。實例22.9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基-1-d)-7-氯-4-甲基-N,N-雙(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺The title compound was prepared using a procedure similar to that described forExample 1 , substituting 2-amino-5-chlorobenzoic acid for 2-amino-5-methylbenzoic acid in step 1 and bis(methyl-d₃ )amine HCl salt for dimethylamine in step 12. The crude product was diluted with MeOH and purified by preparative HPLC (column: Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The eluted fractions were collected and lyophilized to provide the desired product as a white solid as its TFA salt. LCMS m/z calculated for C₂₃ H₁₇ D₆ ClFN₆ O₃ (M+H)⁺ = 491.2; found 491.2.Example 22.9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl-1-d)-7-chloro-4-methyl-N,N-bis(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide

使用與針對實例1所闡述類似之程序，在步驟1中用2-胺基-5-氯苯甲酸替代2-胺基-5-甲基苯甲酸，在步驟8中用NaBD₄替代 NaBH₄，且在步驟12中用雙(甲基-d₃)胺HCl鹽替代二甲胺來製備標題化合物。用MeOH稀釋粗產物，且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₃H₁₆D₇ClFN₆O₃(M+H)⁺m/z計算值= 492.2；實驗值492.2。實例23.9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺The title compound was prepared using a procedure similar to that described forExample 1 , substituting 2-amino-5-chlorobenzoic acid for 2-amino-5-methylbenzoic acid in step 1, substituting NaBD₄ for NaBH₄ in step 8, and substituting bis(methyl-d₃ )amine HCl salt for dimethylamine in step 12. The crude product was diluted with MeOH and purified by preparative HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min); the eluted fractions were collected and lyophilized to provide the desired product as a white solid as its TFA salt. LCMS C₂₃ H₁₆ D₇ ClFN₆ O₃ (M+H)⁺ m/z calcd = 492.2; found 492.2.Example 23.9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide

向9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸(實例8，步驟6) (20 mg, 0.04 mmol)於DMF (0.5 mL)中之混合物中添加HATU (22 mg, 0.06 mmol)、二甲胺(30 uL，2 M THF溶液)及DIEA (10 uL, 0.06 mmol)。攪拌1 h後，用MeOH稀釋反應混合物且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₄H₂₆ClN₁₀O₂(M+H)⁺m/z計算值= 521.2；實驗值521.2。實例24至27.To a mixture of 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid (Example 8, Step 6) (20 mg, 0.04 mmol) in DMF (0.5 mL) were added HATU (22 mg, 0.06 mmol), dimethylamine (30 uL, 2 M THF solution) and DIEA (10 uL, 0.06 mmol). After stirring for 1 hour, the reaction mixture was diluted with MeOH and purified by preparative HPLC (Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The eluted fractions were collected and lyophilized to provide the desired product as_awhite solid_as its TFA salt. LCMS m/z calculated for_{C₂₄H₂₆ClN₁₁O₂} (M+H)^⁺ = 521.2; found 521.2.Examples 24 to 27.

表3中之以下化合物係根據針對實例23所闡述之程序，使用適當中間體類似地製備。表3.實例編號化學名稱結構LCMSm/z (M+H)⁺249-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-N,N-雙(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺527.2259-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,7-三甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺524.2269-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺524.2279-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺534.3實例28.9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基-1-d)-4-甲基-N,N-雙(甲基-d₃)-5-側氧基-7-(三氟甲基)-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺The following compounds in Table 3 were similarly prepared according to the procedures described for Example 23 using appropriate intermediates.Table 3.Instance NumberChemical namestructureLCMSm/z (M+H)⁺twenty four 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide 527.225 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,7-trimethyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide 524.226 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide 524.227 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-_d3 )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide 534.3Example 28.9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl-1-d)-4-methyl-N,N-bis(methyl-d₃ )-5-oxo-7-(trifluoromethyl)-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide

使用與針對實例1所闡述類似之程序，在步驟1中用2-胺基-5-(三氟甲基)苯甲酸替代2-胺基-5-甲基苯甲酸，在步驟8中用NaBD₄替代 NaBH₄，且在步驟12中用雙(甲基-d₃)胺HCl鹽替代二甲胺來製備標題化合物。用MeOH稀釋粗產物，且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₄H₁₆D₇F₄N₆O₃(M+H)⁺m/z計算值= 526.2；實驗值526.2。實例29至46.The title compound was prepared using a procedure similar to that described forExample 1 , substituting 2-amino-5-(trifluoromethyl)benzoic acid for 2-amino-5-methylbenzoic acid in step 1, substituting NaBD₄ for NaBH₄ in step 8, and substituting bis(methyl-d₃ )amine HCl salt for dimethylamine in step 12. The crude product was diluted with MeOH and purified by preparative HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min); the eluted fractions were collected and lyophilized to provide the desired product as a white solid as its TFA salt. LCMS Calcd. for C₂₄ H₁₆ D₇ F₄ N₆ O₃ (M+H)⁺ m/z = 526.2; Found 526.2.Examples 29 to 46.

表4中之以下化合物係根據針對實例8所闡述之程序，使用適當中間體類似地製備。表4.實例編號化學名稱結構LCMSm/z (M+H)⁺299-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(吡啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮530.2309-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(6-(羥基甲基)吡啶-3-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮560.2319-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-3-(6-(羥基甲基)吡啶-3-基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮564.2329-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(2-(羥基甲基)嘧啶-5-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮561.2339-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-3-(2-(羥基甲基)嘧啶-5-基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮565.2349-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(2-(羥基甲基)吡啶-3-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮560.2353-(6-胺基吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮545.2363-(6-胺基吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮549.2379-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(6-(甲基胺基)吡啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮559.2389-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(6-(二甲基胺基)吡啶-3-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮573.2393-(2-胺基吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮545.2409-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(1-(2-羥基乙基)-1H-吡唑-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮563.2419-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(1-甲基-1H-吡唑-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮533.2429-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(1H-吡唑-4-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮519.2439-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(吡唑并[1,5-a]嘧啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮570.2443-(2-胺基-4-甲基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮560.2453-(6-胺基-5-氟吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮563.2469-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(咪唑并[1,5-a]吡啶-6-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮569.2實例47.9-(1-((2-胺甲醯基-6-氯吡啶-3-基)胺基)乙基-1-d)-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺步驟1：9-乙醯基-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺The following compounds in Table 4 were similarly prepared according to the procedures described for Example 8 using appropriate intermediates.Table 4.Instance NumberChemical namestructureLCMSm/z (M+H)⁺29 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(pyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one 530.230 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(6-(hydroxymethyl)pyridin-3-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one 560.231 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-3-(6-(hydroxymethyl)pyridin-3-yl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one 564.232 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(2-(hydroxymethyl)pyrimidin-5-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one 561.233 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-3-(2-(hydroxymethyl)pyrimidin-5-yl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one 565.234 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(2-(hydroxymethyl)pyridin-3-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one 560.235 3-(6-aminopyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one 545.236 3-(6-aminopyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one 549.237 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(6-(methylamino)pyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one 559.238 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(6-(dimethylamino)pyridin-3-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one 573.239 3-(2-aminopyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one 545.240 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one 563.241 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methyl-1H-pyrazol-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one 533.242 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1H-pyrazol-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one 519.243 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(pyrazolo[1,5-a]pyrimidin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one 570.244 3-(2-amino-4-methylpyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one 560.245 3-(6-amino-5-fluoropyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one 563.246 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(imidazo[1,5-a]pyridin-6-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one 569.2Example 47.9-(1-((2-aminoformyl-6-chloropyridin-3-yl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamideStep 1: 9-acetyl-7-methyl-N,N,4-tris(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide

向9-乙醯基-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸(實例20，步驟2) (1.4 g, 4.63 mmol)於DMF (10 mL)中之混合物中添加HATU (1900 mg, 5.0 mmol)、雙(甲基-d₃)胺HCl鹽(435 mg, 5.0 mmol)及DIEA (1.8 mL, 10 mmol)。攪拌1 h後，用冰水稀釋反應混合物且收集所得固體，得到呈白色固體之期望產物，其不經進一步純化即用於下一步驟中。LCMS C₁₇H₁₀D₉N₄O₃(M+H)⁺m/z計算值= 336.2；實驗值336.2。步驟2：9-(1-羥基乙基-1-d)-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺To a mixture of 9-acetyl-7-methyl-4-(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid (Example 20, Step 2) (1.4 g, 4.63 mmol) in DMF (10 mL) was added HATU (1900 mg, 5.0 mmol), bis(methyl-d₃ )amine HCl salt (435 mg, 5.0 mmol), and DIEA (1.8 mL, 10 mmol). After stirring for 1 h, the reaction mixture was diluted with ice water and the resulting solid was collected to give the desired product as a white solid, which was used in the next step without further purification. LCMS C₁₇ H₁₀ D₉ N₄ O₃ (M+H)⁺ m/z calcd = 336.2; found 336.2.Step 2: 9-(1-Hydroxyethyl-1-d)-7-methyl-N,N,4-tris(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide

將9-乙醯基-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺(1.2 g, 3.5 mmol)溶解於MeOH (40 mL)及DCM (40 mL)中，接著在氮氣下在0℃下添加NaBD₄(160 mg, 4 mmol)。將所得混合物在相同溫度下攪拌10 min，之後用0.3 mL飽和NH₄Cl淬滅。使混合物經MgSO₄乾燥，過濾並在減壓下濃縮。收集所得固體，得到呈米色固體之期望產物，其不經進一步純化即用於下一步驟中。LCMS C₁₇H₁₁D₁₀N₄O₃(M+H)⁺m/z計算值= 339.2；實驗值339.2。步驟3：9-(1-溴乙基-1-d)-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺9-Acetyl-7-methyl-N,N,4-tris(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide (1.2 g, 3.5 mmol) was dissolved in MeOH (40 mL) and DCM (40 mL), followed by the addition of NaBD₄ (160 mg, 4 mmol) at 0° C. under nitrogen. The resulting mixture was stirred at the same temperature for 10 min, after which it was quenched with 0.3 mL of saturated NH₄ Cl. The mixture was dried over MgSO₄ , filtered, and concentrated under reduced pressure. The resulting solid was collected to give the desired product as a beige solid, which was used in the next step without further purification. LCMS C₁₇ H₁₁ D₁₀ N₄ O₃ (M+H)⁺ m/z calcd = 339.2; found 339.2.Step 3: 9-(1-bromoethyl-1-d)-7-methyl-N,N,4-tris(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide

在0℃下向9-(1-羥基乙基-1-d)-7-甲基-N,N,4-參(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺(1.0 g, 2.96 mmol)於DCM (200 mL)中之混合物中添加PBr₃(0.33 mL, 3.2 mmol)。使所得混合物升溫至室溫並攪拌2 h。接著用飽和NaHCO₃淬滅混合物且用DCM (2×)萃取。將合併的有機物用飽和NaCl洗滌，且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。殘餘物不經進一步純化即直接用於下一步驟中。步驟4：9-(1-((2-胺甲醯基-6-氯吡啶-3-基)胺基)乙基-1-d)-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺To a mixture of 9-(1-hydroxyethyl-1-d)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide (1.0 g, 2.96 mmol) in DCM (200 mL) was added_PBr3 (0.33 mL, 3.2 mmol) at 0°C. The resulting mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was then quenched with saturated_NaHCO3 and extracted with DCM (2×). The combined organics were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used directly in the next step without further purification.Step 4: 9-(1-((2-aminoformyl-6-chloropyridin-3-yl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide

向9-(1-溴乙基-1-d)-7-甲基-N,N,4-參(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺(20 mg, 0.05 mmol)於DMF (0.3 mL)中之溶液中添加3-胺基-6-氯吡啶醯胺(17 mg, 0.1 mmol)。將混合物加熱至80℃持續2 h。冷卻至室溫後，用MeOH稀釋混合物且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₃H₁₅D₁₀ClN₇O₃(M+H)⁺m/z計算值= 492.2；實驗值492.2。實例48.9-(1-((2-胺甲醯基-6-氯吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺步驟1：9-(1-溴乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺To a solution of 9-(1-bromoethyl-1-d)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide (20 mg, 0.05 mmol) in DMF (0.3 mL) was added 3-amino-6-chloropyridinamide (17 mg, 0.1 mmol). The mixture was heated to 80°C for 2 h. After cooling to room temperature, the mixture was diluted with MeOH and purified by preparative HPLC (column: Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate:_{60 mL/min). The eluted fractions were collected and lyophilized to provide the desired product as a white solid (TFA salt). LCMS m/z calculated for C₂₃H₁₅D₁₀ClN₁₃O₃(M+H} )^⁺ = 492.2; found 492.2.Example 48.9-(1-((2-aminoformyl-6-chloropyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamideStep 1: 9-(1-bromoethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide

使用與針對實例47所闡述類似之程序，在步驟1中用9-乙醯基-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸替代9-乙醯基-7-甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸，用二甲胺替代雙(甲基-d₃)胺，且在步驟2中用NaBH₄替代NaBD₄來製備標題化合物。LCMS C₁₇H₂₀BrN₄O₂(M+H)⁺m/z計算值= 391.1；實驗值391.1。步驟2：9-(1-((2-胺甲醯基-6-氯吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺The title compound was prepared using a procedure similar to that described forExample 47 , substituting 9-acetyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid for 9-acetyl-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid, dimethylamine for bis(methyl-_d3) amine in step 1, and_NaBH4 for_NaBD4 in step_2. LCMS_Calcd . for_Ci7H20BrN4O2 (M+H)⁺ m/z = 391.1; found 391.1.Step 2: 9-(1-((2-aminoformyl-6-chloropyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide

向9-(1-溴乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺(20 mg, 0.05 mmol)於DMF (0.3 mL)中之溶液中添加3-胺基-6-氯吡啶醯胺(17 mg, 0.1 mmol)。將混合物加熱至80℃持續2 h。冷卻至室溫後，用MeOH稀釋混合物且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₃H₂₅ClN₇O₃(M+H)⁺m/z計算值= 482.2；實驗值482.2。實例49至59.To a solution of 9-(1-bromoethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide (20 mg, 0.05 mmol) in DMF (0.3 mL) was added 3-amino-6-chloropyridinamide (17 mg, 0.1 mmol). The mixture was heated to 80°C for 2 h. After cooling to room temperature, the mixture was diluted with MeOH and purified by preparative HPLC (column: Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The eluted fractions were collected and lyophilized to provide the desired product as a white solid as its TFA salt. LCMS Calcd. for C₂₃ H₂₅ ClN₇ O₃ (M+H)⁺ m/z = 482.2; Found 482.2.Examples 49 to 59.

表5中之以下化合物係根據針對實例47或實例48所闡述之程序，使用適當中間體類似地製備。表5.實例編號化學名稱結構LCMSm/z (M+H)⁺499-(1-((2-胺甲醯基-4-氯苯基)胺基)乙基-1-d)-7-甲基-N,N,4-參(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺491.2509-(1-((6-氯-2-(1-環丙基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-N,N,4-參(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺555.351(3-((1-(3-(雙(甲基-d3)胺甲醯基)-7-甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)-6-氯吡啶-2-基)胺基甲酸甲酯522.2529-(1-((2-胺甲醯基-4-氯苯基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺481.2539-(1-((4-氟-2-(1-甲基-1H-四唑-5-基)苯基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺504.2549-(1-((6-氯-2-(1-環丙基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺545.2559-(1-((4-氟-2-(1-甲基-1H-1,2,3-三唑-4-基)苯基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺503.256(6-氯-3-((1-(3-(二甲基胺甲醯基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)吡啶-2-基)胺基甲酸甲酯512.2579-(1-((4-氟-2-胺磺醯基苯基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺501.2589-(1-((5-氯喹啉-8-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺489.259N,N,4,7-四甲基-9-(1-((6-甲基-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺501.2實例60. 2-((1-(3-(1-乙醯基六氫吡啶-4-基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-5-氟苯甲醯胺步驟1：5-氟-2-((1-(3-碘-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)苯甲醯胺The following compounds in Table 5 were similarly prepared according to the procedures described for Example 47 or Example 48 using appropriate intermediates.Table 5.Instance NumberChemical namestructureLCMSm/z (M+H)⁺49 9-(1-((2-aminoformyl-4-chlorophenyl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide 491.250 9-(1-((6-chloro-2-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide 555.351 Methyl (3-((1-(3-(bis(methyl-d3)aminoformyl)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-6-chloropyridin-2-yl)carbamate 522.252 9-(1-((2-aminoformyl-4-chlorophenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide 481.253 9-(1-((4-fluoro-2-(1-methyl-1H-tetrazol-5-yl)phenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide 504.254 9-(1-((6-chloro-2-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide 545.255 9-(1-((4-fluoro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide 503.256 Methyl (6-chloro-3-((1-(3-(dimethylaminoformyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)pyridin-2-yl)carbamate 512.257 9-(1-((4-fluoro-2-aminosulfonylphenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide 501.258 9-(1-((5-chloroquinolin-8-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide 489.259 N,N,4,7-Tetramethyl-9-(1-((6-methyl-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide 501.2Example 60. 2-((1-(3-(1-acetylhexahydropyridin-4-yl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-5-fluorobenzamideStep 1: 5-Fluoro-2-((1-(3-iodo-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)benzamide

在氮氣下在0℃下向9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸(實例1，步驟11) (1.00 g , 2.29 mmol)於DMF (10 mL)中之混合物中添加NaHCO₃(768 mg, 9.14 mmol)，攪拌5 min後，一次性添加1-碘吡咯啶-2,5-二酮(617 mg, 2.74 mmol)。使所得混合物升溫至室溫並攪拌2 h。完成後，用飽和Na₂S₂O₃水溶液淬滅反應物，且用水稀釋。接著用EtOAc萃取混合物。將合併的有機物用水、飽和NaCl洗滌，且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。藉由矽膠管柱層析，用己烷及EtOAc (0至30%)溶析純化殘餘物，提供呈白色固體之期望產物。LCMS C₂₁H₂₀FIN₅O₂(M+H)⁺m/z計算值= 520.1；實驗值520.1。步驟2：4-(9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-基)-3,6-二氫吡啶-1(2H)-甲酸第三丁酯To a mixture of 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid (Example 1, Step 11) (1.00 g, 2.29 mmol) in DMF (10 mL) at 0°C under nitrogen was added_NaHCO₃ (768 mg, 9.14 mmol). After stirring for 5 min, 1-iodopyrrolidine-2,5-dione (617 mg, 2.74 mmol) was added in_{one portion. The resulting mixture was allowed to warm to room temperature and stirred for 2 h. Upon completion, the reaction was quenched with saturated aqueous Na₂S₂O₃anddiluted} with water. The mixture was then extracted with EtOAc. The combined organics were washed with water and saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexanes and EtOAc (0-30%) to provide the desired product as_a white_{solid. LCMS m/z calculated for C₂₁H₂OF₅O₂(} M+H)⁺ = 520.1; found = 520.1.Step 2: 4-(9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

將5-氟-2-((1-(3-碘-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)苯甲醯胺(15 mg, 0.03 mmol)、K₃PO₄(18 mg, 0.09 mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,6-二氫-2H-吡啶-1-甲酸第三丁酯(18 mg, 0.06 mmol)及1,1'-雙(二苯基膦基)二茂鐵-二氯化鈀(II)二氯甲烷錯合物(5 mg, 0.01 mmol)於1 mL二噁烷/H₂O (5:1)中之溶液用N₂鼓泡1 min。將所得反應混合物在90℃下攪拌30 min。用1 mL水稀釋反應混合物且用EtOAc萃取。將有機層濃縮至乾燥。藉由矽膠管柱層析純化殘餘物，提供期望產物。LCMS C₃₁H₃₆FN₆O₄(M+H)⁺m/z計算值= 575.3；實驗值575.2。步驟3：2-((1-(4,7-二甲基-5-側氧基-3-(六氫吡啶-4-基)-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-5-氟苯甲醯胺A solution of 5-fluoro-2-((1-(3-iodo-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)benzamide (15 mg, 0.03 mmol), K₃ PO₄ (18 mg, 0.09 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)-3,6-dihydro-2H -pyridine-1-carboxylic acid tert-butyl ester (18 mg, 0.06 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (5 mg, 0.01 mmol) in 1 mL of dioxane/H₂ O (5:1) was stirred at 4 ℃ for 1 h.₂ was bubbled for 1 min. The resulting reaction mixture was stirred at 90 °C for 30 min. The reaction mixture was diluted with 1 mL of water and extracted with EtOAc. The organic layer was concentrated to dryness. The residue was purified by silica gel column chromatography to provide the desired product. LCMS C₃₁ H₃₆ FN₆ O₄ (M+H)⁺ m/z calculated = 575.3; experimental value 575.2.Step 3: 2-((1-(4,7-dimethyl-5-oxo-3-(hexahydropyridin-4-yl)-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-5-fluorobenzamide

向4-(9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-基)-3,6-二氫吡啶-1(2H)-甲酸第三丁酯(5.0 mg, 0.01 mmol)及活性碳載10%鈀(1.1 mg, 0.001 mmol)於1 mL MeOH中之溶液中添加乙酸銨(2.4 mg, 0.03 mmol)，且將所得混合物在60℃下攪拌12 h。經由矽藻土過濾反應混合物，且將濾液濃縮至乾燥。接著向殘餘物中添加2 mL含4 M HCl之二噁烷，且將所得混合物在室溫下攪拌2 h。在減壓下濃縮反應混合物。殘餘物不經進一步純化即直接用於下一步驟中。LCMS C₂₆H₃₀FN₆O₂(M+H)⁺m/z計算值= 477.2；實驗值477.2。步驟4：2-((1-(3-(1-乙醯基六氫吡啶-4-基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-5-氟苯甲醯胺To a solution of tert-butyl 4-(9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (5.0 mg, 0.01 mmol) and 10% palladium on activated carbon (1.1 mg, 0.001 mmol) in 1 mL of MeOH was added ammonium acetate (2.4 mg, 0.03 mmol), and the resulting mixture was stirred at 60° C. for 12 h. The reaction mixture was filtered through celite, and the filtrate was concentrated to dryness. To the residue was then added 2 mL of 4 M HCl in dioxane, and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was used directly in the next step without further purification. LCMS C₂₆ H₃₀ FN₆ O₂ (M+H)⁺ m/z Calcd = 477.2; Found 477.2.Step 4: 2-((1-(3-(1-acetylhexahydropyridin-4-yl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-5-fluorobenzamide

在0℃下向2-((1-(4,7-二甲基-5-側氧基-3-(六氫吡啶-4-基)-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-5-氟苯甲醯胺(10.0 mg, 0.02 mmol)於DCM中之攪拌溶液中添加N,N-二乙基乙胺(4.3 mg, 0.04 mmol)及乙醯氯(2.0 mg, 0.03 mmol)。將所得混合物在0℃下攪拌10 min並用MeOH稀釋，且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₈H₃₂FN₆O₃(M+H)⁺m/z計算值= 519.2；實驗值519.2。實例61.2-((1-(3-(2-胺基嘧啶-5-基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-5-氟苯甲醯胺To a stirred solution of 2-((1-(4,7-dimethyl-5-oxo-3-(hexahydropyridin-4-yl)-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-5-fluorobenzamide (10.0 mg, 0.02 mmol) in DCM at 0°C were addedN ,N -diethylethanamine (4.3 mg, 0.04 mmol) and acetyl chloride (2.0 mg, 0.03 mmol). The resulting mixture was stirred at 0°C for 10 min, diluted with MeOH, and purified by preparative HPLC (column: Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The eluted fractions were collected and lyophilized_to provide the desired product as_{awhite solid (TFA salt). LCMS calculated for C₂₈H₃₂FN₆O₃(} M+H)^⁺ m/z = 519.2; found 519.2.Example 61.2-((1-(3-(2-aminopyrimidin-5-yl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-5-fluorobenzamide

將5-氟-2-((1-(3-碘-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)苯甲醯胺(實例60，步驟1) (18.0 mg, 0.03 mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)嘧啶-2-胺(15.3 mg, 0.07 mmol)、K₃PO₄(22.1 mg, 0.10 mmol)及XPhos Pd G2 (5.5 mg, 0.01 mmol)於二噁烷(0.5 mL)及水(0.1 mL)中之混合物在氮氣氣氛下在90℃下加熱20 min。冷卻至室溫後，用MeOH稀釋混合物且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₅H₂₄FN₈O₂(M+H)⁺m/z計算值= 487.2；實驗值487.2。實例62.2-((1-(3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)-5-氟苯甲醯胺步驟1：9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基-1-d)-7-甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸A mixture of 5-fluoro-2-((1-(3-iodo-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)benzamide (Example 60, Step 1) (18.0 mg, 0.03 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolacyclopentan-2-yl)pyrimidin-2-amine (15.3 mg, 0.07 mmol), K₃ PO₄ (22.1 mg, 0.10 mmol) and XPhos Pd G 2 (5.5 mg, 0.01 mmol) in dioxane (0.5 mL) and water (0.1 mL) was heated at 90° C. for 20 min under nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with MeOH and purified by preparative HPLC (Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The eluted fractions were collected and lyophilized_to provide the desired product as_a white solid (TFA salt)._LCMS calculated for_{C₂₅H₂₄FN₈O₂} (M+H)^⁺ m/z = 487.2; found 487.2.Example 62.2-((1-(3-(2-aminopyrimidin-5-yl)-7-methyl-4-(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-5-fluorobenzamideStep 1: 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl-1-d)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid

使用與實例1中所闡述類似之程序，在步驟4中用2-胺基-3-溴-5-甲基-N-(甲基-d₃)苯甲醯胺(實例4，步驟1)替代2-胺基-3-溴-N,5-二甲基苯甲醯胺，且在步驟8中用NaBD₄替代NaBH₄來製備標題化合物。完成後，收集所得固體，得到呈淺灰色固體之期望產物。LCMS C₂₂H₁₇D₄FN₅O₄(M+H)⁺m/z計算值= 442.2；實驗值442.2。步驟2：5-氟-2-((1-(3-碘-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)苯甲醯胺The title compound was prepared using a procedure similar to that described in Example1 , substituting 2-amino-3-bromo-5-methyl-N-(methyl-d₃ )benzamide (Example 4, Step 1) for 2-amino-3-bromo-N,5-dimethylbenzamide in Step 4 and substituting NaBD₄ for NaBH₄ in Step 8. After completion, the resulting solid was collected to give the desired product as a light gray solid. LCMS Calcd. for C_{2 2} H_{1 7} D₄ FN₅ O₄ (M+H)⁺ m/z = 442.2; Found 442.2.Step 2: 5-Fluoro-2-((1-(3-iodo-7-methyl-4-(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)benzamide

使用與針對實例60所闡述類似之程序，在步驟1中用9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基-1-d)-7-甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸替代9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸來製備標題化合物。藉由矽膠管柱層析，用己烷及EtOAc (0至30%)溶析純化殘餘物，提供呈白色固體之期望產物。LCMS C₂₁H₁₆D₄FIN₅O₂(M+H)⁺m/z計算值= 524.1；實驗值524.1。步驟3：2-((1-(3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)-5-氟苯甲醯胺The title compound was prepared using a procedure similar to that described forExample 60 , substituting 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl-1-d)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid for 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid in step 1. The residue was purified by silica gel column chromatography eluting with hexanes and EtOAc (0 to 30%) to provide the desired product as a white solid. LCMS C₂₁ H₁₆ D₄ FIN₅ O₂ (M+H)⁺ m/z calcd = 524.1; found 524.1.Step 3: 2-((1-(3-(2-aminopyrimidin-5-yl)-7-methyl-4-(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-5-fluorobenzamide

將5-氟-2-((1-(3-碘-7-甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)苯甲醯胺(18.0 mg, 0.03 mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)嘧啶-2-胺(15.3 mg, 0.07 mmol)、K₃PO₄(22.1 mg, 0.10 mmol)及XPhos Pd G2 (5.5 mg, 0.01 mmol)於二噁烷(0.5 mL)及水(0.1 mL)中之混合物在氮氣氣氛下在90℃下加熱20 min。冷卻至室溫後，用MeOH稀釋混合物且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₅H₂₀D₄FN₈O₂(M+H)⁺m/z計算值= 491.2；實驗值491.2。實例63.2-((1-(4,7-二甲基-3-(1-甲基-1H-吡唑-5-基)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-5-氟苯甲醯胺A mixture of 5-fluoro-2-((1-(3-iodo-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)benzamide (18.0 mg, 0.03 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolacyclopentan-2-yl)pyrimidin-2-_amine (15.3 mg, 0.07 mmol),_K3PO4 (22.1 mg, 0.10 mmol) and XPhosPdG2 (5.5 mg, 0.01 mmol) in dioxane (0.5 mL) and water (0.1 mL) was heated at 90°C for 20 min under nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with MeOH and purified by preparative HPLC (column: Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The eluted fractions were collected and lyophilized to provide the desired product as a_whitesolidas its TFA salt. LCMS m/z calculated_{forC₂₅H₂O₄FN₈O₂} (M+H)^⁺ = 491.2; found 491.2.Example 63.2-((1-(4,7-Dimethyl-3-(1-methyl-1H-pyrazol-5-yl)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-5-fluorobenzamide

使用與針對實例61所闡述類似之程序，用1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡唑替代5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)嘧啶-2-胺來製備標題化合物。用MeOH稀釋混合物，且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₅H₂₅FN₇O₂(M+H)⁺m/z計算值= 474.2；實驗值474.2。實例64.5-氟-2-((1-(7-甲基-4-(甲基-d3)-3-(1-甲基-1H-吡唑-5-基)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)苯甲醯胺The title compound was prepared using a procedure similar to that described forExample 61 , substituting 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatolan-2-yl)pyrimidin-2-amine for 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatolan-2-yl)pyrimidin-2-amine. The mixture was diluted with MeOH and purified by preparative HPLC (column: Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The eluted fractions were collected and lyophilized to provide the desired product as a white solid as its TFA salt. LCMS C₂₅ H₂₅ FN₇ O₂ (M+H)⁺ m/z calcd = 474.2; found 474.2.Example 64.5-Fluoro-2-((1-(7-methyl-4-(methyl-d 3 )-3-(1-methyl-1H-pyrazol-5-yl)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)benzamide

使用與針對實例62所闡述類似之程序，在步驟3中用1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡唑替代5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)嘧啶-2-胺來製備標題化合物。用MeOH稀釋混合物，且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₅H₂₁D₄FN₇O₂(M+H)⁺m/z計算值= 478.2；實驗值478.2。實例65.2-((1-(3-(2-胺基嘧啶-5-基)-7-氯-4-甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-5-氟苯甲醯胺步驟1：9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-7-氯-4-甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸The title compound was prepared using a procedure similar to that described forExample 62 , substituting 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatolan-2-yl)pyrimidin-2-amine for 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatolan-2-yl)pyrimidin-2-amine in Step 3. The mixture was diluted with MeOH and purified by preparative HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min); the eluted fractions were collected and lyophilized to provide the desired product as a white solid as its TFA salt. LCMS C₂₅ H₂₁ D₄ FN₇ O₂ (M+H)⁺ m/z calcd = 478.2; found 478.2.Example 65.2-((1-(3-(2-aminopyrimidin-5-yl)-7-chloro-4-methyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-5-fluorobenzamideStep 1: 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-7-chloro-4-methyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid

使用與針對實例1所闡述類似之程序，在步驟1中用2-胺基-5-氯苯甲醯胺替代2-胺基-5-甲基苯甲醯胺來製備標題化合物。LCMS C₂₁H₁₈ClFN₅O₄(M+H)⁺m/z計算值= 458.1；實驗值458.1。步驟2：2-((1-(7-氯-3-碘-4-甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-5-氟苯甲醯胺The title compound was prepared using a procedure similar to that described forExample 1 , substituting 2-amino-5-chlorobenzamide for 2-amino-5-methylbenzamide in Step 1. LCMS C₂₁ H₁₈ ClFN₅ O₄ (M+H)⁺ m/z calcd = 458.1; found 458.1.Step 2: 2-((1-(7-chloro-3-iodo-4-methyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-5-fluorobenzamide

使用與針對實例60所闡述類似之程序，在步驟1中用9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-7-氯-4-甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸替代9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸來製備標題化合物。LCMS C₂₀H₁₇ClFIN₅O₂(M+H)⁺m/z計算值= 540.0；實驗值540.1。步驟3：2-((1-(3-(2-胺基嘧啶-5-基)-7-氯-4-甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-5-氟苯甲醯胺The title compound was prepared using a procedure similar to that described forExample 60, substituting 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-7-chloro-4-methyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid for 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]_quinazoline -3_- carboxylic acid in step 1._LCMS Calcd. for_{C20H17ClFIN5O2} (M+H)⁺ m/z = 540.0; Found 540.1.Step 3: 2-((1-(3-(2-aminopyrimidin-5-yl)-7-chloro-4-methyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-5-fluorobenzamide

將2-((1-(7-氯-3-碘-4-甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-5-氟苯甲醯胺(20.0 mg, 0.03 mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)嘧啶-2-胺(15 mg, 0.07 mmol)、K₃PO₄(22 mg, 0.10 mmol)及XPhos Pd G2 (4 mg, 0.01 mmol)於二噁烷(0.5 mL)及水(0.1 mL)中之混合物在氮氣氣氛下在80℃下加熱20 min。冷卻至室溫後，用MeOH稀釋混合物且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₄H₂₁ClFN₈O₂(M+H)⁺m/z計算值= 507.1；實驗值507.2。實例66.2-((1-(3-(2-胺基嘧啶-5-基)-7-氯-4-甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)-5-氟苯甲醯胺A mixture of 2-((1-(7-chloro-3-iodo-4-methyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-5-fluorobenzamide (20.0 mg, 0.03 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)pyrimidin-2-amine (15 mg, 0.07 mmol), K₃ PO₄ (22 mg, 0.10 mmol) and XPhos Pd G2 (4 mg, 0.01 mmol) in dioxane (0.5 mL) and water (0.1 mL) was heated at 80° C. for 20 min under nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with MeOH and purified by preparative HPLC (Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The eluted fractions were collected and lyophilized to provide the desired product as_a white solid (TFA salt)_{. LCMS m/z calculated for C₂₄H₂₁ClFN₈O₂(M} +H)^⁺ = 507.1; found 507.2.Example 66.2-((1-(3-(2-aminopyrimidin-5-yl)-7-chloro-4-methyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-5-fluorobenzamide

使用與針對實例65所闡述類似之程序來製備標題化合物。LCMS C₂₄H₂₀DClFN₈O₂(M+H)⁺m/z計算值= 508.1；實驗值508.2。實例67.9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(1-(氧雜環丁-3-基)六氫吡啶-4-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮步驟1：4-(9-乙醯基-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-基)-3,6-二氫吡啶-1(2H)-甲酸第三丁酯The title compound_was prepared using a procedure similar to that described forExample 65. LCMS_Calcd ._{forC24H20DClFN8O2} (M+H)⁺ m/z = 508.1; found 508.2.Example 67.9-(1-((6-Chloro-2-(2-(methyl-_d3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-(oxacyclobutan-3-yl)hexahydropyridin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-oneStep 1: 4-(9-acetyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

使用與針對實例20步驟4所闡述類似之程序來製備標題化合物。步驟2：4-(9-(1-羥基乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-基)-3,6-二氫吡啶-1(2H)-甲酸第三丁酯The title compound was prepared using a procedure similar to that described for Example 20, Step 4.Step 2: 4-(9-(1-hydroxyethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

將4-(9-乙醯基-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-基)-3,6-二氫吡啶-1(2H)-甲酸第三丁酯(1.6 g, 3.67 mmol)溶解於MeOH (30 mL)及DCM (30 mL)中，接著在氮氣下在0℃下分三次添加NaBH₄(208 mg, 5.50 mmol)。將所得混合物在相同溫度下攪拌10 min，之後用飽和NH₄Cl淬滅。用水稀釋混合物且用DCM萃取。將合併的有機物用飽和NaCl洗滌，且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。藉由矽膠管柱層析，用DCM及EA (0至95%)溶析純化殘餘物，提供呈白色固體之期望產物(1.4 g, 87%)。LCMS C₂₄H₃₁N₄O₄(M+H)⁺m/z計算值= 439.2；實驗值439.2。步驟3：4-(9-(1-羥基乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-基)六氫吡啶-1-甲酸第三丁酯4-(9-Acetyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.6 g, 3.67 mmol) was dissolved in MeOH (30 mL) and DCM (30 mL), followed by the addition of_NaBH₄ (208 mg, 5.50 mmol) in three portions at 0°C under nitrogen. The resulting mixture was stirred at the same temperature for 10 min, then quenched with saturated_NH₄Cl . The mixture was diluted with water and extracted with DCM. The combined organics were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM_and EA (0 to 95%) to provide the desired product (1.4 g, 87%) as_a white solid. LCMS_C24H31N4O4 (M+H)⁺ m/z calculated = 439.2; found 439.2. Step 3: tert_-butyl 4-(9-(1-hydroxyethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)hexahydropyridine-1-carboxylate

將4-(9-(1-羥基乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-基)-3,6-二氫吡啶-1(2H)-甲酸第三丁酯(1.4 g, 3.19 mmol)、氯化銨(1.21 g, 19.2 mmol)及碳載10%鈀(300 mg)之混合物添加至40 ml小瓶中。接著添加甲醇(15.0 mL)及乙酸(1 mL)。將所得混合物在氮氣氣氛下在50℃下加熱16小時。經由矽藻土墊過濾所得混合物，且將濾液在減壓下濃縮。藉由矽膠管柱層析，用DCM及EtOAc (0至95%)溶析純化所得混合物，提供呈白色固體之期望產物(1.15 g, 82%)。LCMS C₂₄H₃₃N₄O₄(M+H)⁺m/z計算值= 441.2；實驗值441.2。步驟4：4-(9-(1-溴乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-基)六氫吡啶-1-甲酸第三丁酯A mixture of tert-butyl 4-(9-(1-hydroxyethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.4 g, 3.19 mmol), ammonium chloride (1.21 g, 19.2 mmol), and 10% palladium on carbon (300 mg) was added to a 40 ml vial. Methanol (15.0 mL) and acetic acid (1 mL) were then added. The resulting mixture was heated at 50°C under a nitrogen atmosphere for 16 hours. The resulting mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography eluting with DCM_and EtOAc (0-95%) to provide the desired product (1.15 g, 82%) as_a white solid. LCMS_C24H33N4O4 (M+H)⁺ m/z calculated = 441.2; found 441.2. Step 4: tert_-butyl 4-(9-(1-bromoethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)hexahydropyridine-1-carboxylate

在0℃下向4-(9-(1-羥基乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-基)六氫吡啶-1-甲酸第三丁酯(300 mg, 0.68 mmol)於THF (20 mL)中之混合物中添加吡啶(0.22 mL, 2.72 mmol)及PBr₃(0.13 mL, 1.36 mmol)。使所得混合物升溫至室溫並攪拌2 h。接著用飽和NaHCO₃淬滅混合物，且用EtOAc (2×)萃取。將合併的有機物用飽和NaCl洗滌，且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。殘餘物不經進一步純化即直接用於下一步驟中。步驟5：4-(9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-基)六氫吡啶-1-甲酸第三丁酯To a mixture of tert-butyl 4-(9-(1-hydroxyethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)hexahydropyridine-1-carboxylate (300 mg, 0.68 mmol) in THF (20 mL) at 0°C was added pyridine (0.22 mL, 2.72 mmol) and PBr₃ (0.13 mL, 1.36 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was then quenched with saturated NaHCO₃ and extracted with EtOAc (2×). The combined organics were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used directly in the next step without further purification.Step 5: 4-(9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester

向4-(9-(1-溴乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-基)六氫吡啶-1-甲酸第三丁酯(300 mg, 0.60 mmol)於DMF (2 mL)中之溶液中添加6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-胺(中間體11) (254 mg, 1.2 mmol)。將混合物加熱至80℃持續2 h。用水稀釋混合物且用EtOAC (2×)萃取。將合併的有機物用飽和NaCl洗滌，且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。藉由矽膠管柱層析，用DCM及EtOAc (0至95%)溶析純化所得混合物，提供呈白色固體之期望產物(42 mg, 11%)。LCMS C₃₁H₃₅D₃ClN₁₀O₃(M+H)⁺m/z計算值= 636.3；實驗值636.3。步驟6：9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(六氫吡啶-4-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮To a solution of tert-butyl 4-(9-(1-bromoethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)hexahydropyridine-1-carboxylate (300 mg, 0.60 mmol) in DMF (2 mL) was added 6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-amine (Intermediate 11) (254 mg, 1.2 mmol). The mixture was heated to 80°C for 2 h. The mixture was diluted with water and extracted with EtOAc (2×). The combined organics were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography eluting with DCM and EtOAc (0-95%) to provide the desired product (42 mg, 11%) as a white solid. LCMS C₃₁ H₃₅ D₃ ClN₁₀ O₃ (M+H)⁺ m/z calcd = 636.3; found 636.3.Step 6: 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(hexahydropyridin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one

將4-(9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-基)六氫吡啶-1-甲酸第三丁酯(42 mg, 0.066 mmol)溶解於含4 M HCl之二噁烷(2 mL)中。將所得溶液在室溫下攪拌2小時。在減壓下去除溶劑，且產物不經進一步純化即直接用於下一步驟中。LCMS C₂₆H₂₇D₃ClN₁₀O (M+H)⁺m/z計算值= 536.2；實驗值536.2。步驟7：9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(1-(氧雜環丁-3-基)六氫吡啶-4-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮4-(9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)hexahydropyridine-1-carboxylic acid tert-butyl ester (42 mg, 0.066 mmol) was dissolved in 4 M HCl in dioxane (2 mL). The resulting solution was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the product was used directly in the next step without further purification. LCMS m/z calculated for C₂₆ H₂₇ D₃ ClN₁₀ O (M+H)⁺ = 536.2; found 536.2.Step 7: 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-(oxocyclobutan-3-yl)hexahydropyridin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one

向9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(六氫吡啶-4-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮(10 mg, 0.02 mmol)於MeOH (1 mL)及乙酸(0.5 mL)中之溶液中添加氧雜環丁-3-酮(6.7 mg, 0.1 mmol)。將所得混合物在50℃下加熱2小時。冷卻至室溫後，添加NaBH₃CN (2.34 mg, 0.04 mmol)，且將混合物攪拌30 min。用MeOH稀釋粗產物，且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₉H₃₁D₃ClN₁₀O₂(M+H)⁺m/z計算值= 592.3；實驗值592.3。實例68.3-(1-乙醯基六氫吡啶-4-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮To a solution of 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(hexahydropyridin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one (10 mg, 0.02 mmol) in MeOH (1 mL) and acetic acid (0.5 mL) was added oxadiazol-3-one (6.7 mg, 0.1 mmol). The resulting mixture was heated at 50° C. for 2 h. After cooling to room temperature, NaBH₃ CN (2.34 mg, 0.04 mmol) was added, and the mixture was stirred for 30 min. The crude product was diluted with MeOH and purified by preparative HPLC (Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate:₆₀ mL/min). The_{eluted fractions were collected and lyophilized to provide the desired product as a white solid as its TFA salt. LCMS m/z calculated for C29H31D3ClN10O2(M} +H)₊⁼ 592.3; found 592.3.Example 68.3-(1-acetylhexahydropyridin-4-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one

向9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(六氫吡啶-4-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮(實例67，步驟6) (8 mg, 0.01 mmol) 於DCM (1 mL)中之溶液中添加三乙胺(3.0 mg, 0.03 mmol)及乙醯氯(1.8 mg, 0.02 mmol)。將所得混合物在室溫下攪拌30分鐘。用MeOH稀釋粗產物，且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₈H₂₉D₃ClN₁₀O₂(M+H)⁺m/z計算值= 578.3；實驗值578.3。實例69.9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(1-(2-羥基乙醯基)六氫吡啶-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮To a solution of 9-(1-((6-chloro-2-(2-(methyl-_d3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(hexahydropyridin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one (Example 67, Step 6) (8 mg, 0.01 mmol) in DCM (1 mL) was added triethylamine (3.0 mg, 0.03 mmol) and acetyl chloride (1.8 mg, 0.02 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The crude product was diluted with MeOH and purified by preparative HPLC (Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate:₆₀ mL/min). The_{eluted fractions were collected and lyophilized to provide the desired product as a white solid as its TFA salt. LCMS m/z calculated for C₂₈H₂₆D₃ClN₁₀O₂(M} +H)_⁺⁼ 578.3; found 578.3.Example 69.9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2-hydroxyacetyl)hexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one

向9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(六氫吡啶-4-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮(實例67，步驟6) (8 mg, 0.01 mmol)於DMF (0.5 mL)中之溶液中添加2-羥基乙酸(2.3 mg, 0.03 mmol)、HATU (8.5 mg, 0.02 mmol)及N,N-二異丙基乙胺(13 uL, 0.07 mmol)。將所得混合物在室溫下攪拌30分鐘，接著用MeOH稀釋且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₈H₂₉D₃ClN₁₀O₃(M+H)⁺m/z計算值= 594.3；實驗值594.3。實例70.3-(1-乙醯基六氫吡啶-4-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮To a solution of 9-(1-((6-chloro-2-(2-(methyl-_d3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(hexahydropyridin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one (Example 67, Step 6) (8 mg, 0.01 mmol) in DMF (0.5 mL) were added 2-hydroxyacetic acid (2.3 mg, 0.03 mmol), HATU (8.5 mg, 0.02 mmol) andN ,N -diisopropylethylamine (13 uL, 0.07 mmol). The resulting mixture was stirred at room temperature for 30 minutes, then diluted with MeOH and purified by preparative HPLC (column: Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The eluted fractions were collected and_{lyophilized to provide the desired product as a white solid (TFA salt). LCMS m/z calculated for C₂₈H₂₆D₃ClN₁₀O₃(M+} H)_⁺⁼ 594.3; found 594.3.Example 70.3-(1-acetylhexahydropyridin-4-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one

使用與針對實例68所闡述類似之程序來製備標題化合物。用MeOH稀釋反應混合物，且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₈H₂₅D₇ClN₁₀O₂(M+H)⁺m/z計算值= 582.3；實驗值582.3。實例71至75.The title compound was prepared using a procedure similar to that described forExample 68. The reaction mixture was diluted with MeOH and purified by preparative HPLC (column: Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A_: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The eluted_fractions were collected and_lyophilized to provide the desired product as_a white solid as its TFA salt. LCMS_{C₂₈H₂₈D₁₈ClN₁₁O₂} (M+H)^⁺ m/z calculated = 582.3; found 582.3.Examples 71 to 75.

表6中之以下化合物係根據針對實例68所闡述之程序，使用適當中間體類似地製備。表6.實例編號化學名稱結構LCMSm/z (M+H)⁺719-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(1-異丁醯基六氫吡啶-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮606.3729-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(1-(環丙烷羰基)六氫吡啶-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮604.3739-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(1-(甲基磺醯基)六氫吡啶-4-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮614.2749-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(1-(異丙基磺醯基)六氫吡啶-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮642.3759-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(1-(環丙基磺醯基)六氫吡啶-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮640.2實例76.3-(2-胺基嘧啶-5-基)-9-(1-((6-甲氧基-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮The following compounds in Table 6 were similarly prepared according to the procedures described for Example 68 using appropriate intermediates.Table 6.Instance NumberChemical namestructureLCMSm/z (M+H)⁺71 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-isobutyrylhexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one 606.372 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-(cyclopropanecarbonyl)hexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one 604.373 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-(methylsulfonyl)hexahydropyridin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one 614.274 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-(isopropylsulfonyl)hexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one 642.375 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-(cyclopropylsulfonyl)hexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one 640.2Example 76.3-(2-aminopyrimidin-5-yl)-9-(1-((6-methoxy-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one

將3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮(實例17) (15.0 mg, 0.03 mmol)、[2-(2-胺基苯基)苯基]-甲基磺醯基氧基-鈀;二第三丁基-[3,6-二甲氧基-2-(2,4,6-三異丙基苯基)苯基]磷烷(4.7 mg, 0.01 mmol)、第三丁醇鈉(7.9 mg, 0.08 mmol)於二噁烷(1 mL)及MeOH (0.2 mL)中之混合物在氮氣氣氛下在100℃下加熱1 h。冷卻至室溫後，用MeOH稀釋混合物且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₆H₂₀D₇N₁₂O₂(M+H)⁺m/z計算值= 546.3；實驗值546.2。實例77.3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d3)-9-(1-((6-甲基-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)咪唑并[1,5-a]喹唑啉-5(4H)-酮3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one (Example 17) (15.0 mg, 0.03 mmol), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; di-tert-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (4.7 mg, 0.01 mmol), sodium tert-butoxide (7.9 mg, 0.08 mmol) were dissolved in dioxane (1 mL) and MeOH (0.2 A mixture of 1% dapoxetine (50 mL) was heated at 100°C for 1 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with MeOH and purified by preparative HPLC (column: Sunfire prep C18 column, 30 x 150 mm,₅ μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate:₆₀ mL/min₎ . The eluted fractions were collected and lyophilized to provide the desired product as_{a white solid (TFA salt). LCMS m/z calculated for C₂₆H₂O₂(} M+H)^⁺ = 546.3; found 546.2.Example 77.3-(2-aminopyrimidin-5-yl)-7-methyl-4-(methyl-d3)-9-(1-((6-methyl-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)imidazo[1,5-a]quinazolin-5(4H)-one

將3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮(實例17) (12.00 mg, 0.02 mmol)、[2-(2-胺基苯基)苯基]-氯-鈀;二環己基-[2-(2,4,6-三異丙基苯基)苯基]磷烷(3.4 mg, 0.001 mmol)、K₃PO₄(13.9 mg, 0.07 mmol)及甲基硼酸(2.0 mg, 0.03 mmol)於二噁烷(0.5 mL)及水(0.1 mL)中之混合物在氮氣氣氛下在90℃下加熱1 h。冷卻至室溫後，用MeOH稀釋混合物且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₆H₂₀D₇N₁₂O (M+H)⁺m/z計算值= 530.3；實驗值530.3。實例78.3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d3)-9-(1-((2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)咪唑并[1,5-a]喹唑啉-5(4H)-酮3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one (Example 17) (12.00 mg, 0.02 mmol), [2-(2-aminophenyl)phenyl]-chloro-palladium; dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (3.4 mg, 0.001 mmol),_K3PO4( 13.9 mg, 0.07 mmol) and methylboric acid (2.0 mg, 0.03 mmol) were dissolved in dioxane (0.5 mL) and water (0.1 A mixture of 1% dapoxetine (50 mL) was heated at 90°C for 1 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with MeOH and purified by preparative HPLC (Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate:₆₀ mL/min₎ . The eluted fractions were collected and lyophilized to provide the desired product as a white solid (TFA salt). LCMS Calcd._{forC₂₆H₂O₀N₁₂O} (M+H)^⁺ m/z = 530.3; Found 530.3.Example 78.3-(2-aminopyrimidin-5-yl)-7-methyl-4-(methyl-d3)-9-(1-((2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)imidazo[1,5-a]quinazolin-5(4H)-one

將甲酸銨(4.13 mg, 0.07 mmol)於1 mL MeOH中之溶液添加至填充有氮氣之密封管中之3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮(實例17) (12.00 mg, 0.02 mmol)及活性碳載鈀(2.3 mg, 0.002 mmol)中。將反應混合物在60℃下攪拌3 h。冷卻至室溫後，經由矽藻土過濾反應混合物，且將濾液濃縮至乾燥。用MeOH稀釋殘餘物，且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₅H₁₈D₇N₁₂O (M+H)⁺m/z計算值= 516.2；實驗值516.3。實例79.9-(1-((6-甲氧基-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺A solution of ammonium formate (4.13 mg, 0.07 mmol) in 1 mL of MeOH was added to 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one (Example 17) (12.00 mg, 0.02 mmol) and palladium on activated carbon (2.3 mg, 0.002 mmol) in a sealed tube filled with nitrogen. The reaction mixture was stirred at 60°C for 3 h. After cooling to room temperature, the reaction mixture was filtered through celite, and the filtrate was concentrated to dryness. The residue was diluted with MeOH and purified by preparative HPLC (Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate:₆₀ mL/min). The_eluted fractions were collected and lyophilized to provide the desired product as a white solid (TFA salt). LCMS calculated for_{C₂₅H₁₈D₁₂N₁₂O} (M+H)^⁺ m/z =_516.2 ; found 516.3.Example 79.9-(1-((6-methoxy-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide

將9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺(實例23) (12.5 mg, 0.02 mmol)、[2-(2-胺基苯基)苯基]-甲基磺醯基氧基-鈀;二第三丁基-[3,6-二甲氧基-2-(2,4,6-三異丙基苯基)苯基]磷烷(4.1 mg, 0.001 mmol)及第三丁醇鈉(6.9 mg, 0.07 mmol)於二噁烷(1 mL)及MeOH (0.2 mL)中之混合物在氮氣氣氛下在100℃下加熱1 h。冷卻至室溫後，用MeOH稀釋混合物且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₅H₂₉N₁₀O₃(M+H)⁺m/z計算值= 517.2；實驗值517.2。實例80.9-(1-((4-氟-2-(1-(甲基-d3)-1H-四唑-5-基)苯基)胺基)乙基)-4,7-二甲基-3-(吡啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮步驟1：9-(1-溴乙基)-4,7-二甲基-3-(吡啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮A mixture of 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide (Example 23) (12.5 mg, 0.02 mmol), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; di-tert-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (4.1 mg, 0.001 mmol) and sodium tert-butoxide (6.9 mg, 0.07 mmol) in dioxane (1 mL) and MeOH (0.2 mL) was heated at 100° C. for 1 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with MeOH and purified by preparative HPLC (column: Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate:₆₀ mL/min). The eluted fractions were collected and lyophilized to provide the desired product as a_white solid as its TFA salt._LCMS calculated for_{C₂₅H₂₆N₁₀O₃} (M+H)^⁺ m/z = 517.2; found 517.2.Example 80.9-(1-((4-fluoro-2-(1-(methyl-d3)-1H-tetrazol-5-yl)phenyl)amino)ethyl)-4,7-dimethyl-3-(pyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-oneStep 1: 9-(1-bromoethyl)-4,7-dimethyl-3-(pyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one

使用與針對實例20所闡述類似之程序，在步驟2中用9-乙醯基-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯替代9-乙醯基-7-甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯，在步驟4中用吡啶-3-基硼酸替代4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,6-二氫吡啶-1(2H)-甲酸第三丁酯，且在步驟7中用NaBH₄替代NaBD₄來製備標題化合物。LCMS C₁₉H₁₈BrN₄O (M+H)⁺m/z計算值= 397.1；實驗值397.1。步驟2：9-(1-((4-氟-2-(1-(甲基-d₃)-1H-四唑-5-基)苯基)胺基)乙基)-4,7-二甲基-3-(吡啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮The title compound was prepared using a procedure similar to that described forExample 20, replacing tert-butyl 9-acetyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate with tert-butyl 9-acetyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate in step 2, replacing tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolacyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate with pyridin-3-ylboronic acid in step 4, and replacing_NaBH4 with_NaBD4 in step 7. LCMS C₁₉ H₁₈ BrN₄ O (M+H)⁺ m/z calcd = 397.1; found 397.1.Step 2: 9-(1-((4-fluoro-2-(1-(methyl-d₃ )-1H-tetrazol-5-yl)phenyl)amino)ethyl)-4,7-dimethyl-3-(pyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one

向9-(1-溴乙基)-4,7-二甲基-3-(3-吡啶基)咪唑并[1,5-a]喹唑啉-5-酮(18.0 mg, 0.05 mmol)於DMF (0.7 mL)中之溶液中添加4-氟-2-(1-(甲基-d₃)-1H-四唑-5-基)苯胺(中間體2) (13.3 mg, 0.07 mmol)。將混合物加熱至80℃持續3 h。冷卻至室溫後，用MeOH稀釋混合物且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₇H₂₂D₃FN₉O (M+H)⁺m/z計算值= 513.2；實驗值513.2。實例81.3-(2-胺基嘧啶-5-基)-9-(1-((4-氟-2-(1-甲基-1H-1,2,4-三唑-3-基)苯基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮步驟1：9-[1-[4-氟-2-(1-甲基-1,2,4-三唑-3-基)苯胺基]乙基]-3-碘-4,7-二甲基-咪唑并[1,5-a]喹唑啉-5-酮To a solution of 9-(1-bromoethyl)-4,7-dimethyl-3-(3-pyridinyl)imidazo[1,5-a]quinazolin-5-one (18.0 mg, 0.05 mmol) in DMF (0.7 mL) was added 4-fluoro-2-(1-(methyl-d₃ )-1H-tetrazol-5-yl)aniline (Intermediate 2) (13.3 mg, 0.07 mmol). The mixture was heated to 80° C. for 3 h. After cooling to room temperature, the mixture was diluted with MeOH and purified by preparative HPLC (column: Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The eluted fractions were collected and lyophilized to provide the desired product as a white solid_{as its TFA salt. LCMS m/z calculated for C₂ₐH₂D₃FN₆O(M+} H)^⁺ = 513.2; found 513.2.Example 81.3-(2-aminopyrimidin-5-yl)-9-(1-((4-fluoro-2-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-oneStep 1: 9-[1-[4-fluoro-2-(1-methyl-1,2,4-triazol-3-yl)anilino]ethyl]-3-iodo-4,7-dimethyl-imidazo[1,5-a]quinazolin-5-one

使用與針對實例8所闡述類似之程序，在步驟5中用4-氟-2-(1-甲基-1,2,4-三唑-3-基)苯胺(中間體4)替代6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-胺來製備標題化合物。LCMS C₂₃H₂₂FIN₇O (M+H)⁺m/z計算值= 558.1；實驗值558.1。步驟2：3-(2-胺基嘧啶-5-基)-9-(1-((4-氟-2-(1-甲基-1H-1,2,4-三唑-3-基)苯基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮The title compound was prepared using a procedure analogous to that described forExample 8 , substituting 4-fluoro-2-(1-methyl-1,2,4-triazol-3-yl)aniline (Intermediate 4) for 6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-amine in Step 5. LCMS Calcd. for C₂₃ H₂₂ FIN₇ O (M+H)⁺ m/z = 558.1; Found 558.1.Step 2: 3-(2-Aminopyrimidin-5-yl)-9-(1-((4-fluoro-2-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one

將9-(1-((4-氟-2-(1-甲基-1H-1,2,4-三唑-3-基)苯基)胺基)乙基)-3-碘-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮(18 mg, 0.03 mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)嘧啶-2-胺(10.7 mg, 0.05 mmol)、K₃PO₄(20.57 mg, 0.10 mmol)及XPhos Pd G2 (5 mg, 0.01 mmol)於二噁烷(0.5 mL)及水(0.1 mL)中之混合物在氮氣氣氛下在90℃下加熱20 min。冷卻至室溫後，用MeOH稀釋混合物且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₇H₂₆FN₁₀O (M+H)+ m/z計算值= 525.2；實驗值525.2。實例82至84.A mixture of 9-(1-((4-fluoro-2-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)ethyl)-3-iodo-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (18 mg, 0.03 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolacyclopentan-2-yl)pyrimidin-2-amine (10.7 mg, 0.05 mmol), K₃ PO₄ (20.57 mg, 0.10 mmol) and XPhos Pd G2 (5 mg, 0.01 mmol) in dioxane (0.5 mL) and water (0.1 mL) was heated at 90° C. for 20 min under nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with MeOH and purified by preparative HPLC (Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate:_{60 mL/min). The eluted fractions were collected and lyophilized to provide the desired product as a white solid as its TFA salt. LCMS calculated for C₂ₐH₂₆FN₁₀O(M} +H)⁺ m/z = 525.2; found 525.2.Examples 82 to 84.

表7中之以下化合物係根據針對實例81所闡述之程序，使用適當中間體類似地製備。表7.實例編號化學名稱結構LCMSm/z (M+H)⁺829-(1-((4-氟-2-(1-甲基-1H-1,2,4-三唑-3-基)苯基)胺基)乙基)-4,7-二甲基-3-(1-甲基-1H-吡唑-5-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮512.2833-(2-胺基嘧啶-5-基)-9-(1-((4-氟-2-(1-甲基-1H-1,2,3-三唑-4-基)苯基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮525.2843-(6-胺基-3-吡啶基)-9-[1-[4-氟-2-(1-甲基三唑-4-基)苯胺基]乙基]-4,7-二甲基-咪唑并[1,5-a]喹唑啉-5-酮524.2實例85.3-(1-乙醯基六氫吡啶-4-基)-9-(1-(6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮步驟1：3-(1-乙醯基六氫吡啶-4-基)-9-(1-溴乙基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮The following compounds in Table 7 were similarly prepared according to the procedures described for Example 81 using appropriate intermediates.Table 7.Instance NumberChemical namestructureLCMSm/z (M+H)⁺82 9-(1-((4-fluoro-2-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)ethyl)-4,7-dimethyl-3-(1-methyl-1H-pyrazol-5-yl)imidazo[1,5-a]quinazolin-5(4H)-one 512.283 3-(2-aminopyrimidin-5-yl)-9-(1-((4-fluoro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one 525.284 3-(6-amino-3-pyridyl)-9-[1-[4-fluoro-2-(1-methyltriazol-4-yl)anilino]ethyl]-4,7-dimethyl-imidazo[1,5-a]quinazolin-5-one 524.2Example 85.3-(1-acetylhexahydropyridin-4-yl)-9-(1-(6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-oneStep 1: 3-(1-acetylhexahydropyridin-4-yl)-9-(1-bromoethyl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one

使用與實例20中所闡述類似之程序，在步驟7中用NaBH₄替代NaBD₄來製備標題化合物。LCMS C₂₁H₂₃D₃BrN₄O₂(M+H)⁺：m/z計算值= 448.1；實驗值：448.1；步驟2：3-(1-乙醯基六氫吡啶-4-基)-9-(1-(6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)乙基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮The title compound was prepared using a procedure similar to that described inExample 20 , substituting NaBH₄ for NaBD₄ in step 7. LCMS C₂₁ H₂₃ D₃ BrN₄ O₂ (M+H)⁺ : m/z calcd = 448.1; found: 448.1;Step 2: 3-(1-acetylhexahydropyridin-4-yl)-9-(1-(6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethyl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one

在室溫下向3-(1-乙醯基六氫吡啶-4-基)-9-(1-溴乙基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮(43 mg, 0.10 mmol)於DMF (0.1 mL)中之溶液中添加6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪(24 mg, 0.14 mmol)。將所得混合物在80℃下加熱4小時。完成後，使混合物冷卻至室溫。用MeOH稀釋粗製材料，且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₈H₂₉D₃ClN₆O₃(M+H)⁺m/z計算值= 538.2；實驗值538.2。實例86.9-(1-(6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)乙基)-3-(1-(2-羥基乙醯基)六氫吡啶-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮步驟1：9-(1-(6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)乙基)-4,7-二甲基-3-(六氫吡啶-4-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮To a solution of 3-(1-acetylhexahydropyridin-4-yl)-9-(1-bromoethyl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one (43 mg, 0.10 mmol) in DMF (0.1 mL) was added 6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (24 mg, 0.14 mmol) at room temperature. The resulting mixture was heated at 80°C for 4 hours. Upon completion, the mixture was cooled to room temperature. The crude material was diluted with MeOH and purified by preparative HPLC (Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate:₆₀ mL/min). The_eluted fractions were collected and lyophilized to provide the desired product as_a white solid as its TFA salt. LCMS m/z calculated for_{C₂₈H₂₆D₃ClN₆O₃} (M+H)_⁺⁼ 538.2; found 538.2.Example 86.9-(1-(6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethyl)-3-(1-(2-hydroxyacetyl)hexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-oneStep 1: 9-(1-(6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethyl)-4,7-dimethyl-3-(hexahydropyridin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one

使用與實例67中所闡述類似之程序，在步驟5中用6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪替代6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-胺來製備標題化合物。LCMS C₂₆H₃₀ClN₆O₂(M+H)⁺：m/z計算值= 493.2；實驗值：493.2；步驟2：9-(1-(6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)乙基)-3-(1-(2-羥基乙醯基)六氫吡啶-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮The title compound was prepared using a procedure analogous to that described inExample 67 , substituting 6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine for 6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-amine in step 5. LCMS C₂₆ H₃₀ ClN₆ O₂ (M+H)⁺ : m/z calcd = 493.2; Found: 493.2;Step 2: 9-(1-(6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethyl)-3-(1-(2-hydroxyacetyl)hexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one

在0℃下向9-(1-(6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)乙基)-4,7-二甲基-3-(六氫吡啶-4-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮(40 mg, 0.08 mmol)於DMF中之溶液中添加HATU (40.1 mg, 0.11 mmol)、N-乙基-N-異丙基-丙-2-胺(141 uL, 0.81 mmol)及2-羥基乙酸(6.2 mg, 0.08 mmol)。將所得混合物在室溫下攪拌30 min，接著用MeOH稀釋反應混合物且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₈H₃₂ClN₆O₄(M+H)⁺m/z計算值= 551.2；實驗值551.2。實例87.3-(6-胺基吡啶-3-基)-9-((6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)甲基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮步驟1：9-((6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)甲基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸To a solution of 9-(1-(6-chloro-2,3-dihydro-1H -pyrido[2,3-b][1,4]oxazin-1-yl)ethyl)-4,7-dimethyl-3-(hexahydropyridin-4-yl)imidazo[1,5-a]quinazolin-5(4H )-one (40 mg, 0.08 mmol) in DMF at 0°C were added HATU (40.1 mg, 0.11 mmol),N -ethyl-N -isopropyl-propan-2-amine (141 uL, 0.81 mmol) and 2-hydroxyacetic acid (6.2 mg, 0.08 mmol). The resulting mixture was stirred at room temperature for 30 min, then diluted with MeOH and purified by preparative HPLC (Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The_{eluted fractions were collected and lyophilized to provide the desired product as a white solid (TFA salt). LCMS m/z calculated for C₂₈H₃₂ClN₆O₄(M+} H)^⁺ = 551.2; found 551.2.Example 87.3-(6-aminopyridin-3-yl)-9-((6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-oneStep 1: 9-((6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid

使用與實例1中所闡述類似之程序，在 步驟8中用9-甲醯基-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯(中間體13) 替代9-乙醯基-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯，在步驟10中用 6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪替代2-胺基-5-氟苯甲醯胺來製備標題化合物。LCMS C₂₁H₁₉ClN₅O₄(M+H)⁺m/z計算值= 440.1；實驗值440.1。步驟2：9-((6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)甲基)-3-碘-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮The title compound was prepared using a procedure similar to that described inExample 1 , substituting tert-butyl 9-formyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate (Intermediate 13) for tert-butyl 9-acetyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate in step 8, and substituting 6-chloro-_2,3 -dihydro-1H-pyrido[2,3-b][1,4]oxazine for₂ -amino-5-_{fluorobenzamide} in step 10. LCMS Calcd. for_{C₂₁H₁₆ClN₅O₄} (M+H)^⁺ ; Found.Step 2: 9-((6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-3-iodo-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one

使用與實例8中所闡述類似之程序，在步驟7中用9-((6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)甲基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸替代9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸來製備標題化合物。LCMS C₂₀H₁₈ClIN₅O₂(M+H)⁺m/z計算值= 522.0；實驗值522.0。步驟3：3-(6-胺基吡啶-3-基)-9-((6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)甲基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮The title compound was prepared using a procedure analogous to that described in Example8 , substituting 9-((6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid for 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]_quinazoline -3_- carboxylic acid in step 7. LCMS_Calcd . for_C20H18C1N5O2 (M+H)⁺ m/z = 522.0; Found 522.0.Step 3: 3-(6-aminopyridin-3-yl)-9-((6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one

在室溫下向9-((6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)甲基)-3-碘-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮(11 mg , 0.02 mmol)於二噁烷(0.8 mL)、水(0.2 mL)中之混合物中添加磷酸鉀(13 mg, 0.06 mmol)、Pd(PPh₃)₄(5 mg , 0.001 mmol)及(6-胺基-3-吡啶基)硼酸(4 mg, 0.03 mmol)。藉由三次真空-氮氣循環使所得混合物去氧。將混合物在80℃下加熱1小時，之後用MeOH稀釋且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₅H₂₃ClN₇O₂(M+H)⁺m/z計算值= 488.2；實驗值488.2。實例88至90.To a mixture of 9-((6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-3-iodo-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (11 mg, 0.02 mmol) in dioxane (0.8 mL) and water (0.2 mL) was added potassium phosphate (13 mg, 0.06 mmol), Pd(PPh₃ )₄ (5 mg, 0.001 mmol), and (6-amino-3-pyridyl)boronic acid (4 mg, 0.03 mmol) at room temperature. The resulting mixture was deoxygenated by three vacuum-nitrogen cycles. The mixture was heated at 80°C for 1 hour, then diluted with MeOH and purified by preparative HPLC (Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The eluted fractions were collected and lyophilized to provide the desired product as_{awhite solid as its TFA salt. LCMS m/z calculated for C₂₅H₂₃ClN₁₂O₂(M} +H)^⁺ = 488.2; found 488.2.Examples 88 to 90.

表8中之以下化合物係根據針對實例87所闡述之程序，使用適當中間體類似地製備。表8.實例編號化學名稱結構LCMSm/z (M+H)⁺883-(2-胺基嘧啶-5-基)-9-((6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)甲基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮489.2899-((6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)甲基)-4,7-二甲基-3-(1-甲基-1H-吡唑-5-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮476.2909-((6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)甲基)-3-(2-(羥基甲基)嘧啶-5-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮504.2實例91. 9-(1-((6-氯-2-((3-氟氮雜環丁-1-基)甲基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺步驟1：6-氯-2-乙烯基吡啶-3-胺The following compounds in Table 8 were similarly prepared according to the procedures described for Example 87 using appropriate intermediates.Table 8.Instance NumberChemical namestructureLCMSm/z (M+H)⁺88 3-(2-aminopyrimidin-5-yl)-9-((6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one 489.289 9-((6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-4,7-dimethyl-3-(1-methyl-1H-pyrazol-5-yl)imidazo[1,5-a]quinazolin-5(4H)-one 476.290 9-((6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-3-(2-(hydroxymethyl)pyrimidin-5-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one 504.2Example 91. 9-(1-((6-chloro-2-((3-fluoroazidocyclobutan-1-yl)methyl)pyridin-3-yl)amino)ethyl)-N,N ,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamideStep 1: 6-chloro-2-vinylpyridin-3-amine

在室溫下向四氫呋喃與水之5:1混合物(120 mL)中添加2-溴-6-氯-吡啶-3-胺(5.00 g, 24.10 mmol)、四(三苯基膦)鈀(0) (2.79 g, 2.41 mmol)、乙烯基三氟硼酸鉀(9.69 g, 72.30 mmol)及碳酸鉀(9.99 g, 72.30 mmol)。將所得混合物用氮氣吹掃5分鐘。接著將混合物在80℃下加熱8小時。反應完成後，使反應混合物冷卻至室溫。在減壓下去除溶劑，用乙酸乙酯稀釋殘餘物，用水洗滌兩次。接著使有機層經硫酸鈉乾燥。利用矽膠層析，用含0-50%乙酸乙酯之二氯甲烷溶析純化粗產物，得到期望產物(3.16 g, 84.8%)。LCMS C₇H₈ClN₂(M+H)⁺m/z計算值= 155.0；實驗值155.0。步驟2：9-(1-((6-氯-2-乙烯基吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺To a 5:1 mixture of tetrahydrofuran and water (120 mL) were added 2-bromo-6-chloro-pyridin-3-amine (5.00 g, 24.10 mmol), tetrakis(triphenylphosphine)palladium(0) (2.79 g, 2.41 mmol), vinyl potassium trifluoroborate (9.69 g, 72.30 mmol), and potassium carbonate (9.99 g, 72.30 mmol) at room temperature. The resulting mixture was purged with nitrogen for 5 minutes. The mixture was then heated at 80°C for 8 hours. After the reaction was complete, the reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure, the residue was diluted with ethyl acetate, and washed twice with water. The organic layer was then dried over sodium sulfate. The crude product was purified by silica gel chromatography using 0-50%_ethyl acetate in dichloromethane to give_the desired product (3.16 g, 84.8%). LCMS_C7H8ClN2 (M+H)⁺ m/z calcd = 155.0; found 155.0.Step 2:9-(1-((6-chloro-2-vinylpyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide

使用與實例48中所闡述類似之程序，在步驟2中用6-氯-2-乙烯基吡啶-3-胺替代3-胺基-6-氯吡啶醯胺來製備標題化合物。LCMS C₂₄H₂₆ClN₆O₂(M+H)+ m/z計算值= 465.2；實驗值465.2。步驟3：9-(1-((6-氯-2-乙烯基吡啶-3-基)(4-甲氧基苄基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺The title compound was prepared using a procedure similar to that described in Example 48, substituting 6-chloro-2-vinylpyridin-3-amine for 3-amino-6-chloropyridinamide in Step 2. LCMS C₂₄ H₂₆ ClN₆ O₂ (M+H)+ m/z calcd = 465.2; found 465.2.Step 3:9-(1-((6-chloro-2-vinylpyridin-3-yl)(4-methoxybenzyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide

在0℃下向9-(1-((6-氯-2-乙烯基吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺(326 mg, 0.70 mmol)於無水DMF中之溶液中添加氫化鈉(56 mg, 1.40 mmol)。將混合物攪拌30 min後，在相同溫度下添加1-(溴甲基)-4-甲氧基-苯(202 μL, 1.40 mmol)。將所得混合物在室溫下攪拌1 h。完成後，用含10% MeOH之DCM稀釋反應混合物，用水(3×)洗滌。將有機層合併，且在減壓下去除溶劑。利用矽膠層析純化殘餘物，得到呈黃色固體之期望產物(310 mg, 75.5%)。LCMS C₃₂H₃₄ClN₆O₃(M+H)⁺m/z計算值= 585.2；實驗值585.2。步驟4：9-(1-((6-氯-2-甲醯基吡啶-3-基)(4-甲氧基苄基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺To a solution of 9-(1-((6-chloro-2-vinylpyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide (326 mg, 0.70 mmol) in anhydrous DMF was added sodium hydroxide (56 mg, 1.40 mmol) at 0°C. After the mixture was stirred for 30 min, 1-(bromomethyl)-4-methoxy-benzene (202 μL, 1.40 mmol) was added at the same temperature. The resulting mixture was stirred at room temperature for 1 h. Upon completion, the reaction mixture was diluted with 10% MeOH in DCM and washed with water (3×). The organic layers were combined and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to give the desired product as a yellow solid (310 mg, 75.5%). LCMS C₃₂ H₃₄ ClN₆ O₃ (M+H)⁺ m/z calcd = 585.2; found 585.2.Step 4:9-(1-((6-chloro-2-formylpyridin-3-yl)(4-methoxybenzyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide

在室溫下向四氫呋喃與水之5:1溶液中相繼添加9-(1-((6-氯-2-乙烯基吡啶-3-基)(4-甲氧基苄基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺(540 mg, 0.92 mmol)、OsO₄(4%水溶液， 586 μL, 0.09 mmol)、2,6-二甲基吡啶(213 μL, 1.85 mmol)及過碘酸鈉(987 mg, 4.61 mmol)。將所得混合物在45℃下加熱4 h。反應完成後，使混合物冷卻至室溫。用二氯甲烷稀釋混合物。將有機層用水洗滌兩次，經硫酸鈉乾燥。在減壓下去除溶劑。殘餘物直接用於下一步驟中。LCMS C₃₁H₃₂ClN₆O₄(M+H)⁺m/z計算值= 587.2；實驗值587.2。步驟5：9-(1-((6-氯-2-((3-氟氮雜環丁-1-基)甲基)吡啶-3-基)(4-甲氧基苄基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺To a 5:1 solution of tetrahydrofuran and water were added 9-(1-((6-chloro-2-vinylpyridin-3-yl)(4-methoxybenzyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide (540 mg, 0.92 mmol),_OsO₄ (4% aqueous solution, 586 μL, 0.09 mmol), 2,6-lutidine (213 μL, 1.85 mmol), and sodium periodate (987 mg, 4.61 mmol) at room temperature. The resulting mixture was heated at 45°C for 4 h. After the reaction was complete, the mixture was cooled to room temperature. The mixture was diluted with dichloromethane. The organic layer was washed twice with water and dried over sodium sulfate. The solvent was removed under reduced pressure. The residue was used directly in the next step. LCMS C₃₁ H₃₂ ClN₆ O₄ (M+H)⁺ m/z calcd = 587.2; found 587.2.Step 5:9-(1-((6-chloro-2-((3-fluoroazidocyclobutan-1-yl)methyl)pyridin-3-yl)(4-methoxybenzyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide

在室溫下向9-(1-((6-氯-2-甲醯基吡啶-3-基)(4-甲氧基苄基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺(50 mg, 85.17 umol)於DCM (2 mL)中之溶液中相繼添加3-氟氮雜環丁烷鹽酸鹽(12 mg, 0.11 mmol)及三乙醯氧基硼氫化鈉(36 mg , 0.17 mmol)。將所得混合物攪拌1 h。完成後，用10% MeOH/DCM稀釋反應物，用水洗滌。分離有機層，經硫酸鈉乾燥且在減壓下乾燥。殘餘物直接用於下一步驟中。LCMS C₃₄H₃₈ClFN₇O₃(M+H)⁺m/z計算值= 646.3；實驗值646.3。步驟6：9-(1-((6-氯-2-((3-氟氮雜環丁-1-基)甲基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺To a solution of 9-(1-((6-chloro-2-formylpyridin-3-yl)(4-methoxybenzyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide (50 mg, 85.17 umol) in DCM (2 mL) was added 3-fluoroazidocyclobutane hydrochloride (12 mg, 0.11 mmol) and sodium triacetoxyborohydride (36 mg, 0.17 mmol) at room temperature. The resulting mixture was stirred for 1 h. Upon completion, the reaction was diluted with 10% MeOH/DCM and washed with water. The organic layer was separated, dried over sodium sulfate, and dried under reduced pressure. The residue was used directly in the next step. LCMS C₃₄ H₃₈ ClFN₇ O₃ (M+H)⁺ m/z calcd = 646.3; found 646.3.Step 6:9-(1-((6-chloro-2-((3-fluoroazidocyclobutan-1-yl)methyl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide

在室溫下用三氟乙酸處理2打蘭小瓶中之9-(1-((6-氯-2-((3-氟氮雜環丁-1-基)甲基)吡啶-3-基)(4-甲氧基苄基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺(10 mg, 0.015 mmol)。攪拌2 h後，用甲醇稀釋反應混合物，藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₆H₃₀ClFN₇O₂(M+H)⁺m/z計算值= 526.2；實驗值526.2。實例92. 9-(1-((6-氯-2-((3-氟氮雜環丁-1-基)甲基)吡啶-3-基)胺基)乙基)-N-(2-羥基乙基)-N,4,7-三甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺步驟1：9-(1-((6-氯-2-((3-氟氮雜環丁-1-基)甲基)吡啶-3-基)(4-甲氧基苄基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯9-(1-((6-chloro-2-((3-fluoroazinocyclobutan-1-yl)methyl)pyridin-3-yl)(4-methoxybenzyl)amino)ethyl)-N,N ,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide (10 mg, 0.015 mmol) in a 2-dram vial was treated with trifluoroacetic acid at room temperature. After stirring for 2 h, the reaction mixture was diluted with methanol and purified by preparative HPLC (Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The eluted fractions were collected and lyophilized to provide the desired product as a white solid as its TFA salt. LCMS C₂₆ H₃₀ ClFN₇ O₂ (M+H)⁺ m/z calcd = 526.2; found 526.2.Example 92. 9-(1-((6-chloro-2-((3-fluoroazidocyclobutan-1-yl)methyl)pyridin-3-yl)amino)ethyl)-N-(2-hydroxyethyl)-N,4,7-trimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamideStep 1: 9-(1-((6-chloro-2-((3-fluoroazolocyclobutan-1-yl)methyl)pyridin-3-yl)(4-methoxybenzyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid tert-butyl ester

使用與實例91中所闡述類似之程序，在步驟2中用9-(1-溴乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯(實例1，步驟9)替代9-(1-溴乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺來製備標題化合物。LCMS C₃₆H₄₁ClFN₆O₄(M+H)⁺m/z計算值= 675.3；實驗值675.3。步驟2：9-(1-((6-氯-2-((3-氟氮雜環丁-1-基)甲基)吡啶-3-基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸The title compound was prepared using a procedure similar to that described in Example 91, substituting tert-butyl 9-(1-bromoethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate (Example 1, Step 9) for 9-(1-bromoethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[_1,5 -a]quinazoline-3-_carboxamide in Step 2. LCMS_Calcd . for_C36H41ClF6O4 (M+H)⁺ m/z = 675.3; Found 675.3.Step 2: 9-(1-((6-chloro-2-((3-fluoroazolocyclobutan-1-yl)methyl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid

在室溫下用TFA (1.5 mL)處理9-(1-((6-氯-2-((3-氟氮雜環丁-1-基)甲基)吡啶-3-基)(4-甲氧基苄基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯(530 mg, 0.78 mmol)。將所得混合物在室溫下攪拌4 h，接著在減壓下去除溶劑。使殘餘物與甲苯共沸3次。所得粗製物直接用於下一步驟中。LCMS C₂₄H₂₅ClFN₆O₃(M+H)⁺m/z計算值= 499.2；實驗值499.2。步驟3：9-(1-((6-氯-2-((3-氟氮雜環丁-1-基)甲基)吡啶-3-基)胺基)乙基)-N-(2-羥基乙基)-N,4,7-三甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺tert-Butyl 9-(1-((6-chloro-2-((3-fluoroazinocyclobutan-1-yl)methyl)pyridin-3-yl)(4-methoxybenzyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate (530 mg, 0.78 mmol) was treated with TFA (1.5 mL) at room temperature. The resulting mixture was stirred at room temperature for 4 h, followed by removal of the solvent under reduced_{pressure. The residue was azeotroped with toluene three times. The crude product was used directly in the next step. LCMS m/z calculated for C24H25ClFN6O3(M} +H)₊⁼ 499.2; found 499.2.Step 3: 9-(1-((6-chloro-2-((3-fluoroazolocyclobutan-1-yl)methyl)pyridin-3-yl)amino)ethyl)-N-(2-hydroxyethyl)-N,4,7-trimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide

在室溫下向9-(1-((6-氯-2-((3-氟氮雜環丁-1-基)甲基)吡啶-3-基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸(40 mg, 0.08 mmol)於DMF (0.8 mL)中之溶液中添加HATU (39 mg, 0.10 mmol)、N-乙基-N-異丙基-丙-2-胺(139 μL, 0.80 mmol)及2-(甲基胺基)乙醇(8 μL, 0.10 mmol)。將所得混合物攪拌1小時，之後用甲醇稀釋且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供期望產物TFA鹽。LCMS C₂₇H₃₂ClFN₇O₃(M+H)⁺m/z計算值= 556.2；實驗值556.2。實例93. ((6-氯-3-((1-(3-(二甲基胺甲醯基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)吡啶-2-基)甲基)胺基甲酸甲酯步驟1：9-(1-((6-氯-2-(((4-甲氧基苄基)胺基)甲基)吡啶-3-基)(4-甲氧基苄基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺To a solution of 9-(1-((6-chloro-2-((3-fluoroazidocyclobutan-1-yl)methyl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid (40 mg, 0.08 mmol) in DMF (0.8 mL) at room temperature were added HATU (39 mg, 0.10 mmol),N -ethyl-N -isopropyl-propan-2-amine (139 μL, 0.80 mmol) and 2-(methylamino)ethanol (8 μL, 0.10 mmol). The resulting mixture was stirred for 1 hour, then diluted with methanol and purified by preparative HPLC (Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The_eluted fractions were collected and lyophilized to provide_the desired product as the TFA salt. LCMS m/z calculated for_{C₂ₐH₃₂ClFNₐO₃} (M+H)_⁺⁼ 556.2; found 556.2.Example 93. Methyl ((6-chloro-3-((1-(3-(dimethylaminoformyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)pyridin-2-yl)methyl)carbamateStep1:9-(1-((6-chloro-2-(((4-methoxybenzyl)amino)methyl)pyridin-3-yl)(4-methoxybenzyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide

使用與實例91中所闡述類似之程序，在步驟5中用4-甲氧基苄胺替代3-氟氮雜環丁烷鹽酸鹽來製備標題化合物。LCMS C₃₉H₄₃ClN₇O₄(M+H)⁺m/z計算值= 708.3；實驗值708.3。步驟2：((6-氯-3-((1-(3-(二甲基胺甲醯基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)(4-甲氧基苄基)胺基)吡啶-2-基)甲基)(4-甲氧基苄基)胺基甲酸甲酯The title compound was prepared using a procedure analogous to that described in Example 91, substituting 4-methoxybenzylamine for 3-fluoroazidocyclobutane hydrochloride in Step 5. LCMS C₃₉ H₄₃ ClN₇ O₄ (M+H)⁺ m/z calcd = 708.3; found 708.3.Step2:Methyl ((6-chloro-3-((1-(3-(dimethylaminoformyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)(4-methoxybenzyl)amino)pyridin-2-yl)methyl)(4-methoxybenzyl)carbamate

在0℃下向9-(1-((6-氯-2-(((4-甲氧基苄基)胺基)甲基)吡啶-3-基)(4-甲氧基苄基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺(30 mg, 0.04 mmol)於二氯甲烷(1 mL)中之溶液中逐滴添加氯甲酸甲酯(4 μL, 0.05 mmol)。攪拌30 min後，在減壓下濃縮所得混合物。殘餘物直接用於下一步驟中。LCMS C₄₁H₄₅ClN₇O₆(M+H)⁺m/z計算值= 766.3；實驗值766.3。步驟3：((6-氯-3-((1-(3-(二甲基胺甲醯基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)吡啶-2-基)甲基)胺基甲酸甲酯To a solution of 9-(1-((6-chloro-2-(((4-methoxybenzyl)amino)methyl)pyridin-3-yl)(4-methoxybenzyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide (30 mg, 0.04 mmol) in dichloromethane (1 mL) at 0°_{C was added methyl chloroformate (4 μL, 0.05 mmol) dropwise. After stirring for 30 min, the resulting mixture was concentrated under reduced pressure. The residue was used directly in the next step. LCMS m/z calcd for C₄₁₁H₄₅ClN₁₁O₆(M} +H)_⁺⁼ 766.3; found 766.3.Step 3: Methyl ((6-chloro-3-((1-(3-(dimethylaminoformyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)pyridin-2-yl)methyl)carbamate

在0℃下向來自上一步之((6-氯-3-((1-(3-(二甲基胺甲醯基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)(4-甲氧基苄基)胺基)吡啶-2-基)甲基)(4-甲氧基苄基)胺基甲酸甲酯粗製物中逐滴添加三氟乙酸與三氟甲磺酸之5:1混合物。完成後，用甲醇稀釋混合物，藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供期望產物TFA鹽。LCMS C₂₅H₂₉ClN₇O₄(M+H)⁺m/z計算值= 526.2；實驗值526.2。實例94. (6-氯-3-(((3-(二甲基胺甲醯基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)甲基)胺基)吡啶-2-基)胺基甲酸甲酯步驟1：9-(溴甲基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺To the crude product of methyl ((6-chloro-3-((1-(3-(dimethylaminoformyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)(4-methoxybenzyl)amino)pyridin-2-yl)methyl)(4-methoxybenzyl)carbamate from the previous step was added dropwise a 5:1 mixture of trifluoroacetic acid and trifluoromethanesulfonic acid at 0°C. Upon completion, the mixture was diluted with methanol and purified by preparative HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min); the eluted fractions were collected and lyophilized to provide the desired product as a TFA salt. LCMS_C25H29ClN7O4 (M+H)⁺ m/_z calcd = 526.2; found 526.2. Example 94._Methyl (6-chloro-3-(((3-(dimethylaminoformyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-_a]quinazolin-9-yl)methyl)amino)pyridin-2-yl)carbamateStep 1: 9-(Bromomethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide

使用與實例1中所闡述類似之程序，在 步驟8中用9-甲醯基-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺(中間體14) 替代9-乙醯基-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯來製備標題化合物。LCMS C₁₆H₁₈BrN₄O₂(M+H)⁺m/z計算值= 377.1；實驗值377.1。步驟2：(6-氯-3-(((3-(二甲基胺甲醯基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)甲基)胺基)吡啶-2-基)胺基甲酸甲酯The title compound was prepared using a procedure analogous to that described inExample 1 , substituting 9-formyl-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide (Intermediate 14) for tert-butyl 9-acetyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]_quinazoline -3_- carboxylate in Step 8. LCMS_Calcd . for_Ci6H18BrN4O2 (M+H)⁺ m/z = 377.1; Found 377.1.Step 2: Methyl (6-chloro-3-(((3-(dimethylaminoformyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)methyl)amino)pyridin-2-yl)carbamate

在室溫下向9-(溴甲基)-N,N,4,7-四甲基-5-側氧基-咪唑并[1,5-a]喹唑啉-3-甲醯胺(15 mg, 0.04 mmol)於DMF (0.1 mL)中之溶液中添加N-(3-胺基-6-氯-2-吡啶基)胺基甲酸甲酯(中間體5) (10 mg, 0.05 mmol)。將所得混合物在80℃下加熱1 h。接著用甲醇稀釋混合物，藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供期望產物TFA鹽。LCMS C₂₃H₂₅ClN₇O₄(M+H)⁺m/z計算值= 498.2；實驗值498.2。實例95至96.To a solution of 9-(bromomethyl)-N,N,4,7-tetramethyl-5-oxo-imidazo[1,5-a]quinazoline-3-carboxamide (15 mg, 0.04 mmol) in DMF (0.1 mL) was added methyl N-(3-amino-6-chloro-2-pyridinyl)carbamate (Intermediate 5) (10 mg, 0.05 mmol) at room temperature. The resulting mixture was heated at 80°C for 1 h. The mixture was then diluted with methanol and purified by preparative HPLC (column: Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The eluted fractions were collected and lyophilized to provide the desired product as its TFA salt. LCMS Calcd. for C₂₃ H₂₅ ClN₇ O₄ (M+H)⁺ m/z = 498.2; Found 498.2.Examples 95 to 96.

表9中之以下化合物係根據針對實例94所闡述之程序，使用適當中間體類似地製備。表9.實例編號化學名稱結構LCMSm/z (M+H)⁺959-[(6-氯-2,3-二氫吡啶并[2,3-b][1,4]噁嗪-1-基)甲基]-N,N,4,7-四甲基-5-側氧基-咪唑并[1,5-a]喹唑啉-3-甲醯胺467.2969-[(6-氯-2,3-二氫吡啶并[2,3-b][1,4]噁嗪-1-基)甲基]-4,7-二甲基-5-側氧基-N,N-雙(三氘代甲基)咪唑并[1,5-a]喹唑啉-3-甲醯胺473.2實例97.9-(1-((6-氯-2-(2-(1-甲基氮雜環丁-3-基)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺步驟1：3-(5-(6-氯-3-((1-(3-(二甲基胺甲醯基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)吡啶-2-基)-2H-四唑-2-基)氮雜環丁烷-1-甲酸第三丁酯The following compounds in Table 9 were similarly prepared according to the procedures described for Example 94 using appropriate intermediates.Table 9.Instance NumberChemical namestructureLCMSm/z (M+H)⁺95 9-[(6-chloro-2,3-dihydropyrido[2,3-b][1,4]oxazin-1-yl)methyl]-N ,N ,4,7-tetramethyl-5-oxo-imidazo[1,5-a]quinazoline-3-carboxamide 467.296 9-[(6-chloro-2,3-dihydropyrido[2,3-b][1,4]oxazin-1-yl)methyl]-4,7-dimethyl-5-oxo-N ,N -bis(trideuteriomethyl)imidazo[1,5-a]quinazoline-3-carboxamide 473.2Example 97.9-(1-((6-chloro-2-(2-(1-methylazinocyclobutan-3-yl)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamideStep 1: 3-(5-(6-chloro-3-((1-(3-(dimethylaminoformyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)pyridin-2-yl)-2H-tetrazol-2-yl)azinecyclobutane-1-carboxylic acid tert-butyl ester

使用與實例48中所闡述類似之程序，在步驟2中用3-(5-(3-胺基-6-氯吡啶-2-基)-2H-四唑-2-基)氮雜環丁烷-1-甲酸第三丁酯(中間體8)替代3-胺基-6-氯吡啶醯胺來製備標題化合物。在減壓下濃縮所得混合物。殘餘物直接用於下一步驟中。LCMS C₃₁H₃₇ClN₁₁O₄(M+H)⁺m/z計算值= 662.3；實驗值662.3。步驟2：9-(1-((2-(2-(氮雜環丁-3-基)-2H-四唑-5-基)-6-氯吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺The title compound was prepared using a procedure analogous to that described in Example 48, substituting tert-butyl 3-(5-(3-amino-6-chloropyridin-2-yl)-2H-tetrazol-2-yl)azepanocyclobutane-1-carboxylate (Intermediate 8) for 3-amino-6-chloropyridinamide in Step 2. The resulting mixture was concentrated under reduced pressure. The residue was used directly in the next step. LCMS m/z_{Calcd.forC₃₁H₃ClN₁₁O₄} (M+H)^⁺ = 662.3; Found 662.3.Step 2: 9-(1-((2-(2-(Azocyclobutan-3-yl)-2H-tetrazol-5-yl)-6-chloropyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide

在0℃下向來自上一步之3-(5-(6-氯-3-((1-(3-(二甲基胺甲醯基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)吡啶-2-基)-2H-四唑-2-基)氮雜環丁烷-1-甲酸第三丁酯粗製物中添加純三氟乙酸。攪拌20 min後，用甲醇稀釋混合物，藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供期望產物TFA鹽。LCMS C₂₆H₂₉ClN₁₁O₂(M+H)⁺m/z計算值= 562.2；實驗值562.2。步驟3：9-(1-((6-氯-2-(2-(1-甲基氮雜環丁-3-基)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺To the crude tert-butyl 3-(5-(6-chloro-3-((1-(3-(dimethylaminoformyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)pyridin-2-yl)-2H-tetrazol-2-yl)azinecyclobutane-1-carboxylate from the previous step was added neat trifluoroacetic acid at 0°C. After stirring for 20 minutes, the mixture was diluted with methanol and purified by preparative HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The eluted fractions were collected and lyophilized to provide the desired product as a TFA salt. LCMS C₂₆ H₂₉ ClN₁₁ O₂ (M+H)⁺ m/z calcd = 562.2; found 562.2.Step 3: 9-(1-((6-chloro-2-(2-(1-methylazinocyclobutan-3-yl)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide

在室溫下向9-(1-((2-(2-(氮雜環丁-3-基)-2H-四唑-5-基)-6-氯吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺TFA鹽 (10 mg, 0.018 mmol)於DCM (0.5 mL)中之溶液中相繼添加甲醛(37%水溶液) (10 uL)、DIEA (20 uL)及三乙醯氧基硼氫化鈉(12 mg , 0.06 mmol)。將所得混合物在室溫下攪拌1 h。接著用甲醇稀釋反應物，藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供期望產物TFA鹽。LCMS C₂₇H₃₁ClN₁₁O₂(M+H)⁺m/z計算值= 576.2；實驗值576.2。實例98至100.To a solution of 9-(1-((2-(2-(Azocyclobutan-3-yl)-2H-tetrazol-5-yl)-6-chloropyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide TFA salt (10 mg, 0.018 mmol) in DCM (0.5 mL) was added formaldehyde (37% aqueous solution) (10 uL), DIEA (20 uL), and sodium triacetoxyborohydride (12 mg, 0.06 mmol) sequentially at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction was then diluted with methanol and purified by preparative HPLC (Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate:_{60 mL/min). The eluted fractions were collected and lyophilized to provide the desired product as the TFA salt. LCMS calculated for C₂₇H₃ClN₁₁O₂(M+} H)^⁺ m/z = 576.2; found 576.2.Examples 98 to 100.

表10中之以下化合物係根據針對實例97所闡述之程序，使用適當中間體類似地製備。表10.實例編號化學名稱結構LCMSm/z (M+H)⁺989-(1-((6-氯-2-(2-(1-甲基六氫吡啶-4-基)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺604.3999-(1-((6-氯-2-(2-(1-甲基氮雜環丁-3-基)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺585.31009-(1-((6-氯-2-(2-(1-甲基六氫吡啶-4-基)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺613.3實例101.3-(2-胺基嘧啶-5-基)-9-((6-氯-3,4-二氫-1,5-萘啶-1(2H)-基)甲基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮The following compounds in Table 10 were similarly prepared according to the procedures described for Example 97 using appropriate intermediates.Table 10.Instance NumberChemical namestructureLCMSm/z (M+H)⁺98 9-(1-((6-chloro-2-(2-(1-methylhexahydropyridin-4-yl)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide 604.399 9-(1-((6-chloro-2-(2-(1-methylazinocyclobutan-3-yl)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-N,N,4-tris(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide 585.3100 9-(1-((6-chloro-2-(2-(1-methylhexahydropyridin-4-yl)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-N,N,4-tris(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide 613.3Example 101.3-(2-aminopyrimidin-5-yl)-9-((6-chloro-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)methyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one

使用與針對實例87所闡述類似之程序，在步驟1中用6-氯-1,2,3,4-四氫-1,5-萘啶(中間體10)替代6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪，且在步驟3中用5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)嘧啶-2-胺替代(6-胺基-3-吡啶基)硼酸來製備標題化合物。用MeOH稀釋粗產物，且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₅H₂₄ClN₈O (M+H)⁺m/z計算值= 487.2；實驗值487.2。實例102.9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-((3,3-二氟氮雜環丁-1-基)甲基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮步驟1：9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-碘-4,7 二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮The title compound was prepared using procedures analogous to those described for Example87 , substituting 6-chloro-1,2,3,4-tetrahydro-1,5-naphthyridine (Intermediate 10) for 6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine in step 1 and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolacyclopentan-2-yl)pyrimidin-2-amine for (6-amino-3-pyridyl)boronic acid in step 3. The crude product was diluted with MeOH and purified by preparative HPLC (Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate:₆₀ mL/min). The eluted fractions were collected and lyophilized to provide the desired product as_a white solid as its TFA salt. LCMS m/z calculated for_{C₂₅H₂₄ClN₈O} (M+H)^⁺ = 487.2; found 487.2.Example 102.9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-((3,3-difluoroazolocyclobutan-1-yl)methyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-oneStep 1: 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-iodo-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one

使用與針對實例8步驟7所闡述類似之程序來製備標題化合物。步驟2：9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)(4-甲氧基苄基)胺基)乙基)-3-碘-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮The title compound was prepared using a procedure similar to that described for Example 8, Step 7.Step 2: 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)(4-methoxybenzyl)amino)ethyl)-3-iodo-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one

在0℃下向9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-碘-4,7 二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮(150 mg, 0.26 mmol)於DMF (5 mL)中之溶液中添加氫化鈉(於礦物油中之60%分散液，20.7 mg, 0.52 mmol)。使所得溶液升溫至室溫並攪拌30 min。接著添加4-甲氧基苄基溴(74.4 uL, 0.52 mmol)，且將反應物攪拌4 h。接著用飽和NH₄Cl溶液淬滅混合物，且用EA (2×)萃取。將合併的有機物用飽和NaCl洗滌，且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。藉由矽膠管柱層析，用DCM及EA (0至95%)溶析純化殘餘物，提供呈白色固體之期望產物(85 mg, 47%)。LCMS C₂₉H₂₅D₃ClIN₉O₂(M+H)⁺m/z計算值= 699.1；實驗值699.1。步驟3：9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)(4-甲氧基苄基)胺基)乙基)-4,7-二甲基-3-乙烯基咪唑并[1,5-a]喹唑啉-5(4H)-酮To a solution of 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-iodo-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (150 mg, 0.26 mmol) in DMF (5 mL) was added sodium hydroxide (60% dispersion in mineral oil, 20.7 mg, 0.52 mmol) at 0°C. The resulting solution was allowed to warm to room temperature and stirred for 30 min. 4-Methoxybenzyl bromide (74.4 uL, 0.52 mmol) was then added, and the reaction was stirred for 4 h. The mixture was then quenched with saturated NH₄ Cl solution and extracted with EA (2×). The combined organics were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM and EA (0 to 95%) to_{provide the desired product (85 mg, 47%) as a white solid. LCMS m/z calculated for C29H25D3ClIN9O2(M+} H)₊⁼ 699.1; found 699.1.Step 3: 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)(4-methoxybenzyl)amino)ethyl)-4,7-dimethyl-3-vinylimidazo[1,5-a]quinazolin-5(4H)-one

向9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)(4-甲氧基苄基)胺基)乙基)-3-碘-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮(85 mg, 0.12 mmol)、雙(三苯基膦)二氯化鈀(II) (8.5 mg, 0.01 mmol)及三丁基(乙烯基)錫(46 uL, 0.16 mmol)之混合物中添加二噁烷(3 mL)。將所得混合物在氮氣氣氛下在100℃下攪拌8 h。冷卻至室溫後，接著用水淬滅混合物且用EA (2×)萃取。將合併的有機物用飽和NaCl洗滌，且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。藉由矽膠管柱層析，用DCM及EA (0至95%)溶析純化殘餘物，提供呈白色固體之期望產物(55 mg, 76%)。LCMS C₃₁H₂₈D₃ClN₉O₂(M+H)⁺m/z計算值= 599.2；實驗值599.2。步驟4：9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)(4-甲氧基苄基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醛To a mixture of 9-(1-((6-chloro-2-(2-(methyl-_d3 )-2H-tetrazol-5-yl)pyridin-3-yl)(4-methoxybenzyl)amino)ethyl)-3-iodo-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (85 mg, 0.12 mmol), bis(triphenylphosphine)palladium(II) dichloride (8.5 mg, 0.01 mmol), and tributyl(vinyl)tin (46 uL, 0.16 mmol) was added dioxane (3 mL). The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 8 h. After cooling to room temperature, the mixture was quenched with water and extracted with EA (2×). The combined organics were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM and EA (0 to 95%) to provide the desired product (55 mg, 76%) as a white solid. LCMS m/z calculated for C₃₁ H₂₈ D₃ ClN₉ O₂ (M+H)⁺ = 599.2; found 599.2.Step 4: 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)(4-methoxybenzyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carbaldehyde

在0℃下向9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)(4-甲氧基苄基)胺基)乙基)-4,7-二甲基-3-乙烯基咪唑并[1,5-a]喹唑啉-5(4H)-酮(55 mg, 0.09 mmol)於THF (4 mL)及水(1 mL)中之溶液中添加 2,6-二甲基吡啶(21.4 uL, 0.18 mmol)、四氧化鋨溶液(4 wt.%於H₂O中，29.2 uL, 0.0045 mmol)及過碘酸鈉(78.5 mg, 0.37 mmol)。使所得混合物升溫至室溫並攪拌4 h。接著用水淬滅混合物且用EA (2×)萃取。將合併的有機物用飽和NaCl洗滌，且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。藉由矽膠管柱層析，用DCM及EA (0至95%)溶析純化殘餘物，提供呈白色固體之期望產物(34 mg, 62%)。LCMS C₃₀H₂₆D₃ClN₉O₃(M+H)⁺m/z計算值= 601.2；實驗值601.2。步驟5：9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-((3,3-二氟氮雜環丁-1-基)甲基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮To a solution of 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)(4-methoxybenzyl)amino)ethyl)-4,7-dimethyl-3-vinylimidazo[1,5-a]quinazolin-5(4H)-one (55 mg, 0.09 mmol) in THF (4 mL) and water (1 mL) at 0° C. were added 2,6-lutidine (21.4 uL, 0.18 mmol), boron tetroxide solution (4 wt.% in H₂ O, 29.2 uL, 0.0045 mmol), and sodium periodate (78.5 mg, 0.37 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 4 h. The mixture was then quenched with water and extracted with EA (2×). The combined organics were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM and EA (0 to 95%) to provide the desired product (34 mg, 62%) as a white solid. LCMS m/z calculated for C₃₀ H₂₆ D₃ ClN₉ O₃ (M+H)⁺ = 601.2; found 601.2.Step 5: 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-((3,3-difluoroazolocyclobutan-1-yl)methyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one

向9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)(4-甲氧基苄基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醛(10 mg, 0.01 mmol)於DCM (1 mL)中之溶液中添加3,3-二氟氮雜環丁烷鹽酸鹽(4.3 mg, 0.03 mmol)。將反應物在室溫下攪拌2小時。接著添加三乙醯氧基硼氫化鈉(7.0 mmol, 0.03 mmol)，且將反應物攪拌30 min。接著添加三氟乙酸(2 mL)，且將反應物再攪拌2小時。用MeOH稀釋粗產物，且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₅H₂₃D₃ClF₂N₁₀O (M+H)⁺m/z計算值= 558.2；實驗值558.2。實例103：3-(2-胺基嘧啶-5-基)-9-(1-(6-氯-3,4-二氫-1,5-萘啶-1(2H)-基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮To a solution of 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)(4-methoxybenzyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carbaldehyde (10 mg, 0.01 mmol) in DCM (1 mL) was added 3,3-difluoroazanacyclobutane hydrochloride (4.3 mg, 0.03 mmol). The reaction was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (7.0 mmol, 0.03 mmol) was then added, and the reaction was stirred for 30 minutes. Trifluoroacetic acid (2 mL) was then added, and the reaction was stirred for an additional 2 hours. The crude product was diluted with MeOH and purified by preparative HPLC (column: Sunfire prep C18 column, 30*150 mm,₅ μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The eluted fractions were collected and lyophilized to provide the desired product as a white solid as its TFA salt._{LCMSC25H23D3ClF2N10O} (M+H)⁺ m/z calculated =_558.2 ; experimental value 558.2. Example 103: 3-(2-aminopyrimidin_-5-yl)-9-(1-(6-chloro-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one

使用與實例8中所闡述類似之程序，在步驟5中用6-氯-1,2,3,4-四氫-1,5-萘啶(中間體10)替代6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-胺來製備標題化合物。藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)純化粗產物；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₆H₂₆ClN₈O (M+H)⁺m/z計算值= 501.2；實驗值501.2。實例104至125.The title compound was prepared using a procedure similar to that described in Example 8, substituting 6-chloro-1,2,3,4-tetrahydro-1,5-naphthyridine (Intermediate 10) for 6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-amine in Step 5. The crude product was purified by preparative HPLC (Sunfire prep C18 column, 30 x 150 mm,_{5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The eluted fractions were collected and lyophilized to provide the desired product as a white solid as its TFA salt. LCMS m/z calculated for C₂₆H₂₆ClN₈O(M} +H)^⁺ = 501.2; found 501.2.Examples 104-125.

實例之所選外消旋化合物可藉由手性HPLC來拆分，得到表11中所提供之鏡像純化合物。表11.實例編號化學名稱結構LCMSm/z (M+H)⁺1043-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮(鏡像異構物1)543.21053-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮(鏡像異構物2)543.21063-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮(鏡像異構物1)547.21073-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮(鏡像異構物2)547.21083-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮(鏡像異構物1)544.21093-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮(鏡像異構物2)544.21103-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮(鏡像異構物1)547.21113-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮(鏡像異構物2)547.21123-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮(鏡像異構物1)546.21133-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮(鏡像異構物2)546.21143-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮(鏡像異構物1)549.21153-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮(鏡像異構物2)549.21163-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮(鏡像異構物1)550.21173-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮(鏡像異構物2)550.21189-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-N,N-雙(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺(鏡像異構物1)527.21199-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-N,N-雙(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺(鏡像異構物2)527.21209-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(2-(羥基甲基)嘧啶-5-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮(鏡像異構物1)561.21219-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(2-(羥基甲基)嘧啶-5-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮(鏡像異構物2)561.21229-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-3-(2-(羥基甲基)嘧啶-5-基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮(鏡像異構物1)565.21239-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-3-(2-(羥基甲基)嘧啶-5-基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮(鏡像異構物2)565.21242-((1-(3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)-5-氟苯甲醯胺(鏡像異構物1)491.21252-((1-(3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)-5-氟苯甲醯胺(鏡像異構物2)491.2實例126.3-(2-胺基嘧啶-5-基)-9-(1-(6-氯-3,4-二氫-1,5-萘啶-1(2H)-基)乙基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮步驟1：(5-(9-乙醯基-7-甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-基)嘧啶-2-基)胺基甲酸第三丁酯The selected racemic compounds of the examples can be resolved by chiral HPLC to give the mirror-pure compounds provided in Table 11.Table 11.Instance NumberChemical namestructureLCMSm/z (M+H)⁺104 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (mirror image isomer 1) 543.2105 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (mirror image isomer 2) 543.2106 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (mirror image isomer 1) 547.2107 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (mirror image isomer 2) 547.2108 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (mirror image isomer 1) 544.2109 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (mirror image isomer 2) 544.2110 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one (mirror image isomer 1) 547.2111 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one (mirror image isomer 2) 547.2112 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one (mirror image isomer 1) 546.2113 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one (mirror image isomer 2) 546.2114 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one (mirror image isomer 1) 549.2115 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one (mirror image isomer 2) 549.2116 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one (mirror isomer 1) 550.2117 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one (mirror image isomer 2) 550.2118 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide (mirror isomer 1) 527.2119 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide (mirror isomer 2) 527.2120 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(2-(hydroxymethyl)pyrimidin-5-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (mirror image isomer 1) 561.2121 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(2-(hydroxymethyl)pyrimidin-5-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (mirror image isomer 2) 561.2122 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-3-(2-(hydroxymethyl)pyrimidin-5-yl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one (mirror isomer 1) 565.2123 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-3-(2-(hydroxymethyl)pyrimidin-5-yl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one (mirror image isomer 2) 565.2124 2-((1-(3-(2-aminopyrimidin-5-yl)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-5-fluorobenzamide (mirror isomer 1) 491.2125 2-((1-(3-(2-aminopyrimidin-5-yl)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-5-fluorobenzamide (mirror isomer 2) 491.2Example 126.3-(2-aminopyrimidin-5-yl)-9-(1-(6-chloro-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethyl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-oneStep 1: tert-butyl (5-(9-acetyl-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)pyrimidin-2-yl)carbamate

將9-乙醯基-3-碘-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮(實例20，步驟3) (1.0 g, 2.6 mmol)、(5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)嘧啶-2-基)胺基甲酸第三丁酯(963 mg, 3 moml)、K₃PO₄(0.96 g, 4.5 mmol)及Xphos-PdG2 (204 mg, 0.26 mmol)於二噁烷(10 mL)及水(1 mL)中之混合物在氮氣氣氛下在100℃下加熱1 h。冷卻至室溫後，用水稀釋反應混合物且用乙酸乙酯(3×)萃取。將合併的有機物用水、飽和NaCl洗滌，且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。藉由矽膠管柱層析純化殘餘物，提供呈淺黃色固體之期望產物(891 mg, 76%)。LCMS C₂₃H₂₂D₃N₆O₄(M+H)⁺m/z計算值= 452.2；實驗值452.2。步驟2：(5-(9-(1-羥基乙基)-7-甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-基)嘧啶-2-基)胺基甲酸第三丁酯A mixture of 9-acetyl-3-iodo-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one (Example 20, Step 3) (1.0 g, 2.6 mmol), tert_- butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)pyrimidin-2-yl)carbamate (963 mg, 3 mmol),_K3PO4 (0.96 g, 4.5 mmol), and Xphos-PdG2 (204 mg, 0.26 mmol) in dioxane (10 mL) and water (1 mL) was heated at 100°C for 1 h under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organics were washed with water, saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by_silica gel column chromatography to provide the desired product (891 mg, 76%) as_alightyellow solid. LCMS_C23H22D3N6O4 (M+H)⁺ m/z calculated = 452.2; found 452.2.Step 2: tert-Butyl (5-(9-(1-hydroxyethyl)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)pyrimidin-2-yl)carbamate

將(5-(9-乙醯基-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-基)嘧啶-2-基)胺基甲酸第三丁酯(891 mg, 1.97 mmol)溶解於MeOH (10 mL)及DCM (10 mL)中，接著在氮氣下在0℃下分三次添加NaBH₄(94 mg, 2.4 mmol)。將所得混合物在相同溫度下攪拌10 min，之後用飽和NH₄Cl淬滅。用水稀釋混合物且用DCM萃取。將合併的有機物用飽和NaCl洗滌，且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。藉由矽膠管柱層析，用DCM及MeOH (0至4%)溶析純化殘餘物，提供呈淺棕色固體之期望產物(687 mg 77%)。LCMS C₂₃H₂₄D₃N₆O₄(M+H)⁺m/z計算值= 454.2；實驗值454.2。步驟3：(5-(9-(1-溴乙基)-7-甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-基)嘧啶-2-基)胺基甲酸第三丁酯tert-Butyl (5-(9-acetyl-7-methyl-4-(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)pyrimidin-2-yl)carbamate (891 mg, 1.97 mmol) was dissolved in MeOH (10 mL) and DCM (10 mL), followed by the addition of NaBH₄ (94 mg, 2.4 mmol) in three portions at 0° C. under nitrogen. The resulting mixture was stirred at the same temperature for 10 min, then quenched with saturated NH₄ Cl. The mixture was diluted with water and extracted with DCM. The combined organics were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure._The residue_was purified by silica gel column chromatography eluting with DCM_and MeOH (0-4%) to provide the desired product (687 mg, 77%) as a light brown solid. LCMS_C23H24D3N6O4 (M+H)⁺ m/z calcd = 454.2; found 454.2. Step 3: tert-_Butyl(5-(9-(1-bromoethyl)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)pyrimidin-2-yl)carbamate

在0℃下向(5-(9-(1-羥基乙基)-7-甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-基)嘧啶-2-基)胺基甲酸第三丁酯(687 mg, 1.51 mmol)於DCM (100 mL)中之混合物中添加吡啶(134 mg, 1.7 mmol)及 PBr₃(0.16 mL, 1.6 mmol)。使所得混合物升溫至室溫並攪拌2 h。接著用飽和NaHCO₃淬滅混合物且用DCM (2×)萃取。將合併的有機物用飽和NaCl洗滌，且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。殘餘物不經進一步純化即直接用於下一步驟中。步驟4：3-(2-胺基嘧啶-5-基)-9-(1-(6-氯-3,4-二氫-1,5-萘啶-1(2H)-基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮To a mixture of tert-butyl (5-(9-(1-hydroxyethyl)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)pyrimidin-2-yl)carbamate (687 mg, 1.51 mmol) in DCM (100 mL) at 0°C was added pyridine (134 mg, 1.7 mmol) and_PBr3 (0.16 mL, 1.6 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was then quenched with saturated_NaHCO3 and extracted with DCM (2×). The combined organics were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used directly in the next step without further purification.Step 4: 3-(2-aminopyrimidin-5-yl)-9-(1-(6-chloro-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one

向(5-(9-(1-溴乙基)-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-基)嘧啶-2-基)胺基甲酸第三丁酯(20 mg, 0.04 mmol)於DMF (0.5 mL)中之溶液中添加6-氯-1,2,3,4-四氫-1,5-萘啶(20 mg, 0.12 mmol)。將混合物在80℃下加熱2 h。冷卻至室溫後，去除溶劑，且將殘餘物溶解於TFA (0.5 mL)中。將所得混合物攪拌30 min，之後用MeOH稀釋且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₆H₂₃D₃ClN₈O (M+H)⁺m/z計算值= 504.2；實驗值504.3。實例127.3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-乙基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮To a solution of tert-butyl (5-(9-(1-bromoethyl)-7-methyl-4-(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)pyrimidin-2-yl)carbamate (20 mg, 0.04 mmol) in DMF (0.5 mL) was added 6-chloro-1,2,3,4-tetrahydro-1,5-naphthyridine (20 mg, 0.12 mmol). The mixture was heated at 80° C. for 2 h. After cooling to room temperature, the solvent was removed and the residue was dissolved in TFA (0.5 mL). The resulting mixture was stirred for 30 min, then diluted with MeOH and purified by preparative HPLC (Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The eluted fractions were collected and lyophilized to provide the desired product as_{a white solid (TFA salt). LCMS m/z calculated for C₂₆H₂₃D₃ClN₈O(M+} H)^⁺ = 504.2; found 504.3.Example 127.3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-ethyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one

步驟1：2-(6-氯-2-(2-乙基-2H-四唑-5-基)吡啶-3-基)異吲哚啉-1,3-二酮Step1:2-(6-chloro-2-(2-ethyl-2H-tetrazol-5-yl)pyridin-3-yl)isoindole-1,3-dione

向2-[6-氯-2-(1H-四唑-5-基)-3-吡啶基]異吲哚啉-1,3-二酮(實例8，步驟2) (1.55 g , 4.74 mmol)於10 mL DMF中之溶液中添加碘乙烷(0.57 mL, 7.12 mmol)及碳酸鉀(1.97 g, 14.2 mmol)。將反應混合物在室溫下攪拌2 h，接著用水稀釋且用EtOAc萃取。將合併的有機物用鹽水洗滌且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。藉由矽膠管柱層析，用己烷及乙酸乙酯溶析純化所得混合物，提供呈黃色固體之期望產物(0.46 g, 27.3%)及呈黃色固體之另一區域異構物(0.19 g, 11.3%)。LCMS C₁₆H₁₂ClN₆O₂(M+H)⁺m/z計算值= 355.1；實驗值355.1。步驟2：6-氯-2-(2-乙基-2H-四唑-5-基)吡啶-3-胺To a solution of 2-[6-chloro-2-(1H -tetrazol-5-yl)-3-pyridyl]isoindoline-1,3-dione (Example 8, Step 2) (1.55 g, 4.74 mmol) in 10 mL of DMF was added iodoethane (0.57 mL, 7.12 mmol) and potassium carbonate (1.97 g, 14.2 mmol). The reaction mixture was stirred at room temperature for 2 h, then diluted with water and extracted with EtOAc. The combined organics were washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography using hexane and ethyl acetate to provide the desired product (0.46 g, 27.3%) as a yellow solid and another regioisomer (0.19 g, 11.3%)_asa yellow solid. LCMS_C16H12ClN6O2 (M+H)⁺ m/z calculated = 355.1; found 355.1. Step 2:₆-Chloro-2-(2-ethyl-2H-tetrazol-5-yl)pyridin-3-amine

將2-(6-氯-2-(2-乙基-2H-四唑-5-基)吡啶-3-基)異吲哚啉-1,3-二酮(0.46 g, 1.30 mmol)於2 mL一水合肼中之混合物在45℃下攪拌2 h，接著使反應混合物冷卻至室溫且藉由過濾收集所得沈澱物並用水洗滌，得到呈白色固體之期望產物(160 mg, 55%)。LCMS C₈H₁₀ClN₆(M+H)⁺m/z計算值= 225.1；實驗值225.1。步驟3：3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-乙基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮A mixture of 2-(6-chloro-2-(2-ethyl-2H-tetrazol-5-yl)pyridin-3-yl)isoindoline-1,3-dione (0.46 g, 1.30 mmol) in 2 mL of hydrazine monohydrate was stirred at₄₅ °C for 2 h. The reaction mixture was then cooled to room temperature, and the resulting precipitate was collected by filtration_{and washed with water to give the desired product as a white solid (160 mg, 55%). LCMS calculated for C₈H₁₀ClN₆(} M+H)^⁺ m/z = 225.1; found 225.1.Step 3: 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-ethyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one

向(5-(9-(1-溴乙基)-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-基)嘧啶-2-基)胺基甲酸第三丁酯(實例126，步驟3：30 mg, 0.06 mmol)於DMF (0.5 mL)中之溶液中添加6-氯-2-(2-乙基-2H-四唑-5-基)吡啶-3-胺(17 mg, 0.08 mmol)。將混合物在80℃下加熱2 h。冷卻至室溫後，去除溶劑，且將殘餘物溶解於TFA (0.5 mL)中。將所得混合物攪拌30 min，之後用MeOH稀釋且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₆H₂₃D₃ClN₁₂O (M+H)⁺m/z計算值= 560.2；實驗值560.3。實例128至141.To a solution of tert-butyl (5-(9-(1-bromoethyl)-7-methyl-4-(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)pyrimidin-2-yl)carbamate (Example 126, Step 3: 30 mg, 0.06 mmol) in DMF (0.5 mL) was added 6-chloro-2-(2-ethyl-2H-tetrazol-5-yl)pyridin-3-amine (17 mg, 0.08 mmol). The mixture was heated at 80° C. for 2 h. After cooling to room temperature, the solvent was removed, and the residue was dissolved in TFA (0.5 mL). The resulting mixture was stirred for 30 min, then diluted with MeOH and purified by preparative HPLC (Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The eluted fractions were collected and lyophilized to provide the desired product as a_white solid_{as its TFA salt. LCMS calculated for C₂₆H₂₃D₃ClN₁₂O(} M+H)^⁺ m/z =_560.2 ; found 560.3.Examples 128 to 141.

表12中之以下化合物係如針對實例126所闡述，使用適當中間體類似地製備。表12.實例編號化學名稱結構LCMSm/z(M+H)⁺128(3-((1-(3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-6-氯吡啶-2-基)胺基甲酸甲酯537.21293-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1-甲基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮544.21303-(2-胺基嘧啶-5-基)-9-(1-((6-氟-2-(1-甲基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮528.21313-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1-環丙基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮570.21323-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1-(氧雜環丁-3-基)-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮586.21333-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(嘧啶-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮542.21343-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(4-羥基六氫吡啶-1-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮563.21353-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-嗎啉基吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮549.21363-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1,3-二甲基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮558.21373-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1,5-二甲基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮558.21383-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(5-甲基-1,3,4-噁二唑-2-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮546.21393-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1,3,4-噁二唑-2-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮532.21403-(3-((1-(3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-6-氯吡啶-2-基)-1,2,4-噁二唑-5(4H)-酮548.21413-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1-甲基-5-側氧基-4,5-二氫-1H-1,2,4-三唑-3-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮561.2實例142. (3-(((3-(2-胺基嘧啶-5-基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)甲基)胺基)-6-氯吡啶-2-基)胺基甲酸甲酯The following compounds in Table 12 were prepared similarly as described for Example 126 using appropriate intermediates.Table 12.Instance NumberChemical namestructureLCMSm/z(M+H)⁺128 Methyl (3-((1-(3-(2-aminopyrimidin-5-yl)-7-methyl-4-(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-6-chloropyridin-2-yl)carbamate 537.2129 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one 544.2130 3-(2-aminopyrimidin-5-yl)-9-(1-((6-fluoro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one 528.2131 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one 570.2132 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1-(oxacyclobutan-3-yl)-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one 586.2133 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(pyrimidin-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one 542.2134 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(4-hydroxyhexahydropyridin-1-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one 563.2135 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-oxolinylpyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one 549.2136 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one 558.2137 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one 558.2138 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one 546.2139 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1,3,4-oxadiazol-2-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one 532.2140 3-(3-((1-(3-(2-aminopyrimidin-5-yl)-7-methyl-4-(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-6-chloropyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one 548.2141 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one 561.2Example 142. Methyl (3-(((3-(2-aminopyrimidin-5-yl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)methyl)amino)-6-chloropyridin-2-yl)carbamate

使用與針對實例87所闡述類似之程序，在步驟1中用(3-胺基-6-氯吡啶-2-基)胺基甲酸甲酯(中間體5)替代6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪，且在步驟2中用5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)嘧啶-2-胺替代(6-胺基-3-吡啶基)硼酸來製備標題化合物。用MeOH稀釋粗產物，且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₄H₂₃ClN₉O₃(M+H)⁺m/z計算值= 520.2；實驗值520.2。實例143至149.The title compound was prepared using procedures analogous to those described for Example 87, substituting methyl (3-amino-6-chloropyridin-2-yl)carbamate (Intermediate 5) for 6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine in step 1 and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolacyclopentan-2-yl)pyrimidin-2-amine for (6-amino-3-pyridinyl)boronic acid in step 2. The crude product was diluted with MeOH and purified by preparative HPLC (Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate:₆₀ mL/min). The eluted fractions were collected and lyophilized to provide the desired product as_a white solid as its TFA salt. LCMS m/z calculated for_{C₂₄H₂₃ClN₆O₃} (M+H)^⁺ = 520.2; found 520.2.Examples 143 to 149_.

表13中之以下化合物係如針對實例8所闡述，使用適當中間體類似地製備。表13.實例編號化學名稱結構LCMSm/z(M+H)⁺1439-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(1H-吡唑-5-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮519.21443-(6-胺基-5-氯吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮579.21453-(6-胺基-5-甲基吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮559.21463-(6-胺基-5-甲氧基吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮575.21473-(2-胺基-4-甲氧基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮576.21489-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(2-甲基-2H-吡唑并[3,4-b]吡啶-5-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮584.21499-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(吡唑并[1,5-a]吡啶-6-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮569.2實例150.3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮The following compounds in Table 13 were prepared similarly as described for Example 8 using appropriate intermediates.Table 13.Instance NumberChemical namestructureLCMSm/z(M+H)⁺143 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1H-pyrazol-5-yl)imidazo[1,5-a]quinazolin-5(4H)-one 519.2144 3-(6-amino-5-chloropyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one 579.2145 3-(6-amino-5-methylpyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one 559.2146 3-(6-amino-5-methoxypyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one 575.2147 3-(2-amino-4-methoxypyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one 576.2148 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinazolin-5(4H)-one 584.2149 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(pyrazolo[1,5-a]pyridin-6-yl)imidazo[1,5-a]quinazolin-5(4H)-one 569.2Example 150.3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one

使用與針對實例8所闡述類似之程序，在步驟5中用6-氯-2-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-3-胺(中間體27)替代6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-胺來製備標題化合物。用MeOH稀釋最終粗產物，且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₆H₂₅ClN₁₁O (M+H)⁺m/z計算值= 542.2；實驗值542.2。實例151.3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-乙基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮The title compound was prepared using a procedure similar to that described for Example 8, substituting 6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-amine (Intermediate 27) for 6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-amine in Step 5. The final crude product was diluted with MeOH and purified by preparative HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min); the eluted fractions were collected and lyophilized to provide the desired product as a white solid as its TFA salt. LCMS C₂₆ H₂₅ ClN₁₁ O (M+H)⁺ m/z calcd = 542.2; found 542.2.Example 151.3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-ethyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one

使用與針對實例8所闡述類似之程序，在步驟5中用6-氯-2-(2-乙基-2H-四唑-5-基)吡啶-3-胺(實例127，步驟2)替代6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-胺來製備標題化合物。用MeOH稀釋最終粗產物，且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈白色固體之期望產物TFA鹽。LCMS C₂₆H₂₆ClN₁₂O (M+H)⁺m/z計算值= 557.2；實驗值557.2。實例152.3-(6-胺基-5-氟吡啶-3-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮步驟1：9-(1-疊氮基乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯The title compound was prepared using a procedure similar to that described for Example 8, substituting 6-chloro-2-(2-ethyl-2H-tetrazol-5-yl)pyridin-3-amine (Example 127, Step 2) for 6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-amine in Step 5. The final crude product was diluted with MeOH and purified by preparative HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min); the eluted fractions were collected and lyophilized to provide the desired product as a white solid as its TFA salt. LCMS C₂₆ H₂₆ ClN₁₂ O (M+H)⁺ m/z calcd = 557.2; found 557.2.Example 152.3-(6-Amino-5-fluoropyridin-3-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-oneStep 1: 9-(1-azidoethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid tert-butyl ester

向9-(1-羥基乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯(實例1，步驟8) (12.40 g, 34.7 mmol)於甲苯(125 mL)中之溶液中逐滴添加疊氮磷酸二苯酯(8.95 mL, 11.46 g, 41.63 mmol)持續10 min，之後經30 min逐滴添加2,3,4,6,7,8,9,10-八氫嘧啶并[1,2-a]氮呯(6.21 mL, 6.34 g, 41.63 mmol)。使所得渾濁混合物升溫至80℃，且在80℃下繼續攪拌4 h。使所得紅色漿液冷卻至室溫，且在真空下蒸發溶劑。用H₂O (200 mL)處理殘餘物，且用EtOAc (5×50 mL)萃取所得混合物。接著將合併的有機層用10 wt%檸檬酸水溶液(50 mL)且接著10 wt% NaHCO₃水溶液(50 mL)洗滌，經Na₂SO₄乾燥，過濾且在真空下濃縮，得到標題化合物(12.50 g, 94.2%)。步驟2：9-(1-胺基乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯To a solution of tert-butyl 9-(1-hydroxyethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate (Example 1, Step 8) (12.40 g, 34.7 mmol) in toluene (125 mL) was added diphenylphosphoryl azide (8.95 mL, 11.46 g, 41.63 mmol) dropwise over 10 min, followed by the addition of 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]aziridine (6.21 mL, 6.34 g, 41.63 mmol) dropwise over 30 min. The resulting turbid mixture was warmed to 80°C and stirred at 80°C for 4 h. The resulting red slurry was cooled to room temperature and the solvent was evaporated under vacuum. The residue was treated with H₂ O (200 mL) and the resulting mixture was extracted with EtOAc (5×50 mL). The combined organic layers were then washed with 10 wt % aqueous citric acid solution (50 mL) and then 10 wt % aqueous NaHCO₃ solution (50 mL), dried over Na₂ SO₄ , filtered and concentrated under vacuum to give the title compound (12.50 g, 94.2%).Step 2: 9-(1-aminoethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid tert-butyl ester

向圓底燒瓶中裝填9-(1-疊氮基乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯(12.50 g, 32.69 mmol)及活性碳載鈀(10%，50%用水潤濕) (1.74 g, 1.63 mmol)，用氫氣吹掃，接著添加MeOH。接著將氫氣囊連接至燒瓶，且將反應混合物在室溫下攪拌12 h。經由矽藻土床過濾反應混合物且使濾液經Na₂SO₄乾燥，過濾且在真空下濃縮，得到標題化合物(9.50 g, 81.5%)。LCMS C₁₉H₂₅N₄O₃(M+H)⁺m/z計算值= 357.2；實驗值357.2。A round-bottom flask was charged with tert-butyl 9-(1-azidoethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate (12.50 g, 32.69 mmol) and palladium on activated carbon (10%, 50% moistened with water) (1.74 g, 1.63 mmol), purged with hydrogen, and then MeOH was added. A hydrogen balloon was then attached to the flask, and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was filtered through a bed of celite, and the filtrate was dried_{overNa₂SO₄} , filtered, and concentrated under vacuum to yield the title compound (9.50 g, 81.5%). LCMS calcd for C₁₉ H₂₅ N₄ O₃ (M+H)⁺ m/z = 357.2; found 357.2.

使用手性SFC分離外消旋材料，第一峰用於隨後步驟中。步驟3：6-氯-3-碘-2-(2-甲基-2H-四唑-5-基)吡啶The racemic material was separated using chiral SFC and the first peak was used in the subsequent step.Step 3: 6-Chloro-3-iodo-2-(2-methyl-2H-tetrazol-5-yl)pyridine

將6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-胺(實例8，步驟4) (2.37 g, 11.25 mmol)懸浮於水(11 mL)中，同時攪拌。於冰浴中冷卻混合物，且緩慢添加硫酸(10.92 mL, 19.98 g, 203.67 mmol)(黃色懸浮液變成黃色溶液)。逐滴添加亞硝酸鈉(1.40 g, 20.25 mmol)於水(11 mL)中之溶液(生成棕色煙霧)。將反應混合物在0℃-5℃下再攪拌15 min。將混合物傾倒至碘化鉀(2.80 g, 16.88 mmol)於水(23 mL)中之充分攪拌溶液中。將所得混合物在室溫下攪拌30 min。反應完成後，藉由過濾收集固體。將所收集之固體溶解於乙酸乙酯中，用20%亞硫酸氫鈉水溶液洗滌。分離有機層，用飽和鹽水洗滌，經硫酸鈉乾燥，且在減壓下濃縮，得到橙色殘餘物。利用矽膠層析，用0-50% EtOAc/DCM溶析純化殘餘物，得到呈淺黃色固體之期望產物(3.00 g, 82.9%)。步驟4：9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯6-Chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-amine (Example 8, Step 4) (2.37 g, 11.25 mmol) was suspended in water (11 mL) while stirring. The mixture was cooled in an ice bath, and sulfuric acid (10.92 mL, 19.98 g, 203.67 mmol) was slowly added (the yellow suspension turned into a yellow solution). A solution of sodium nitrite (1.40 g, 20.25 mmol) in water (11 mL) was added dropwise (brown smoke formed). The reaction mixture was stirred at 0°C-5°C for an additional 15 min. The mixture was poured into a well-stirred solution of potassium iodide (2.80 g, 16.88 mmol) in water (23 mL). The resulting mixture was stirred at room temperature for 30 min. After the reaction was complete, the solid was collected by filtration. The collected solid was dissolved in ethyl acetate and washed with a 20% aqueous sodium bisulfite solution. The organic layer was separated, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain an orange residue. The residue was purified by silica gel chromatography using 0-50% EtOAc/DCM to obtain the desired product (3.00 g, 82.9%) as a light yellow solid.Step 4: 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid tert-butyl ester

將9-(1-胺基乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯(來自步驟2之峰1) (1.00 g, 2.81 mmol)、6-氯-3-碘-2-(2-甲基-2H-四唑-5-基)吡啶(1.08 g, 3.37 mmol)、Cs₂CO₃(1.83 g, 5.61 mmol)及XantPhos-Pd-G2 (0.50 g, 0.56 mmol)於二噁烷(3.0 mL)中之混合物用N₂吹掃，接著在氮氣氣氛下在100℃下加熱18 h。冷卻至室溫後，用水稀釋反應物且用EtOAc萃取。將合併的有機物用鹽水洗滌且經無水硫酸鈉乾燥，過濾並在減壓下濃縮。藉由矽膠管柱層析，用DCM及乙酸乙酯溶析純化所得混合物，提供呈固體之期望產物(850 mg, 55%)。LCMS C₂₆H₂₉ClN₉O₃(M+H)⁺m/z計算值= 550.2；實驗值550.2。步驟5：9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸A mixture of tert-butyl 9-(1-aminoethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate (peak 1 from step 2) (1.00 g, 2.81 mmol), 6-chloro-3-iodo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (1.08 g, 3.37 mmol), Cs₂ CO₃ (1.83 g, 5.61 mmol), and XantPhos-Pd-G 2 (0.50 g, 0.56 mmol) in dioxane (3.0 mL) was purged with N₂ and then heated at 100 ° C. under nitrogen atmosphere for 18 h. After cooling to room temperature, the reaction was diluted with water and extracted with EtOAc. The combined organics were washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel_column chromatography eluting with DCM and_ethyl acetate to provide the desired product as a solid (850 mg, 55%). LCMS_C26H29ClN9O3 (M+H)⁺ m/z calculated =_550.2 ; found 550.2.Step 5: 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid

將9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸第三丁酯(850 mg, 1.54 mmol)溶解於TFA (10 mL)中。將混合物在室溫下攪拌3 h。完成後，在真空下去除TFA。向反應殘餘物中添加EtOAc (20 mL)及己烷(20 mL)，同時攪拌。攪拌20 min後，收集所得固體，得到白色固體，用己烷/EtOAc (1:1)洗滌。使固體在真空下乾燥，提供純產物(607 mg, 80%)。LCMS C₂₂H₂₁ClN₉O₃(M+H)⁺m/z計算值= 494.1；實驗值494.2。步驟6：9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-碘-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮tert-Butyl 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate (850 mg, 1.54 mmol) was dissolved in TFA (10 mL). The mixture was stirred at room temperature for 3 h. Upon completion, the TFA was removed under vacuum. EtOAc (20 mL) and hexane (20 mL) were added to the reaction residue while stirring. After stirring for 20 min, the resulting solid was collected to give a white solid, which was washed with hexane/EtOAc (1:1). The solid was dried under vacuum to provide the pure product (607 mg, 80%). LCMS C₂₂ H₂₁ ClN₉ O₃ (M+H)⁺ m/z calcd = 494.1; found 494.2.Step 6: 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-iodo-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one

在氮氣下在0℃下向9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲酸(607 mg, 1.23 mmol)於DMF (10 mL)中之混合物中添加NaHCO₃(252 mg, 3 mmol)，攪拌5 min後，一次性添加NIS (281 mg, 1.23 mmol)。使所得混合物升溫至室溫且在真空下攪拌2 h。完成後，用飽和Na₂S₂O₃淬滅反應混合物，且用水稀釋。藉由過濾收集呈棕色固體之所得固體，藉由矽膠管柱層析，用DCM及EtOAc溶析進行純化，提供呈白色固體之期望產物(337 mg, 72%)。LCMS C₂₁H₂₀ClIN₉O (M+H)⁺m/z計算值= 576.1；實驗值576.1。步驟7：3-(6-胺基-5-氟吡啶-3-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮To a mixture of 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid (607 mg, 1.23 mmol) in DMF (10 mL) at 0° C. under nitrogen was added NaHCO₃ (252 mg, 3 mmol) and stirred for 5 min. NIS (281 mg, 1.23 mmol) was added in one portion. The resulting mixture was allowed to warm to room temperature and stirred under vacuum for 2 h. Upon completion, the reaction mixture was quenched with saturated Na₂ S₂ O₃ and diluted with water. The resulting brown solid was collected by filtration and purified by silica gel column chromatography eluting with DCM and EtOAc to provide the desired product as a white solid (337 mg,₇₂ %). LCMS_C21H20C1N9O (M+H)⁺ m/z calculated = 576.1; found 576.1. Step 7: 3-(6-amino_-5-fluoropyridin-3-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one

將 9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-碘-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮(10 mg, 0.017 mmol)、3-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶-2-胺(7 mg, 0.03 mmol)、K₃PO₄(5 mg, 0.024 mmol)及Pd(amphos)Cl₂(2 mg, 0.003 mmol)於二噁烷(1.0 mL)及水(0.2 mL)中之混合物在氮氣氣氛下在80℃下加熱4 h。用MeOH稀釋反應物，且藉由製備型HPLC (管柱：Sunfire prep C18管柱，30*150 mm，5 μm；移動相A：水(0.1% TFA)，移動相B：乙腈；流量：60 mL/min)進行純化；收集溶析流份並凍乾，提供呈淺黃色之期望產物TFA鹽。LCMS C₂₆H₂₄ClFN₁₁O (M+H)⁺m/z計算值= 560.2；實驗值560.2。實例153至157.A mixture of 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-iodo-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (10 mg, 0.017 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)pyridin-2-amine (7 mg, 0.03 mmol), K₃ PO₄ (5 mg, 0.024 mmol) and Pd(amphos)Cl₂ (2 mg, 0.003 mmol) in dioxane (1.0 mL) and water (0.2 mL) was heated at 80° C. for 4 h under nitrogen atmosphere. The reaction was diluted with MeOH and purified by preparative HPLC (Sunfire prep C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL/min). The_{eluted fractions were collected and lyophilized to provide the desired product as a light yellow TFA salt. LCMS m/z calculated for C₂₆H₂₄ClFN₁₁O(M} +H)^⁺ = 560.2; found 560.2.Examples 153 to 157.

表14中之以下化合物係如針對實例152所闡述，使用適當中間體類似地製備。表14.實例編號化學名稱結構LCMSm/z(M+H)⁺1533-(2-胺基-4-甲基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮(來自實例152步驟6之中間體)557.21549-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(1-甲基-1H-咪唑-5-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮 (來自實例152步驟6之中間體)530.21559-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪-3-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮 (來自實例8步驟7之中間體)572.21563-(2-胺基噻唑-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮 (來自實例8步驟7之中間體)548.11573-(2-胺基-4-甲基噻唑-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮 (來自實例8步驟7之中間體)562.2實例A. pS473 AKT分析方案The following compounds in Table 14 were prepared similarly as described for Example 152 using appropriate intermediates.Table 14.Instance NumberChemical namestructureLCMSm/z(M+H)⁺153 3-(2-amino-4-methylpyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (intermediate from Step 6 of Example 152) 557.2154 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methyl-1H-imidazol-5-yl)imidazo[1,5-a]quinazolin-5(4H)-one (intermediate from Step 6 of Example 152) 530.2155 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (from the intermediate in Step 7 of Example 8) 572.2156 3-(2-Aminothiazol-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (intermediate from Step 7 of Example 8) 548.1157 3-(2-amino-4-methylthiazol-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (intermediate from step 7 of Example 8) 562.2Example A. pS473 AKT Analysis Protocol

使用10-cm皮氏培養皿(petri dish)用推薦培養基加10%胎牛血清培養T47D (PIK3CA H1047R)細胞。在分析前一天，將細胞接種於96孔板中。隔夜培育後，將培養基換成含有2.5%胎牛血清(FBS)之DMEM，且將細胞用不同濃度之化合物處理2 h。接著使用4%多聚甲醛將細胞在室溫下固定20 min。吸出4%多聚甲醛，且使用1×常規磷酸鹽緩衝鹽水將細胞洗滌3次，每次5 min。吸出任何殘餘磷酸鹽緩衝鹽水，且使用含有1%牛血清白蛋白及0.3% Triton X-100之10%山羊血清將細胞在室溫下封阻1 h。在不進行任何額外洗滌之情形下，使用封阻緩衝液稀釋一級抗體(兔抗pSer473 AKT)，且以50微升/孔之最終體積添加。將含有一級抗體之分析板置於4℃下隔夜。使用1×常規磷酸鹽緩衝鹽水將細胞洗滌3次，每次5 min。在最後一次洗滌後，使細胞與使用相同封阻緩衝液稀釋之辣根過氧化物酶結合之二級抗體(山羊抗兔IgG)一起在室溫下培育1 h。使用1×常規磷酸鹽緩衝鹽水將細胞充分洗滌3次，每次5 min。吸出任何殘餘磷酸鹽緩衝鹽水。以100微升/孔之最終體積添加Super-Signal ELISA Pico化學發光受質。在i3x多模式微量板讀數儀上讀板，且使用GraphPad Prism軟體計算IC₅₀值。T47D (PIK3CA H1047R) cells were cultured in 10-cm petri dishes using the recommended medium supplemented with 10% fetal bovine serum. The day before analysis, cells were seeded in 96-well plates. After overnight incubation, the medium was replaced with DMEM supplemented with 2.5% fetal bovine serum (FBS), and the cells were treated with various concentrations of compound for 2 hours. Cells were then fixed with 4% paraformaldehyde for 20 minutes at room temperature. The 4% paraformaldehyde was aspirated, and the cells were washed three times with 1× phosphate-buffered saline for 5 minutes each. Aspirate any residual phosphate-buffered saline and block the cells with 10% goat serum containing 1% bovine serum albumin and 0.3% Triton X-100 for 1 hour at room temperature. Without any additional washes, dilute the primary antibody (rabbit anti-pSer473 AKT) in blocking buffer and add a final volume of 50 μl/well. Incubate the assay plate containing the primary antibody at 4°C overnight. Wash the cells three times for 5 minutes each with 1× regular phosphate-buffered saline. After the final wash, incubate the cells with a horseradish peroxidase-conjugated secondary antibody (goat anti-rabbit IgG) diluted in the same blocking buffer for 1 hour at room temperature. Wash cells extensively three times with 1× regular phosphate-buffered saline (PBS) for 5 minutes each. Aspirate any residual PBS. Add Super-Signal ELISA Pico chemiluminescent substrate to a final volume of 100 μl/well. Read the plate on an i3x Multimode Microplate Reader, and calculate_IC50 values using GraphPad Prism software.

表A中呈現上述分析之結果。「+」指示IC₅₀小於100 nM；「++」指示IC₅₀大於或等於100 nM，但小於500 nM；「+++」指示IC₅₀大於或等於500 nM，但小於1000 nM；且「++++」指示IC₅₀大於或等於1000 nM。表A.實例T47D_IC₅₀(nM)實例T47D_IC₅₀(nM)實例T47D_IC₅₀(nM)1+2++++3+4+5+6+7+8+9+10+11+12+13+14+15+16++++17+18+19+20+21+22+23+24+25+26+27+28++29+30+31+32+33+34+35+36+37+38+39+40+41+42+43+44+45+46++47+48+49+50+51++52+53++54+55+56++57+58+59++60+61+62+63+64+65+66+67+68+69+70+71+72+73+74+75+76++77+78++79++80+81+82+83+84+85+86+87+88+89+90+91+92++93++94+95++96++97++98++99++100++101+102+127+128+129+130+131+132+133+134+150+151+152+153+154+155+156+157+The results of the above analysis are presented in Table A. "+" indicates an_IC50 less than 100 nM; "++" indicates an_IC50 greater than or equal to 100 nM but less than 500 nM; "+++" indicates an_IC50 greater than or equal to 500 nM but less than 1000 nM; and "++++" indicates an_IC50 greater than or equal to 1000 nM.Table A.ExampleT47D_IC₅₀ (nM)ExampleT47D_IC₅₀ (nM)ExampleT47D_IC₅₀ (nM)1 +2 ++++3 +4 +5 +6 +7 +8 +9 +10 +11 +12 +13 +14 +15 +16 ++++17 +18 +19 +20 +twenty one +twenty two +twenty three +twenty four +25 +26 +27 +28 ++29 +30 +31 +32 +33 +34 +35 +36 +37 +38 +39 +40 +41 +42 +43 +44 +45 +46 ++47 +48 +49 +50 +51 ++52 +53 ++54 +55 +56 ++57 +58 +59 ++60 +61 +62 +63 +64 +65 +66 +67 +68 +69 +70 +71 +72 +73 +74 +75 +76 ++77 +78 ++79 ++80 +81 +82 +83 +84 +85 +86 +87 +88 +89 +90 +91 +92 ++93 ++94 +95 ++96 ++97 ++98 ++99 ++100 ++101 +102 +127 +128 +129 +130 +131 +132 +133 +134 +150 +151 +152 +153 +154 +155 +156 +157 +

除本文所闡述之彼等修改以外，熟習此項技術者根據前述說明亦將明瞭對本發明之各種修改。此等修改亦意欲屬於隨附申請專利範圍之範圍內。本申請案中所引用之每一參考文獻(包括所有專利、專利申請案及公開案)係以全文引用的方式併入本文中。In addition to those modifications described herein, various modifications of the present invention will become apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the accompanying patent applications. Each reference cited in this application (including all patents, patent applications, and publications) is incorporated herein by reference in its entirety.

Claims (42)

Translated fromChinese

一種式I化合物或其醫藥學上可接受之鹽，I其中： n為0、1、2、3、4、5或6； 環A為C_3-14環烷基、C_6-10芳基、4-14員雜環烷基或5-10員雜芳基； L¹為C_1-4伸烷基，其中該C_1-4伸烷基視情況經1、2、3或4個獨立選擇之R^G取代基取代； L²係選自鍵、-O-及-N(R^L)-； R^L係選自H、C_1-6烷基及C_1-6鹵烷基； R¹係選自H、鹵基、C_1-4烷基、C_1-4鹵烷基、C_1-4烷氧基、C_1-4鹵烷氧基及-CN； R²係選自H、C_1-6烷基、C_1-6鹵烷基、C_3-7環烷基及C_3-7環烷基-C_1-4烷基，其中R²之該C_1-6烷基、該C_1-6鹵烷基、該C_3-7環烷基及該C_3-7環烷基-C_1-4烷基各自視情況經1、2、3或4個獨立選擇之R^G取代基取代； R³係選自H、鹵基、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6鹵烷基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基、(5-10員雜芳基)-C_1-4烷基、-CN、-OR^a3、-SR^a3、-NR^c3R^d3、-NO₂、-C(O)R^a3、-C(O)OR^a3、-C(O)NR^c3R^d3、-C(O)NR^c3(OR^a3)、-OC(O)R^a3、-OC(O)NR^c3R^d3、-OC(O)OR^a3、-OS(O)₂R^b3、-OS(O)₂NR^c3R^d3、-NR^c3C(O)R^a3、-NR^c3C(O)OR^a3、-NR^c3C(O)NR^c3R^d3、-NR^c3S(O)₂R^b3、-NR^c3S(O)₂NR^c3R^d3、-NR^c3OR^a3、-NR^c3S(O)R^b3、-NR^c3S(O)NR^c3R^d3、-S(O)R^b3、-S(O)₂R^b3、-S(O)NR^c3R^d3、-S(O)₂NR^c3R^d3、-C(=NR^e3)R^a3、-C(=NR^e3)NR^c3R^d3、-NR^c3C(=NR^e3)R^a3、-NR^c3C(=NR^e3)NR^c3R^d3、-NR^c3S(O)(=NR^e3)R^b3、-NR^c3S(O)(=NR^e3)NR^c3R^d3、-OS(O)(=NR^e3)R^b3、-S(O)(=NR^e3)R^b3、-S(O)(=NR^e3)NR^c3R^d3、-C(O)NR^c3S(O)₂R^b3、-C(O)NR^c3S(O)₂NR^c3R^d3、-S(O)₂NR^c3C(O)R^b3、-NR^c3S(O)NR^c3C(O)R^b3及-P(O)R^f3R^g3，其中R³之該C_1-6烷基、該C_2-6烯基、該C_2-6炔基、該C_1-6鹵烷基、該C_3-10環烷基、該C_6-10芳基、該4-10員雜環烷基、該5-10員雜芳基、該C_3-10環烷基-C_1-4烷基、該C_6-10芳基-C_1-4烷基、該(4-10員雜環烷基)-C_1-4烷基及該(5-10員雜芳基)-C_1-4烷基各自視情況經1、2、3、4、5或6個獨立選擇之R^3A取代基取代； 每一R^a3、R^c3及R^d3獨立地選自H、C_1-6烷基、C_1-6鹵烷基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基，其中R^a3、R^c3及R^d3之該C_1-6烷基、該C_2-6烯基、該C_2-6炔基、該C_1-6鹵烷基、該C_3-10環烷基、該C_6-10芳基、該4-10員雜環烷基、該5-10員雜芳基、該C_3-10環烷基-C_1-4烷基、該C_6-10芳基-C_1-4烷基、該(4-10員雜環烷基)-C_1-4烷基及該(5-10員雜芳基)-C_1-4烷基各自視情況經1、2、3、4、5或6個獨立選擇之R^3A取代基取代； 或連接至同一N原子之任何R^c3及R^d3與其所連接之該N原子一起形成4-10員雜環烷基，其中該4-10員雜環烷基視情況經1、2、3、4、5或6個獨立選擇之R^3A取代基取代； 每一R^b3獨立地選自C_1-6烷基、C_1-6鹵烷基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基，其中R^b3之該C_1-6烷基、該C_1-6鹵烷基、該C_2-6烯基、該C_2-6炔基、該C_3-10環烷基、該C_6-10芳基、該4-10員雜環烷基、該5-10員雜芳基、該C_3-10環烷基-C_1-4烷基、該C_6-10芳基-C_1-4烷基、該(4-10員雜環烷基)-C_1-4烷基及該(5-10員雜芳基)-C_1-4烷基各自視情況經1、2、3、4、5或6個獨立選擇之R^3A取代基取代； 每一R^e3獨立地選自H、OH、CN、C_1-6烷基、C_1-6烷氧基、C_1-6鹵烷基、C_1-6鹵烷氧基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基； 每一R^f3及R^g3獨立地選自H、C_1-6烷基、C_1-6烷氧基、C_1-6鹵烷基、C_1-6鹵烷氧基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基； 每一R^3A獨立地選自側氧基、H、鹵基、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6鹵烷基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基、(5-10員雜芳基)-C_1-4烷基、-CN、-OR^a3A、-SR^a3A、-NR^c3AR^d3A、-NO₂、-C(O)R^a3A、-C(O)OR^a3A、-C(O)NR^c3AR^d3A、-C(O)NR^c3A(OR^a3A)、-OC(O)R^a3A、-OC(O)NR^c3AR^d3A、-OC(O)OR^a3A、-OS(O)₂R^b3A、-OS(O)₂NR^c3AR^d3A、-NR^c3AC(O)R^a3A、-NR^c3AC(O)OR^a3A、-NR^c3AC(O)NR^c3AR^d3A、-NR^c3AS(O)₂R^b3A、-NR^c3AS(O)₂NR^c3AR^d3A、-NR^c3AOR^a3A、-NR^c3AS(O)R^b3A、-NR^c3AS(O)NR^c3AR^d3A、-S(O)R^b3A、-S(O)₂R^b3A、-S(O)NR^c3AR^d3A、-S(O)₂NR^c3AR^d3A、-C(=NR^e3A)R^a3A、-C(=NR^e3A)NR^c3AR^d3A、-NR^c3AC(=NR^e3A)R^a3A、-NR^c3AC(=NR^e3A)NR^c3AR^d3A、-NR^c3AS(O)(=NR^e3A)R^b3A、-NR^c3AS(O)(=NR^e3A)NR^c3AR^d3A、-OS(O)(=NR^e3A)R^b3A、-S(O)(=NR^e3A)R^b3A、-S(O)(=NR^e3A)NR^c3AR^d3A、-C(O)NR^c3AS(O)₂R^b3A、-C(O)NR^c3AS(O)₂NR^c3AR^d3A、-S(O)₂NR^c3AC(O)R^b3A、-NR^c3AS(O)NR^c3AC(O)R^b3A及-P(O)R^f3AR^g3A，其中R^3A之該C_1-6烷基、該C_2-6烯基、該C_2-6炔基、該C_1-6鹵烷基、該C_3-10環烷基、該C_6-10芳基、該4-10員雜環烷基、該5-10員雜芳基、該C_3-10環烷基-C_1-4烷基、該C_6-10芳基-C_1-4烷基、該(4-10員雜環烷基)-C_1-4烷基及該(5-10員雜芳基)-C_1-4烷基各自視情況經1、2、3、4、5或6個獨立選擇之R^G取代基取代； 每一R^a3A、R^c3A及R^d3A獨立地選自H、C_1-6烷基、C_1-6鹵烷基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基，其中R^a3A、R^c3A及R^d3A之該C_1-6烷基、該C_2-6烯基、該C_2-6炔基、該C_1-6鹵烷基、該C_3-10環烷基、該C_6-10芳基、該4-10員雜環烷基、該5-10員雜芳基、該C_3-10環烷基-C_1-4烷基、該C_6-10芳基-C_1-4烷基、該(4-10員雜環烷基)-C_1-4烷基及該(5-10員雜芳基)-C_1-4烷基各自視情況經1、2、3、4、5或6個獨立選擇之R^G取代基取代； 或連接至同一N原子之任何R^c3A及R^d3A與其所連接之該N原子一起形成4-10員雜環烷基，其中該4-10員雜環烷基視情況經1、2、3、4、5或6個獨立選擇之R^G取代基取代； 每一R^b3A獨立地選自C_1-6烷基、C_1-6鹵烷基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基，其中R^b3A之該C_1-6烷基、該C_1-6鹵烷基、該C_2-6烯基、該C_2-6炔基、該C_3-10環烷基、該C_6-10芳基、該4-10員雜環烷基、該5-10員雜芳基、該C_3-10環烷基-C_1-4烷基、該C_6-10芳基-C_1-4烷基、該(4-10員雜環烷基)-C_1-4烷基及該(5-10員雜芳基)-C_1-4烷基各自視情況經1、2、3、4、5或6個獨立選擇之R^G取代基取代； 每一R^e3A獨立地選自H、OH、CN、C_1-6烷基、C_1-6烷氧基、C_1-6鹵烷基、C_1-6鹵烷氧基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基； 每一R^f3A及R^g3A獨立地選自H、C_1-6烷基、C_1-6烷氧基、C_1-6鹵烷基、C_1-6鹵烷氧基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基； R⁴係選自側氧基、鹵基、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6鹵烷基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基、(5-10員雜芳基)-C_1-4烷基、-CN、-OR^a4、-SR^a4、-NR^c4R^d4、-NO₂、-C(O)R^a4、-C(O)OR^a4、-C(O)NR^c4R^d4、-C(O)NR^c4(OR^a4)、-OC(O)R^a4、-OC(O)NR^c4R^d4、-OC(O)OR^a4、-OS(O)₂R^b4、-OS(O)₂NR^c4R^d4、-NR^c4C(O)R^a4、-NR^c4C(O)OR^a4、-NR^c4C(O)NR^c4R^d4、-NR^c4S(O)₂R^b4、-NR^c4S(O)₂NR^c4R^d4、-NR^c4OR^a4、-NR^c4S(O)R^b4、-NR^c4S(O)NR^c4R^d4、-S(O)R^b4、-S(O)₂R^b4、-S(O)NR^c4R^d4、-S(O)₂NR^c4R^d4、-C(=NR^e4)R^a4、-C(=NR^e4)NR^c4R^d4、-NR^c4C(=NR^e4)R^a4、-NR^c4C(=NR^e4)NR^c4R^d4、-NR^c4S(O)(=NR^e4)R^b4、-NR^c4S(O)(=NR^e4)NR^c4R^d4、-OS(O)(=NR^e4)R^b4、-S(O)(=NR^e4)R^b4、-S(O)(=NR^e4)NR^c4R^d4、-C(O)NR^c4S(O)₂R^b4、-C(O)NR^c4S(O)₂NR^c4R^d4、-S(O)₂NR^c4C(O)R^b4、-NR^c4S(O)NR^c4C(O)R^b4及-P(O)R^f4R^g4，其中R⁴之該C_1-6烷基、該C_2-6烯基、該C_2-6炔基、該C_1-6鹵烷基、該C_3-10環烷基、該C_6-10芳基、該4-10員雜環烷基、該5-10員雜芳基、該C_3-10環烷基-C_1-4烷基、該C_6-10芳基-C_1-4烷基、該(4-10員雜環烷基)-C_1-4烷基及該(5-10員雜芳基)-C_1-4烷基各自視情況經1、2、3、4、5或6個獨立選擇之R^4A取代基取代； 每一R^a4、R^c4及R^d4獨立地選自H、C_1-6烷基、C_1-6鹵烷基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基，其中R^a4、R^c4及R^d4之該C_1-6烷基、該C_2-6烯基、該C_2-6炔基、該C_1-6鹵烷基、該C_3-10環烷基、該C_6-10芳基、該4-10員雜環烷基、該5-10員雜芳基、該C_3-10環烷基-C_1-4烷基、該C_6-10芳基-C_1-4烷基、該(4-10員雜環烷基)-C_1-4烷基及該(5-10員雜芳基)-C_1-4烷基各自視情況經1、2、3、4、5或6個獨立選擇之R^4A取代基取代； 或連接至同一N原子之任何R^c4及R^d4與其所連接之該N原子一起形成4-10員雜環烷基，其中該4-10員雜環烷基視情況經1、2、3、4、5或6個獨立選擇之R^4A取代基取代； 每一R^b4獨立地選自C_1-6烷基、C_1-6鹵烷基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基，其中R^b4之該C_1-6烷基、該C_1-6鹵烷基、該C_2-6烯基、該C_2-6炔基、該C_3-10環烷基、該C_6-10芳基、該4-10員雜環烷基、該5-10員雜芳基、該C_3-10環烷基-C_1-4烷基、該C_6-10芳基-C_1-4烷基、該(4-10員雜環烷基)-C_1-4烷基及該(5-10員雜芳基)-C_1-4烷基各自視情況經1、2、3、4、5或6個獨立選擇之R^4A取代基取代； 每一R^e4獨立地選自H、OH、CN、C_1-6烷基、C_1-6烷氧基、C_1-6鹵烷基、C_1-6鹵烷氧基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基； 每一R^f4及R^g4獨立地選自H、C_1-6烷基、C_1-6烷氧基、C_1-6鹵烷基、C_1-6鹵烷氧基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基； 每一R^4A獨立地選自側氧基、H、鹵基、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6鹵烷基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基、(5-10員雜芳基)-C_1-4烷基、-CN、-OR^a4A、-SR^a4A、-NR^c4AR^d4A、-NO₂、-C(O)R^a4A、-C(O)OR^a4A、-C(O)NR^c4AR^d4A、-C(O)NR^c4A(OR^a4A)、-OC(O)R^a4A、-OC(O)NR^c4AR^d4A、-OC(O)OR^a4A、-OS(O)₂R^b4A、-OS(O)₂NR^c4AR^d4A、-NR^c4AC(O)R^a4A、-NR^c4AC(O)OR^a4A、-NR^c4AC(O)NR^c4AR^d4A、-NR^c4AS(O)₂R^b4A、-NR^c4AS(O)₂NR^c4AR^d4A、-NR^c4AOR^a4A、-NR^c4AS(O)R^b4A、-NR^c4AS(O)NR^c4AR^d4A、-S(O)R^b4A、-S(O)₂R^b4A、-S(O)NR^c4AR^d4A、-S(O)₂NR^c4AR^d4A、-C(=NR^e4A)R^a4A、-C(=NR^e4A)NR^c4AR^d4A、-NR^c4AC(=NR^e4A)R^a4A、-NR^c4AC(=NR^e4A)NR^c4AR^d4A、-NR^c4AS(O)(=NR^e4A)R^b4A、-NR^c4AS(O)(=NR^e4A)NR^c4AR^d4A、-OS(O)(=NR^e4A)R^b4A、-S(O)(=NR^e4A)R^b4A、-S(O)(=NR^e4A)NR^c4AR^d4A、-C(O)NR^c4AS(O)₂R^b4A、-C(O)NR^c4AS(O)₂NR^c4AR^d4A、-S(O)₂NR^c4AC(O)R^b4A、-NR^c4AS(O)NR^c4AC(O)R^b4A及-P(O)R^f4AR^g4A，其中R^4A之該C_1-6烷基、該C_2-6烯基、該C_2-6炔基、該C_1-6鹵烷基、該C_3-10環烷基、該C_6-10芳基、該4-10員雜環烷基、該5-10員雜芳基、該C_3-10環烷基-C_1-4烷基、該C_6-10芳基-C_1-4烷基、該(4-10員雜環烷基)-C_1-4烷基及該(5-10員雜芳基)-C_1-4烷基各自視情況經1、2、3、4、5或6個獨立選擇之R^G取代基取代； 每一R^a4A、R^c4A及R^d4A獨立地選自H、C_1-6烷基、C_1-6鹵烷基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基，其中R^a4A、R^c4A及R^d4A之該C_1-6烷基、該C_2-6烯基、該C_2-6炔基、該C_1-6鹵烷基、該C_3-10環烷基、該C_6-10芳基、該4-10員雜環烷基、該5-10員雜芳基、該C_3-10環烷基-C_1-4烷基、該C_6-10芳基-C_1-4烷基、該(4-10員雜環烷基)-C_1-4烷基及該(5-10員雜芳基)-C_1-4烷基各自視情況經1、2、3、4、5或6個獨立選擇之R^G取代基取代； 或連接至同一N原子之任何R^c4A及R^d4A與其所連接之該N原子一起形成4-10員雜環烷基，其中該4-10員雜環烷基視情況經1、2、3、4、5或6個獨立選擇之R^G取代基取代； 每一R^b4A獨立地選自C_1-6烷基、C_1-6鹵烷基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基，其中R^b4A之該C_1-6烷基、該C_1-6鹵烷基、該C_2-6烯基、該C_2-6炔基、該C_3-10環烷基、該C_6-10芳基、該4-10員雜環烷基、該5-10員雜芳基、該C_3-10環烷基-C_1-4烷基、該C_6-10芳基-C_1-4烷基、該(4-10員雜環烷基)-C_1-4烷基及該(5-10員雜芳基)-C_1-4烷基各自視情況經1、2、3、4、5或6個獨立選擇之R^G取代基取代； 每一R^e4A獨立地選自H、OH、CN、C_1-6烷基、C_1-6烷氧基、C_1-6鹵烷基、C_1-6鹵烷氧基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基； 每一R^f4A及R^g4A獨立地選自H、C_1-6烷基、C_1-6烷氧基、C_1-6鹵烷基、C_1-6鹵烷氧基、C_2-6烯基、C_2-6炔基、C_3-10環烷基、C_6-10芳基、4-10員雜環烷基、5-10員雜芳基、C_3-10環烷基-C_1-4烷基、C_6-10芳基-C_1-4烷基、(4-10員雜環烷基)-C_1-4烷基及(5-10員雜芳基)-C_1-4烷基； 每一R^G獨立地選自H、D、OH、CN、鹵基、側氧基、C_1-4烷基、C_2-4烯基、C_2-4炔基、C_1-4鹵烷基、氰基-C_1-4烷基、HO-C_1-4烷基、C_1-4烷氧基-C_1-4烷基、C_3-7環烷基、4-7員雜環烷基、C_1-4烷氧基、C_1-4鹵烷氧基、胺基、C_1-3烷基胺基、二(C_1-3烷基)胺基、硫基、C_1-3烷基硫基、C_1-3烷基亞磺醯基、C_1-3烷基磺醯基、胺甲醯基、C_1-3烷基胺甲醯基、二(C_1-3烷基)胺甲醯基、羧基、C_1-3烷基羰基、C_1-3烷氧基羰基、C_1-3烷基羰基氧基、C_1-3烷基羰基胺基、C_1-3烷氧基羰基胺基、胺基羰基氧基、C_1-3烷基胺基羰基氧基、二(C_1-3烷基)胺基羰基氧基、C_1-3烷基磺醯基胺基、胺基磺醯基、C_1-3烷基胺基磺醯基、二(C_1-3烷基)胺基磺醯基、胺基磺醯基胺基、C_1-3烷基胺基磺醯基胺基、二(C_1-3烷基)胺基磺醯基胺基、胺基羰基胺基、C_1-3烷基胺基羰基胺基及二(C_1-3烷基)胺基羰基胺基。A compound of formula I or a pharmaceutically acceptable salt thereof,wherein : n is 0, 1, 2, 3, 4, 5 or 6; ring A is C_3-14 cycloalkyl, C_6-10 aryl, 4-14 membered heterocycloalkyl or 5-10 membered heteroaryl; L¹ is C_1-4 alkylene, wherein the C_1-4 alkylene is optionally substituted with 1, 2, 3 or 4 independently selected^RG substituents; L² is selected from a bond, -O- and -N(^RL )-;^RL is selected from H, C_1-6 alkyl and C_1-6 haloalkyl; R¹ is selected from H, halo, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, C_1-4 haloalkoxy and -CN; R² is selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C C_3-7 cycloalkyl and C_3-7 cycloalkyl-C_1-4 alkyl, wherein the C_1-6 alkyl, the C_1-6 haloalkyl, the C_3-7 cycloalkyl and the C_3-7 cycloalkyl-C_1-4 alkyl of R² are each optionally substituted with 1, 2, 3 or 4 independently selected R^G substituents; R³ is selected from H, halo, C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C_3-10 cycloalkyl-C_1-4 alkyl, C_6-10 aryl-C_1-4 alkyl, (4-10 membered heterocycloalkyl)-C_1-4 alkyl, (5-10 membered heteroaryl)-C_1-4 alkyl, -CN, -OR^a3 , -SR^a3 , -NR^c3 R^d3 , -NO₂ , -C(O)R^a3 , -C(O)OR^a3 , -C(O)NR^c3 R^d3 , -C(O)NR^c3 (OR^a3 ), -OC(O)R^a3 , -OC(O)NR^c3 R^d3 , -OC(O)OR^a3 , -OS(O)₂ R^b3 , -OS(O)₂ NR^c3 R^d3 , -NR^c3 C(O)R^a3 , -NR^c3 C(O)OR^a3 , -NR^c3 C(O)NR^c3 R^d3 , -NR^c3 S(O)₂ R^b3 , -NR^c3 S(O)₂ NR^c3 R^d3 , -NR^c3 OR^a3 , -NR^c3 S(O)R^b3 , -NR^c3 S(O)NR^c3 R^d3 , -S(O)R^b3 , -S(O)₂ R^b3 , -S(O)NR^c3 R^d3 , -S(O)₂ NR^c3 R^d3 , -C(=NR^e3 )R^a3 , -C(=NR^e3 )NR^c3 R^d3 , -NR^c3 C(=NR^e3 )R^a3 , -NR^c3 C(=NR^e3 )NR^c3 R^d3 , -NR^c3 S(O)(=NR^e3 )R^b3 , -NR^c3 S(O)(=NR^e3 )NR^c3 R^d3 , -OS(O)(=NR^e3 )R^b3 , -S(O)(=NR^e3 )R^b3 ,-S(O)(=NR^e3 )NR^c3 R^d3 , -C(O)NR^c3 S(O)₂ R^b3 , -C(O)NR^c3 S(O)₂ NR^c3 R^d3 , -S(O)₂ NR^c3 C(O)R^b3 , -NR^c3 S(O)NR^c3 C(O)R^b3 and -P(O)R^f3 R^g3 , wherein R³ is the C_1-6 alkyl, the C_2-6 alkenyl, the C_2-6 alkynyl, the C_1-6 haloalkyl, the C_3-10 cycloalkyl, the C_6-10 aryl, the 4-10 membered heterocycloalkyl, the 5-10 membered heteroaryl, the C_3-10 cycloalkyl-C_1-4 alkyl, the C_6-10 aryl-C The (4-10 membered heterocycloalkyl)-C_1-4 alkyl, the (5-10 membered heteroaryl)-C_1-4 alkyl, and the (4-10 membered heterocycloalkyl)-C_1-4 alkyl are each optionally substituted with 1, 2, 3,^{4, 5} , or 6 independently selected R^3A substituents; each of^Ra3 , Rc3, and^Rd3 is independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C_3-10 cycloalkyl-C_1-4 alkyl, C_6-10 aryl-C_1-4 alkyl, (4-10 membered heterocycloalkyl)-C R^a3 , R^c3 and R^d3 are each_optionally substituted with_1,2,3,4,5or6 independently selected^R_{3Asubstituents;} or any R^c3 and R^d3 attached to the same N atom together with the N atom to which they are attached form a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R^3A substituents; each R^b3 is independently selected from C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C_3-10 cycloalkyl-C_1-4 alkyl, C_6-10 aryl-C_1-4 alkyl, (4-10 membered heterocycloalkyl)-C_1-4 alkyl and (5-10 membered heteroaryl)-C 1-6 alkyl.^wherein the C_1-6 alkyl, the C_1-6 haloalkyl, the C_2-6 alkenyl, the C_2-6 alkynyl, the C_3-10 cycloalkyl, the C_6-10 aryl, the_4-10 membered heterocycloalkyl, the 5-10 membered heteroaryl, the C_3-10 cycloalkyl-C_1-4 alkyl, the C_6-10 aryl-C_1-4 alkyl, the (4-10 membered heterocycloalkyl)-C_1-4 alkyl and the (5-10 membered heteroaryl)-C 1-4 alkyl of R b3 are each optionally substituted with 1, 2, 3,₄ , 5 or 6 independently selected R^3A substituents; each R^e3 is independently selected from H, OH, CN, C_1-6 alkyl, C_1-6 alkoxy, C Rf3 and Rg3 are independently selected from H,_C1-6 alkyl,_C1-6 alkoxy,_C1-6 haloalkyl,_C1-6 haloalkoxy,_C2-6 alkenyl, C2-6 alkynyl,_C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl,_C3-10 cycloalkyl-_C1-4 alkyl,_C6-10 aryl-_C1-4 alkyl, (4-10 membered heterocycloalkyl)_-C1-4 alkyl and (5-10 membered heteroaryl)_-C1-4 alkyl; each^Rf3 and^Rg3 are independently selected from H,_C1-6 alkyl, C1-6 alkoxy,_C1-6 haloalkyl, C1-6 haloalkoxy,_C2-6 alkenyl,_C2-6 alkynyl, C3-10 cycloalkyl,_C6-10 aryl, C1-4 alkyl, (_4-10 membered heterocycloalkyl)-C1-4 alkyl and_(5-10 membered heteroaryl)-C1-4 alkyl. C_6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C_3-10 cycloalkyl-C_1-4 alkyl, C_6-10 aryl-C_1-4 alkyl, (4-10 membered heterocycloalkyl)-C_1-4 alkyl and (5-10 membered heteroaryl)-C_1-4 alkyl; each R^3A is independently selected from a pendoxy group, H, a halogen group, a C 1-6 alkyl group, a C_2-6 alkenyl group, a C_2-6 alkynyl group, a C_1-6 halogen group, a C_3-10 cycloalkyl, a C_6-10 aryl, a 4-10 membered heterocycloalkyl, a 5-10 membered heteroaryl, a C 3-10 cycloalkyl-C_1-4 alkyl group, a C_6-10 aryl-C_1-4 alkyl group, a C 6-10 aryl-C_1-4 alkyl group_1-4 alkyl, (4-10 membered heterocycloalkyl)-C_1-4 alkyl, (5-10 membered heteroaryl)-C_1-4 alkyl, -CN, -OR^a3A , -SR^a3A , -NR^c3A R^d3A , -NO₂ , -C(O)R^a3A , -C(O)OR^a3A , -C(O)NR^c3A R^d3A , -C(O)NR^c3A (OR^a3A ), -OC(O)R^a3A , -OC(O)NR^c3A R^d3A , -OC(O)OR^a3A , -OS(O)₂ R^b3A , -OS(O)₂ NR^c3A R^d3A , -NR^c3A C(O)R^a3A , -NR^c3A C(O)OR^a3A , -NR^c3A C(O)NR^c3A R^d3A , -NR^c3A S(O)₂ R^b3A , -NR^c3A S(O)₂ NR^c3A R^d3A , -NR^c3A OR^a3A , -NR^c3A S(O)R^b3A , -NR^c3A S(O)NR^c3A R^d3A , -S(O)R^b3A , -S(O)₂ R^b3A , -S(O)NR^c3A R^d3A , -S(O)₂ NR^c3A R^d3A , -C(=NR^e3A )R^a3A , -C(=NR^e3A )NR^c3A R^d3A , -NR^c3A C(=NR^e3A )R^a3A , -NR^c3A C(=NR^e3A )NR^c3A R^d3A ,-NR^c3AS (O)(=^NRe3A )^Rb3A , -NRc3AS(O)(=^NRe3A )^NRc3ARd3A, -OS(O)(=^NRe3A )^Rb3A , -S(O)(=^NRe3A )^Rb3A_, -S(O)⁽ =^NRe3A )^NRc3ARd3A , -C^{(O)NRc3AS(O)2Rb3A, -C(O)NRc3AS(O)2NRc3ARd3A,}_-S^(O)_2NRc3AC^(O )^Rb3A ,^-NRc3AS (O)^NRc3AC (O)^Rb3A and^-P (O)^Rf3ARg3A , wherein the^C1-6 alkyl, the_C2-6 alkenyl, the_C the C_2-6 alkynyl, the C_1-6 haloalkyl, the C_3-10 cycloalkyl, the C_6-10 aryl, the 4-10 membered heterocycloalkyl, the 5-10 membered heteroaryl, the C_3-10 cycloalkyl-C_1-4 alkyl, the C_6-10 aryl-C_1-4 alkyl, the (4-10 membered heterocycloalkyl)-C_1-4 alkyl and the (5-10 membered heteroaryl)-C_1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected^RG substituents; each R^a3A , R^c3A and R^d3A are independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C 2-6 alkenyl, C_2-6 alkynyl, C 3-10 cycloalkyl, C_1-4 alkyl, C_{6-10 aryl-C 1-4} alkyl, C_1-4 alkyl, (4-10 membered heterocycloalkyl)-C_1-4 alkyl and (5-10 membered heteroaryl)-C_1-4 alkyl, wherein the C_1-6 alkyl, the C_2-6 alkenyl, the C_2-6 alkynyl, the C_1-6 haloalkyl, the C 3-10 cycloalkyl, the C_6-10^aryl , the^4-10 membered heterocycloalkyl, the^5-10 membered heteroaryl, the C_3-10 cycloalkyl-C_1-4 alkyl, the C 6-10 aryl-C_1-4 alkyl, the C_6-10 aryl-C 1-4 alkyl, the C_6-10 aryl-C 1-4 alkyl, the C 6-10 aryl-C 1-4 alkyl, the C_6-10 aryl-C_1-4 alkyl, the C_6-10 aryl-C wherein the (4-10 membered heterocycloalkyl)-C_1-4 alkyl, the (4-10 membered heterocycloalkyl)-C_1-4 alkyl and the (5-10 membered heteroaryl)-C_1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected^RG substituents; or any R^c3A and R^d3A attached to the same N atom together with the N atom to which they are attached form a 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected^RG substituents; each R^b3A is independently selected from C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C R b3A is a C_1-6 alkyl, a C 1-6 halogenalkyl, a C_2-6 alkenyl, a C_2-6 alkynyl, a C 3-10 cycloalkyl, a C_6-10 aryl,_{a 4-10} membered heterocycloalkyl, a 5-10 membered heteroaryl, a C_3-10 cycloalkyl-C_1-4 alkyl, a C 6-10 aryl-C 1-4 alkyl, a (4-10 membered heterocycloalkyl)-C_1-4 alkyl and a (^5-10 membered heteroaryl)-C 1-4 alkyl, wherein the C_1-6 alkyl, the C_1-6 halogenalkyl, the C_2-6 alkenyl, the C_2-6 alkynyl, the C_3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocycloalkyl, the 5-10 membered heteroaryl, the C_3-10 cycloalkyl-C_1-4 alkyl, the C_6-10 aryl-C The (4-10 membered heterocycloalkyl)-C_1-4 alkyl, the (5-10 membered heteroaryl)-C_1-4 alkyl, and the (4-10 membered heterocycloalkyl)-C_1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected^R substituents; each R^e3A is independently selected from H, OH, CN, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 halogenalkyl, C_1-6 halogenalkoxy, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C_3-10 cycloalkyl-C_1-4 alkyl, C_6-10 aryl-C_1-4 alkyl, (4-10 membered heterocycloalkyl)-C each^Rf3A and^Rg3A is independently selected from H,_C1-6 alkyl,_C1-6 alkoxy, C1-6 halogenalkyl,_C1-6 halogenalkoxy, C2-6 alkenyl, C2-6 alkynyl,_C3-10 cycloalkyl, C6-10 aryl,_4-10 membered heterocycloalkyl,_5-10 membered heteroaryl, C3-10 cycloalkyl-_C1-4 alkyl,_C6-10 aryl-_C1-4 alkyl, (_4-10 membered heterocycloalkyl)-C1-4 alkyl and (5-10 membered heteroaryl)-C1-4 alkyl; R4 is selected from pendoxy, halogen,_C1-6 alkyl,_C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl,_4-10 membered heterocycloalkyl,_5-10 membered heteroaryl,^C3-10 cycloalkyl-_C1-4 alkyl, C6-10 aryl-_C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl and (_5-10 membered heteroaryl)-C1-4 alkyl; C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C_3-10 cycloalkyl-C_1-4 alkyl, C_6-10 aryl-C_1-4 alkyl, (4-10 membered heterocycloalkyl)-C_1-4 alkyl, (5-10 membered heteroaryl)-C_1-4 alkyl, -CN, -OR^a4 , -SR^a4 , -NR^c4 R^d4 , -NO₂ , -C(O)R^a4 , -C(O)OR^a4 , -C(O)NR^c4 R^d4 , -C(O)NR^c4 (OR^a4 ), -OC(O)R^a4 , -OC(O)NR^c4 R^d4 , -OC(O)OR^a4 , -OS(O)₂ R^b4 , -OS(O)₂ NR^c4 R^d4 , -NR^c4 C(O)R^a4 , -NR^c4 C(O)OR^a4 , -NR^c4 C(O)NR^c4 R^d4 , -NR^c4 S(O)₂ R^b4 , -NR^c4 S(O)₂ NR^c4 R^d4 , -NR^c4 OR^a4 , -NR^c4 S(O)R^b4 , -NR^c4 S(O)NR^c4 R^d4 , -S(O)R^b4 , -S(O)₂ R^b4 , -S(O)NR^c4 R^d4 , -S(O)₂ NR^c4 R^d4 , -C(=NR^e4 )R^a4 , -C(=NR^e4 )NR^c4 R^d4 , -NR^c4 C(=NR^e4 )R^a4 , -NR^c4 C(=NR^e4 )NR^c4 R^d4 , -NR^c4 S(O)(=NR^e4 )R^b4 , -NR^c4 S(O)(=NR^e4 )NR^c4 R^d4 , -OS(O)(=NR^e4 )R^b4 , -S(O)(=NR^e4 )R^b4 , -S(O)(=NR^e4 )NR^c4 R^d4 , -C(O)NR^c4 S(O)₂ R^b4 , -C(O)NR^c4 S(O)₂ NR^c4 R^d4 , -S(O)₂ NR^c4 C(O)R^b4 , -NR^c4 S(O)NR^c4 C(O)R^b4 and -P(O)R^f4 R^g4 , where R⁴ is the C_1-6 alkyl, the C The C_2-6 alkenyl, the C_2-6 alkynyl, the C_1-6 haloalkyl, the C_3-10 cycloalkyl, the C_6-10 aryl, the 4-10 membered heterocycloalkyl, the 5-10 membered heteroaryl, the C_3-10 cycloalkyl-C_1-4 alkyl, the C_6-10 aryl-C_1-4 alkyl, the (4-10 membered heterocycloalkyl)-C_1-4 alkyl and the (5-10 membered heteroaryl)-C_1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R^4A substituents; each R^a4 , R^c4 and R^d4 are independently selected from H, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C C_3-10 cycloalkyl, C_6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C_3-10 cycloalkyl-C_1-4 alkyl, C_6-10 aryl-C_1-4 alkyl, (4-10 membered heterocycloalkyl)-C_1-4 alkyl and (5-10 membered heteroaryl)-C_1-4 alkyl, wherein R^a4 , R^c4 and R^d4 are the C_1-6 alkyl, the C_2-6 alkenyl, the C_2-6 alkynyl, the C_1-6 haloalkyl, the C_3-10 cycloalkyl, the C_6-10 aryl, the 4-10 membered heterocycloalkyl, the 5-10 membered heteroaryl, the C_3-10 cycloalkyl-C_1-4 alkyl, the C_6-10 membered heterocycloalkyl-C_1-4 alkyl, the (4-10 membered heterocycloalkyl)-C_1-4 alkyl and the (5-10 membered heteroaryl)-C_1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R^4A substituents; or any R^c4 and R^d4 attached to the same N atom together with the N atom to which they are attached form a 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R^4A substituents; each R^b4 is independently selected from C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C R b4 is a C_1-6 alkyl, a C 1-6 halogen alkyl, a C_2-6 alkenyl, a C_2-6 alkynyl, a C 3-10 cycloalkyl, a C_6-10 aryl,_{a 4-10} membered heterocycloalkyl, a 5-10 membered heteroaryl, a C 3-10 cycloalkyl-C_1-4 alkyl, a C_6-10 aryl-C_1-4 alkyl, a (4-10 membered heterocycloalkyl)-C 1-4 alkyl and a (5-10 membered heteroaryl)-C_1-4 alkyl, wherein R^b4 is a C_1-6 alkyl, a C_1-6 halogen alkyl, a C 2-6 alkenyl, a C_2-6 alkynyl, a C_3-10 cycloalkyl, a C 6-10 aryl, a 4-10 membered heterocycloalkyl, a 5-10 membered heteroaryl, a C_3-10 cycloalkyl-C_1-4 alkyl, a C_6-10 aryl-C The (4-10 membered heterocycloalkyl)-C_1-4 alkyl, the (5-10 membered heteroaryl)-C_1-4 alkyl, and the (4-10 membered heterocycloalkyl)-C_1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R^4A substituents; each R^e4 is independently selected from H, OH, CN, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 halogenalkyl, C_1-6 halogenalkoxy, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C_3-10 cycloalkyl-C_1-4 alkyl, C_6-10 aryl-C_1-4 alkyl, (4-10 membered heterocycloalkyl)-C each^Rf4 and^Rg4 are independently selected from H,_C1-6 alkyl,_C1-6 alkoxy, C1-6 halogenalkyl,_C1-6 halogenalkoxy, C2-6 alkenyl, C2-6 alkynyl,_C3-10 cycloalkyl, C6-10 aryl,_4-10 membered heterocycloalkyl,_5-10 membered heteroaryl, C3-10 cycloalkyl-_C1-4 alkyl,_C6-10 aryl-C1-4 alkyl, (_4-10 membered heterocycloalkyl)-C1-4 alkyl and_(5-10 membered heteroaryl)-C1-4 alkyl; each R4A is independently selected from pendoxy, H, halogen, C1-6 alkyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl,_5-10 membered heteroaryl, C3-10 cycloalkyl-_C1-4 alkyl,_C6-10 aryl-_C1-4 alkyl, (4-10 membered heterocycloalkyl)_-C1-4 alkyl and (5-10 membered heteroaryl)-C1-4 alkyl; each^R4A is independently selected from pendoxy, H, halogen, C1-6 alkyl, C2-6 alkynyl, C2-6 alkynyl, C3-10 cycloalkyl,_C6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl,_C6-10 aryl-C1-4 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 haloalkyl, C_3-10 cycloalkyl, C_6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C_3-10 cycloalkyl-C_1-4 alkyl, C_6-10 aryl-C_1-4 alkyl, (4-10 membered heterocycloalkyl)-C_1-4 alkyl, (5-10 membered heteroaryl)-C_1-4 alkyl, -CN, -OR^a4A , -SR^a4A , -NR^c4A R^d4A , -NO₂ , -C(O)R^a4A , -C(O)OR^a4A , -C(O)NR^c4A R^d4A , -C(O)NR^c4A (OR^a4A ), -OC(O)R^a4A , -OC(O)NR^c4A R^d4A , -OC(O)OR^a4A , -OS(O)₂ R^b4A , -OS(O)₂ NR^c4A R^d4A , -NR^c4A C(O)R^a4A , -NR^c4A C(O)OR^a4A , -NR^c4A C(O)NR^c4A R^d4A , -NR^c4A S(O)₂ R^b4A , -NR^c4A S(O)₂ NR^c4A R^d4A , -NR^c4A OR^a4A , -NR^c4A S(O)R^b4A , -NR^c4A S(O)NR^c4A R^d4A , -S(O)R^b4A , -S(O)₂ R^b4A , -S(O)NR^c4A R^d4A , -S(O)₂ NR^c4A R^d4A , -C(=NR^e4A )R^a4A , -C(=NR^e4A )NR^c4A R^d4A , -NR^c4A C(=NR^e4A )R^a4A , -NR^c4A C(=NR^e4A )NR^c4A R^d4A , -NR^c4A S(O)(=NR^e4A )R^b4A , -NR^c4A S(O)(=NR^e4A )NR^c4A R^d4A , -OS(O)(=NR^e4A )R^b4A , -S(O)(=NR^e4A )R^b4A , -S(O)(=NR^e4A )NR^c4A R^d4A , -C(O)NR^c4A S(O)₂ R^b4A , -C(O)NR^c4A S(O)₂ NR^c4A R^d4A , -S(O)₂ NR^c4A C(O)R^b4A , -NR^c4A S(O)NR^c4A C(O)R^b4A and -P(O)R^f4A R^g4A , wherein R^4A is the C_1-6 alkyl, the C_2-6 alkenyl, the C_2-6 alkynyl, the C_1-6 haloalkyl, the C_3-10 cycloalkyl, the C_6-10 aryl, the 4-10 membered heterocycloalkyl, the 5-10 membered heteroaryl, the C_3-10 cycloalkyl-C_1-4 alkyl, the C_6-10 aryl-C_1-4 alkyl, the (4-10 membered heterocycloalkyl)-C_1-4 alkyl and the (5-10 membered heteroaryl)-C wherein each of^Ra4A ,^Rc4A and Rd4A is optionally substituted with_1, 2, 3, 4, 5 or 6 independently selected^R substituents; each of Ra4A, Rc4A and^Rd4A is independently selected from H,_C1-6 alkyl,_C1-6 haloalkyl, C2-6 alkenyl,_C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl,_4-10 membered heterocycloalkyl,_5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-_C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl and_(5-10 membered heteroaryl)-C1-4 alkyl, wherein the C1-6 alkyl, C2-6 haloalkyl,_{C2-6 alkenyl, C2-6} alkynyl,_C3-10 cycloalkyl, C6-10 aryl,_4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl, C6-10 aryl-_C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl and (5-10 membered heteroaryl)_-C1-4 alkyl, wherein the C1-6^alkyl , C2-6 haloalkyl, C2-6^{alkenyl, C2-6 alkynyl} ,^C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heterocycloalkyl,_5-10 membered heteroaryl the C_2-6 alkenyl, the C_2-6 alkynyl, the C_1-6 haloalkyl, the C_3-10 cycloalkyl, the C_6-10 aryl, the 4-10 membered heterocycloalkyl, the 5-10 membered heteroaryl, the C_3-10 cycloalkyl-C_1-4 alkyl, the C_6-10 aryl-C_1-4 alkyl, the (4-10 membered heterocycloalkyl)-C_1-4 alkyl and the (5-10 membered heteroaryl)-C_1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R^G substituents; or any R^c4A and R c4A attached to the same N atom^d4A together with the N atom to which it is attached forms a 4-10 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R^G substituents; each R^b4A is independently selected from C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C_3-10 cycloalkyl-C_1-4 alkyl, C_6-10 aryl-C_1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C_1-4 alkyl, wherein the C 1-6 alkyl group of R^b4A is C 6-10 aryl-C_1-4 alkyl, The C_1-6 alkyl, the C_1-6 halogenalkyl, the C_2-6 alkenyl, the C_2-6 alkynyl, the C_3-10 cycloalkyl, the C_6-10 aryl, the 4-10 membered heterocycloalkyl, the 5-10 membered heteroaryl, the C_3-10 cycloalkyl-C_1-4 alkyl, the C_6-10 aryl-C_1-4 alkyl, the (4-10 membered heterocycloalkyl)-C_1-4 alkyl and the (5-10 membered heteroaryl)-C_1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R^G substituents; each R^e4A is independently selected from H, OH, CN, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 halogenalkyl, C_1-6 halogenalkoxy, C Rf4A and Rg4A are independently selected from H,_C1-6 alkyl,_C1-6 alkoxy,_C1-6 halogenalkyl, C1-6 halogenalkoxy,_C2-6 alkenyl, C2-6 alkynyl,_C3-10 cycloalkyl, C6-10 aryl,_{4-10 membered heterocycloalkyl, 5-10 memberedheteroaryl} , C3-10 cycloalkyl-_C1-4 alkyl, C6-10 aryl-_C1-4 alkyl, (4-10 membered heterocycloalkyl)-C1-4 alkyl and (5-10 membered heteroaryl)_-C1-4 alkyl; each^Rf4A and^Rg4A are independently selected from H,_C1-6 alkyl,_C1-6 alkoxy,_C1-6 halogenalkyl, C1-6 halogenalkoxy,_C2-6 alkenyl,_C2-6 alkynyl, C3-10 cycloalkyl,_C1-4 alkyl,_C6-10 aryl-C1-4 alkyl,_{C 6-10} membered heteroaryl, C 1-4 alkyl, C_6-10 membered heterocycloalkyl, C_1-4 alkyl, (_4-10 membered heterocycloalkyl)-C_1-4 alkyl and (5-10 membered heteroaryl)-C_1-4 alkyl_; each^RG is independently selected from H, D, OH, CN, halogen, pendoxy, C_1-4 alkyl, C 2-4 alkenyl, C_2-4 alkynyl, C_1-4 haloalkyl, cyano-C_1-4 alkyl, HO-C_{1-4 alkyl, C 1-4alkoxy} -_{C 1-4alkyl} , C_3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C_1-4 alkoxy, C a_1-4 halogen alkoxy group, an amino group, a C_1-3 alkylamino group, a di(C_1-3 alkyl)amino group, a thio group,_{a C 1-3alkylthio} group, a C_1-3 alkylsulfinyl group, a C_1-3 alkylsulfonyl group, an aminoformyl group, a C 1-3 alkylaminoformyl group, a di(C_1-3 alkyl)aminoformyl group, a carboxyl group,_{a C 1-3alkylcarbonyl} group, a C_1-3 alkoxycarbonyl group, a C_1-3 alkylcarbonyloxy group, a C_1-3 alkylcarbonylamino group, a C 1-3 alkoxycarbonylamino group, an aminocarbonyloxy group, a C_1-3 alkylaminocarbonyloxy group, a di(C_1-3 alkyl)aminocarbonyloxy group, a C_1-3 alkylsulfonylamino group, an aminosulfonyl group, a C_1-3 alkylaminosulfonyl group, a di(C 1-3 alkyl) The present invention also comprises a_{C 1-3} alkyl)aminosulfonyl group, an aminosulfonylamino group, a C_1-3 alkylaminosulfonylamino group, a di(C_1-3 alkyl)aminosulfonylamino group, an aminocarbonylamino group, a C_1-3 alkylaminocarbonylamino group and a di(C_1-3 alkyl)aminocarbonylamino group.如請求項1之化合物，其中該式I化合物為式II化合物：II或其醫藥學上可接受之鹽，其中： R¹係選自鹵基、C_1-3烷基及C_1-3鹵烷基； R²為C_1-3烷基； R³係選自吡唑基、嘧啶基、六氫吡啶基及C(O)NR^c3R^d3，其中R³之該吡唑基、該吡啶基、該嘧啶基及該六氫吡啶基各自視情況經一個選自C_1-3烷基、胺基及-C(O)C_1-3烷基之R^3A取代基取代； 每一R^c3及R^d3獨立地選自C_1-3烷基及C_1-3鹵烷基； R⁴為鹵基；且 R^G為H或D。The compound of claim 1, wherein the compound of formula I is a compound of formula II:II or a pharmaceutically acceptable salt thereof, wherein: R¹ is selected from halogen, C_1-3 alkyl and C_1-3 haloalkyl; R² is C_1-3 alkyl; R³ is selected from pyrazolyl, pyrimidinyl, hexahydropyridinyl and C(O)NR^c3 R^d3 , wherein the pyrazolyl, pyridinyl, pyrimidinyl and hexahydropyridinyl of R³ are each optionally substituted with an R^3A substituent selected from C_1-3 alkyl, amino and -C(O)C_1-3 alkyl; each R^c3 and R^d3 are independently selected from C_1-3 alkyl and C_1-3 haloalkyl; R⁴ is halo; and^RG is H or D.如請求項1或2之化合物或其醫藥學上可接受之鹽，其中R¹係選自氯、甲基及三氟甲基。The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from chloro, methyl and trifluoromethyl.如請求項1至3中任一項之化合物或其醫藥學上可接受之鹽，其中R²係選自甲基及三氘代甲基。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R² is selected from methyl and trideuterated methyl.如請求項1至4中任一項之化合物或其醫藥學上可接受之鹽，其中R³為C(O)NR^c3R^d3。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R³ is C(O)NR^{c 3} R^{d 3} .如請求項1至5中任一項之化合物或其醫藥學上可接受之鹽，其中R^c3及R^d3各自獨立地選自甲基及三氘代甲基。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R^c3 and R^d3 are each independently selected from methyl and trideuterated methyl.如請求項1至5中任一項之化合物或其醫藥學上可接受之鹽，其中R^c3及R^d3各自為甲基。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R^c3 and R^d3 are each methyl.如請求項1至5中任一項之化合物或其醫藥學上可接受之鹽，其中R^c3及R^d3各自為三氘代甲基。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R^c3 and R^d3 are each trideuterated methyl.如請求項1至4中任一項之化合物或其醫藥學上可接受之鹽，其中R³係選自吡唑基、嘧啶基及六氫吡啶基，其中R³之該吡唑基、該嘧啶基及該六氫吡啶基各自視情況經一個選自C_1-3烷基、胺基及-C(O)C_1-3烷基之R^3A取代基取代。The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R³ is selected from pyrazolyl, pyrimidinyl and hexahydropyridinyl, wherein the pyrazolyl, pyrimidinyl and hexahydropyridinyl of R³ are each optionally substituted with an R^3A substituent selected from C_1-3 alkyl, amino and -C(O)C_1-3 alkyl.如請求項1至4中任一項之化合物或其醫藥學上可接受之鹽，其中R³係選自吡唑基、吡啶基、嘧啶基及六氫吡啶基，其中R³之該吡唑基、該嘧啶基及該六氫吡啶基各自視情況經一個選自甲基、胺基及甲基羰基之R^3A取代基取代。The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R³ is selected from pyrazolyl, pyridinyl, pyrimidinyl and hexahydropyridinyl, wherein the pyrazolyl, pyrimidinyl and hexahydropyridinyl of R 3 are each optionally substituted with an R^3A substituent selected from methyl, amino and methylcarbonyl^.如請求項1至4中任一項之化合物或其醫藥學上可接受之鹽，其中R³係選自甲基吡唑基、胺基嘧啶基及(甲基羰基)六氫吡啶基。The compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R³ is selected from methylpyrazolyl, aminopyrimidinyl and (methylcarbonyl)hexahydropyridinyl.如請求項1至11中任一項之化合物或其醫藥學上可接受之鹽，其中R⁴為氟或氯。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R⁴ is fluorine or chlorine.如請求項1至12中任一項之化合物或其醫藥學上可接受之鹽，其中R^G為H。The compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein^RG is H.如請求項1至12中任一項之化合物或其醫藥學上可接受之鹽，其中R^G為D。The compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein^RG is D.如請求項1或2之化合物或其醫藥學上可接受之鹽，其中： R¹係選自氯、甲基及三氟甲基； R²係選自甲基及三氘代甲基； R³係選自吡唑基、吡啶基、嘧啶基、六氫吡啶基及C(O)NR^c3R^d3，其中R³之該吡唑基、該嘧啶基及該六氫吡啶基各自視情況經一個選自甲基、胺基及甲基羰基之R^3A取代基取代； R^c3及R^d3各自獨立地選自甲基及三氘代甲基； R⁴為氟或氯；且 R^G為H或D。The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: R¹ is selected from chloro, methyl and trifluoromethyl; R² is selected from methyl and trideuterated methyl; R³ is selected from pyrazolyl, pyridyl, pyrimidinyl, hexahydropyridinyl and C(O)NR^c3 R^d3 , wherein the pyrazolyl, the pyrimidinyl and the hexahydropyridinyl of R³ are each optionally substituted with an R^3A substituent selected from methyl, amino and methylcarbonyl; R^c3 and R^d3 are each independently selected from methyl and trideuterated methyl; R⁴ is fluoro or chloro; and^RG is H or D.如請求項1之化合物，其中該式I化合物為式III化合物：III或其醫藥學上可接受之鹽，其中： R¹為鹵基或C_1-3烷基； R²為C_1-3烷基； R³係選自嘧啶基、氮雜環丁烷基甲基、吡唑基、吡啶基、六氫吡啶基、2H-吡唑并[3,4-b]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,5-a]吡啶基、咪唑基、噻唑基、6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪基及C(O)NR^c3R^d3，其中R³之該嘧啶基、該氮雜環丁烷基甲基、該吡唑基、該吡啶基、該六氫吡啶基、該2H-吡唑并[3,4-b]吡啶基、該吡唑并[1,5-a]吡啶基、該吡唑并[1,5-a]嘧啶基、該咪唑并[1,5-a]吡啶基、該咪唑基、該噻唑基及該6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪基各自視情況經1或2個R^3A取代基取代； 每一R^3A獨立地選自鹵基、C_1-3烷基、C_1-3羥基烷基、C_1-3烷氧基、氧雜環丁烷基、胺基、C_1-3烷基胺基、二(C_1-3烷基)胺基、-C(O)C_1-3烷基、-C(O)C_1-3羥基烷基、-C(O)C_3-6環烷基及-S(O)₂C_1-3烷基； R⁴係選自H、鹵基、C_1-3烷基及C_1-3烷氧基； R^4A係選自C_1-3烷基、氮雜環丁烷基及六氫吡啶基，其中R⁴之該氮雜環丁烷基及該六氫吡啶基各自視情況經C_1-3烷基取代；且 R^G為H或D。The compound of claim 1, wherein the compound of formula I is a compound of formula III:III or a pharmaceutically acceptable salt thereof, wherein: R¹ is a halogen group or a C_1-3 alkyl group; R² is a C_1-3 alkyl group; R³ is selected from pyrimidinyl, azacyclobutanylmethyl, pyrazolyl, pyridinyl, hexahydropyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,5-a]pyridinyl, imidazolyl, thiazolyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl and C(O)NR^c3 R^d3 , wherein R³ , the pyrimidinyl, the azacyclobutanylmethyl, the pyrazolyl, the pyridinyl, the hexahydropyridinyl, the 2H-pyrazolo[3,4-b]pyridinyl, the pyrazolo[1,5-a]pyridinyl, the pyrazolo[1,5-a]pyrimidinyl, the imidazo[1,5-a]pyridinyl, the imidazolyl, the thiazolyl and the 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl are each optionally substituted with 1 or 2 R^3A substituents; each R^3A is independently selected from halogen, C_1-3 alkyl, C_1-3 hydroxyalkyl, C_1-3 alkoxy, oxacyclobutanyl, amino, C_1-3 alkylamino, di(C_1-3 alkyl)amino, -C(O)C_wherein the_{azacyclobutane} group and the_{hexahydropyridinyl} group of^{R4 are each}_optionally substituted^with a_{C1-3alkylgroup} ; and^RG is_H^or_D.如請求項1或16之化合物或其醫藥學上可接受之鹽，其中R¹為氯或甲基。The compound of claim 1 or 16 or a pharmaceutically acceptable salt thereof, wherein R¹ is chloro or methyl.如請求項1、16及17中任一項之化合物或其醫藥學上可接受之鹽，其中R²為甲基或三氘代甲基。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1, 16 and 17, wherein R² is methyl or trideuterated methyl.如請求項1及16至18中任一項之化合物或其醫藥學上可接受之鹽，其中R³係選自嘧啶基、氮雜環丁烷基甲基、吡唑基、吡啶基、六氫吡啶基、2H-吡唑并[3,4-b]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基及咪唑并[1,5-a]吡啶基，其中R³之該嘧啶基、該氮雜環丁烷基甲基、該吡唑基、該吡啶基、該六氫吡啶基、該2H-吡唑并[3,4-b]吡啶基、該吡唑并[1,5-a]吡啶基、該吡唑并[1,5-a]嘧啶基及該咪唑并[1,5-a]吡啶基各自視情況經1或2個R^3A取代基取代。The compound of any one of claims 1 and 16 to 18, or a pharmaceutically acceptable salt thereof, wherein R³ is selected from pyrimidinyl, azacyclobutanylmethyl, pyrazolyl, pyridinyl, hexahydropyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl and imidazo[1,5-a]pyridinyl, wherein the^pyrimidinyl , the azacyclobutanylmethyl, the pyrazolyl, the pyridinyl, the hexahydropyridinyl, the 2H-pyrazolo[3,4-b]pyridinyl, the pyrazolo[1,5-a]pyridinyl, the pyrazolo[1,5-a]pyrimidinyl and the imidazo[1,5-a]pyridinyl of R 3 are each optionally substituted by 1 or 2 R^3A Substituent substitution.如請求項1及16至19中任一項之化合物或其醫藥學上可接受之鹽，其中每一R^3A獨立地選自甲基、氟、氯、甲氧基、胺基、甲基胺基、二甲基胺基、羥基甲基、羥基乙基、氧雜環丁烷基、甲基羰基、異丙基羰基、羥基甲基羰基、環丙基羰基、甲基磺醯基、異丙基磺醯基及環丙基磺醯基。The compound of any one of claims 1 and 16 to 19, or a pharmaceutically acceptable salt thereof, wherein each R^3A is independently selected from methyl, fluoro, chloro, methoxy, amino, methylamino, dimethylamino, hydroxymethyl, hydroxyethyl, oxacyclobutane, methylcarbonyl, isopropylcarbonyl, hydroxymethylcarbonyl, cyclopropylcarbonyl, methylsulfonyl, isopropylsulfonyl, and cyclopropylsulfonyl.如請求項1及16至18中任一項之化合物或其醫藥學上可接受之鹽，其中R³係選自(二氟氮雜環丁烷基)甲基、氧雜環丁烷基六氫吡啶基、(甲基羰基)六氫吡啶基、(異丙基羰基)六氫吡啶基、(羥基甲基羰基)六氫吡啶基、(環丙基羰基)六氫吡啶基、(甲基磺醯基)六氫吡啶基、(異丙基磺醯基)六氫吡啶基、(環丙基磺醯基)六氫吡啶基、吡唑基、甲基吡唑基、(羥基乙基)吡唑基、吡啶基、(羥基甲基)吡啶基、胺基吡啶基、(胺基)(氯)吡啶基、(甲基胺基)吡啶基、(二甲基胺基)吡啶基、胺基嘧啶基、(羥基甲基)嘧啶基、(胺基)(氟)嘧啶基、(胺基)(甲基)嘧啶基、(胺基)(甲氧基)嘧啶基、甲基-2H-吡唑并[3,4-b]吡啶、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,5-a]吡啶基、(胺基)(氟)吡啶基、甲基咪唑基、胺基噻唑基、(胺基)(甲基)噻唑基及6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪基。The compound of any one of claims 1 and 16 to 18 or a pharmaceutically acceptable salt thereof, wherein R³ is selected from (difluoroazolocyclobutane)methyl, oxocyclobutane hexahydropyridinyl, (methylcarbonyl)hexahydropyridinyl, (isopropylcarbonyl)hexahydropyridinyl, (hydroxymethylcarbonyl)hexahydropyridinyl, (cyclopropylcarbonyl)hexahydropyridinyl, (methylsulfonyl)hexahydropyridinyl, (isopropylsulfonyl)hexahydropyridinyl, (cyclopropylsulfonyl)hexahydropyridinyl, pyrazolyl, methylpyrazolyl, (hydroxyethyl)pyrazolyl, pyridinyl, (hydroxymethyl)pyridinyl, aminopyridinyl, (amino)(chloro)pyridinyl, (methylamino)pyridinyl, (dichloropyridinyl) pyrimidinyl, (amino)(methyl)pyrimidinyl, (amino)(fluoro)pyrimidinyl, (amino)(methyl)pyrimidinyl, (amino)(methoxy)pyrimidinyl, methyl-2H-pyrazolo[3,4-b]pyridine, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,5-a]pyridinyl, (amino)(fluoro)pyridinyl, methylimidazolyl, aminothiazolyl, (amino)(methyl)thiazolyl, and 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl.如請求項1及16至18中任一項之化合物或其醫藥學上可接受之鹽，其中R³為C(O)NR^c3R^d3。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 and 16 to 18, wherein R³ is C(O)NR^{c 3} R^{d 3} .如請求項1、16至18及22中任一項之化合物或其醫藥學上可接受之鹽，其中R^c3及R^d3各自獨立地選自甲基及三氘代甲基。The compound of any one of claims 1, 16 to 18 and 22, or a pharmaceutically acceptable salt thereof, wherein R^c3 and R^d3 are each independently selected from methyl and trideuterated methyl.如請求項1、16至18及22中任一項之化合物或其醫藥學上可接受之鹽，其中R^c3及R^d3各自為甲基。The compound of any one of claims 1, 16 to 18 and 22, or a pharmaceutically acceptable salt thereof, wherein R^c3 and R^d3 are each methyl.如請求項1、16至18及22中任一項之化合物或其醫藥學上可接受之鹽，其中R^c3及R^d3各自為三氘代甲基。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1, 16 to 18 and 22, wherein R^c3 and R^d3 are each trideuteromethyl.如請求項1及16至25中任一項之化合物或其醫藥學上可接受之鹽，其中R⁴係選自H、氟、氯、甲基及甲氧基。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 and 16 to 25, wherein R⁴ is selected from H, fluoro, chloro, methyl and methoxy.如請求項1及16至26中任一項之化合物或其醫藥學上可接受之鹽，其中R^4A係選自甲基、三氘代甲基、乙基、氮雜環丁烷基及六氫吡啶基，其中R^4A之該氮雜環丁烷基及該六氫吡啶基各自視情況經甲基取代。The compound of any one of claims 1 and 16 to 26, or a pharmaceutically acceptable salt thereof, wherein R^4A is selected from methyl, trideuterated methyl, ethyl, azacyclobutane and hexahydropyridinyl, wherein the azacyclobutane and hexahydropyridinyl of R^4A are each optionally substituted with methyl.如請求項1及16至26中任一項之化合物或其醫藥學上可接受之鹽，其中R^4A係選自甲基、三氘代甲基、乙基、甲基氮雜環丁烷基及甲基六氫吡啶基。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 and 16 to 26, wherein R^4A is selected from methyl, trideuteromethyl, ethyl, methylazacyclobutane and methylhexahydropyridinyl.如請求項1及16至28中任一項之化合物或其醫藥學上可接受之鹽，其中R^G為H。The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 and 16 to 28, wherein^RG is H.如請求項1及16至28中任一項之化合物或其醫藥學上可接受之鹽，其中R^G為D。The compound of any one of claims 1 and 16 to 28, or a pharmaceutically acceptable salt thereof, wherein^RG is D.如請求項1或16之化合物或其醫藥學上可接受之鹽，其中： R¹為氯或甲基； R²為甲基或三氘代甲基； R³係選自嘧啶基、氮雜環丁烷基甲基、吡唑基、吡啶基、六氫吡啶基、2H-吡唑并[3,4-b]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,5-a]吡啶基、咪唑基、噻唑基、6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪基及C(O)NR^c3R^d3，其中R³之該嘧啶基、該氮雜環丁烷基甲基、該吡唑基、該吡啶基、該六氫吡啶基、該2H-吡唑并[3,4-b]吡啶基、該吡唑并[1,5-a]吡啶基、該吡唑并[1,5-a]嘧啶基、該咪唑并[1,5-a]吡啶基、該咪唑基、該噻唑基及該6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪基各自視情況經1或2個R^3A取代基取代； 每一R^3A獨立地選自甲基、氟、氯、甲氧基、胺基、甲基胺基、二甲基胺基、羥基甲基、羥基乙基、氧雜環丁烷基、甲基羰基、異丙基羰基、羥基甲基羰基、環丙基羰基、甲基磺醯基、異丙基磺醯基及環丙基磺醯基； R^c3及R^d3各自獨立地選自甲基及三氘代甲基； R⁴係選自H、氟、氯、甲基及甲氧基； R^4A係選自甲基、乙基、三氘代甲基、氮雜環丁烷基及六氫吡啶基，其中R^4A之該氮雜環丁烷基及該六氫吡啶基各自視情況經甲基取代；且 R^G為H或D。The compound of claim 1 or 16, or a pharmaceutically acceptable salt thereof, wherein: R¹ is chloro or methyl; R² is methyl or trideuterated methyl; R³ is selected from pyrimidinyl, azacyclobutanylmethyl, pyrazolyl, pyridinyl, hexahydropyridinyl, 2H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,5-a]pyridinyl, imidazolyl, thiazolyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl and C(O)NR^c3 R^d3 , wherein R³ , the pyrimidinyl, the azacyclobutanylmethyl, the pyrazolyl, the pyridinyl, the hexahydropyridinyl, the 2H-pyrazolo[3,4-b]pyridinyl, the pyrazolo[1,5-a]pyridinyl, the pyrazolo[1,5-a]pyrimidinyl, the imidazo[1,5-a]pyridinyl, the imidazolyl, the thiazolyl and the 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl are each optionally substituted with 1 or 2 R^3A substituents; each R^{R 3A} is independently selected from methyl, fluoro, chloro, methoxy, amino, methylamino, dimethylamino, hydroxymethyl, hydroxyethyl, oxacyclobutane, methylcarbonyl, isopropylcarbonyl, hydroxymethylcarbonyl, cyclopropylcarbonyl, methylsulfonyl, isopropylsulfonyl, and cyclopropylsulfonyl; R^c3 and R^d3 are each independently selected from methyl and trideuterated methyl; R⁴ is selected from H, fluoro, chloro, methyl, and methoxy; R^4A is selected from methyl, ethyl, trideuterated methyl, azacyclobutane, and hexahydropyridinyl, wherein the azacyclobutane and the hexahydropyridinyl of R^4A are each optionally substituted with methyl; and^RG is H or D.如請求項1之化合物，其中該化合物係選自： 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； (R)-9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-N,N-雙(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； (S)-9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-N,N-雙(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-7-甲基-N,N,4-參(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-N,N,7-三甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基-1-d)-4,7-二甲基-N,N-雙(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基-1-d)-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (R)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； (S)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(吡啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)-3-(吡啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 2-((1-(3-(1-乙醯基六氫吡啶-4-基)-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)-5-氟苯甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-7-氯-4-甲基-N,N-雙(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基-1-d)-7-氯-4-甲基-N,N-雙(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-N,N-雙(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,7-三甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基-1-d)-4-甲基-N,N-雙(甲基-d₃)-5-側氧基-7-(三氟甲基)-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(吡啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(6-(羥基甲基)吡啶-3-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-3-(6-(羥基甲基)吡啶-3-基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(2-(羥基甲基)嘧啶-5-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-3-(2-(羥基甲基)嘧啶-5-基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(2-(羥基甲基)吡啶-3-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(6-(甲基胺基)吡啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(6-(二甲基胺基)吡啶-3-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(1-(2-羥基乙基)-1H-吡唑-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(1-甲基-1H-吡唑-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(1H-吡唑-4-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(吡唑并[1,5-a]嘧啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基-4-甲基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基-5-氟吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(咪唑并[1,5-a]吡啶-6-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((2-胺甲醯基-6-氯吡啶-3-基)胺基)乙基-1-d)-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-6-氯吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((2-胺甲醯基-4-氯苯基)胺基)乙基-1-d)-7-甲基-N,N,4-參(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(1-環丙基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-N,N,4-參(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； (3-((1-(3-(雙(甲基-d3)胺甲醯基)-7-甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)-6-氯吡啶-2-基)胺基甲酸甲酯； 9-(1-((2-胺甲醯基-4-氯苯基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((4-氟-2-(1-甲基-1H-四唑-5-基)苯基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(1-環丙基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((4-氟-2-(1-甲基-1H-1,2,3-三唑-4-基)苯基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； (6-氯-3-((1-(3-(二甲基胺甲醯基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)吡啶-2-基)胺基甲酸甲酯； 9-(1-((4-氟-2-胺磺醯基苯基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((5-氯喹啉-8-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； N,N,4,7-四甲基-9-(1-((6-甲基-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 2-((1-(3-(1-乙醯基六氫吡啶-4-基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-5-氟苯甲醯胺； 2-((1-(3-(2-胺基嘧啶-5-基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-5-氟苯甲醯胺； 2-((1-(3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)-5-氟苯甲醯胺； 2-((1-(4,7-二甲基-3-(1-甲基-1H-吡唑-5-基)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-5-氟苯甲醯胺； 5-氟-2-((1-(7-甲基-4-(甲基-d3)-3-(1-甲基-1H-吡唑-5-基)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)苯甲醯胺； 2-((1-(3-(2-胺基嘧啶-5-基)-7-氯-4-甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-5-氟苯甲醯胺； 2-((1-(3-(2-胺基嘧啶-5-基)-7-氯-4-甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)-5-氟苯甲醯胺； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(1-(氧雜環丁-3-基)六氫吡啶-4-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(1-乙醯基六氫吡啶-4-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(1-(2-羥基乙醯基)六氫吡啶-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(1-乙醯基六氫吡啶-4-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(1-異丁醯基六氫吡啶-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(1-(環丙烷羰基)六氫吡啶-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(1-(甲基磺醯基)六氫吡啶-4-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(1-(異丙基磺醯基)六氫吡啶-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(1-(環丙基磺醯基)六氫吡啶-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-甲氧基-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d3)-9-(1-((6-甲基-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d3)-9-(1-((2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-甲氧基-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((4-氟-2-(1-(甲基-d3)-1H-四唑-5-基)苯基)胺基)乙基)-4,7-二甲基-3-(吡啶-3-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((4-氟-2-(1-甲基-1H-1,2,4-三唑-3-基)苯基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((4-氟-2-(1-甲基-1H-1,2,4-三唑-3-基)苯基)胺基)乙基)-4,7-二甲基-3-(1-甲基-1H-吡唑-5-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((4-氟-2-(1-甲基-1H-1,2,3-三唑-4-基)苯基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基-3-吡啶基)-9-[1-[4-氟-2-(1-甲基三唑-4-基)苯胺基]乙基]-4,7-二甲基-咪唑并[1,5-a]喹唑啉-5-酮； 3-(1-乙醯基六氫吡啶-4-基)-9-(1-(6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-(6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)乙基)-3-(1-(2-羥基乙醯基)六氫吡啶-4-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基吡啶-3-基)-9-((6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)甲基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-((6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)甲基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-((6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)甲基)-4,7-二甲基-3-(1-甲基-1H-吡唑-5-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-((6-氯-2,3-二氫-1H-吡啶并[2,3-b][1,4]噁嗪-1-基)甲基)-3-(2-(羥基甲基)嘧啶-5-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-((3-氟氮雜環丁-1-基)甲基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-((3-氟氮雜環丁-1-基)甲基)吡啶-3-基)胺基)乙基)-N-(2-羥基乙基)-N,4,7-三甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； ((6-氯-3-((1-(3-(二甲基胺甲醯基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)吡啶-2-基)甲基)胺基甲酸甲酯； (6-氯-3-(((3-(二甲基胺甲醯基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)甲基)胺基)吡啶-2-基)胺基甲酸甲酯； 9-[(6-氯-2,3-二氫吡啶并[2,3-b][1,4]噁嗪-1-基)甲基]-N,N,4,7-四甲基-5-側氧基-咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-[(6-氯-2,3-二氫吡啶并[2,3-b][1,4]噁嗪-1-基)甲基]-4,7-二甲基-5-側氧基-N,N-雙(三氘代甲基)咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-(1-甲基氮雜環丁-3-基)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-(1-甲基六氫吡啶-4-基)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-N,N,4,7-四甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-(1-甲基氮雜環丁-3-基)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 9-(1-((6-氯-2-(2-(1-甲基六氫吡啶-4-基)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-N,N,4-參(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； 3-(2-胺基嘧啶-5-基)-9-((6-氯-3,4-二氫-1,5-萘啶-1(2H)-基)甲基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-((3,3-二氟氮雜環丁-1-基)甲基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-(6-氯-3,4-二氫-1,5-萘啶-1(2H)-基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； (S)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； (R)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； (S)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； (R)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； (S)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； (R)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； (S)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (R)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (S)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (R)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (S)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (R)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (S)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (R)-3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (S)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-N,N-雙(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； (R)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-N,N-雙(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺； (S)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(2-(羥基甲基)嘧啶-5-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； (R)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(2-(羥基甲基)嘧啶-5-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； (S)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-3-(2-(羥基甲基)嘧啶-5-基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (R)-9-(1-((6-氯-2-(2-(甲基-d3)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-3-(2-(羥基甲基)嘧啶-5-基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (S)-2-((1-(3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)-5-氟苯甲醯胺； (R)-2-((1-(3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基-1-d)胺基)-5-氟苯甲醯胺； 3-(2-胺基嘧啶-5-基)-9-(1-(6-氯-3,4-二氫-1,5-萘啶-1(2H)-基)乙基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-乙基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d3)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (3-((1-(3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-6-氯吡啶-2-基)胺基甲酸甲酯； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1-甲基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氟-2-(1-甲基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1-環丙基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1-(氧雜環丁-3-基)-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(嘧啶-5-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(4-羥基六氫吡啶-1-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-嗎啉基吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1,3-二甲基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1,5-二甲基-1H-吡唑-4-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(5-甲基-1,3,4-噁二唑-2-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1,3,4-噁二唑-2-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(3-((1-(3-(2-胺基嘧啶-5-基)-7-甲基-4-(甲基-d₃)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)乙基)胺基)-6-氯吡啶-2-基)-1,2,4-噁二唑-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1-甲基-5-側氧基-4,5-二氫-1H-1,2,4-三唑-3-基)吡啶-3-基)胺基)乙基)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮； (3-(((3-(2-胺基嘧啶-5-基)-4,7-二甲基-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-9-基)甲基)胺基)-6-氯吡啶-2-基)胺基甲酸甲酯； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(1H-吡唑-5-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基-5-氯吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基-5-甲基吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(6-胺基-5-甲氧基吡啶-3-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基-4-甲氧基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(2-甲基-2H-吡唑并[3,4-b]吡啶-5-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(吡唑并[1,5-a]吡啶-6-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮；及 3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-乙基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 或其醫藥學上可接受之鹽。The compound of claim 1, wherein the compound is selected from: 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; (R )-9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; (S )-9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-N,N,7-trimethyl-4-(methyl-_d3) )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl-1-d)-4,7-dimethyl-N,N-bis(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d_{3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2} -Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d 3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)_-one )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; (R )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; (S )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)_-one )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-1-d)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(pyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )-3-(pyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 2-((1-(3-(1-acetylhexahydropyridin-4-yl)-7-methyl-4-(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-5-fluorobenzamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-7-chloro-4-methyl-N,N-bis(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl-1-d)-7-chloro-4-methyl-N,N-bis(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,7-trimethyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-(methyl-d 3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl-1-d)-4-methyl-N,N-bis(methyl-d₃ )-5-oxo-7-(trifluoromethyl)-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-(methyl-d₃ 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(6-(hydroxymethyl)pyridin-3-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-3-(6-(hydroxymethyl)pyridin-3-yl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(2-(hydroxymethyl)pyrimidin-5-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-3-(2-(hydroxymethyl)pyrimidin-5-yl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(2-(hydroxymethyl)pyridin-3-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-aminopyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-aminopyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(6-(methylamino)pyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(6-(dimethylamino)pyridin-3-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methyl-1H-pyrazol-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1H-pyrazol-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(pyrazolo[1,5-a]pyrimidin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one); 3-(2-amino-4-methylpyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-amino-5-fluoropyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(imidazo[1,5-a]pyridin-6-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((2-aminoformyl-6-chloropyridin-3-yl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-_d3) )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-6-chloropyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((2-aminoformyl-4-chlorophenyl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; methyl (3-((1-(3-(bis(methyl-d3)aminocarboxyl)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-6-chloropyridin-2-yl)carbamate; 9-(1-((2-aminoformyl-4-chlorophenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((4-fluoro-2-(1-methyl-1H-tetrazol-5-yl)phenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((4-fluoro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; Methyl (6-chloro-3-((1-(3-(dimethylaminoformyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)pyridin-2-yl)carbamate; 9-(1-((4-fluoro-2-sulfaminylphenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((5-chloroquinolin-8-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; N,N,4,7-Tetramethyl-9-(1-((6-methyl-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 2-((1-(3-(1-acetylhexahydropyridin-4-yl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-5-fluorobenzamide; 2-((1-(3-(2-aminopyrimidin-5-yl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-5-fluorobenzamide; 2-((1-(3-(2-aminopyrimidin-5-yl)-7-methyl-4-(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-5-fluorobenzamide; 2-((1-(4,7-dimethyl-3-(1-methyl-1H-pyrazol-5-yl)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-5-fluorobenzamide; 5-Fluoro-2-((1-(7-methyl-4-(methyl-d3)-3-(1-methyl-1H-pyrazol-5-yl)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)benzamide; 2-((1-(3-(2-aminopyrimidin-5-yl)-7-chloro-4-methyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-5-fluorobenzamide; 2-((1-(3-(2-aminopyrimidin-5-yl)-7-chloro-4-methyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-5-fluorobenzamide; 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-(oxocyclobutan-3-yl)hexahydropyridin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(1-acetylhexahydropyridin-4-yl)-9-(1-((6-chloro-2-(2-(methyl-d_{3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d 3} )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)_-one )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2-hydroxyacetyl)hexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(1-acetylhexahydropyridin-4-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-_d3) )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-isobutyrylhexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-(cyclopropanecarbonyl)hexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one_; )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-(methylsulfonyl)hexahydropyridin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-(isopropylsulfonyl)hexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d 3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-(isopropylsulfonyl)hexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)_-one )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-(cyclopropylsulfonyl)hexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-methoxy-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-7-methyl-4-(methyl-d3)-9-(1-((6-methyl-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-7-methyl-4-(methyl-d3)-9-(1-((2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-methoxy-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((4-fluoro-2-(1-(methyl-d3)-1H-tetrazol-5-yl)phenyl)amino)ethyl)-4,7-dimethyl-3-(pyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((4-fluoro-2-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((4-fluoro-2-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)ethyl)-4,7-dimethyl-3-(1-methyl-1H-pyrazol-5-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((4-fluoro-2-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-amino-3-pyridinyl)-9-[1-[4-fluoro-2-(1-methyltriazol-4-yl)anilino]ethyl]-4,7-dimethylimidazo[1,5-a]quinazolin-5-one; 3-(1-acetylhexahydropyridin-4-yl)-9-(1-(6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-(6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethyl)-3-(1-(2-hydroxyacetyl)hexahydropyridin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-aminopyridin-3-yl)-9-((6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-((6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-((6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-4,7-dimethyl-3-(1-methyl-1H-pyrazol-5-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-((6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-3-(2-(hydroxymethyl)pyrimidin-5-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-((3-fluoroazidocyclobutan-1-yl)methyl)pyridin-3-yl)amino)ethyl)-N,N ,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-((3-fluoroazidocyclobutan-1-yl)methyl)pyridin-3-yl)amino)ethyl)-N-(2-hydroxyethyl)-N,4,7-trimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; methyl ((6-chloro-3-((1-(3-(dimethylaminocarbonyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)pyridin-2-yl)methyl)carbamate; Methyl (6-chloro-3-(((3-(dimethylaminocarbonyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)methyl)amino)pyridin-2-yl)carbamate; 9-[(6-chloro-2,3-dihydropyrido[2,3-b][1,4]oxazin-1-yl)methyl]-N ,N ,4,7-tetramethyl-5-oxo-imidazo[1,5-a]quinazoline-3-carboxamide; 9-[(6-chloro-2,3-dihydropyrido[2,3-b][1,4]oxazin-1-yl)methyl]-4,7-dimethyl-5-oxo-N ,N -Bis(trideuteriomethyl)imidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-(1-methylazinocyclobutan-3-yl)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-(1-methylhexahydropyridin-4-yl)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-(1-methylhexahydropyridin-4-yl)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-N,N,4-tris(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 9-(1-((6-chloro-2-(2-(1-methylhexahydropyridin-4-yl)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-N,N,4-tris(methyl-d₃ )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; 3-(2-aminopyrimidin-5-yl)-9-((6-chloro-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)methyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-((3,3-difluoroazolobutyl-1-yl)methyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-(6-chloro-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; (S )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; (R )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; (S )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-1-d)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; (R )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; (S )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; (R )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; (S )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; (R )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; (S )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; (R )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; (S )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; (R )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; (S )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; (R )-3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; (S )-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide; (R )-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; (S )-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(2-(hydroxymethyl)pyrimidin-5-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; (R )-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(2-(hydroxymethyl)pyrimidin-5-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; (S )-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-3-(2-(hydroxymethyl)pyrimidin-5-yl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; (R )-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-3-(2-(hydroxymethyl)pyrimidin-5-yl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; (S )-2-((1-(3-(2-aminopyrimidin-5-yl)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-5-fluorobenzamide; (R )-2-((1-(3-(2-aminopyrimidin-5-yl)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-5-fluorobenzamide; 3-(2-aminopyrimidin-5-yl)-9-(1-(6-chloro-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)ethyl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-ethyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one; methyl (3-((1-(3-(2-aminopyrimidin-5-yl)-7-methyl-4-(methyl-_d3 )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-6-chloropyridin-2-yl)carbamate; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-fluoro-2-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1-(oxacyclobutan-3-yl)-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(pyrimidin-5-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(4-hydroxyhexahydropyridin-1-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(4-hydroxyhexahydropyridin-1-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1,3,4-oxadiazol-2-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one; 3-(3-((1-(3-(2-aminopyrimidin-5-yl)-7-methyl-4-(methyl-d₃ )-5-(1-((6-chloro-2-(1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one); (3-(((3-(2-aminopyrimidin-5-yl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)methyl)amino)-6-chloropyridin-2-yl)carbamate; 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1H-pyrazol-5-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-amino-5-chloropyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d 3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1H-pyrazol-5-yl)imidazo[1,5-a]quinazolin-5(4H)_-one )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-amino-5-methylpyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(6-amino-5-methoxypyridin-3-yl)-9-(1-((6-chloro-2-(2-(methyl-d 3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)_-one )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-amino-4-methoxypyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(pyrazolo[1,5-a]pyridin-6-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; and 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-ethyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; or pharmaceutically acceptable salts thereof.如請求項1之化合物，其中該化合物係選自： 3-(6-胺基-5-氟吡啶-3-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； (R)-3-(6-胺基-5-氟吡啶-3-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； (S)-3-(6-胺基-5-氟吡啶-3-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基-4-甲基嘧啶-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基-3-(1-甲基-1H-咪唑-5-基)咪唑并[1,5-a]喹唑啉-5(4H)-酮； 9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-3-(6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪-3-基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 3-(2-胺基噻唑-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮；及 3-(2-胺基-4-甲基噻唑-5-基)-9-(1-((6-氯-2-(2-甲基-2H-四唑-5-基)吡啶-3-基)胺基)乙基)-4,7-二甲基咪唑并[1,5-a]喹唑啉-5(4H)-酮； 或其醫藥學上可接受之鹽。The compound of claim 1, wherein the compound is selected from: 3-(6-amino-5-fluoropyridin-3-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; (R )-3-(6-amino-5-fluoropyridin-3-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; (S )-3-(6-amino-5-fluoropyridin-3-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-amino-4-methylpyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-methyl-1H-imidazol-5-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(2-Aminothiazol-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; and 3-(2-Amino-4-methylthiazol-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; or pharmaceutically acceptable salts thereof.如請求項1或2之化合物，該化合物為(R)-9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-N,N-雙(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺或其醫藥學上可接受之鹽。The compound of claim 1 or 2, wherein the compound is (R )-9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide or a pharmaceutically acceptable salt thereof.如請求項1或2之化合物，該化合物為(S)-9-(1-((2-胺甲醯基-4-氟苯基)胺基)乙基)-4,7-二甲基-N,N-雙(甲基-d3)-5-側氧基-4,5-二氫咪唑并[1,5-a]喹唑啉-3-甲醯胺或其醫藥學上可接受之鹽。The compound of claim 1 or 2, wherein the compound is (S )-9-(1-((2-aminoformyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide or a pharmaceutically acceptable salt thereof.如請求項1或16之化合物，該化合物為3-(2-胺基嘧啶-5-基)-9-(1-((6-氯-2-(2-(甲基-d₃)-2H-四唑-5-基)吡啶-3-基)胺基)乙基-1-d)-7-甲基-4-(甲基-d₃)咪唑并[1,5-a]喹唑啉-5(4H)-酮或其醫藥學上可接受之鹽。The compound of claim 1 or 16, wherein the compound is 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d₃ )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d₃ )imidazo[1,5-a]quinazolin-5(4H)-one or a pharmaceutically acceptable salt thereof.一種醫藥組合物，該醫藥組合物包含如請求項1至36中任一項之化合物或其醫藥學上可接受之鹽以及醫藥學上可接受之載劑。A pharmaceutical composition comprising the compound of any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.一種抑制PI3Kα激酶活性之方法，該方法包括使該激酶與如請求項1至36中任一項之化合物或其醫藥學上可接受之鹽接觸。A method for inhibiting PI3Kα kinase activity, comprising contacting the kinase with the compound of any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof.一種治療患者之PI3Kα介導之疾病或病症之方法，該方法包括向該患者投與治療有效量的如請求項1至36中任一項之化合物或其醫藥學上可接受之鹽。A method for treating a PI3Kα-mediated disease or condition in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof.如請求項39之方法，其中該疾病或病症為癌症。The method of claim 39, wherein the disease or condition is cancer.如請求項40之方法，其中該癌症係選自乳癌、腦癌、前列腺癌、子宮內膜癌、胃癌、白血病、淋巴瘤、肉瘤、結腸直腸癌、肺癌、卵巢癌、皮膚癌及頭頸癌。The method of claim 40, wherein the cancer is selected from breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, and head and neck cancer.如請求項39之方法，其中該疾病或病症為CLOVES症候群(先天性脂肪瘤過度生長、血管畸形、表皮痣、脊柱側彎/骨骼及脊柱症候群)或PIK3CA相關之過度生長症候群(PROS)。The method of claim 39, wherein the disease or condition is CLOVES syndrome (congenital hyperplasia of lipomatous tissues, vascular malformations, epidermal nevus, scoliosis/skeletal and spinal syndrome) or PIK3CA-related hyperplasia syndrome (PROS).