5-oxo-4, 5-dihydroimidazo [1, 5-a] quinazoline compounds as PI3K [alpha] inhibitors

Abstract

The present application provides tricyclic compounds that modulate PI3K [alpha] activity, which are useful in the treatment of various diseases, including cancer.

Description

Technical Field

[0001] This disclosure provides tricyclic compounds and pharmaceutical compositions thereof that modulate PI3Kα activity and can be used to treat various PI3Kα-related diseases, including cancer. Background Technology

[0002] Over the past few decades, signal transduction events have been studied to demonstrate their crucial role in regulating almost all aspects of biological responses. Aberrant activation of signaling pathways regulating cell survival and proliferation is frequently observed in many human cancers. The phosphoinositol 3-kinase (PI3K) signaling pathway has been documented as 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., 2013, 339(6127), 1546-1558). Front Oncol. , 2021, 11, 644737).

[0003] PI3Ks belong to the lipid kinase family, catalyzing the phosphorylation of lipids contained in or associated with the cell membrane. The PI3K family comprises 15 kinases with different substrates, expression patterns, and regulatory mechanisms. 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 of Akt, mTOR, or RhoGTPases (Fruman et al.). Nat. Rev. Drug Discov. , 2014, 13(2), 140-156).

[0004] Genetic mutations in the gene encoding PI3Kα are hotspot point mutations within the helical and kinase domains, such as E542K, E545K, and H1047R. These mutations have been observed in many cancer types, including lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, and skin cancer. Because these gain-of-function mutations in PI3Kα are associated with tumor progression, targeting this pathway could offer valuable therapeutic opportunities (Courtney et al., ...). J. Clin. Oncol., 2010, 28 (6), 1075-1083). Although a variety of PI3K inhibitors have been developed (such as taselisib, alpelisib, buparlisib, and others), these molecules inhibit multiple PI3K isoforms. These “pan-PI3K” inhibitors have encountered significant obstacles in clinical development because they cannot achieve the desired tumor-targeting inhibition levels while avoiding toxicity to cancer patients (Fruman et al., 2010, 28 (6), 1075-1083). 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, myelosuppression, and elevated transaminases (Hanker et al., 2014, 13(2), 140-156). Cancer Discov ., 2019, 9(4), 482-491). Therefore, selective inhibitors of PI3Kα can prolong the therapeutic window, enabling sufficient target inhibition in tumors while avoiding dose-limiting toxicities in cancer patients. However, given the central role of PI3Kα in regulating glucose homeostasis and other key physiological processes, current selective inhibitors of PI3Kα with equivalent potency to wild-type and mutant PI3Kα often cause hyperglycemia and / or hyperinsulinemia (Busaidy et al., 2019, 9(4), 482-491). J. Clin. Oncol (2012, 30, 2919-2928). In conclusion, developing inhibitors with stronger selectivity for mutant PI3Kα than for wild-type PI3Kα could overcome the problems of compensatory insulin production and hyperglycemia. Summary of the Invention

[0005] This disclosure particularly provides compounds of formula I:

[0006] I

[0007] Or a pharmaceutically acceptable salt thereof, wherein the constituent members are defined herein.

[0008] This 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.

[0009] This disclosure further provides a method for inhibiting PI3Kα activity, the method comprising contacting PI3Kα with a compound described herein or a pharmaceutically acceptable salt thereof.

[0010] This disclosure further provides a method for treating a patient with a PI3Kα-related disease or condition, the method being carried out by administering to the patient a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0011] This disclosure further provides the compounds described herein or their pharmaceutically acceptable salts for use in any of the methods described herein.

[0012] This disclosure further provides the use of the compounds described herein or pharmaceutically acceptable salts thereof for the preparation of pharmaceutical agents used in any of the methods described herein. Detailed Implementation

[0013] This disclosure provides compounds of formula I:

[0014] I

[0015] Or its pharmaceutically acceptable salt, 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 heterocyclic alkyl or 5-10 membered heteroaryl; L 1 C 1-4 alkylene, wherein the C 1-4 The alkylene group is optionally represented by 1, 2, 3 or 4 independently selected R groups. G Substituent substitution; L 2 Selected from -O- and -N(R) L )-; R L Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 1 Selected from H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups and -CN; R 2 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl and C 3-7 cycloalkyl-C 1-4 Alkyl, wherein R 2 The C mentioned 1-6 Alkyl, the C 1-6 Halogenated alkyl groups, the C 3-7cycloalkyl and the C 3-7 cycloalkyl-C 1-4 Each alkyl group is optionally represented by one, two, three, or four independently selected R groups. G Substituent substitution; R 3 Selected from H, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-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)2R b3 -OS(O)2NR 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)2R b3 -NR c3 S(O)2NR c3 R d3 -NR c3 OR a3 -NR c3 S(O)R b3 -NR c3 S(O)NR c3 Rd3 -S(O)R b3 -S(O)2R b3 -S(O)NR c3 R d3 -S(O)2NR 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)2R b3 -C(O)NR c3 S(O)2NR c3 R d3 -S(O)2NR c3 C(O)R b3 -NR c3 S(O)NR c3 C(O)R b3 and -P(O)R f3 R g3 , where R 3 The C mentioned 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 1-6 Halogenated alkyl groups, the C 3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocyclic alkyl, the 5-10 membered heteroaryl, the C 3-10 cycloalkyl-C 1-4 Alkyl, the C6-10 Aryl-C 1-4 Alkyl, the (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl groups and the (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally represented by one, two, three, four, five, or six independently selected R groups. 3A Substituent substitution; Each R a3 R c3 and R d3 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 Alkyl, wherein R a3 R c3 and R d3 The C mentioned 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 1-6 Halogenated alkyl groups, the C 3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocyclic alkyl, 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 heterocyclic alkyl)-C 1-4 Alkyl groups and the (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally represented by one, two, three, four, five, or six independently selected R groups. 3A Substituent substitution; Or, any R connected to the same N atom c3 and R d3 Together with the N atom to which it is attached, a 4-10 membered heterocyclic alkyl group is formed, wherein the 4-10 membered heterocyclic alkyl group is optionally supported by 1, 2, 3, 4, 5 or 6 independently selected R atoms. 3A Substituent substitution; Each R b3 Selected independently from C 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 Alkyl, wherein R b3 The C mentioned 1-6 Alkyl, the C 1-6 Halogenated alkyl groups, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocyclic alkyl, 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 heterocyclic alkyl)-C 1-4 Alkyl groups and the (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally represented by one, two, three, four, five, or six independently selected R groups. 3A Substituent substitution; Each R e3 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 alkyl; Each R f3 and R g3 Independently selected from H and C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 alkyl; Each R 3A Independently selected from oxo group, H, halogen group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-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)2R b3A -OS(O)2NR 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)2Rb3A 、 -NR c3A S(O)2NR 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)2R b3A 、 -S(O)NR c3A R d3A 、 -S(O)2NR 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 c3A S(O)(=NR e3A )R b3A 、 -NR c3A S(O)(=NR e3A )NR c3A R d3A 、 -OS(O)(=NR e3A )R b3A 、 -S(O)(=NR e3A )R b3A 、 -S(O)(=NR e3A )NR c3A R d3A 、 -C(O)NR c3A S(O)2R b3A 、 -C(O)NR c3A S(O)2NR c3A R d3A 、 -S(O)2NR c3A C(O)R b3A 、 -NR c3A S(O)NR c3A C(O)R b3A and -P(O)R f3A R g3A , where R 3A of the said C 1-6Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 1-6 Halogenated alkyl groups, the C 3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocyclic alkyl, 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 heterocyclic alkyl)-C 1-4 Alkyl groups and the (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally represented by one, two, three, four, five, or six independently selected R groups. G Substituent substitution; Each R a3A R c3A and R d3A Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 Alkyl, wherein R a3A R c3A and R d3A The C mentioned 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 1-6 Halogenated alkyl groups, the C 3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocyclic alkyl, 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 heterocyclic alkyl)-C 1-4 Alkyl groups and the (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally represented by one, two, three, four, five, or six independently selected R groups. G Substituent substitution; Or, any R connected to the same N atom c3A and R d3A Together with the N atom to which it is attached, a 4-10 membered heterocyclic alkyl group is formed, wherein the 4-10 membered heterocyclic alkyl group is optionally supported by 1, 2, 3, 4, 5 or 6 independently selected R atoms. G Substituent substitution; Each R b3A Selected independently from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 Alkyl, wherein R b3A The C mentioned 1-6 Alkyl, the C 1-6 Halogenated alkyl groups, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocyclic alkyl, 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 heterocyclic alkyl)-C 1-4 Alkyl groups and the (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally represented by one, two, three, four, five, or six independently selected R groups. G Substituent substitution; Each R e3A Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 alkyl; Each R f3A and R g3A Independently selected from H and C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 alkyl; R 4 Selected from oxo groups, halogen groups, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-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)2R b4 -OS(O)2NRc4 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)2R b4 、-NR c4 S(O)2NR 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)2R b4 、-S(O)NR c4 R d4 、-S(O)2NR 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)2R b4 、-C(O)NR c4 S(O)2NR c4 Rd4 -S(O)2NR c4 C(O)R b4 -NR c4 S(O)NR c4 C(O)R b4 and -P(O)R f4 R g4 , where R 4 The C mentioned 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 1-6 Halogenated alkyl groups, the C 3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocyclic alkyl, 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 heterocyclic alkyl)-C 1-4 Alkyl groups and the (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally represented by one, two, three, four, five, or six independently selected R groups. 4A Substituent substitution; Each R a4 R c4 and R d4 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 Alkyl, wherein R a4 R c4 and R d4 The C mentioned 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 1-6 Halogenated alkyl groups, the C 3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocyclic alkyl, the 5-10 membered heteroaryl, the C 3-10 cycloalkyl-C1-4 Alkyl, the C 6-10 Aryl-C 1-4 Alkyl, the (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl groups and the (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally represented by one, two, three, four, five, or six independently selected R groups. 4A Substituent substitution; Or, any R connected to the same N atom c4 and R d4 Together with the N atom to which it is attached, a 4-10 membered heterocyclic alkyl group is formed, wherein the 4-10 membered heterocyclic alkyl group is optionally supported by 1, 2, 3, 4, 5 or 6 independently selected R atoms. 4A Substituent substitution; Each R b4 Selected independently from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 Alkyl, wherein R b4 The C mentioned 1-6 Alkyl, the C 1-6 Halogenated alkyl groups, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocyclic alkyl, 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 heterocyclic alkyl)-C 1-4 Alkyl groups and the (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally represented by one, two, three, four, five, or six independently selected R groups. 4A Substituent substitution; Each R e4 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 alkyl; Each R f4 and R g4 Independently selected from H and C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 alkyl; Each R 4A Independently selected from oxo group, H, halogen group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-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)NRc4A R d4A 、-C(O)NR c4A (OR a4A )、-OC(O)R a4A 、-OC(O)NR c4A R d4A 、-OC(O)OR a4A 、-OS(O)2R b4A 、-OS(O)2NR 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)2R b4A 、-NR c4A S(O)2NR 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)2R b4A 、-S(O)NR c4A R d4A 、-S(O)2NR 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)2R b4A -C(O)NR c4A S(O)2NR c4A R d4A -S(O)2NR c4A C(O)R b4A -NR c4A S(O)NR c4A C(O)R b4A and -P(O)R f4A R g4A , where R 4A The C mentioned 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 1-6 Halogenated alkyl groups, the C 3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocyclic alkyl, 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 heterocyclic alkyl)-C 1-4 Alkyl groups and the (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally represented by one, two, three, four, five, or six independently selected R groups. G Substituent substitution; Each R a4A R c4A and R d4A Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 Alkyl, wherein R a4A R c4A and Rd4A The C mentioned 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 1-6 Halogenated alkyl groups, the C 3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocyclic alkyl, 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 heterocyclic alkyl)-C 1-4 Alkyl groups and the (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally represented by one, two, three, four, five, or six independently selected R groups. G Substituent substitution; Or, any R connected to the same N atom c4A and R d4A Together with the N atom to which it is attached, a 4-10 membered heterocyclic alkyl group is formed, wherein the 4-10 membered heterocyclic alkyl group is optionally supported by 1, 2, 3, 4, 5 or 6 independently selected R atoms. G Substituent substitution; Each R b4A Selected independently from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 Alkyl, wherein R b4A The C mentioned 1-6 Alkyl, the C 1-6 Halogenated alkyl groups, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocyclic alkyl, 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 heterocyclic alkyl)-C1-4 Alkyl groups and the (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally represented by one, two, three, four, five, or six independently selected R groups. G Substituent substitution; Each R e4A Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 alkyl; Each R f4A and R g4A Independently selected from H and C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 alkyl; Each R G Independently selected from H, D, OH, CN, halogen, oxo group, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Halogenated alkyl, cyano-C 1-4 Alkyl, HO-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 3-7 Cycloalkyl, 4-7 membered heterocycloalkyl, C 1-4 Alkoxy, C1-4 Halogenated alkoxy, amino, C 1-3 Alkylamino, di(C) 1-3 Alkyl)amino, thio, C 1-3 Alkyl thio, C 1-3 alkylsulfinyl, C 1-3 alkylsulfonyl, carbamoyl, C 1-3 Alkyl carbamoyl, di(C 1-3 Alkyl) carbamoyl, carboxyl, C 1-3 alkyl carbonyl, C 1-3 alkoxycarbonyl, C 1-3 alkyl carbonyloxy group, C 1-3 Alkyl carbonyl amino, C 1-3 alkoxycarbonylamino, aminocarbonyloxy, C 1-3 Alkylaminocarbonyloxy, di(C 1-3 alkyl)aminocarbonyloxy, C 1-3 Alkylsulfonylamino, aminosulfonyl, C 1-3 alkylaminosulfonyl, di(C 1-3 alkyl)aminosulfonyl, aminosulfonylamino, C 1-3 Alkylaminosulfonylamino, di(C 1-3 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3 Alkylaminocarbonylamino and di(C) 1-3 Alkyl)aminocarbonylamino.

[0016] In some implementations, L 1 Ethylene, wherein the ethylene is optionally converted by an R G Substituent substitution.

[0017] In some implementations, L 1 The ethylene is substituted with deuterium.

[0018] In some implementations, L 2 -N(R) L )-.

[0019] In some implementations, L 2 It is -NH-.

[0020] In some implementation schemes, R 1 Selected from halogen groups, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

[0021] In some implementation schemes, R 1 Selected from chloro, methyl and trifluoromethyl.

[0022] In some implementation schemes, R1 Halogenated or C 1-3 alkyl.

[0023] In some implementation schemes, R 1 It can be chlorine or methyl.

[0024] In some implementation schemes, R 1 It is chlorine.

[0025] In some implementation schemes, R 1 It is a methyl group.

[0026] In some implementation schemes, R 1 It is trifluoromethyl.

[0027] In some implementation schemes, R 2 C 1-3 alkyl.

[0028] In some implementation schemes, R 2 Selected from methyl and trideuterated methyl.

[0029] In some implementation schemes, R 2 It is a methyl group.

[0030] In some implementation schemes, R 2 It is a trideuterated methyl group.

[0031] In some implementation schemes, R 3 Selected from pyrimidinyl, azacyclic butylmethyl, pyrazolyl, pyridinyl, piperidinyl, 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 , where R 3 The pyrimidinyl group, the azacyclobutylmethyl group, the pyrazolyl group, the pyridyl group, the piperidinyl group, the 2H-pyrazolo[3,4-b]pyridyl group, the pyrazolo[1,5-a]pyridyl group, the pyrazolo[1,5-a]pyrimidinyl group, the imidazo[1,5-a]pyridyl group, the imidazoyl group, the thiazolyl group, and the 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl group are each optionally selected by 1, 2, 3, or 4 independently chosen R groups. 3A Substituent substitution.

[0032] In some implementation schemes, R 3Selected from pyrimidinyl, azacyclic butylmethyl, pyrazolyl, pyridinyl, piperidinyl, 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 , where R 3 The pyrimidinyl group, the azacyclobutylmethyl group, the pyrazolyl group, the pyridyl group, the piperidinyl group, the 2H-pyrazolo[3,4-b]pyridyl group, the pyrazolo[1,5-a]pyridyl group, the pyrazolo[1,5-a]pyrimidinyl group, the imidazo[1,5-a]pyridyl group, the imidazoyl group, the thiazolyl group, and the 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl group are each optionally selected by one or two independently chosen R groups. 3A Substituent substitution.

[0033] In some implementation schemes, R 3 Selected from pyrazolyl, pyrimidinyl, piperidinyl, azacyclic butylmethyl, 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 , where R 3 The pyrazolyl group, the pyrimidinyl group, the piperidinyl group, the azacyclobutylmethyl group, the pyridinyl group, the 2H-pyrazolo[3,4-b]pyridinyl group, the pyrazolo[1,5-a]pyridinyl group, the pyrazolo[1,5-a]pyrimidinyl group, and the imidazo[1,5-a]pyridinyl group are each optionally selected by 1, 2, 3, or 4 independently chosen R groups. 3A Substituent substitution.

[0034] In some implementation schemes, R 3 Selected from pyrazolyl, pyrimidinyl, piperidinyl and C(O)NR c3 R d3 , where R 3 The pyrazolyl group, the pyridyl group, the pyrimidinyl group, and the piperidinyl group are each optionally represented by an R 3A Substituent substitution.

[0035] In some implementations, each R 3A Independently selected from halogen groups, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, oxetane, amino, C 1-3 Alkylamino, di(C) 1-3alkyl)amino, -C(O)C 1-3 Alkyl, -C(O)C 1-3 Hydroxyalkyl, -C(O)C 3-6 cycloalkyl groups and -S(O)2C 1-3 alkyl; In some implementation schemes, R 3 Selected from pyrazolyl, pyrimidinyl, piperidinyl and C(O)NR c3 R d3 , where R 3 The pyrazolyl group, the pyridyl group, and the piperidinyl group are each optionally represented by a group selected from C. 1-3 Alkyl, amino and -C(O)C 1-3 alkyl R 3A Substituent substitution.

[0036] In some implementation schemes, R 3 Selected from pyrazolyl, pyrimidinyl, and piperidinyl, wherein R 3 The pyrazolyl group, the pyrimidinyl group, and the piperidinyl group are each optionally represented by a group selected from C. 1-3 Alkyl, amino and -C(O)C 1-3 alkyl R 3A Substituent substitution.

[0037] In some implementation schemes, R 3 Selected from pyrazolyl, pyridyl, pyrimidinyl, and piperidinyl, wherein R 3 The pyrazolyl group, the pyrimidinyl group, and the piperidinyl group are each optionally surrounded by an R group selected from methyl, amino, and methyl carbonyl groups. 3A Substituent substitution.

[0038] In some implementation schemes, R 3 It is selected from methylpyrazolyl, aminopyrimidinyl and (methylcarbonyl)piperidinyl.

[0039] In some implementation schemes, R 3 Selected from pyrimidinyl, azacyclic butylmethyl, pyrazolyl, pyridinyl, piperidinyl, 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 , where R 3 The pyrimidinyl group, the azacyclobutylmethyl group, the pyrazolyl group, the pyridyl group, the piperidinyl group, the 2H-pyrazolo[3,4-b]pyridyl group, the pyrazolo[1,5-a]pyridyl group, the pyrazolo[1,5-a]pyrimidinyl group, and the imidazo[1,5-a]pyridyl group are each optionally surrounded by one or two R groups. 3A Substituent substitution.

[0040] In some implementation schemes, R 3 Selected from pyrimidinyl, azacyclic butylmethyl, pyrazolyl, pyridinyl, piperidinyl, 2H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, and imidazo[1,5-a]pyridinyl, wherein R 3 The pyrimidinyl group, the azacyclobutylmethyl group, the pyrazolyl group, the pyridyl group, the piperidinyl group, the 2H-pyrazolo[3,4-b]pyridyl group, the pyrazolo[1,5-a]pyridyl group, the pyrazolo[1,5-a]pyrimidinyl group, and the imidazo[1,5-a]pyridyl group are each optionally surrounded by one or two R groups. 3A Substituent substitution.

[0041] In some implementations, each R 3A It is independently selected from methyl, fluorine, chlorine, methoxy, amino, methylamino, dimethylamino, hydroxymethyl, hydroxyethyl, oxetane, methyl carbonyl, isopropyl carbonyl, hydroxymethyl carbonyl, cyclopropyl carbonyl, methylsulfonyl, isopropylsulfonyl and cyclopropylsulfonyl.

[0042] In some implementation schemes, R 3 Selected from (difluoroazacyclobutane)methyl, oxacyclobutanepiperidinyl, (methylcarbonyl)piperidinyl, (isopropylcarbonyl)piperidinyl, (hydroxymethylcarbonyl)piperidinyl, (cyclopropylcarbonyl)piperidinyl, (methylsulfonyl)piperidinyl, (isopropylsulfonyl)piperidinyl, (cyclopropylsulfonyl)piperidinyl, pyrazolyl, methylpyrazolyl, (hydroxyethyl)pyrazolyl, pyridinyl, (hydroxymethyl)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, 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.

[0043] In some implementation schemes, R 3Selected from (difluoroazacyclobutane)methyl, oxacyclobutanepiperidinyl, (methylcarbonyl)piperidinyl, (isopropylcarbonyl)piperidinyl, (hydroxymethylcarbonyl)piperidinyl, (cyclopropylcarbonyl)piperidinyl, (methylsulfonyl)piperidinyl, (isopropylsulfonyl)piperidinyl, (cyclopropylsulfonyl)piperidinyl, pyrazolyl, methylpyrazolyl, (hydroxyethyl)pyrazolyl, pyridinyl, (hydroxymethyl)pyridinyl, aminopyridinyl. (methylamino)pyridyl, (dimethylamino)pyridyl, (amino)(chloro)pyridyl, aminopyrimidinyl, (hydroxymethyl)pyrimidinyl, (amino)(fluoro)pyrimidinyl, (amino)(methyl)pyrimidinyl, (amino)(methoxy)pyrimidinyl, methyl-2H-pyrazolo[3,4-b]pyridine, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl and imidazo[1,5-a]pyridyl.

[0044] In some implementation schemes, R 3 For C(O)NR c3 R d3 .

[0045] In some implementation schemes, R c3 and R d3 Each is independently selected from C 1-3 alkyl.

[0046] In some implementation schemes, R c3 and R d3 Each is independently selected from methyl and trideuterated methyl.

[0047] In some implementation schemes, R c3 and R d3 Each is a methyl group.

[0048] In some implementation schemes, R c3 and R d3 Each is a trideuterated methyl group.

[0049] In some embodiments, ring A is selected from phenyl and pyridyl.

[0050] In some implementations, ring A is a phenyl group.

[0051] In some implementations, ring A is pyridinyl.

[0052] In some implementations, n is 1, 2, or 3.

[0053] In some implementations, n is 1 or 2.

[0054] In some implementations, n is 2.

[0055] In some implementations, each R 4 Independently selected from H, halogen, C1-3 Alkyl, C 1-3 Alkoxy, C(O)NR c4 R d4 and tetrazolium, wherein R 4 The tetrazolium group is optionally surrounded by an R 4A Substituent substitution.

[0056] In some implementations, each R c4 and R d4 Independently selected from H and C 1-3 Alkyl and C 1-3 Halogenated alkyl groups.

[0057] In some implementations, each R c4 and R d4 For H.

[0058] In some implementations, each R 4 Independently selected from H, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C(O)NH2 and tetrazolium, wherein R 4 The tetrazolium group is optionally surrounded by an R 4A Substituent substitution.

[0059] In some implementations, at least one R 4 It is C(O)NH2.

[0060] In some implementations, at least one R 4 It is a tetrazolium group, where R 4 The tetrazolium group is optionally surrounded by an R 4A Substituent substitution.

[0061] In some implementations, at least one R 4 For C(O)NH2; and for each additional R 4 Independently selected from H, halogen, C 1-3 Alkyl and C 1-3 Alkyl group.

[0062] In some implementations, at least one R 4 It is a tetrazolium group, where R 4 The tetrazolium group is optionally surrounded by an R 4A Substituent substitution; and each additional R 4 Independently selected from H, halogen, C 1-3 Alkyl and C 1-3 Alkyl group.

[0063] In some implementations, each R 4 Independently selected from H, halogen, C 1-3 Alkyl and C1-3 Alkyl group.

[0064] In some implementations, each R 4 It is independently selected from H, fluorine, chlorine, methyl and methoxy.

[0065] In some implementation schemes, R 4 It is a halogen group.

[0066] In some implementation schemes, R 4 It is either fluorine or chlorine.

[0067] In some implementation schemes, R 4 It is fluorine.

[0068] In some implementation schemes, R 4 It is chlorine.

[0069] In some implementation schemes, R 4 For H.

[0070] In some implementation schemes, R 4 It is a methyl group.

[0071] In some implementation schemes, R 4 It is a methoxy group.

[0072] In some implementations, each R 4A Selected independently from C 1-3 Alkyl, azacyclic butyl and piperidinyl, wherein R 4 The nitrogen-containing heterocyclic butyl group and the piperidinyl group are each optionally C 1-3 Alkyl substitution.

[0073] In some implementations, each R 4A Selected from C 1-3 Alkyl, azacyclic butyl and piperidinyl, wherein R 4 The nitrogen-containing heterocyclic butyl group and the piperidinyl group are each optionally C 1-3 Alkyl substitution.

[0074] In some implementation schemes, R 4A Selected from methyl, trideuterated methyl, ethyl, aziridine, and piperidinyl, wherein R 4A The nitrogen-containing heterocyclic butyl group and the piperidinyl group are each optionally substituted with methyl.

[0075] In some implementation schemes, R 4A It is selected from methyl, trideuterated methyl, ethyl, methylazacyclobutane and methylpiperidinyl.

[0076] In some implementation schemes, R 4A It is a methyl group.

[0077] In some implementation schemes, R 4A It is an ethyl group.

[0078] In some implementation schemes, R 4A It is a trideuterated methyl group.

[0079] In some implementation schemes, R 4A It is a selected methylazonicyclobutane.

[0080] In some implementation schemes, R 4A It is methylpiperidinyl.

[0081] In some implementation schemes, R G It can be H or D.

[0082] In some implementation schemes, R G For H.

[0083] In some implementation schemes, R G The answer is D.

[0084] In some implementation schemes: R 1 Selected from chloro, methyl, and trifluoromethyl; R 2 Selected from methyl and trideuterated methyl; R 3 Selected from pyrazolyl, pyridyl, pyrimidinyl, piperidinyl and C(O)NR c3 R d3 , where R 3 The pyrazolyl group, the pyrimidinyl group, and the piperidinyl group are each optionally surrounded by an R group selected from methyl, amino, and methyl carbonyl groups. 3A Substituent substitution; R c3 and R d3 Each is independently selected from methyl and trideuterated methyl groups; R 4 It is either fluorine or chlorine; and R G It can be H or D.

[0085] In some implementation schemes: R 1 It is chlorine or methyl; R 2 It is methyl or trideuterated methyl; R 3Selected from pyrimidinyl, azacyclic butylmethyl, pyrazolyl, pyridinyl, piperidinyl, 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 , where R 3 The pyrimidinyl group, the azacyclobutylmethyl group, the pyrazolyl group, the pyridyl group, the piperidinyl group, the 2H-pyrazolo[3,4-b]pyridyl group, the pyrazolo[1,5-a]pyridyl group, the pyrazolo[1,5-a]pyrimidinyl group, the imidazo[1,5-a]pyridyl group, the imidazoyl group, the thiazolyl group, and the 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl group are each optionally selected by one or two independently chosen R groups. 3A Substituent substitution; Each R 3A Independently selected from methyl, fluorine, chlorine, methoxy, amino, methylamino, dimethylamino, hydroxymethyl, hydroxyethyl, oxetyl, methylcarbonyl, isopropylcarbonyl, hydroxymethylcarbonyl, cyclopropylcarbonyl, methylsulfonyl, isopropylsulfonyl, and cyclopropylsulfonyl; R c3 and R d3 Each is independently selected from methyl and trideuterated methyl groups; R 4 Selected from H, fluorine, chlorine, methyl, and methoxy; R 4A Selected from methyl, trideuterated methyl, ethyl, aziridine, and piperidinyl, wherein R 4A The aziridine and piperidinyl groups are each optionally substituted with methyl groups; and R G It can be H or D.

[0086] In some implementation schemes: R 1 It is chlorine or methyl; R 2 It is methyl or trideuterated methyl; R 3 Selected from pyrimidinyl, azacyclic butylmethyl, pyrazolyl, pyridinyl, piperidinyl, 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 , where R 3The pyrimidinyl group, the azacyclobutylmethyl group, the pyrazolyl group, the pyridyl group, the piperidinyl group, the 2H-pyrazolo[3,4-b]pyridyl group, the pyrazolo[1,5-a]pyridyl group, the pyrazolo[1,5-a]pyrimidinyl group, and the imidazo[1,5-a]pyridyl group are each optionally surrounded by one or two R groups. 3A Substituent substitution; Each R 3A Independently selected from methyl, fluorine, chlorine, methoxy, amino, methylamino, dimethylamino, hydroxymethyl, hydroxyethyl, oxetyl, methylcarbonyl, isopropylcarbonyl, hydroxymethylcarbonyl, cyclopropylcarbonyl, methylsulfonyl, isopropylsulfonyl, and cyclopropylsulfonyl; R c3 and R d3 Each is independently selected from methyl and trideuterated methyl groups; R 4 Selected from H, fluorine, chlorine, methyl, and methoxy; R 4A Selected from methyl, trideuterated methyl, ethyl, aziridine, and piperidinyl, wherein R 4A The aziridine and piperidinyl groups are each optionally substituted with methyl groups; and R G It can be H or D.

[0087] In some embodiments, the compound of formula I is a compound of formula II:

[0088] II

[0089] Or its pharmaceutically acceptable salt.

[0090] In some embodiments, the compound of formula I is a compound of formula II:

[0091] II

[0092] Or its pharmaceutically acceptable salt, wherein: R 1 Selected from halogen groups, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; R 2 C 1-3 alkyl; R 3 Selected from pyrazolyl, pyrimidinyl, piperidinyl and C(O)NR c3 R d3 , where R 3The pyrazolyl group, the pyridyl group, and the piperidinyl group are each optionally represented by a group selected from C. 1-3 Alkyl, amino and -C(O)C 1-3 alkyl R 3A Substituent substitution; Each R c3 and R d3 Selected independently from C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; R 4 It is a halogenated group; and R G It can be H or D.

[0093] In some implementations of Formula II, R 1 Selected from chloro, methyl and trifluoromethyl.

[0094] In some implementations of Formula II, R 1 It is chlorine.

[0095] In some implementations of Formula II, R 1 It is a methyl group.

[0096] In some implementations of Formula II, R 1 It is trifluoromethyl.

[0097] In some implementations of Formula II, R 2 Selected from methyl and trideuterated methyl.

[0098] In some implementations of Formula II, R 2 It is a methyl group.

[0099] In some implementations of Formula II, R 2 It is a trideuterated methyl group.

[0100] In some implementations of Formula II, R 3 For C(O)NR c3 R d3 .

[0101] In some implementations of Formula II, R c3 and R d3 Each is independently selected from methyl and trideuterated methyl.

[0102] In some implementations of Formula II, R c3 and R d3 Each is a methyl group.

[0103] In some implementations of Formula II, R c3 and R d3 Each is a trideuterated methyl group.

[0104] In some implementations of Formula II, R 3 Selected from pyrazolyl, pyrimidinyl, and piperidinyl, wherein R 3 The pyrazolyl group, the pyrimidinyl group, and the piperidinyl group are each optionally represented by a group selected from C. 1-3 Alkyl, amino and -C(O)C 1-3 alkyl R 3A Substituent substitution.

[0105] In some implementations of Formula II, R 3 Selected from pyrazolyl, pyridyl, pyrimidinyl, and piperidinyl, wherein R 3 The pyrazolyl group, the pyrimidinyl group, and the piperidinyl group are each optionally surrounded by an R group selected from methyl, amino, and methyl carbonyl groups. 3A Substituent substitution.

[0106] In some implementations of Formula II, R 3 It is selected from methylpyrazolyl, aminopyrimidinyl and (methylcarbonyl)piperidinyl.

[0107] In some implementations of Formula II, R 3 It is a methylpyrazolyl group.

[0108] In some implementations of Formula II, R 3 It is an aminopyrimidine group.

[0109] In some implementations of Formula II, R 3 It is (methylcarbonyl)piperidinyl.

[0110] In some implementations of Formula II, R 4 It is either fluorine or chlorine.

[0111] In some implementations of Formula II, R 4 It is fluorine.

[0112] In some implementations of Formula II, R 4 It is chlorine.

[0113] In some implementations of Formula II, R G For H.

[0114] In some implementations of Formula II, R G The answer is D.

[0115] In some implementation schemes of Formula II: R 1 Selected from chloro, methyl, and trifluoromethyl; R 2 Selected from methyl and trideuterated methyl; R 3Selected from pyrazolyl, pyridyl, pyrimidinyl, piperidinyl and C(O)NR c3 R d3 , where R 3 The pyrazolyl group, the pyrimidinyl group, and the piperidinyl group are each optionally surrounded by an R group selected from methyl, amino, and methyl carbonyl groups. 3A Substituent substitution; R c3 and R d3 Each is independently selected from methyl and trideuterated methyl groups; R 4 It is either fluorine or chlorine; and R G It can be H or D.

[0116] In some embodiments, the compound of formula I or formula II is a compound of formula IIa:

[0117] IIa

[0118] Or its pharmaceutically acceptable salt.

[0119] In some embodiments, the compound of formula I or formula II is a compound of formula IIb:

[0120] IIb

[0121] Or its pharmaceutically acceptable salt.

[0122] In some embodiments, the compound of formula I is a compound of formula III:

[0123] III

[0124] Or its pharmaceutically acceptable salt.

[0125] In some embodiments, the compound of formula I is a compound of formula III:

[0126] III

[0127] Or its pharmaceutically acceptable salt, wherein: R 1 Halogenated or C 1-3 alkyl; R 2 C 1-3 alkyl; R 3Selected from pyrimidinyl, azacyclic butylmethyl, pyrazolyl, pyridinyl, piperidinyl, 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 , where R 3 The pyrimidinyl group, the azacyclobutylmethyl group, the pyrazolyl group, the pyridyl group, the piperidinyl group, the 2H-pyrazolo[3,4-b]pyridyl group, the pyrazolo[1,5-a]pyridyl group, the pyrazolo[1,5-a]pyrimidinyl group, the imidazo[1,5-a]pyridyl group, the imidazoyl group, the thiazolyl group, and the 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl group are each optionally surrounded by one or two R groups. 3A Substituent substitution; Each R 3A Independently selected from halogen groups, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, oxetane, 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 groups and -S(O)2C 1-3 alkyl; R 4 Selected from H, halogen, C 1-3 Alkyl and C 1-3 Alkoxy; R 4A Selected from C 1-3 Alkyl, azacyclic butyl and piperidinyl, wherein R 4 The nitrogen-containing heterocyclic butyl group and the piperidinyl group are each optionally C 1-3 Alkyl substitution; and R G It can be H or D.

[0128] In some embodiments, the compound of formula I is a compound of formula III:

[0129] III

[0130] Or its pharmaceutically acceptable salt, wherein: R 1 Halogenated or C 1-3 alkyl; R 2 C 1-3 alkyl; R 3 Selected from pyrimidinyl, azacyclic butylmethyl, pyrazolyl, pyridinyl, piperidinyl, 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 , where R 3 The pyrimidinyl group, the azacyclobutylmethyl group, the pyrazolyl group, the pyridyl group, the piperidinyl group, the 2H-pyrazolo[3,4-b]pyridyl group, the pyrazolo[1,5-a]pyridyl group, the pyrazolo[1,5-a]pyrimidinyl group, and the imidazo[1,5-a]pyridyl group are each optionally surrounded by one or two R groups. 3A Substituent substitution; Each R 3A Independently selected from halogen groups, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, oxetane, 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 groups and -S(O)2C 1-3 alkyl; R 4 Selected from H, halogen, C 1-3 Alkyl and C 1-3 Alkoxy; R 4A Selected from C 1-3 Alkyl, azacyclic butyl and piperidinyl, wherein R 4 The nitrogen-containing heterocyclic butyl group and the piperidinyl group are each optionally C 1-3 Alkyl substitution; and R G It can be H or D.

[0131] In some implementations of Formula III, R 1 It can be chlorine or methyl.

[0132] In some implementations of Formula III, R 1 It is chlorine.

[0133] In some implementations of Formula III, R 1 It is a methyl group.

[0134] In some implementations of Formula III, R 2 It is methyl or trideuterated methyl.

[0135] In some implementations of Formula III, R 2 It is a methyl group.

[0136] In some implementations of Formula III, R 2 It is a trideuterated methyl group.

[0137] In some implementations of Formula III, R 3 Selected from pyrimidinyl, azacyclic butylmethyl, pyrazolyl, pyridinyl, piperidinyl, 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 , where R 3 The pyrimidinyl group, the azacyclobutylmethyl group, the pyrazolyl group, the pyridyl group, the piperidinyl group, the 2H-pyrazolo[3,4-b]pyridyl group, the pyrazolo[1,5-a]pyridyl group, the pyrazolo[1,5-a]pyrimidinyl group, and the imidazo[1,5-a]pyridyl group are each optionally surrounded by one or two R groups. 3A Substituent substitution.

[0138] In some implementations of Formula III, R 3 Selected from pyrimidinyl, azacyclic butylmethyl, pyrazolyl, pyridinyl, piperidinyl, 2H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, and imidazo[1,5-a]pyridinyl, wherein R 3 The pyrimidinyl group, the azacyclobutylmethyl group, the pyrazolyl group, the pyridyl group, the piperidinyl group, the 2H-pyrazolo[3,4-b]pyridyl group, the pyrazolo[1,5-a]pyridyl group, the pyrazolo[1,5-a]pyrimidinyl group, and the imidazo[1,5-a]pyridyl group are each optionally surrounded by one or two R groups. 3A Substituent substitution.

[0139] In some implementations of Formula III, each R 3A It is independently selected from methyl, fluorine, chlorine, methoxy, amino, methylamino, dimethylamino, hydroxymethyl, hydroxyethyl, oxetane, methyl carbonyl, isopropyl carbonyl, hydroxymethyl carbonyl, cyclopropyl carbonyl, methylsulfonyl, isopropylsulfonyl and cyclopropylsulfonyl.

[0140] In some implementations of Formula III, R 3Selected from (difluoroazacyclobutane)methyl, oxacyclobutanepiperidinyl, (methylcarbonyl)piperidinyl, (isopropylcarbonyl)piperidinyl, (hydroxymethylcarbonyl)piperidinyl, (cyclopropylcarbonyl)piperidinyl, (methylsulfonyl)piperidinyl, (isopropylsulfonyl)piperidinyl, (cyclopropylsulfonyl)piperidinyl, pyrazolyl, methylpyrazolyl, (hydroxyethyl)pyrazolyl, pyridinyl, (hydroxymethyl)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, 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.

[0141] In some implementations of Formula III, R 3 Selected from (difluoroazacyclobutane)methyl, oxacyclobutanepiperidinyl, (methylcarbonyl)piperidinyl, (isopropylcarbonyl)piperidinyl, (hydroxymethylcarbonyl)piperidinyl, (cyclopropylcarbonyl)piperidinyl, (methylsulfonyl)piperidinyl, (isopropylsulfonyl)piperidinyl, (cyclopropylsulfonyl)piperidinyl, pyrazolyl, methylpyrazolyl, (hydroxyethyl)pyrazolyl, pyridinyl, (hydroxymethyl)pyridinyl, aminopyridinyl. (amino)(chloro)pyridyl, (methylamino)pyridyl, (dimethylamino)pyridyl, aminopyrimidinyl, (hydroxymethyl)pyrimidinyl, (amino)(fluoro)pyrimidinyl, (amino)(methyl)pyrimidinyl, (amino)(methoxy)pyrimidinyl, methyl-2H-pyrazolo[3,4-b]pyridine, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl and imidazo[1,5-a]pyridyl.

[0142] In some implementations of Formula III, R 3 It is (difluoroazacyclobutane)methyl.

[0143] In some implementations of Formula III, R 3 Selected from oxoheterocyclic butylpiperidinyl.

[0144] In some implementations of Formula III, R 3 It is (methylcarbonyl)piperidinyl.

[0145] In some implementations of Formula III, R 3 It is (isopropylcarbonyl)piperidinyl.

[0146] In some implementations of Formula III, R 3 It is (hydroxymethylcarbonyl)piperidinyl.

[0147] In some implementations of Formula III, R 3 It is (cyclopropylcarbonyl)piperidinyl.

[0148] In some implementations of Formula III, R 3 It is (methylsulfonyl)piperidinyl.

[0149] In some implementations of Formula III, R 3 It is (isopropylsulfonyl)piperidinyl.

[0150] In some implementations of Formula III, R 3 It is (cyclopropylsulfonyl)piperidinyl.

[0151] In some implementations of Formula III, R 3 It is a pyrazole group.

[0152] In some implementations of Formula III, R 3 It is a methylpyrazolyl group.

[0153] In some implementations of Formula III, R 3 It is (hydroxyethyl)pyrazolyl.

[0154] In some implementations of Formula III, R 3 It is pyridyl.

[0155] In some implementations of Formula III, R 3 It is (hydroxymethyl)pyridyl.

[0156] In some implementations of Formula III, R 3 It is an aminopyridinyl group.

[0157] In some implementations of Formula III, R 3 It is (amino)(chloro)pyridinyl.

[0158] In some implementations of Formula III, R 3 It is (methylamino)pyridyl.

[0159] In some implementations of Formula III, R 3 It is (dimethylamino)pyridyl.

[0160] In some implementations of Formula III, R 3 It is an aminopyrimidine group.

[0161] In some implementations of Formula III, R 3 It is (hydroxymethyl)pyrimidinyl.

[0162] In some implementations of Formula III, R 3 It is (amino)(fluoro)pyrimidine group.

[0163] In some implementations of Formula III, R 3 It is (amino)(methyl)pyrimidinyl.

[0164] In some implementations of Formula III, R 3 It is (amino)(methoxy)pyrimidinyl.

[0165] In some implementations of Formula III, R 3 It is methyl-2H-pyrazolo[3,4-b]pyridine.

[0166] In some implementations of Formula III, R 3 It is pyrazolo[1,5-a]pyridyl.

[0167] In some implementations of Formula III, R 3 It is pyrazolo[1,5-a]pyrimidinyl.

[0168] In some implementations of Formula III, R 3 It is imidazo[1,5-a]pyridyl.

[0169] In some implementations of Formula III, R 3 It is (amino)(fluoro)pyridyl.

[0170] In some implementations of Formula III, R 3 It is a methylimidazolium group.

[0171] In some implementations of Formula III, R 3 It is an aminothiazole group.

[0172] In some implementations of Formula III, R 3 It is (amino)(methyl)thiazolyl.

[0173] In some implementations of Formula III, R 3 It is 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl.

[0174] In some implementations of Formula III, R 3 For C(O)NR c3 R d3 .

[0175] In some implementations of Formula III, R c3 and R d3 Each is independently selected from methyl and trideuterated methyl.

[0176] In some implementations of Formula III, R c3 and R d3 Each is a methyl group.

[0177] In some implementations of Formula III, R c3 and R d3 Each is a trideuterated methyl group.

[0178] In some implementations of Formula III, R 4 Selected from H, fluorine, chlorine, methyl and methoxy.

[0179] In some implementations of Formula III, R 4 For H.

[0180] In some implementations of Formula III, R 4 It is fluorine.

[0181] In some implementations of Formula III, R 4 It is chlorine.

[0182] In some implementations of Formula III, R 4 It is a methyl group.

[0183] In some implementations of Formula III, R 4 It is a methoxy group.

[0184] In some implementations of Formula III, R 4A Selected from methyl, trideuterated methyl, ethyl, aziridine, and piperidinyl, wherein R 4A The nitrogen-containing heterocyclic butyl group and the piperidinyl group are each optionally substituted with methyl.

[0185] In some implementations of Formula III, R 4A It is selected from methyl, trideuterated methyl, ethyl, methylazacyclobutane and methylpiperidinyl.

[0186] In some implementations of Formula III, R 4A It is a methyl group.

[0187] In some implementations of Formula III, R 4A It is a trideuterated methyl group.

[0188] In some implementations of Formula III, R 4A It is an ethyl group.

[0189] In some implementations of Formula III, R 4A It is a methylazonicyclobutane.

[0190] In some implementations of Formula III, R4A It is methylpiperidinyl.

[0191] In some implementations of Formula III, R G For H.

[0192] In some implementations of Formula III, R G The answer is D.

[0193] In some implementations of Equation III: R 1 It is chlorine or methyl; R 2 It is methyl or trideuterated methyl; R 3 Selected from pyrimidinyl, azacyclic butylmethyl, pyrazolyl, pyridinyl, piperidinyl, 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 , where R 3 The pyrimidinyl group, the azacyclobutylmethyl group, the pyrazolyl group, the pyridyl group, the piperidinyl group, the 2H-pyrazolo[3,4-b]pyridyl group, the pyrazolo[1,5-a]pyridyl group, the pyrazolo[1,5-a]pyrimidinyl group, the imidazo[1,5-a]pyridyl group, the imidazoyl group, the thiazolyl group, and the 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl group are each optionally surrounded by one or two R groups. 3A Substituent substitution; Each R 3A Independently selected from methyl, fluorine, chlorine, methoxy, amino, methylamino, dimethylamino, hydroxymethyl, hydroxyethyl, oxetyl, methylcarbonyl, isopropylcarbonyl, hydroxymethylcarbonyl, cyclopropylcarbonyl, methylsulfonyl, isopropylsulfonyl, and cyclopropylsulfonyl; R c3 and R d3 Each is independently selected from methyl and trideuterated methyl groups; R 4 Selected from H, fluorine, chlorine, methyl, and methoxy; R 4A Selected from methyl, trideuterated methyl, ethyl, aziridine, and piperidinyl, wherein R 4A The aziridine and piperidinyl groups are each optionally substituted with methyl groups; and R G It can be H or D.

[0194] In some implementations of Equation III: R 1 It is chlorine or methyl; R 2 It is methyl or trideuterated methyl; R 3 Selected from pyrimidinyl, azacyclic butylmethyl, pyrazolyl, pyridinyl, piperidinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,5-a]pyridinyl and C(O)NR c3 R d3 , where R 3 The pyrimidinyl group, the azacyclobutylmethyl group, the pyrazolyl group, the pyridyl group, the piperidinyl group, the 2H-pyrazolo[3,4-b]pyridyl group, the pyrazolo[1,5-a]pyridyl group, the pyrazolo[1,5-a]pyrimidinyl group, and the imidazo[1,5-a]pyridyl group are each optionally surrounded by one or two R groups. 3A Substituent substitution; Each R 3A Independently selected from methyl, fluorine, chlorine, methoxy, amino, methylamino, dimethylamino, hydroxymethyl, hydroxyethyl, oxetyl, methylcarbonyl, isopropylcarbonyl, hydroxymethylcarbonyl, cyclopropylcarbonyl, methylsulfonyl, isopropylsulfonyl, and cyclopropylsulfonyl; R c3 and R d3 Each is independently selected from methyl and trideuterated methyl groups; R 4 Selected from H, fluorine, chlorine, methyl, and methoxy; R 4A Selected from methyl, trideuterated methyl, ethyl, aziridine, and piperidinyl, wherein R 4A The aziridine and piperidinyl groups are each optionally substituted with methyl groups; and R G It can be H or D.

[0195] In some embodiments, the compound of formula III is a compound of formula IIIa:

[0196] IIIa

[0197] Or its pharmaceutically acceptable salt.

[0198] In some embodiments, the compound of formula III is a compound of formula IIIb:

[0199] IIIb

[0200] Or its pharmaceutically acceptable salt.

[0201] In some embodiments, the compounds provided herein are selected from: 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-N,N,7-trimethyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl-1-d)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-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-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)-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-acetylpiperidin-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-carbamoyl-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-carbamoyl-4-fluorophenyl)amino)ethyl-1-d)-7-chloro-4-methyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-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]quinazolin-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]quinazolin-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]quinazolin-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]quinazolin-3-carboxamide; 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]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl-1-d)-4-methyl-N,N-bis(methyl-d3)-5-oxo-7-(trifluoromethyl)-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 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; 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-carbamoyl-6-chloropyridin-3-yl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-6-chloropyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-4-chlorophenyl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-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]quinazolin-3-carboxamide; (3-((1-(3-(bis(methyl-d3)carbamoyl)-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-carbamoyl-4-chlorophenyl)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-1H-tetrazol-5-yl)phenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-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]quinazolin-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]quinazolin-3-carboxamide; (6-chloro-3-((1-(3-(dimethylcarbamoyl)-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-aminosulfonylphenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((5-chloroquinoline-8-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-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]quinazolin-3-carboxamide; 2-((1-(3-(1-acetylpiperidin-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-(oxecyclobut-3-yl)piperidin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(1-acetylpiperidin-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; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2-hydroxyacetyl)piperidin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(1-acetylpiperidin-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-isobutyrylpiperidin-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)piperidin-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)piperidin-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)piperidin-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)piperidin-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-tetrazole-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-pyridyl)-9-[1-[4-fluoro-2-(1-methyltriazol-4-yl)anilino]ethyl]-4,7-dimethyl-imidazo[1,5-a]quinazolin-5-one; 3-(1-acetylpiperidin-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)piperidin-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-fluoroazacyclobut-1-yl)methyl)pyridin-3-yl)amino)ethyl)- N,N ,4,7-Tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((6-chloro-2-((3-fluoroazacyclobut-1-yl)methyl)pyridin-3-yl)amino)ethyl)-N-(2-hydroxyethyl)-N,4,7-trimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; ((6-chloro-3-((1-(3-(dimethylcarbamoyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)pyridin-2-yl)methyl)carbamate; (6-chloro-3-(((3-(dimethylcarbamoyl)-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]quinazolin-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(trideuterated methyl)imidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((6-chloro-2-(2-(1-methylazacyclobut-3-yl)-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-((6-chloro-2-(2-(1-methylpiperidin-4-yl)-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-((6-chloro-2-(2-(1-methylazacyclobut-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]quinazolin-3-carboxamide; 9-(1-((6-chloro-2-(2-(1-methylpiperidin-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]quinazolin-3-carboxamide; 3-(2-aminopyrimidin-5-yl)-9-((6-chloro-3,4-dihydro-1,5-naphthidin-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-difluoroazacyclobut-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-naphthidin-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-naphthidin-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; (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-(oxecyclobut-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-hydroxypiperidin-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-morpholinylpyridin-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-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-6-chloropyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 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; (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-d3)-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-d3)-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-aminothiazolyl-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-methylthiazolyl-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 its pharmaceutically acceptable salt.

[0202] In some embodiments, the compounds provided herein are selected from: 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; ( R )-9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; ( S)-9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-N,N,7-trimethyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl-1-d)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-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; ( 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-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-acetylpiperidin-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-carbamoyl-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-carbamoyl-4-fluorophenyl)amino)ethyl-1-d)-7-chloro-4-methyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-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]quinazolin-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]quinazolin-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]quinazolin-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]quinazolin-3-carboxamide; 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]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl-1-d)-4-methyl-N,N-bis(methyl-d3)-5-oxo-7-(trifluoromethyl)-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 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; 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-carbamoyl-6-chloropyridin-3-yl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-6-chloropyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-4-chlorophenyl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-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]quinazolin-3-carboxamide; (3-((1-(3-(bis(methyl-d3)carbamoyl)-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-carbamoyl-4-chlorophenyl)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-1H-tetrazol-5-yl)phenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-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]quinazolin-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]quinazolin-3-carboxamide; (6-chloro-3-((1-(3-(dimethylcarbamoyl)-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-aminosulfonylphenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((5-chloroquinoline-8-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-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]quinazolin-3-carboxamide; 2-((1-(3-(1-acetylpiperidin-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-(oxecyclobut-3-yl)piperidin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(1-acetylpiperidin-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; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2-hydroxyacetyl)piperidin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(1-acetylpiperidin-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-isobutyrylpiperidin-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)piperidin-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)piperidin-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)piperidin-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)piperidin-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-tetrazole-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-pyridyl)-9-[1-[4-fluoro-2-(1-methyltriazol-4-yl)anilino]ethyl]-4,7-dimethyl-imidazo[1,5-a]quinazolin-5-one; 3-(1-acetylpiperidin-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)piperidin-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-fluoroazacyclobut-1-yl)methyl)pyridin-3-yl)amino)ethyl)- N,N ,4,7-Tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((6-chloro-2-((3-fluoroazacyclobut-1-yl)methyl)pyridin-3-yl)amino)ethyl)-N-(2-hydroxyethyl)-N,4,7-trimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; ((6-chloro-3-((1-(3-(dimethylcarbamoyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)pyridin-2-yl)methyl)carbamate; (6-chloro-3-(((3-(dimethylcarbamoyl)-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]quinazolin-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(trideuterated methyl)imidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((6-chloro-2-(2-(1-methylazacyclobut-3-yl)-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-((6-chloro-2-(2-(1-methylpiperidin-4-yl)-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-((6-chloro-2-(2-(1-methylazacyclobut-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]quinazolin-3-carboxamide; 9-(1-((6-chloro-2-(2-(1-methylpiperidin-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]quinazolin-3-carboxamide; 3-(2-aminopyrimidin-5-yl)-9-((6-chloro-3,4-dihydro-1,5-naphthidin-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-difluoroazacyclobut-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-naphthidin-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]quinazolin-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-naphthidin-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; (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-(oxecyclobut-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-hydroxypiperidin-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-morpholinylpyridin-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-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-6-chloropyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 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; (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-d3)-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-d3)-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-aminothiazolyl-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-methylthiazolyl-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 its pharmaceutically acceptable salt.

[0203] In some embodiments, the compounds provided herein are selected from: 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-N,N,7-trimethyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl-1-d)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; and 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; Or its pharmaceutically acceptable salt.

[0204] In some embodiments, the compounds provided herein are 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; 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-d3)-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 its pharmaceutically acceptable salt.

[0205] In some embodiments, the compound provided herein is 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide or a pharmaceutically acceptable salt thereof.

[0206] In some embodiments, the compounds provided herein are ( R )-9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide or a pharmaceutically acceptable salt thereof.

[0207] In some embodiments, the compounds provided herein are ( S )-9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide or a pharmaceutically acceptable salt thereof.

[0208] In some embodiments, the compound provided herein is 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazole-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.

[0209] It should be further understood that certain features of the invention set forth in the context of a single embodiment for clarity may also be provided in combination in a single embodiment. Conversely, various features of the invention set forth in the context of a single embodiment for simplicity may also be provided individually or in any suitable sub-combination.

[0210] Divalent linking substituents are described in various places throughout this specification. Each divalent linking substituent is explicitly intended to include both the forward and reverse forms of the linking substituent. For example, -NR(CR'R''). n -Including-NR(CR'R'') n - and -(CR'R'') n NR - Both. If the structure clearly requires a linking group, then the Markush variable listed for that group should be understood as the linking group.

[0211] The term "n-membered" (where n is an integer) typically describes the number of cyclic atoms in a portion, where the number of cyclic atoms is n. For example, piperidinyl is an example of a 6-membered heterocyclic alkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridinyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cyclic alkyl ring.

[0212] As used herein, the phrase “optionally substituted” means either unsubstituted or substituted. Substituents are chosen independently, and substitution can occur at any chemically accessible position. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent (e.g., an oxo group) can replace two hydrogen atoms. It should be understood that substitution at a given atom is limited by valence.

[0213] As used in this article, the phrase “each ‘variable’ is selected independently” means essentially the same as “the ‘variable’ is selected each time it appears”.

[0214] Throughout the definition, the term "C" n-m "and "C m-n The indicator includes a range of endpoints, where n and m are integers and indicate the number of carbons. Examples include C. 1-3 C 1-4 C 1-6 wait.

[0215] As used herein, the term "C" is used alone or in combination with other terms. n-m "Alkyl" refers to a saturated hydrocarbon group having n to m carbon atoms, which can be straight-chain or branched. Examples of alkyl moiety include (but are not limited to) chemical groups such as: methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologues, such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, etc. The term "C" n-m "Alkyl" should be understood to include deuterated analogs of saturated hydrocarbon groups as defined herein, including (but not limited to) groups such as trideuterated methyl (CD3), pentadeuterated ethyl (CD2CD3), etc. 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.

[0216] As used in this article, "C" n-m "Alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds and having n to m carbon atoms. Examples of alkenyl groups include (but are not limited to) vinyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, etc. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0217] As used in this article, "C" n-m "Alynyl" refers to an alkyl group having one or more carbon-carbon triple bonds and having n to m carbon atoms. Examples of alkynyl groups include (but are not limited to) ethynyl, propyn-1-yl, propyn-2-yl, etc. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0218] As used herein, the term "C" is used alone or in combination with other terms. n-m "Alkoxy" refers to a group of the formula -O-alkyl, wherein the alkyl group has n to m carbon atoms. Examples of 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), etc. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0219] As used herein, the term "aryl" alone or in combination with other terms refers to an aromatic hydrocarbon group, which can be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings). The term "C n-m "Aryl" refers to an aryl group having n to m ring carbon atoms. Aryl groups include, for example, phenyl, naphthyl, anthraceneyl, phenanthryl, etc. In some embodiments, the aryl group has 5 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. In some embodiments, the aryl group is phenyl.

[0220] As used herein, "halogen group" 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.

[0221] As used in this article, "C" n-m "Haloalkoxy" refers to a group of the formula -O-haloalkyl having n to m carbon atoms. Examples of haloalkoxy groups include OCF3 and OCHF2. In some embodiments, the haloalkoxy group is only fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0222] As used herein, the term "C" is used alone or in combination with other terms. n-m "Halogenated alkyl" refers to an alkyl group having 1 to 2s+1 possibly identical or different halogen atoms, where "s" is the number of carbon atoms in the alkyl group, and the alkyl group has n to m carbon atoms. In some embodiments, the halogenated alkyl group is only fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of halogenated alkyl groups include CF3, C2F5, CHF2, CH2F, CCl3, CHCl2, C2Cl5, etc.

[0223] As used herein, “cycloalkyl” refers to a non-aromatic cyclic hydrocarbon, including cycloalkyl and alkenyl groups. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having two fused rings) groups, spirocyclic, and bridged rings (e.g., bridged bicyclic alkyl). The cyclic carbon atom of a cycloalkyl group may optionally be substituted with an oxo group or a thio-bridged group (e.g., C(O) or C(S)). The definition of cycloalkyl also includes portions having one or more aromatic rings fused to (i.e., having a common bond) with the cycloalkyl ring, such as benzo or thiophene derivatives of cyclopentane, cyclohexane, etc. Cycloalkyl groups containing fused aromatic rings may be linked via any cyclic atom, including the cyclic atom of the fused aromatic ring. Cycloalkyl groups may have 3, 4, 5, 6, 7, 8, 9, or 10 cyclic carbons (i.e., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 3-10 In some embodiments, the cycloalkyl group is C10. 3-10 Monocyclic or bicyclic cycloalkyl group. In some embodiments, the cycloalkyl group is C10. 3-7 Monocyclic cycloalkyl group. In some embodiments, the cycloalkyl group is C10. 4-7 Monocyclic cycloalkyl group. In some embodiments, the cycloalkyl group is C10. 4-10 Spirocyclic or bridged cycloalkyl groups (e.g., bridged bicycloalkyl groups). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cyclohepttrienyl, 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, etc. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0224] 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 cyclic N in the heteroaryl moiety may be an N-oxide. In some embodiments, the heteroaryl is a 5- to 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 is a 5-, 7-, 8-, 9-, or 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 is a 5- to 10-membered monocyclic or bicyclic heteroaryl 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-membered, 7-membered, 8-membered, 9-membered, 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 cyclic atoms. In some embodiments, the heteroaryl group has 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomum. When a 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 (or thiophenyl), furanyl (or furanyl), 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, Pyrimidinyl, pyrazinyl, pyridazinyl, azolyl, triazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indoleyl, benzothiopheneyl, benzofuranyl, benzoisoxazolyl, imidazo[1,2-b]thiazolyl, purineyl, triazinyl, thiophene[3,2-b]pyridyl, imidazo[1,2-a]pyridyl, 1,5-naphthidyl, 1H-pyrazolo[4,3-b]pyridyl, triazolo[4,3-a]pyridyl, 1H-pyrrolo[3,2-b]pyridyl, 1H-pyrrolo[2,3-b]pyridyl, pyrazolo[1,5-a]pyridyl, indazoleyl, etc.

[0225] As used herein, “heterocyclic alkyl” means a monocyclic or polycyclic heterocycle having at least one non-aromatic ring (saturated or partially unsaturated ring), wherein one or more cyclic carbon atoms of the heterocyclic alkyl group are replaced by heteroatoms selected from N, O, S, and B, and wherein the cyclic carbon atoms and heteroatoms of the heterocyclic alkyl group may optionally be replaced by one or more oxo groups or thiobridging groups (e.g., C(O), S(O), C(S), or S(O)2, etc.). When the cyclic carbon atoms or heteroatoms of the heterocyclic alkyl group are optionally replaced by one or more oxo groups or thiobridging groups, the O or S of said group is other than the number of cyclic atoms specified herein (e.g., 1-methyl-6-oxo-1,6-dihydropyridazin-3-yl is a 6-membered heterocyclic alkyl group in which one cyclic carbon atom is replaced by an oxo group, and wherein said 6-membered heterocyclic alkyl group is further methylated). Heterocyclic alkyl groups include monocyclic and polycyclic (e.g., having two fused rings) systems. Heterocyclic alkyl groups include 3- to 10-membered, 4- to 10-membered, 5- to 10-membered, 4- to 7-membered, 5- to 7-membered, or 5- to 6-membered monocyclic and polycyclic heterocyclic alkyl groups. Heterocyclic alkyl groups may also include spirocyclic and bridging rings (e.g., 5- to 10-membered bridged bicyclic alkyl rings, where one or more cyclic carbon atoms are replaced by heteroatoms independently selected from N, O, S, and B). Heterocyclic alkyl groups may be linked via cyclic carbon atoms or cyclic heteroatoms. In some embodiments, the heterocyclic alkyl group contains 0 to 3 double bonds. In some embodiments, the heterocyclic alkyl group contains 0 to 2 double bonds.

[0226] The definition of heterocyclic alkyl also includes portions having one or more aromatic rings fused with (i.e., sharing a common bond) a non-aromatic heterocycle, such as benzo or thiophene derivatives of piperidine, morpholine, azepine, etc. Heterocyclic alkyl containing a fused aromatic ring can be linked via any cyclizing atom, including the cyclizing atom of the fused aromatic ring.

[0227] In some embodiments, the heterocyclic alkyl group contains 3 to 10 cyclic atoms, 4 to 10 cyclic atoms, 4 to 8 cyclic atoms, 3 to 7 cyclic atoms, or 5 to 6 cyclic atoms. In some embodiments, the heterocyclic alkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatomation. In some embodiments, the heterocyclic alkyl group is a 4-6 member monocyclic heterocyclic alkyl 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 heterocyclic alkyl group is a 5-10 member monocyclic or bicyclic heterocyclic alkyl 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 heterocyclic alkyl group is a 5-10 member monocyclic or bicyclic heterocyclic alkyl 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 heterocyclic alkyl group is a 5- to 6-membered monocyclic heterocyclic alkyl group having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S and having one or more oxidized ring members.

[0228] Examples of heterocyclic alkyl groups include pyrrolidine-2-one (or 2-oxopyrrolidine), 1,3-isooxazolidine-2-one, pyranyl, tetrahydropyran, oxacyclobutane, aziridine, morpholinyl, thiomorpholinyl, piperazine, tetrahydrofuranyl, tetrahydrothiophene, piperidinyl, pyrrolidine, isoxazolidine, isothiazolidine, pyrazolidine, oxazolidine, thiazolyl, imidazolyl, aziridine-heptane, 1,2,3,4-tetrahydroisoquinoline, tetrahydrothiophene, tetrahydrothiophene 1,1-dioxide, and benzo[a]azine. Heterocyclic heptatriene (benzazapene), azabicyclo[3.1.0]hexyl, diazabicyclo[3.1.0]hexyl, oxobicyclo[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, oxobicyclo[2.2.2]octyl, nitrogen Heterobicyclo[2.2.2]octyl, aziradamane, diaziradamane, oxo-adamantyl, aziraspiro[3.3]heptyl, 2-aziraspiro[3.3]heptyl, diaziraspiro[3.3]heptyl, aziraspiro[3.5]nonyl, 7-aziraspiro[3.5]nonyl, oxo-aziraspiro[3.3]heptyl, aziraspiro[3.4]octyl, diaziraspiro[3.4]octyl, oxo-aziraspiro[3.4]octyl, aziraspiro[2.5]octyl, diaziraspiro [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-dihydropyridazinyl, oxo-2,6-diazaspiro[3.4]octyl, oxohexahydropyrrolo[1,2-a]pyrazinyl, 3-oxopiperazinyl, oxo-pyrrolidinyl, oxo-pyridinyl, etc.

[0229] As used in this article, "C" o-p cycloalkyl-C n-m "alkyl-" refers to a group of the formula cycloalkyl-alkylene-, wherein the cycloalkyl group has 0 to p carbon atoms and the alkylene linking group has n to m carbon atoms.

[0230] As used in this article, "C" o-p Aryl-C n-m "alkyl-" refers to a group of the formula aryl-alkylene-, wherein the aryl group has 0 to p carbon atoms and the alkylene linking group has n to m carbon atoms.

[0231] As used in this article, "heteroaryl-C" n-m"alkyl-" refers to a group of the formula heteroaryl-alkylene-, wherein the alkylene linking group has n to m carbon atoms.

[0232] As used in this article, "heterocyclic alkyl-C" n-m "alkyl-" refers to a group of the formula heterocyclic alkyl-alkylene-, wherein the alkylene linking group has n to m carbon atoms.

[0233] As used herein, "alkyl linking group" or "alkylene linking group" refers to a divalent straight-chain or branched alkyl linking group ("alkylene"). For example, "C o-p cycloalkyl-C n-m Alkyl-", "C o-p Aryl-C n-m Alkyl-", "Phenyl-C" n-m Alkyl-", "Heteroaryl-C" n-m alkyl- and heterocyclic alkyl-C n-m "alkyl-" contains an alkyl linking group. Examples of "alkyl linking group" or "alkylene" include methylene, ethyl-1,1-diyl, ethyl-1,2-diyl, propyl-1,3-diyl, propyl-1,2-diyl, propyl-1,1-diyl, etc.

[0234] As used herein, "haloalkyl linking group" or "haloalkylene linking group" is a divalent straight-chain or branched haloalkyl linking group ("haloalkylene"). Examples of haloalkylene include -CF2-, -C2F4-, -CHF-, -CCl2-, -CHCl-, -C2Cl4-, etc.

[0235] As used herein, “cycloalkyl linking group” or “cycloalkylene linking group” refers to a divalent straight-chain or branched cycloalkyl linking group (“cycloalkylene”). Examples of “cycloalkyl linking group” or “cycloalkylene” include cyclopropyl-1,1,-diyl, cyclopropyl-1,2-diyl, cyclobut-1,3,-diyl, cyclopentyl-1,3,-diyl, cyclopentyl-1,4,-diyl, cyclohexyl-1,2,-diyl, cyclohexyl-1,3,-diyl, cyclohexyl-1,4,-diyl, etc.

[0236] As used herein, "heterocyclic alkyl linker" or "heterocyclic alkyl linker" refers to a divalent straight-chain or branched heterocyclic alkyl linker ("heterocyclic alkyl"). Examples of "heterocyclic alkyl linker" or "heterocyclic alkyl" include aziridine-1,2-diyl, aziridine-1,3-diyl, pyrrolidine-1,2-diyl, pyrrolidine-1,3-diyl, pyrrolidine-2,3-diyl, piperidine-1,2-diyl, piperidine-1,3-diyl, piperidine-1,4-diyl, piperidine-2,3-diyl, piperidine-2,4-diyl, etc.

[0237] As used herein, "heteroaryl linking group" or "heteroaryl linking group" refers to a divalent straight-chain or branched heteroaryl linking group ("heteroaryl"). Examples of "heteroaryl linking group" or "heteroaryl" include pyrazole-1,3-diyl, imidazole-1,2,2-diyl, pyridine-2,3-diyl, pyridine-2,4-diyl, pyridine-3,4-diyl, etc.

[0238] In some contexts, the definition or embodiment refers to a specific ring (e.g., an azacyclic butane ring, a pyridine ring, etc.). Unless otherwise indicated, these rings may be attached to any ring member, provided that the valence of the atom does not exceed the valence. For example, an azacyclic butane ring may be attached at any position on the ring, while a pyridine-3-yl ring may be attached at the 3-position.

[0239] As used herein, the term "oxo-substituent" refers to an oxygen atom (i.e., =O) that is a divalent substituent, which forms a carbonyl group (e.g., C=O or C(O)) when attached to a carbon atom, or forms a nitrosyl, sulfinyl, or sulfonyl group when attached to a nitrogen or sulfur heteroatom.

[0240] As used in this article, the term "independently selected" means each occurrence of a variable or substituent (e.g., each R) G Each time it appears, it is selected independently from the applicable list.

[0241] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are contemplated. Compounds of this 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, for example by resolving racemic mixtures or by stereoselective synthesis. Many geometric isomers of alkenes, C=N double bonds, etc., may also be present in the compounds described herein, and all such stable isomers are contemplated in this invention. Cis and trans geometric isomers of the compounds of this disclosure have been described and can be isolated in the form of mixtures of isomers or in separate isomeric forms. In some embodiments, the compound has an (R)-configuration. In some embodiments, the compound has an (S)-configuration. The various formulas provided herein (e.g., Formula I, Formula II, etc.) include stereoisomers of the compound.

[0242] The resolution of racemic mixtures of compounds can be carried out by any of the numerous methods known in the art. Example methods include fractional recrystallization using chiral resolving acids, which are optically active salt-forming organic acids. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids such as tartaric acid in D and L forms, 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 fractional crystallization methods include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms or diastereoisomerically pure forms), 2-phenylglycine, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc.

[0243] Racemic mixtures can also be separated by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). The suitable composition of the elution solvent can be determined by those skilled in the art.

[0244] The compounds described herein also include tautomers. Tautomers arise from the interchange of single and adjacent double bonds and the accompanying proton migration. Tautomers include proton-shift tautomers, which are isomeric protonated states with the same empirical formula and total charge. Examples of proton-shift tautomers include keto-enol pairs, amide-imine pairs, lactam-lactamimide pairs, enamine-imide pairs, and cyclic forms in which protons can occupy two or more positions in the heterocyclic system, such as 1H- and 3H-imidazolium, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindole, 2-hydroxypyridine and 2-pyridone, and 1H- and 2H-pyrazoles. Tautomers can exist in equilibrium or be spatially locked into one form through appropriate substitution.

[0245] All compounds and their pharmaceutically acceptable salts can be found together with other substances (e.g., water and solvents) (e.g., hydrates and solvates) or can be separated.

[0246] In some embodiments, the preparation of the compound may involve adding an acid or base to influence, for example, the catalysis of the desired reaction or the formation of a salt form (e.g., an acid addition salt).

[0247] In some embodiments, the compounds or salts thereof provided herein are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially isolated from the environment in which it is formed or detected. Partial isolation may include, for example, compositions rich in the compounds provided herein. Substantially isolated may include compositions containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compounds or salts thereof provided herein.

[0248] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the illustrated structures. Unless otherwise specified, compounds identified herein as a particular tautomer by name or structure are intended to include other tautomers.

[0249] The phrase “pharmaceutically acceptable” is used in this document to refer to compounds, materials, compositions, and / or dosage forms that are suitable for contact with human and animal tissues to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0250] This application also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salt” refers to a derivative of the disclosed compound, wherein the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include (but are not limited to) inorganic or organic acid salts of basic residues (e.g., amines); basic or organic salts of acidic residues (e.g., carboxylic acids); etc. Pharmaceutically acceptable salts of this disclosure include conventional non-toxic salts of parent compounds formed from, for example, non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of this disclosure can be synthesized by conventional chemical methods from parent compounds containing a basic or acidic moiety. Typically, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water, in an organic solvent, or in a mixture of both; typically, non-aqueous media such as diethyl ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (ACN) are preferred. For a list of suitable salts, see Remington's Pharmaceutical Sciences, 17th edition, 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.

[0251] synthesis

[0252] The compounds of the present invention (including their salts) can be prepared using known organic synthesis techniques and according to a variety of possible synthetic routes. Example synthetic methods for preparing the compounds of the present invention are provided below.

[0253] Compound I-12 can be synthesized, for example, using the method shown in Scheme I. Halogenation of I-1 with a suitable reagent (e.g., N-bromosuccinimide) yields I-2. Compound I-2 can be converted to I-3 via amide coupling, and after treatment with a suitable reagent (e.g., triphosgene), it is then converted to I-4. Intermediate I-5 can be prepared by treating I-4 with a suitable reagent (e.g., POCl3). Compound I-7 can be prepared by a method involving contacting intermediate I-5 with reagent I-6. Compound I-8 can be prepared from I-7 via a suitable reaction (e.g., a transition metal-catalyzed cross-coupling reaction) followed by a reduction reaction. Intermediate I-9 can be prepared by treating I-8 with a suitable reagent (e.g., PBr3). I-11 can be obtained by reacting I-9 with a suitable nucleophile followed by deprotection. Finally, I-11 can be converted to I-12 via an amide coupling reaction.

[0254] Option I.

[0255] Compound II-3 can be synthesized, for example, using the method shown in Scheme II. Compound II-2 can be prepared by decarboxylation and halogenation of II-1 under basic conditions in the presence of a suitable reagent (e.g., N-iodosuccinimide). II-2 can be converted to II-3 via suitable conditions (e.g., metal-catalyzed cross-coupling reaction).

[0256] Option II.

[0257] The reactions used to prepare the compounds of the present invention can be carried out in a suitable solvent, which can be readily selected by those skilled in the art of organic synthesis. A suitable solvent is substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out (e.g., a temperature ranging from the freezing temperature to the boiling temperature of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, those skilled in the art can select a suitable solvent for that particular reaction step.

[0258] The preparation of the compounds of this 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, as well as the selection of appropriate protecting groups. The chemistry of protecting groups can be found, for example, in TWGreene and PGM Wuts. Protective Groups in Organic Synthesis , 3rd edition, Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0259] The reaction can be monitored using any suitable method known in the art. For example, product formation can be detected by spectroscopic means (e.g., nuclear magnetic resonance spectroscopy, e.g.) 1 H or 13 C) Detection can be performed by infrared spectroscopy, spectrophotometry (e.g., UV-Vis or mass spectrometry) or by chromatography (e.g., high performance liquid chromatography (HPLC) or thin layer chromatography).

[0260] As used herein, the terms “ambient temperature,” “room temperature,” and “rt” are as understood in the art and generally refer to a temperature approximately equal to the room temperature at which the reaction is carried out (e.g., the reaction temperature), such as approximately 20°C to approximately 30°C.

[0261] How to use

[0262] This disclosure provides for the use of the compounds and compositions described herein. The compounds described herein inhibit the activity of PI3Kα kinase. In some embodiments, the provided compounds and compositions are intended for medical use (e.g., as a therapy). In some embodiments, the provided compounds and compositions are intended to treat diseases, conditions, or disorders in which the underlying pathology is wholly or partially mediated by PI3Kα. In some embodiments, the provided compounds and compositions are intended to be used in studies as analytical tools and / or control compounds, for example, in bioassays.

[0263] In some embodiments, this disclosure provides a method of administering the provided compound or composition to a subject in need. In some embodiments, this disclosure provides a method of administering the provided compound or composition to a subject who has or is susceptible to a disease, condition, or disorder related to PI3Kα. In some embodiments, this disclosure provides a method of administering the provided compound or composition to a subject who has or is susceptible to a disease, condition, or disorder, wherein the underlying pathology is wholly or partially mediated by PI3Kα.

[0264] In some embodiments, the compounds provided herein can be used as PI3Kα inhibitors. In some embodiments, this disclosure provides a method for inhibiting PI3Kα in a subject, comprising administering the provided compound or composition. In some embodiments, this disclosure provides a method for inhibiting PI3Kα in a biological sample, comprising contacting the sample with the provided compound or composition.

[0265] In some embodiments, this disclosure provides a method of treating a PI3Kα-related disease, condition, or disorder in a subject of need, comprising administering a compound, salt, or composition of this disclosure to the subject. In some embodiments, the disease, condition, or disorder is associated with a mutation in PI3Kα. In some embodiments, this disclosure provides a method of treating a disease, condition, or disorder in a subject of need, wherein the underlying pathology is wholly or partially mediated by PI3Kα, the method comprising administering the provided compound or composition to the subject.

[0266] In some embodiments, this disclosure provides methods for treating a variety of PI3Kα-dependent diseases and conditions. In some embodiments, the diseases or conditions are cancers (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 implementations, diseases or conditions associated with PI3Kα include (but are not limited to) CLOVES syndrome (congenital lipoma overgrowth, vascular malformation, epidermal nevus, scoliosis / skeletal and spinal syndrome), PIK3CA-associated overgrowth syndrome (PROS), endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophageal and gastric cancer, schwannoma, head and neck squamous cell carcinoma, melanoma, esophageal and gastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, biliary tract cancer, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, non-clear cell renal carcinoma, clear cell renal carcinoma, germ cell carcinoma, thymic tumor, pheochromocytoma, mixed neuroepithelial tumor, thyroid cancer, leukemia, and encapsulated glioma. In some implementations, the cancer is breast cancer.

[0267] In some embodiments, this document provides a method for prolonging a patient's survival or progression-free survival, comprising administering the compound provided herein to the patient. In some embodiments, the patient has cancer. In some embodiments, the patient has the disease or condition described herein. As used herein, progression-free survival refers to the length of time a patient coexists with a disease without its progression during and after treatment for a solid tumor. Progression-free survival may refer to the length of time from the first administration of the compound until death or disease progression, whichever is earlier. Disease progression may be defined by RECIST version 1.1 (Responsiveness Evaluation Criteria in Solid Tumors), as assessed by an independent centralized radiology review committee. In some embodiments, administration of the compound produces progression-free survival of more 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, application of the compound produces 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, application of the compound extends the 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.

[0268] This disclosure further provides the compounds described herein or their pharmaceutically acceptable salts for use in any of the methods described herein.

[0269] This disclosure further provides the use of the compounds described herein or pharmaceutically acceptable salts thereof for the preparation of pharmaceutical agents used in any of the methods described herein.

[0270] As used herein, the term "cell" is intended to refer to cells in vitro, ex vivo, or in vivo. In some embodiments, ex vivo cells may be a portion of a tissue sample excised from an organism (e.g., a mammal). In some embodiments, in vitro cells may be cells in a cell culture. In some embodiments, in vivo cells are cells living in an organism (e.g., a mammal).

[0271] As used herein, the term “contact” means bringing together the indicative portions of an in vitro or in vivo system. For example, “contacting” a PI3Kα kinase with a compound described herein includes administering the compound described herein to a subject or patient (e.g., a human) who has a PI3Kα kinase, and, for example, introducing the compound described herein into a sample containing cells or a purified formulation of a PI3Kα kinase.

[0272] 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, cattle, sheep, horses, or primates, and most preferably humans.

[0273] As used herein, the phrase “therapeutic effective amount” refers to the amount of an active compound or pharmaceutical agent that elicits a biological or medical response in a tissue, system, animal, individual, or human that is sought by an investigator, veterinarian, physician, or other clinician, such as the amount of any solid form or salt thereof disclosed herein. Appropriate “effective” amounts in any individual case can be determined using techniques known to those skilled in the art.

[0274] The phrase “pharmaceutically acceptable” is used herein to refer to compounds, materials, compositions, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0275] As used herein, the phrase "pharmaceutically acceptable carrier or excipient" refers to a pharmaceutically acceptable material, composition, or medium, 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 acceptable for both veterinary and human pharmaceutical use. In one embodiment, each component is "pharmaceutically acceptable" as defined herein. For example, see [link to relevant documentation]. Remington: The Science and Practice of Pharmacy , 21st edition; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 6th Edition; Rowe et al. (eds.); The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd edition; Edited by Ash and Ash; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd Edition;Edited by Gibson; CRC Press LLC: Boca Raton, Fla., 2009.

[0276] As used herein, the term “treating” refers to suppressing a disease; for example, suppressing the disease, ailment, or condition of a subject who is experiencing or exhibiting lesions or symptoms of a disease, disorder, or symptom (i.e., preventing further development of lesions and / or symptoms), or improving a disease; for example, improving the disease, ailment, or symptom of a subject who is experiencing or exhibiting lesions or symptoms of a disease, disorder, or symptom (i.e., reversing lesions and / or symptoms), such as reducing the severity of the disease.

[0277] In some embodiments, the compounds of the present 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 said disease, illness or condition in an individual who may be susceptible to the disease, illness or condition but has not yet experienced or exhibited lesions or symptoms of the disease.

[0278] It should be understood that certain features set forth in the context of individual embodiments of this disclosure for clarity may also be provided in combination in a single embodiment (which is intended to be combined as if written in the form of multiple dependencies). Conversely, various features set forth in the context of a single embodiment of this disclosure for simplicity may also be provided individually or in any suitable sub-combination.

[0279] Combination therapy

[0280] One or more additional therapeutic agents, such as chemotherapy agents or other anticancer agents, anti-inflammatory agents, steroids, immunosuppressants, anesthetics (e.g., for use in conjunction with surgical procedures), or other agents that can be used to treat diseases related to PI3Kα, may be used in combination with the compounds and salts provided herein. These agents may be combined with the compounds of the present invention in a single dosage form, or they may be administered simultaneously or sequentially as separate dosage forms.

[0281] The compounds described herein can be used in combination with one or more other kinase inhibitors for the treatment of diseases affected by multiple signaling pathways, such as cancer. For example, combinations may include one or more inhibitors of the following kinases for cancer treatment: 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. Additionally, as described herein, the solid form of the inhibitors can be combined with inhibitors of kinases associated with the PIK3 / Akt / mTOR signaling pathway (e.g., PI3K, Akt (including Akt1, Akt2, and Akt3), and mTOR kinases).

[0282] 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 selective JAK1 / 2 and JAK1 inhibitors, baricitinib, or itacitinib), Pim kinase inhibitors (e.g., LGH447, INCB053914, and SGI-1776), and PI3 kinase inhibitors (including selective and broad-spectrum PI3K inhibitors such as persatinib). Parsaclisib and INCB50797), PI3K-γ inhibitors (e.g., selective PI3K-γ inhibitors), MEK inhibitors, CSF1R inhibitors (e.g., PLX3397 and LY3022855), TAM receptor tyrosine kinase inhibitors (Tyro-3, Axl, and Mer; e.g., INCB81776), angiogenesis inhibitors, interleukin receptor inhibitors, and cyclin-dependent kinase inhibitors (e.g., palbociclib and ribociclib). In addition to abemaciclib, BRAF inhibitors, mTOR inhibitors, proteasome inhibitors (bortezomib, carfilzomib), HDAC-inhibitors (panobinostat, vorinostat), DNA methyltransferase inhibitors, dexamethasone, and inhibitors of bromine and extra-terminal family members (e.g., bromine domain 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-inducible factor-2α inhibitors (e.g., belzutifan), export protein-1 (XPO-1) inhibitors (e.g., selinexor), KRAS inhibitors (e.g., sotorasib), arginase 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).

[0283] 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 antiproliferative agents. The compounds described herein can also be used in combination with medical therapies such as surgery or radiation therapy, including gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes.

[0284] Examples of suitable chemotherapy agents include any of the following: abarrelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol, hexamethylmelamine, amidox, amsacrine, anastrozole, and aphidilone. dicolon), arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab, bexarotene, baricitinib, bendamustine, bicalutamide, bleomycin, bortezombi, bortezomib, brivanib, buparys, intravenous busulfan Intravenous, oral busulfan, calusterone, camptosar, capecitabine, carboplatin, carmustine, cediranib, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin D, dalteparin Sodium, dasatinib, actinomycin D, daunorubicin, decitabine, degarelix, denileukin, denileukin diftitox, deoxycoformycin, dexrazoxane, didox, docetaxel, doxorubicin, droloxafine, dromostanolone propionateEculizumab, Enzalutamide, Epipodophyllotoxin, Epirubicin, Epothilone, Erlotinib, Estramustine, Etoposide phosphate, Etoposide, Exemestane, Fentanyl citrate, Filgrastim, Fluuridine, Fludarabine, Fluuridine, Flutamide, Fulvestrant, Gefitinib, Gemcitabine, Gemtuzumab ozogamicin, Goserelin acetate, Histrelin acetate Acetate), ibritumomabtiuxetan, idarubicin, idelalisib, ifosfamide, imatinib mesylate, interferon alpha-2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leuprolide, leuprolide Acetate), levamisole, lonafarnib, lomustine, meclorethamine, megestrolacetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, navelbene, necitumumab, nelarabine, neratinib, nilotinib, nilutamide, niraparib, nofetumomab, oserelin, oxaliplatinPacific paclitaxel, pamidronate, panitumumab, pabistatin, pazopanib, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pilaralisib, pipobroman, plicamycin, ponati nib), porfimer, prednisone, procarbazine, quinacrine, ranibizumab, rasburicase, regorafenib, reloxafine, revlimid, rituximab, rucapranib, ruxotinib, sorafenib, streptozocin, sunitinib Inib, sunitinib maleate, tamoxifen, tegafur, temozolomide, teniposide, testrolide, tezacitabine, thalidomide, thioguanine, thiotepa, tipifranib, topotecan, toremifene, tositumomab, trastuzumab Retinoin, triapine, trimidox, triptorelin, uracil mustard, valrubicin, vandetanib, vinblastine, vincristine, vindesine, vinorelbine, vorinostat, veliparib, talazoparib, and zoledronate.

[0285] Methods for the 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 stated in its entirety.

[0286] Examples of anti-inflammatory agents include (but are not limited to) aspirin, choline salicylate, celecoxib, diclofenac potassium, diclofenac sodium, diclofenac sodium combined with misoprostol, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, meclofenamate sodium, mefenamic acid, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxican, rofecoxib, bis(salicylate), sodium salicylate, sulindac, tolmetin sodium, and valdecoxib.

[0287] Examples of steroids include (but are not limited to) corticosteroids such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisolone.

[0288] Examples of immunosuppressants include (but are not limited to) azathioprine, chlorambucil, cyclophosphamide, cyclosporine, daclizumab, infliximab, methotrexate, and tacrolimus.

[0289] Examples of anesthetic agents include (but are not limited to) local anesthetics (such as lidocaine, procaine, ropivacaine) and general anesthetics (such as desflurane, enflurane, halothane, isoflurane, methoxyflurane, nitrous oxide, sevoflurane, methylbarbital, methophenoxate, thiamylal, thiopental, diazepam, lorazepam, etc.). Dazolam, etomidate, ketamine, propofol, alfentanil, fentanyl, remifentanil, buprenorphine, butorphanol, hydromorphone, levorphanol, meperidine, methadone, morphine, nalbuphine, oxymorphone, pentazocine.

[0290] In some embodiments, the additional therapeutic agent is administered concurrently with the compounds or salts provided herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compounds or salts provided herein. In some embodiments, the additional therapeutic agent is administered before the administration of the compounds or salts provided herein. In some embodiments, the compounds or salts provided herein are administered during the surgical procedure. In some embodiments, the compounds or salts provided herein are administered in combination with the additional therapeutic agent during the surgical procedure.

[0291] As provided herein, additional compounds, inhibitors, agents, etc., may be combined with the compounds provided herein in single or sequential dosage forms, or may be administered simultaneously or sequentially as individual dosage forms.

[0292] Pharmaceutical formulations and dosage forms

[0293] When used as a medicine, the compounds of the present invention can be administered in the form of pharmaceutical compositions, which are combinations of the compounds of the present invention or pharmaceutically acceptable salts thereof with at least one pharmaceutically acceptable carrier. These compositions can be prepared in ways well known in the pharmaceutical field and can be administered via 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 mucosal delivery, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or blowing of powders or aerosols, including via nebulizers; intratracheal, intranasal, epidermal, and transdermal), ocular, oral, or parenteral. Methods of ocular delivery can include topical application (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, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial (e.g., intrathecal or intraventricular) administration. Parenteral administration can be in the form of a single concentrated dose or can be performed, for example, by a continuous infusion pump. Pharmaceutical compositions and formulations for external application may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional drug carriers, aqueous, powdered, or oily bases, thickeners, etc., may be necessary or desired.

[0294] The present invention also includes pharmaceutical compositions comprising one or more compounds of the present invention as active ingredients and one or more pharmaceutically acceptable carriers. In preparing the compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted with the excipient, or encapsulated in such a carrier, for example, in the form of capsules, pouches, paper, or other containers. When the excipient is used as a diluent, it can be a solid, semi-solid, or liquid material that acts as a medium, carrier, or mediator for the active ingredient. Therefore, the compositions can be in the following forms: tablets, pills, powders, rhomboid tablets, pouches, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (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.

[0295] When preparing a formulation, the active compound can be milled to provide an appropriate particle size before being combined with other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially soluble in water, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, for example, about 40 mesh.

[0296] Active compounds are effective over a wide dose range and are typically administered at a pharmaceutically effective amount. However, it should be understood that the actual amount of compound administered will usually be determined by the physician based on relevant circumstances, including the disease to be treated, the chosen route of administration, the actual compound administered, the individual patient's age, weight and response, and the severity of the patient's symptoms.

[0297] To prepare solid compositions (e.g., tablets), the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformed composition containing a homogeneous mixture of compounds of the present invention. When these preformed compositions are referred to as homogeneous, the active ingredient is typically uniformly dispersed throughout the composition, making it easy to subdivide the composition into equally effective unit dosage forms, such as tablets, pills, and capsules. This solid preformed composition is then subdivided into unit dosage forms of the types described above.

[0298] The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form with the advantage of prolonged action. For example, the tablets or pills may comprise an internal dose component and an external dose component, the latter being coated on the former. The two components may be separated by an enteric coating layer, which resists disintegration in the stomach and allows the internal component to pass intact into the duodenum or delays release.

[0299] Compounds and compositions that can be incorporated into the present invention in liquid form for oral or injectable administration include aqueous solutions, suitable flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils.

[0300] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered via oral or nasal inhalation to achieve local or systemic effects. The composition may be nebulized using an inert gas. The nebulized solution may be inhaled directly from a nebulizer or the nebulizer may be connected to a face mask, hood, or intermittent positive pressure ventilator. Solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in a suitable manner.

[0301] The amount of compound or composition administered to a patient will vary depending on the drug being administered, the purpose of administration (e.g., prevention or treatment), the patient's condition, the method of administration, etc. In therapeutic applications, the composition may be administered to a patient suffering from the disease in an amount sufficient to cure or at least partially stop 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 physician based on factors such as the severity of the disease, the patient's age, weight, and general condition.

[0302] Compositions administered to patients may be in the form of pharmaceutical compositions as described above. These compositions may be sterilized using conventional sterilization techniques or by sterile filtration. Aqueous solutions may be used as is or lyophilized, with the lyophilized formulation 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 should be understood that the use of certain of the excipients, carriers, or stabilizers described above will result in the formation of pharmaceutical salts.

[0303] The therapeutic dose of the compounds of this invention may vary depending on, for example, the specific use of the treatment, the route of administration of the compound, the patient's health and condition, and the prescribing physician's judgment. The proportion or concentration of the compounds of this invention in the pharmaceutical composition may vary depending on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. Dosage may depend on variables such as, for example, the type and progression of the disease or condition, the overall health status of the specific patient, the relative biological efficacy of the selected compound, the formulation of the excipients, and their route of administration. The effective dose can be obtained by extrapolation from dose-response curves obtained from in vitro or animal model testing systems.

[0304] The compositions disclosed herein may also include one or more additional pharmaceutical agents, such as chemotherapeutic agents, steroids, anti-inflammatory compounds, or immunosuppressants, examples of which are provided herein.

[0305] Labeled compounds and assay methods

[0306] Another aspect of the invention relates to compounds of the invention labeled with fluorescent dyes, spin labels, heavy metals, or radioactive materials, which can be used not only for imaging but also for in vitro and in vivo assays to locate and quantify PI3Kα enzymes in tissue samples (including human samples) and to identify PI3Kα enzyme ligands by inhibiting the binding of the labeled compounds. Therefore, the invention includes PI3Kα enzyme assays containing such labeled compounds.

[0307] This invention also includes isotopically labeled compounds of the invention. An "isotopically labeled" or "radioactively labeled" compound is a compound of the invention in which one or more atoms are replaced or substituted with atoms of atomic mass or mass number different from those normally found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated into the compounds of the invention include (but are not limited to) [the following]. 2 H (also written as D) 3 H (also written as T) 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、18 F, 35 S, 36 Cl、 82 Br、 75 Br、 76 Br、 77 Br、 123 I, 124 I, 125 I and 131 I. The radionuclides incorporated into the radiolabeled compounds of this invention will depend on the specific application of the radiolabeled compounds. For example, for in vitro FGFR enzyme labeling and competitive assays, and with 3 H, 14 C 82 Br、 125 I, 131 I or 35 Compounds of S will generally be most useful. For radiographic imaging applications, 11 C 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br、 76 Br or 77 Br will usually be the most useful.

[0308] One or more constituent atoms of the compounds presented herein may be replaced or substituted by isotopes of said atoms in natural or non-natural abundance. In some embodiments, one or more atoms are replaced or substituted by deuterium. For example, one or more hydrogen atoms in the compounds of this disclosure may be replaced by deuterium atoms (e.g., C of Formula I). 1-6 One or more hydrogen atoms of the alkyl group may optionally be substituted with deuterium atoms, for example, -CD3 substituted for -CH3. In some embodiments, the alkyl group of the disclosed formula (e.g., compounds of any of formulas I to VIIa) may be fully deuterated.

[0309] In some embodiments, the compounds provided herein (e.g., compounds of any of Formulas I to IIIb) or their pharmaceutically acceptable salts contain at least one deuterium atom.

[0310] In some embodiments, the compounds provided herein (e.g., compounds of any of Formulas I to IIIb) or their pharmaceutically acceptable salts contain two or more deuterium atoms.

[0311] In some embodiments, the compounds provided herein (e.g., compounds of any of Formulas I to IIIb) or their pharmaceutically acceptable salts contain three or more deuterium atoms.

[0312] In some embodiments, for the compounds provided herein (e.g., compounds of any of Formulas I to IIIb) or their pharmaceutically acceptable salts, all hydrogen atoms are replaced by deuterium atoms (i.e., the compound is “fully deuterated”).

[0313] It should be understood that "radiolabeled" or "labeled compound" is a compound containing at least one radioactive nuclide. In some embodiments, the radioactive nuclide is selected from the group consisting of: 3 H, 14 C 125 I, 35 S and 82 Br.

[0314] Synthetic methods that incorporate isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry, Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971; The Renaissance of H / D Exchange, Jens Atzrodt, Volker Derdau, ThorstenFey 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 assays.

[0315] Substitution with a heavier isotope (e.g., deuterium) can provide certain therapeutic advantages due to its greater metabolic stability, such as a longer in vivo half-life or a reduced dose requirement, and may therefore be preferred in some cases. (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). Specifically, substitution at one or more metabolic sites can provide one or more therapeutic advantages.

[0316] The radiolabeled compounds of this invention can be used in screening assays to identify / evaluate compounds. Generally, newly synthesized or identified compounds (i.e., test compounds) reduce the binding affinity of the radiolabeled compounds of this invention to the PI3Kα enzyme. Therefore, the ability of the test compound to compete with the radiolabeled compound for binding to the PI3Kα enzyme is directly related to its binding affinity.

[0317] medicine box

[0318] The present invention also includes a kit for use, for example, in treating or preventing PI3Kα-related diseases or conditions mentioned herein, comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention. As will be readily apparent to those skilled in the art, such kits may also include one or more of a variety of conventional kit components, such as containers containing one or more pharmaceutically acceptable carriers, additional containers, etc., where necessary. The kit may also include instructions (as an insert or label) indicating the amount of the component to be administered, an administration guide, and / or a guide for mixing the components.

[0319] The invention will be described in more detail with the aid of specific embodiments. The following embodiments are provided for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily identify several non-critical parameters that can be changed or modified to obtain substantially the same results. As described below, the compounds in the examples are found to be PI3Kα inhibitors.

[0320] Example

[0321] The experimental procedures for the compounds of this invention are provided below. Preparative LC-MS purification of some of the prepared compounds was performed on a Waters quality-guided grading system. The basic equipment setup, procedures, and control software used to operate these systems have been described in detail in the literature. For example, see “Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K. Blom. J. Combi. Chem ., 4, 295 (2002); "OptimizingPreparative LC-MS Configurations and Methods for Parallel SynthesisPurification", 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 are usually subjected to analytical liquid chromatography-mass spectrometry (LCMS) for purity checks.

[0322] As indicated in the examples, some of the prepared compounds were separated on a preparative scale by reversed-phase high-performance liquid chromatography (RP-HPLC) with an MS detector or by rapid chromatography (silica gel).

[0323] Intermediate 1. 6-Methyl-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-amine

[0324] 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), K3PO4 (166.3 mg, 0.78 mmol), and methylboronic acid (31.3 mg, 0.52 mmol) in 3 mL dioxane / H2O (5:1) was bubbled with N2 for 1 min. The resulting reaction mixture was stirred at 100 °C for 2 h. LCMS analysis indicated the completion of the reaction. The mixture was diluted with water and extracted with EtOAc. The combined organic matter was 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 to 100%), to give the desired product as a white solid. LCMS C8H 11 N6(M+H) + Calculated m / z value = 191.1; Experimental value = 191.1.

[0325] 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).

[0326] Step 1: 2-(4-fluoro-2-(1H-tetrazol-5-yl)phenyl)isoindoline-1,3-dione

[0327] Use and targeting Example 8 A similar procedure was described, in which 2-amino-5-fluorobenzonitrile was used instead of 3-amino-6-chloro-pyridin-2-carboxynitrile in step 1 to prepare the title intermediate. 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 C 15 H9FN5O2 (M+H) + Calculated m / z value = 310.1; Experimental value 310.1.

[0328] Step 2: 2-(4-fluoro-2-(1-(methyl-d3)-1H-tetrazol-5-yl)phenyl)isoindoline-1,3-dione and 2- (4-Fluoro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)phenyl)isoindololin-1,3-dione

[0329] CD3I (0.70 mL, 11.27 mmol) and K2CO3 (3.34 g, 24.15 mmol) were added 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 DMF. After stirring at room temperature for 2 h, the mixture was diluted with water and extracted with EtOAc. The combined organic matter was washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography, eluting with DCM and ethyl acetate, to give two product isomers, 1 and 2. LCMS C 16 H8D3FN5O2 (M+H) + Calculated m / z value: 327.1; Experimental value: 327.1

[0330] Step 3: 4-Fluoro-2-(1-(methyl-d) 3 )-1H-tetrazole-5-yl)aniline

[0331] A mixture of 0.13 g (0.40 mmol) of 2-(4-fluoro-2-(1-(methyl-d3)-1H-tetrazol-5-yl)phenyl)isoindoline-1,3-dione 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 a product as a white solid. LCMS C8H6D3FN5 (M+H) + Calculated m / z value = 197.1; Experimental value = 197.1.

[0332] Step 4: 4-Fluoro-2-(2-(methyl-d3)-2H-tetrazole-5-yl)aniline

[0333] The title intermediate was prepared using a procedure similar to that described in step 3, replacing 2-(4-fluoro-2-(1-(methyl-d3)-1H-tetrazol-5-yl)phenyl)isoindoline-1,3-dione. LCMS C8H6D3FN5 (M+H) + Calculated m / z value = 197.1; Experimental value = 197.1.

[0334] Intermediate 4. 4-Fluoro-2-(1-methyl-1,2,4-triazol-3-yl)aniline

[0335] A solution of 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-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]phosphine (663.8 mg, 0.84 mmol) in 15 mL dioxane / H2O (5:1) was bubbled with N2 for 1 min. The resulting reaction mixture was stirred at 90 °C for 2 h. LCMS analysis indicated the reaction was complete. The mixture was diluted with water and extracted with EtOAc. The combined organic compounds 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 to 100%) to give the desired product as a white solid. LCMS C9H 10 FN4 (M+H) + Calculated m / z value = 193.1; Experimental value = 193.1.

[0336] Intermediate 5. Methyl (3-amino-6-chloropyridin-2-yl)carbamate

[0337] Step 1. Methyl (6-chloro-3-nitropyridin-2-yl)carbamate

[0338] Add to the suspension of 6-chloro-3-nitropyridine-2-amine (5.00 g, 28.81 mmol) in DCM N,N-Diisopropylethylamine (24 mL, 172.85 mmol) was added dropwise, followed by the addition of methyl chloroformate (26.8 mL, 345.71 mmol). The resulting mixture was heated at 45 °C for 1 hour. The reaction mixture was then cooled to room temperature. The reaction mixture was concentrated under vacuum and loaded onto silica gel (20 g), eluted with hexane containing 0-50% ethyl acetate, to give the desired product (1.14 g, 17.1%) as a yellow solid. LCMS C7H7ClN3O4 (M+H) + Calculated m / z value = 232.0; Experimental value 232.0.

[0339] Step 2. Methyl (3-amino-6-chloropyridin-2-yl)carbamate

[0340] Iron (0.94 g, 16.78 mmol) and ammonium chloride (0.90 g, 16.78 mmol) were added to a solution of N-(6-chloro-3-nitro-2-pyridyl)carbamate (1.11 g, 4.79 mmol) in a 5:1 mixture of ethanol and water 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 diatomaceous earth mat, and concentrated. The residue was purified by silica gel chromatography, eluting with dichloromethane containing 0-100% ethyl acetate, to give the desired product (0.33 g, 34.2%) as a yellow solid. LCMS C7H9ClN3O2 (M+H) + Calculated m / z value = 202.0; Experimental value = 202.0.

[0341] Intermediate 6. N,N,4,7-Tetramethyl-5-oxo-9-vinyl-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide

[0342] Step 1. 9-Bromo-4,7-dimethyl-5-oxo-imidazo[1,5-a]quinazolin-3-carboxylic acid

[0343] Solid tert-butyl 9-bromo-4,7-dimethyl-5-oxo-imidazo[1,5-a]quinazolin-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. After completion, the solvent was removed under reduced pressure. The residue was azeotropically treated three times with toluene (20 mL) to give a crude product, which was used directly in the next step. LCMS C 13 H 11 BrN3O3 (M+H) + Calculated m / z value = 336.0; Experimental value 336.0.

[0344] Step 2. 9-Bromo-N,N,4,7-Tetramethyl-5-oxo-imidazo[1,5-a]quinazolin-3-carboxamide

[0345] At room temperature, a solution of 9-bromo-4,7-dimethyl-5-oxo-imidazo[1,5-a]quinazolin-3-carboxylic acid (3.43 g, 10.20 mmol) in DMF (20 mL) was supplemented with [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium; hexafluorophosphate (5.82 g, 15.31 mmol), N-ethyl-N-isopropyl-propyl-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. After 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 x 3). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the desired product (2.54 g, 68.5%) as a pale yellow solid. (LCMS C) 15 H 16 BrN4O2 (M+H)+ m / z calculated value = 363.0; experimental value 363.0.

[0346] Step 3. N,N,4,7-Tetramethyl-5-oxo-9-vinyl-4,5-dihydroimidazo[1,5-a]quinazoline-3- formamide

[0347] At room temperature, 9-bromo-N,N,4,7-tetramethyl-5-oxo-imidazo[1,5-a]quinazolin-3-carboxamide (0.94 g, 2.59 mmol), a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 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) were added to a 5:1 mixture (25 mL) of THF and water. 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 give the desired product (0.50 g, 62.3%) as a yellow solid. LC-MSC 17 H 19 N4O2 (M+H) + Calculated m / z value = 311.2; Experimental value 311.2.

[0348] Intermediate 7. 4-(5-(3-amino-6-chloropyridin-2-yl)-2H-tetrazole-2-yl)piperidine-1-carboxylic acid tert-butyl ester

[0349] Step 1. 4-(5-(6-chloro-3-(1,3-dioxoisoindoline-2-yl)pyridin-2-yl)-2H-tetrazole-2-yl) Piperidine-1-carboxylic acid tert-butyl ester

[0350] K₂CO₃ (63 mg, 0.46 mmol) and tert-butyl 4-((methanesulfonyl)oxy)piperidine-1-carboxylic acid (171 mg, 0.61 mmol) were added 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. The resulting mixture was heated at 80 °C overnight. The reaction mixture was then cooled to room temperature. The reaction mixture was concentrated under vacuum and purified by silica gel chromatography to give the desired product. LCMS C 24 H 25 ClN7O4 (M+H) + Calculated m / z value = 510.2; Experimental value 510.2.

[0351] Step 2. 4-(5-(3-amino-6-chloropyridin-2-yl)-2H-tetrazole-2-yl)piperidine-1-carboxylic acid tert-butyl ester

[0352] A mixture of tert-butyl 4-(5-(6-chloro-3-(1,3-dioxoisoindoline-2-yl)pyridin-2-yl)-2H-tetrazol-2-yl)piperidin-1-carboxylic acid (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 obtain the desired product. LC-MSC 16 H 23 ClN7O2 (M+H) + Calculated m / z value = 380.2; Experimental value 380.2.

[0353] Intermediate 8. tert-butyl 3-(5-(3-amino-6-chloropyridin-2-yl)-2H-tetrazole-2-yl)azacyclobutane-1-carboxylate

[0354] The title intermediate was prepared in step 1 using a procedure similar to that described in intermediate 7, with tert-butyl 3-((methanesulfonyl)oxy)azacyclobutane-1-carboxylate instead of tert-butyl 4-((methanesulfonyl)oxy)piperidine-1-carboxylate. LCMS C 14 H 19ClN7O2 (M+H) + Calculated m / z value = 352.1; Experimental value 352.1.

[0355] Intermediate 9. 4-Fluoro-2-(1-methyl-1H-1,2,3-triazol-4-yl)aniline

[0356] The title compound was prepared using a procedure similar to that described for intermediate 4, replacing 3-bromo-1-methyl-1H-1,2,3-triazole with 4-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 give the desired product as a white solid. LCMS C9H 10 FN4 (M+H) + Calculated m / z value = 193.1; Experimental value = 193.1.

[0357] Intermediate 10. 6-Chloro-1,2,3,4-Tetrahydro-1,5-Naphthidine

[0358] Step 1. Methyl (E)-3-(3-amino-6-chloro-2-pyridyl)prop-2-enoate

[0359] Pd(OAc)₂ (88 mg, 0.39 mmol), tri-o-tolylphosphine (84 mg, 0.28 mmol), methyl propionate (605.43 μL, 6.68 mmol), and N-ethyl-N-isopropyl-propion-2-amine (2.05 mL, 11.79 mmol) were added to a solution of 6-chloro-2-iodopyridin-3-amine (1.00 g, 3.93 mmol) in anhydrous DMF (3.33 mL) at room temperature. 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 x 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 DCM containing 0-100% EA, yielding the desired product (740 mg, 88.6%) as a yellow solid. LCMS C9H 10 ClN2O2 (M+H) + Calculated m / z value = 213.0; Experimental value 213.0.

[0360] Step 2. Methyl 3-(3-amino-6-chloro-2-pyridyl)propionate

[0361] A dry vial was filled with copper diacetoxy (55 mg, 0.30 mmol) and (2-diphenylphosphine)-diphenylphosphine (13 mg, 0.03 mmol) in 2-methylprop-2-ol (857 μL, 9.03 mmol) and anhydrous toluene (2.0 mL). The resulting mixture was stirred at room temperature under nitrogen for 20 min. Then, polymethylhydrosiloxane (557 μL) was added via syringe, and the solution changed from blue to deep yellow in about 5 min. Then, methyl (E)-3-(3-amino-6-chloro-2-pyridyl)prop-2-enoate (640 mg, 3.01 mmol) was added in a single batch. The resulting mixture was stirred at room temperature for 2 days, then diluted with DCM, washed with water, the organic layer was separated, dried over Na2SO4, and the solvent was 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 using silica gel elution with 0-100% DCM / EA followed by 0-30% MeOH / EA to give the desired product (362 mg, 56.1%) as a white solid. LCMSC9H 12 ClN2O2 (M+H) + Calculated m / z value = 215.1; Experimental value 215.1.

[0362] Step 3. 6-Chloro-3,4-dihydro-1H-1,5-naphthid-2-one

[0363] A 10:1 mixture of ethanol and acetic acid (10 mL) was added to methyl 3-(3-amino-6-chloro-2-pyridyl)propionate (362 mg, 1.69 mmol) at room temperature. The resulting mixture was heated overnight at 70 °C. The solvent was removed under reduced pressure. The residue was azeotropically reacted twice with EA / DCM to give the desired crude material as a yellow solid, which was used directly in the next step. LCMSC8H8ClN2O (M+H) + Calculated m / z value = 183.0; Experimental value = 183.0.

[0364] Step 4. 6-Chloro-1,2,3,4-Tetrahydro-1,5-Naphthidine

[0365] LAH (THF solution, 5.61 mL, 5.61 mmol) was added to a solution of 6-chloro-3,4-dihydro-1H-1,5-naphthid-2-one (512 mg, 2.80 mmol) in anhydrous THF (5.6 mL) at 0 °C. The resulting mixture was heated at 60 °C for 14 hours. The reaction mixture 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%, 2 steps). LCMSC8H 10 ClN2 (M+H) + Calculated m / z value = 169.1; Experimental value = 169.1.

[0366] Intermediate 11. 6-Chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-amine

[0367] Use and targeting Example 8 The procedure described herein uses iodomethane-d3 instead of iodomethane in step 3 to prepare the title compound. LCMS C7H5D3ClN6 (M+H) + Calculated m / z value = 214.1; Experimental value 214.1.

[0368] Intermediate 12. 9-(1-bromoethyl-1-d)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid tert-butyl ester

[0369] Use and targeting Example 1 The procedure described herein involves replacing 2-amino-3-bromo-5-methyl-N-(methyl-d3)benzamide (Example 4, step 1) with 2-amino-3-bromo-N,5-dimethylbenzamide in step 4, and replacing NaBH4 with NaBD4 in step 8 to prepare the title compound. LCMS C 19 H 19 D4BrN3O3 (M+H) + Calculated m / z value = 424.1; Experimental value 424.1.

[0370] Intermediate 13. 9-Formyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid tert-butyl ester

[0371] Step 1: tert-4,7-dimethyl-5-oxo-9-vinyl-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid Butyl acetate

[0372] At room temperature, a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (416.4 mg, 0.51 mmol), potassium carbonate (2.11 g, 15.30 mmol), and potassium vinyltrifluoroborate (2.05 g, 15.30 mmol) was added to a mixture of 9-bromo-4,7-dimethyl-5-oxoimidazo[1,5-a]quinazolino-3-carboxylate (Example 1, step 6) (2.00 g, 5.10 mmol) in a 5:1 mixture of THF and water (75 mL). 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 reduced pressure. The residue was purified by silica gel chromatography to give the desired product (1.21 g, 69.9%) as a yellow solid. (LCMS C) 19 H 22 The calculated value of N3O3 (M+H)+ m / z is 340.2; the experimental value is also 340.2.

[0373] Step 2: 9-Formyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid tert- Butyl acetate

[0374] To a 5:1 mixture of THF and water, tert-butyl 4,7-dimethyl-5-oxo-9-vinyl-imidazo[1,5-a]quinazolin-3-carboxylate (1.21 g, 3.57 mmol), OsO4 (4% aqueous solution, 679 μL, 0.11 mmol), 2,6-dimethylpyridine (826 μL, 7.13 mmol), and sodium periodate (3.05 g, 14.26 mmol) were added sequentially. 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 x 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 C 18 H 20 N3O4 (M+H) + Calculated m / z value = 342.1; Experimental value 342.1.

[0375] Intermediate 14. 9-Formyl-N,N,4,7-Tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide

[0376] The title compound was prepared in step 2 using a procedure similar to that described for intermediate 13, with N,N,4,7-tetramethyl-5-oxo-9-vinyl-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide (intermediate 6) instead of tert-butyl 4,7-dimethyl-5-oxo-9-vinyl-imidazo[1,5-a]quinazoline-3-carboxylate. LCMS C 16 H 17 N4O3 (M+H) + Calculated m / z value = 313.1; Experimental value 313.1.

[0377] Intermediate 15. 6-Chloro-2-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridine-3-amine

[0378] Under nitrogen atmosphere, 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 supplemented with 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-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). After stirring at 85 °C for 1 h, the mixture was diluted with water and extracted with EtOAc. The combined organic matter was 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 give the desired product as a yellow solid. LCMS C 11 H 12 ClN4 (M+H) + Calculated m / z value = 235.1; Experimental value 235.1.

[0379] Intermediates 16 to 21.

[0380] The following intermediates in Table I-1 are prepared similarly to those described for intermediate 15.

[0381] Table I-1.

[0382] Intermediate 22. 1-(3-amino-6-chloropyridin-2-yl)piperidin-4-ol

[0383] Piperidine-4-ol (57.3 mg, 0.57 mmol) was added to a solution of 6-chloro-2-fluoro-3-nitropyridine (100 mg, 0.57 mmol) in 3 mL of EtOH. The reaction mixture was stirred at 45 °C for 1 h. Potassium tert-butoxide (127 mg, 1.13 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhecyclopentane) (432 mg, 1.70 mmol) were added to this mixture. After stirring overnight at 80 °C, the mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic matter was 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 give the desired product (90 mg, 70%) as a yellow solid. LCMS C 10 H 15 ClN3O (M+H) + Calculated m / z value = 228.1; Experimental value 228.1.

[0384] Intermediate 23. 6-Chloro-2-morpholinylpyridine-3-amine

[0385] The title compound was prepared using a procedure similar to that described for intermediate 22, with morpholine instead of piperidine-4-ol. LCMS C9H 13 ClN3O (M+H) + Calculated m / z value = 214.1; Experimental value 214.1.

[0386] Intermediate 24: 3-(3-amino-6-chloropyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one

[0387] Step 1: 3-Amino-6-chloro-N-hydroxypyridine formamidin

[0388] A mixture of 3-amino-6-chloropyridinium carboxynitrile (5.0 g, 32.5 mmol) and 50% hydroxylamine aqueous 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 C6H8ClN4O (M+H) + Calculated m / z value = 187.0; Experimental value = 187.0.

[0389] Step 2: 3-(3-amino-6-chloropyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one

[0390] At 0 °C, a solution of 3-amino-6-chloro-N-hydroxypyridine formamidinium (5.1 g, 27.3 mmol) in THF (100 mL) was added with 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, and the pH was adjusted 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 (4.9 g, 84% yield) as a brown solid. LCMS C7H6ClN4O2 (M+H) + Calculated m / z value = 213.0; Experimental value = 213.0.

[0391] Intermediate 25. 6-Chloro-2-(1,3,4-oxadiazol-2-yl)pyridin-3-amine

[0392] Add (N-isocyanoimino)triphenylphosphine (175 mg, 0.58 mmol) to a solution of 3-amino-6-chloropyridinecarboxylic acid (100 mg, 0.58 mmol) in 2 mL of DCM. After stirring overnight at room temperature, dilute the mixture with water and extract with DCM. Wash the combined organic matter with brine and dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel column chromatography, eluting with DCM and ethyl acetate, to give the desired product (84 mg, 74%) as a yellow solid. LCMS C7H6ClN4O (M+H) + Calculated m / z value = 197.0; Experimental value = 197.0.

[0393] Intermediate 26. 6-Chloro-2-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-amine

[0394] A solution of 500 mg (2.55 mmol) of 6-chloro-2-(1H-tetrazol-5-yl)pyridin-3-amine (Example 8, Step 1) in 2 mL of acetic anhydride was stirred overnight at 110 °C, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM and ethyl acetate, to give the desired product (187 mg, 35%) as a brown solid. LCMS C8H8ClN4O(M+H)+ Calculated m / z value = 211.0; Experimental value 211.0.

[0395] Intermediate 27. 6-Chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-amine

[0396] Step 1: 3-Amino-6-chloro-N'-methylpyridinylimine hydrazide

[0397] Methylhydrazine (1.03 mL, 19.54 mmol) was added to a solution of 3-amino-6-chloro-pyridin-2-carboxynitrile (500 mg, 3.26 mmol) in 10 mL of EtOH at room temperature. After stirring at 100 °C for 24 h, the solvent was removed under vacuum to give the desired product (600 mg, 92%) as a yellow solid. LCMS C7H 11 ClN5 (M+H) + Calculated m / z value = 200.1; Experimental value = 200.1.

[0398] Step 2: 6-Chloro-2-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-3-amine

[0399] A solution of 600 mg, 3 mmol, of 3-amino-6-chloro-N'-methylpyridinamide hydrazide in 5 mL of formic acid was stirred overnight at 105 °C. After cooling to room temperature, the solvent was removed under vacuum. Then, a solution of ammonium hydroxide in water and EtOH was added to the residue, and the mixture was stirred overnight at 100 °C. The mixture was diluted with water and extracted with EtOAc. The combined organic matter was washed with brine and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was ground with diethyl ether, filtered, and washed with diethyl ether to give the desired product (420 mg, 67%) as a yellow solid. LCMS C8H9ClN5 (M+H) + Calculated m / z value = 210.1; Experimental value 210.1.

[0400] Intermediate 28. 5-(3-amino-6-chloropyridin-2-yl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0401] CDI (230 mg, 1.43 mmol) was added to a solution of 200 mg (1.3 mmol) of 3-amino-6-chloro-N'-methylpyridinamide hydrazide (intermediate 27, step 1) in 2 mL of THF, 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 organic matter was 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 give the desired product as a brown solid. LCMS C8H9ClN5O (M+H) + Calculated m / z value = 226.0; Experimental value 226.0.

[0402] Example 1. 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide

[0403] Step 1: 2-Amino-3-bromo-5-methylbenzoic acid

[0404] NBS (117 g, 660 mmol) was added to a mixture of 2-amino-5-methylbenzoic acid (100 g, 660 mmol) and DMF (300 mL) at 0 °C under a nitrogen atmosphere. The reaction mixture was then slowly heated to room temperature and stirred for 1 h. After completion, the reaction mixture was diluted with ice water while stirring. The resulting solid was collected to give the desired product (127 g, 85%) as a light brown solid, which was used in the next step without further purification. LCMS C8H9BrNO2 (M+H) + Calculated m / z value = 230.0; Experimental value = 230.1.

[0405] Step 2: 8-Bromo-6-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione

[0406] Triphosgene (57 g, 192 mmol) was added to a mixture of 2-amino-3-bromo-5-methylbenzoic acid (110 g, 480 mmol) and dioxane (1000 mL) 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.

[0407] Step 3: 2-Amino-3-bromo-N,5-dimethylbenzamide

[0408] Methylamine (175 mL, 2 M solution in THF) was added to a mixture of 90 g, 354 mmol of 8-bromo-6-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (THF) in 900 mL of THF at 0 °C. The resulting mixture was heated 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.

[0409] Step 4: 8-Bromo-2-hydroxy-3,6-dimethylquinazolin-4(3H)-one

[0410] At room temperature to from Step 3 The solid was supplemented with THF (700 mL) and triphosgene (70 g, 237 mmol). The resulting mixture was heated at 70 °C for 2 h, cooled to room temperature, and half of the solvent was removed under vacuum. The resulting solid was collected. The solid product was then washed with a 4:1 mixture of hexane and ethyl acetate, and dried under vacuum overnight to give a pure product as a white solid, which was used in the next step without further purification.

[0411] Step 5: 8-Bromo-2-chloro-3,6-dimethylquinazolin-4(3H)-one

[0412] DIEA (182 mL, 1.1 mmol) was added to a mixture of 72 g (269 mmol) of 8-bromo-2-hydroxy-3,6-dimethylquinazolin-4(3H)-one and 374 mL of POCl3 at 0 °C. The resulting mixture was stirred at 120 °C for 12 h in a pressure vessel. After cooling to room temperature, the mixture was carefully and slowly poured 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.

[0413] Step 6: 9-Bromo-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid tert-butyl ester

[0414] At 0°C under nitrogen atmosphere, towards KO tBu (29 g, 260 mmol) was added dropwise to a mixture in anhydrous DMF (700 mL) with tert-butyl 2-isocyanoacetate (27 mL, 191.3 mmol). The resulting mixture was stirred at 0 °C for 10 min, followed by the addition of 8-bromo-2-chloro-3,6-dimethylquinazoline-4(3H)-one (50 g, 173 mmol) in a single batch. The mixture was then heated to room temperature and stirred for 2 h. After this, the reaction mixture was poured into 1000 mL of saturated NH4Cl solution and diluted with 800 mL of water. The resulting solid was collected by filtration, washed with water, and then dried under vacuum to give the desired product (59 g, 90%) as a beige solid. LCMS C 17 H 19 BrN3O3 (M+H) + Calculated m / z value = 392.1; Experimental value 392.1.

[0415] Step 7: 9-Acetyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid tert-ethyl Butyl acetate

[0416] A mixture of tert-butyl 9-bromo-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylate (22.8 g, 58.1 mmol), PdCl₂(PPh₃)₂ (4.1 g, 5.8 mmol), and tributyl(1-ethoxyvinyl)stanane (25 g, 69.9 mmol) in dioxane (750 mL) was heated at 100 °C for 8 h. After cooling to room temperature, 2 N HCl was added to the reaction mixture, and the mixture was stirred for 4 h. The mixture was diluted with water and extracted with EtOAc. The combined organic matter was washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After removing most of the solvent, a 4:1 mixture of hexane and EtOAc was added. The mixture was stirred for 2 h, and the precipitated solid was collected by filtration and washed with a mixture of 4:1 hexane and EtOAc to give the desired product (17 g, 84%) as a brown solid. LCMS C 19 H 22 N3O4 (M+H) + Calculated m / z value = 356.2; Experimental value 356.2.

[0417] Step 8: 9-(1-hydroxyethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3- tert-butyl formate

[0418] 9-Acetyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid tert-butyl ester (7 g, 19.6 mmol) was dissolved in MeOH (200 mL) and DCM (200 mL), and then NaBH4 (771.4 mg, 20.4 mmol) was added in three portions at 0 °C under nitrogen. The resulting mixture was stirred at the same temperature for 10 min and then quenched with saturated NH4Cl. The mixture was diluted with water and extracted with DCM. The combined organic matter was 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 to 4%), to give the desired product (5.3 g 75%) as a pale yellow solid. LCMS C 19 H 24 N3O4 (M+H) + Calculated m / z value = 358.2; Experimental value = 358.2.

[0419] Step 9: 9-(1-Bromoethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-methyl tert-butyl ester

[0420] Pyridine (1.7 g, 22 mmol) and PBr3 (1.26 mL, 13.3 mmol) were added to a mixture of 9-(1-hydroxyethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid tert-butyl ester (4.0 g, 11.2 mmol) in THF (300 mL) at 0 °C. The resulting mixture was heated to room temperature and stirred for 2 h. The mixture was then quenched with saturated NaHCO3 and extracted with DCM (2x). The combined organic matter was 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.

[0421] Step 10: 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-di Hydroimidazole[1,5-a]quinazolin-3-carboxylic acid tert-butyl ester

[0422] Add 2-amino-5-fluorobenzamide (770 mg, 5 mmol) to a solution of 9-(1-bromoethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid tert-butyl ester (1.6 g, 3.8 mmol) in DMF (50 mL). Heat the mixture to 80 °C for 2 h. After cooling to room temperature, dilute the mixture with water and extract with ethyl acetate (3X). Wash the combined organic matter with water and saturated NaCl, dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel column chromatography, eluting with hexane and EtOAc (0 to 100%), to give the desired product (1.5 g, 80%) as a pale yellow solid. LCMS C 26 H 29 FN5O4 (M+H) + Calculated m / z value = 494.2; Experimental value 494.2.

[0423] Step 11: 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-di Hydroimidazole[1,5-a]quinazolin-3-carboxylic acid

[0424] 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid tert-butyl ester (1.5 g, 3.0 mmol) was dissolved in TFA (20 mL). The mixture was stirred at room temperature for 3 h. After 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 give the pure product (1.1 g, 83%). LCMS C 22 H 21 FN5O4 (M+H) + Calculated m / z value = 438.2; Experimental value = 438.2.

[0425] Step 12: 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4, 5-Dihydroimidazo[1,5-a]quinazolin-3-carboxamide

[0426] To a mixture of 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid (20 mg, 0.045 mmol) in DMF (0.5 mL), HATU (22 mg, 0.06 mmol), dimethylamine (30 μL, 2 M THF solution), and DIEA (10 μL, 0.06 mmol) were added. After stirring for 1 h, the reactants were diluted with MeOH and passed by preparative HPLC (column: Sunfire prep C18 column, 30 mL). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LCMS C 24 H 26 FN6O3(M+H) + Calculated m / z value = 465.2; Experimental value 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).

[0427] Example 2. 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide (peak 1)

[0428] Step 1: 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-di Hydroimidazole[1,5-a]quinazolin-3-carboxylic acid tert-butyl ester

[0429] The racemic compound in the title was separated by chiral HPLC (Example 1, step 10) to obtain two enantiomers, and peak 1 was used in the next step.

[0430] Step 2: 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-di Hydroimidozono[1,5-a]quinazoline-3-carboxylic acid (peak 1)

[0431] Peak 1 (60 mg, 0.12 mmol) of 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid tert-butyl ester was added to a 2-daramid reaction flask. 0.5 mL of pure TFA was added to the flask, and the reaction mixture was stirred at room temperature for 1 h. After completion, the TFA was removed under vacuum. 1 mL of EtOAc and 1 mL of hexane were added to the flask, and the mixture was stirred. After stirring for 20 min, the resulting solid was collected to obtain a white solid, which was washed with hexane / EtOAc (1:1). The solid was dried under vacuum to give the pure product (48 mg, 91%). LCMS C 22 H 21 FN5O4 (M+H) + Calculated m / z value = 438.2; Experimental value 438.2.

[0432] Step 3: 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl- d 3 )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide (peak 1)

[0433] To a mixture of 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid (peak 1) (20 mg, 0.045 mmol) in DMF (0.5 mL), HATU (22 mg, 0.06 mmol), bis(methyl-d3)amine HCl salt (5 mg, 0.06 mmol), and DIEA (20 μL, 0.12 mmol) were added. After stirring for 1 h, the reactants were diluted with MeOH and passed by preparative HPLC (column: Sunfire prep C18 column, 30 μL). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LCMS C 24 H 20 D6FN6O3 (M+H) +Calculated m / z value = 471.2; Experimental value 471.2.

[0434] Example 3. 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide (peak 2)

[0435] Use and targeting Example 2 The procedure described above, in step 2, uses 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid tert-butyl ester (Example 2, step 1, peak 2) instead of 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid tert-butyl ester (peak 1) to prepare the title compound. The crude product was diluted with MeOH and analyzed by preparative HPLC (column: Sunfire prep C18 column, 30...). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LCMS C 24 H 20 D6FN6O3 (M+H) + Calculated m / z value = 471.2; Experimental value 471.2.

[0436] Example 4. 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide

[0437] Step 1: 2-Amino-3-bromo-5-methyl-N-(methyl-d3)benzamide

[0438] HATU (14.83 g, 39 mmol), methyl-d3-amine HCl salt (2.33 g, 33 mmol), and DIEA (20.96 mL, 120 mmol) were added to a mixture of 2-amino-3-bromo-5-methylbenzoic acid (6.90 g, 30 mmol) and DMF (80 mL) at 0 °C. After stirring at room temperature for 3 h, the mixture was poured into 1000 mL of ice water. The resulting solid was collected, yielding a light brown solid, which was washed with water and dried under vacuum to give the desired product as a light brown solid. LCMS C9H9D3BrN2O (M+H) + Calculated m / z value = 246.0; Experimental value 246.0.

[0439] Step 2: 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-7-methyl-4-(methyl-d3)-5-oxo 4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid

[0440] Use and targeting Example 1 The procedure described herein involves replacing 2-amino-3-bromo-5-methyl-N-(methyl-d3)benzamide with 2-amino-3-bromo-N,5-dimethylbenzamide in step 4 to prepare the title compound. LCMSC 22 H 18 D3FN5O4 (M+H) + Calculated m / z value = 441.2; Experimental value 441.2.

[0441] Step 3: 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-7-methyl-N,N,4-tris(methyl-d3)- 5-O-4,5-Dihydroimidazo[1,5-a]quinazolin-3-carboxamide

[0442] To a mixture of 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid (20 mg, 0.045 mmol) in DMF (0.5 mL), HATU (22 mg, 0.06 mmol), bis(methyl-d3)amine HCl salt (10 mg, 0.25 mmol), and DIEA (100 μL, 0.6 mmol) were added. After stirring for 1 h, the reactants were diluted with MeOH and passed by preparative HPLC (column: Sunfire prep C18 column, 30 μL). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LCMS C 24 H 17 D9FN6O3(M+H)+ Calculated m / z value = 474.3; Experimental value 474.3.

[0443] Examples 5 to 7.

[0444] The following compounds in Table 1 were prepared similarly using appropriate intermediates according to the procedure described in Example 1.

[0445] Table 1.

[0446] Example 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

[0447] Step 1: 6-Chloro-2-(1H-tetrazol-5-yl)pyridin-3-amine

[0448] Sodium azide (1.3 g, 20.00 mmol) and ammonium hydrochloride (1.7 g, 20.00 mmol) were added in a single addition to a solution of 3-amino-6-chloro-pyridin-2-carboxynitrile (1.54 g, 10.00 mmol) in 20 mL of DMF. 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 a product as a white solid (1.8 g, 92%). LCMS C6H6ClN6 (M+H) + Calculated m / z value = 197.0; Experimental value = 197.0.

[0449] Step 2: 2-(6-chloro-2-(1H-tetrazol-5-yl)pyridin-3-yl)isoindoline-1,3-dione

[0450] At room temperature, isobenzofuran-1,3-dione (3.4 g, 22.89 mmol) was added 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. After stirring overnight at 120 °C, the solvent was removed under vacuum to give the desired product (2.9 g, 97%) as a yellow solid. LCMS C 14 H8ClN6O2 (M+H) + Calculated m / z value = 327.0; Experimental value 327.0.

[0451] Step 3: 2-(6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)isoindoline-1,3-dione

[0452] To 2-[6-chloro-2-(1 H [-tetrazol-5-yl)-3-pyridyl]isoindoline-1,3-dione (3.00 g, 9.18 mmol) was dissolved in 10 mL DMF with 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 mixture was purified by silica gel column chromatography by elution with hexane and ethyl acetate to give the desired product (540 mg, 17%) as a yellow solid and another regioisomer (570 mg, 18%) as a yellow solid. LCMS C 15 H 10 ClN6O2 (M+H) + Calculated m / z value = 341.1; Experimental value = 341.1.

[0453] Step 4: 6-Chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-amine

[0454] 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 at 45 °C for 2 h, then cooled to room temperature. The resulting precipitate was collected by filtration and washed with water to give a white solid product (330 mg, 100%). LCMS C7H8ClN6 (M+H) + Calculated m / z value = 211.0; Experimental value 211.0.

[0455] Step 5: 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-di tert-butyl methyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid

[0456] To a solution of tert-butyl 9-(1-bromoethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylate (Example 1, step 9) (3.2 g, 7.6 mmol) in DMF (70 mL), 6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-amine (1.8 g, 8.5 mmol) was added. 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 (3X). The combined organic matter was 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 to give the desired product (1.25 g, 30%) as a pale yellow solid. LCMS C 26 H 29 ClN9O3 (M+H) + Calculated m / z value = 550.2; Experimental value 550.2.

[0457] Step 6: 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-di Methyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid

[0458] 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]quinazolin-3-carboxylic acid tert-butyl ester (1.25 g, 2.27 mmol) was dissolved in TFA (10 mL). The mixture was stirred at room temperature for 3 h. After 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 give a pure product (1.0 g, 90%). LCMSC 22 H 21 ClN9O3 (M+H) + Calculated m / z value = 494.1; experimental value = 494.2.

[0459] Step 7: 9-(1-((6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-iodine-4, 7-Dimethylimidazo[1,5-a]quinazolin-5(4H)-one

[0460] NaHCO3 (336 mg, 4 mmol) was added 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]quinazolin-3-carboxylic acid (1.0 g, 1.05 mmol) in DMF (10 mL) at 0 °C under nitrogen atmosphere. After stirring for 5 min, NIS (234 mg, 1.05 mmol) was added in a single batch. The resulting mixture was heated to room temperature and stirred under vacuum for 2 h. After completion, the reaction mixture was quenched with saturated Na2S2O3 and diluted with water. The resulting solid, which was brown, was collected by filtration and purified by silica gel column chromatography with elution of DCM and EtOAc to give the desired product (470 mg, 78%) as a white solid. LC-MSC 21 H 20 ClIN9O (M+H) + Calculated m / z value = 576.1; Experimental value 576.1.

[0461] Step 8: 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-methyl-2H-tetrazole-5-yl)pyridine-3- (1,5-a)quinazolin-5(4H)-one (amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one

[0462] 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-dioxaborhexacyclopentan-2-yl)pyrimidin-2-amine (27 mg, 0.12 mmol), K3PO4 (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 a nitrogen atmosphere. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM containing 0-95% EA, followed by DCM containing 0-20% MeOH) to obtain the crude product. The product was diluted with MeOH and purified by preparative HPLC (column: Sunfire prep C18 column, 30). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a pale yellow solid. LC-MSC 25 H 24 ClN 12 O (M+H) +Calculated m / z value = 543.2; Experimental value 543.2.

[0463] Examples 9 to 14.

[0464] The following compounds in Table 2 were prepared similarly using appropriate intermediates according to the procedure described in Example 8.

[0465] Table 2.

[0466] Example 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)

[0467] Step 1: 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3- Iodine-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one

[0468] Use and targeting Example 8 The procedure described herein involves replacing 6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-amine (intermediate 11) in step 5 to prepare the title compound. LCMS C 21 H 17 D3ClIN9O (M+H) + Calculated m / z value = 579.1; Experimental value 579.1.

[0469] Racemic compounds were separated by chiral HPLC to obtain two enantiomers, with peak 1 used in the next step.

[0470] Step 2: 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d)) 3 )-2H-tetrazole-5-yl)pyridine (Pyridine-3-yl)amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (peak 1)

[0471] 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-dioxaborhecyclopentan-2-yl)pyrimidin-2-amine (27 mg, 0.12 mmol), K3PO4 (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 a nitrogen atmosphere. The solvent was removed under reduced vacuum, and the residue was purified by silica gel column chromatography (DCM containing 0-95% EA, followed by DCM containing 0-20% MeOH) to obtain the crude product. The crude product was diluted with MeOH and purified by preparative HPLC (column: Sunfire prep C18 column, 30). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, which was pale yellow. LCMS C 25 H 21 D3ClN 12 O (M+H) + Calculated m / z value = 546.2; Experimental value 546.2.

[0472] 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)

[0473] Use and targeting Example 15The procedure described above, in step 2, uses 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-iodine-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (Example 15, step 1, peak 2) instead of 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-iodine-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one (peak 1) to prepare the title compound. The crude product was diluted with MeOH and analyzed by preparative HPLC (column: Sunfire prep C18 column, 30). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a pale yellow solid. LCMS C 25 H 21 D3ClN 12 O (M+H) + Calculated m / z value = 546.2; Experimental value 546.2.

[0474] 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)-one

[0475] Step 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

[0476] Use and targeting Example 8 The procedure described herein involves replacing 9-(1-bromoethyl-1-d)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid tert-butyl ester (intermediate 12) with 9-(1-bromoethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid tert-butyl ester and 6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridine-3-amine (intermediate 11) with 6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridine-3-amine to prepare the title compound. LCMS C 21 H 13 D7ClIN9O (M+H) +Calculated m / z value = 583.1; Experimental value 583.1.

[0477] Step 2: 3-(2-aminopyrimidin-5-yl)-9-(1-((6-chloro-2-(2-(methyl-d)) 3 )-2H-tetrazole-5-yl)pyridine (Pyridin-3-yl)amino)ethyl-1-d)-7-methyl-4-(methyl-d) 3 Imidazolo[1,5-a]quinazolin-5(4H)-one

[0478] A mixture of 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-dioxaborhecyclopentan-2-yl)pyrimidin-2-amine (62.0 mg, 0.45 mmol), K3PO4 (218.5 mg, 1.03 mmol) and Pd(PPh3)4 (39.7 mg, 0.03 mmol) in dioxane (6.0 mL) and water (1.2 mL) was heated at 80 °C for 8 h under a nitrogen atmosphere. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (DCM containing 0-95% EA, followed by DCM containing 0-20% MeOH) to obtain the crude product. The crude product was diluted with MeOH and purified by preparative HPLC (column: Sunfire prep C18 column, 30). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, which was pale yellow. LCMS C 25 H 17 D7ClN 12 O (M+H) + Calculated m / z value = 550.2; Experimental value 550.2.

[0479] 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

[0480] 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), K3PO4 (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 a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with MeOH and analyzed by preparative HPLC (column: Sunfire prep C18 column, 30). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LCMS C 26 H 24 ClN 10 O (M+H) + Calculated m / z value = 527.2; Experimental value 527.2.

[0481] 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

[0482] Use and targeting Example 18 A similar procedure was described to prepare the title compound. The crude product was diluted with MeOH and then analyzed by preparative HPLC (column: Sunfire prep C18 column, 30). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LCMS C 26 H 18 D6ClN 10 O (M+H) + Calculated m / z value = 533.2; Experimental value 533.2.

[0483] Example 20. 2-((1-(3-(1-acetylpiperidin-4-yl)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-5-fluorobenzamide

[0484] Step 1: 9-Acetyl-7-methyl-4-(methyl-d) 3 )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline- tert-butyl 3-carboxylate

[0485] Use and targeting Example 1 A similar procedure was described, in which 2-amino-3-bromo-5-methyl-N-(methyl-d3)benzamide (Example 4, step 1) was used instead of 2-amino-3-bromo-N,5-dimethylbenzamide to prepare the title compound. LCMS C 19 H 19 D3N3O4 (M+H) + Calculated m / z value = 359.2; Experimental value 359.2.

[0486] Step 2: 9-Acetyl-7-methyl-4-(methyl-d) 3 )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline- 3-Formic acid

[0487] 9-Acetyl-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid tert-butyl ester (2.0 g, 5.5 mmol) was dissolved in TFA (20 mL). The mixture was stirred at room temperature for 3 h. After 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 give the pure product (1.5 g, 90%). LCMS C 15 H 11 D3N3O4 (M+H) + Calculated m / z value = 303.1; Experimental value = 303.1.

[0488] Step 3: 9-Acetyl-3-iodo-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one

[0489] Under nitrogen atmosphere and at 0 °C, NaHCO3 (1.68 g, 20 mmol) was added to a mixture of 9-acetyl-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid (1.5 g, 4.9 mmol) in DMF (20 mL). After stirring for 5 min, NIS (1.1 g, 5 mmol) was added in a single batch. The resulting mixture was heated to room temperature and stirred under vacuum for 2 h. After completion, the reaction mixture was quenched with saturated Na2S2O3 and diluted with water. The crude product, a brown solid, was collected by filtration and purified by silica gel column chromatography, eluting with DCM and EtOAc, to give the desired product (1.5 g, 84%) as a white solid. LCMS C 14 H 10 D3IN3O2 (M+H) + Calculated m / z value = 385.0; Experimental value 385.0.

[0490] Step 4: 4-(9-acetyl-7-methyl-4-(methyl-d) 3 )-5-oxo-4,5-dihydroimidazole[1,5-a]quinazole tert-butyl lin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0491] 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), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.29 g, 4.2 mmol), K3PO4 (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 (3X). The combined organic matter was 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 to obtain the desired product (1.2 g, 70%) as a pale yellow solid. LCMS C 24 H 26 D3N4O4 (M+H) + Calculated m / z value = 440.2; Experimental value 440.2.

[0492] Step 5: 9-Acetyl-7-methyl-4-(methyl-d) 3 )-3-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1, [5-a]quinazolin-5(4H)-one

[0493] 1.2 g (2.7 mmol) of 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)-carboxylic acid was dissolved in TFA (10 mL). The mixture was stirred at room temperature for 3 h. After stirring, 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 organic matter was washed with water and 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 C 19 H 18 D3N4O2(M+H) + Calculated m / z value = 340.2; Experimental value 340.2.

[0494] Step 6: 9-Acetyl-3-(1-Acetyl-1,2,3,6-Tetrahydropyridin-4-yl)-7-methyl-4-(methyl-d) 3 ) Imidazolo[1,5-a]quinazolin-5(4H)-one

[0495] 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, and then DIEA (619 mg, 4.8 mmol). The resulting mixture was stirred at the same temperature for 20 min, and then diluted with saturated NaHCO3. The mixture was diluted with water and extracted with DCM. The combined organic matter was 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 C 21 H 20 D3N4O3(M+H) + Calculated m / z value = 382.2; Experimental value 382.2.

[0496] 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

[0497] 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), and then NaBD4 (107 mg, 2.5 mmol) was added in three portions at 0 °C under nitrogen. The resulting mixture was stirred at the same temperature for 10 min and then quenched with saturated NH4Cl. The mixture was diluted with water and extracted with DCM. The combined organic matter was 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 to 4%), to give the desired product (781 mg 87%) as a light brown solid. LC-MSC 21 H 21 D4N4O3 (M+H) + Calculated m / z value = 385.2; experimental value = 385.3.

[0498] Step 8: 3-(1-acetylpiperidin-4-yl)-9-(1-hydroxyethyl-1-d)-7-methyl-4-(methyl-d3)imidazolium [1,5-a]quinazolin-5(4H)-one

[0499] 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 AcOH. The reaction vial was purged with nitrogen, and the mixture was stirred overnight at 60 °C. After completion, the reaction mixture was filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM and MeOH (0 to 8%), to give the desired product (631 mg 81%) as a light-colored solid. LCMS C 21 H 23 D4N4O3 (M+H) + Calculated m / z value = 387.2; experimental value = 387.3.

[0500] Step 9: 3-(1-acetylpiperidin-4-yl)-9-(1-bromoethyl-1-d)-7-methyl-4-(methyl-d) 3 Imidazolidine [1,5-a]quinazolin-5(4H)-one

[0501] PBr3 (0.33 mL, 3.2 mmol) was added to a mixture of 3-(1-acetylpiperidin-4-yl)-9-(1-hydroxyethyl-1-d)-7-methyl-4-(methyl-d3)imidazo[1,5-a]quinazolin-5(4H)-one (631 mg, 1.63 mmol) in DCM (100 mL) at 0 °C. The resulting mixture was heated to room temperature and stirred for 2 h. The mixture was then quenched with saturated NaHCO3 and extracted with DCM (2x). The combined organic matter was 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.

[0502] Step 10: 2-((1-(3-(1-acetylpiperidin-4-yl)-7-methyl-4-(methyl-d) 3 )-5-oxo-4,5-di Hydroimidazole[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-5-fluorobenzamide

[0503] Add 2-amino-5-fluorobenzamide (20 mg, 0.13 mmol) to a solution of 3-(1-acetylpiperidin-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). Heat the mixture to 80 °C for 2 h. After cooling to room temperature, dilute the mixture with MeOH and pass it by preparative HPLC (column: Sunfire prep C18 column, 30 mL). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LCMS C 28 H 28 D4FN6O3(M+H) + Calculated m / z value = 523.3; Experimental value 523.3.

[0504] Example 21. 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-7-chloro-4-methyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide

[0505] Use and targeting Example 1The procedure described herein involves replacing 2-amino-5-chlorobenzoic acid with 2-amino-5-methylbenzoic acid in step 1 and replacing dimethylamine with bis(methyl-d3)amine HCl salt in step 12 to prepare the title compound. The crude product was diluted with MeOH and analyzed by preparative HPLC (column: Sunfire prep C18 column, 30 °C). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LCMS C 23 H 17 D6ClFN6O3 (M+H) + Calculated m / z value = 491.2; Experimental value 491.2.

[0506] Example 22. 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl-1-d)-7-chloro-4-methyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide

[0507] Use and targeting Example 1 The procedure described above involves replacing 2-amino-5-chlorobenzoic acid with 2-amino-5-methylbenzoic acid in step 1, replacing NaBH4 with NaBD4 in step 8, and replacing dimethylamine with bis(methyl-d3)amine HCl salt in step 12 to prepare the title compound. The crude product was diluted with MeOH and subjected to preparative HPLC (column: Sunfire prepC18 column, 30). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LCMS C 23 H 16 D7ClFN6O3 (M+H) + Calculated m / z value = 492.2; Experimental value 492.2.

[0508] 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]quinazolin-3-carboxamide

[0509] 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]quinazolin-3-carboxylic acid (Example 8, step 6) (20 mg, 0.04 mmol) in DMF (0.5 mL), HATU (22 mg, 0.06 mmol), dimethylamine (30 μL, 2 M THF solution), and DIEA (10 μL, 0.06 mmol) were added. After stirring for 1 h, the reaction mixture was diluted with MeOH and passed by preparative HPLC (column: Sunfire prep C18 column, 30 mL). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LC-MSC 24 H 26 ClN 10 O2(M+H) + Calculated m / z value = 521.2; Experimental value 521.2.

[0510] Examples 24 to 27.

[0511] The following compounds in Table 3 were prepared similarly using appropriate intermediates according to the procedure described for Example 23.

[0512] Table 3.

[0513] Example 28. 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl-1-d)-4-methyl-N,N-bis(methyl-d3)-5-oxo-7-(trifluoromethyl)-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide

[0514] Use and targeting Example 1 The procedure described herein involves replacing 2-amino-5-methylbenzoic acid with 2-amino-5-methylbenzoic acid in step 1, replacing NaBH4 with NaBD4 in step 8, and replacing dimethylamine with bis(methyl-d3)amine HCl salt in step 12 to prepare the title compound. The crude product was diluted with MeOH and analyzed by preparative HPLC (column: Sunfire prep C18 column, 30). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LC-MSC 24 H 16 D7F4N6O3 (M+H) + Calculated m / z value = 526.2; Experimental value 526.2.

[0515] Examples 29 to 46.

[0516] The following compounds in Table 4 were prepared similarly using appropriate intermediates according to the procedure described in Example 8.

[0517] Table 4.

[0518] Example 47. 9-(1-((2-carbamoyl-6-chloropyridin-3-yl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide

[0519] Step 1: 9-Acetyl-7-methyl-N,N,4-tris(methyl-d) 3 )-5-oxo-4,5-dihydroimidazo[1,5-a] Quinazoline-3-formamide

[0520] To a mixture of 9-acetyl-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid (Example 20, Step 2) (1.4 g, 4.63 mmol) in DMF (10 mL), HATU (1900 mg, 5.0 mmol), bis(methyl-d3)amine HCl salt (435 mg, 5.0 mmol), and DIEA (1.8 mL, 10 mmol) were added. 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 C 17 H 10 D9N4O3 (M+H) + Calculated m / z value = 336.2; Experimental value 336.2.

[0521] Step 2: 9-(1-hydroxyethyl-1-d)-7-methyl-N,N,4-tris(methyl-d)3 )-5-oxo-4,5-dihydroimidazole [1,5-a]quinazolin-3-carboxamide

[0522] 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), and then NaBD4 (160 mg, 4 mmol) was added under nitrogen at 0 °C. The resulting mixture was stirred at the same temperature for 10 min, and then quenched with 0.3 mL of saturated NH4Cl. 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 C 17 H 11 D 10 N4O3 (M+H) + Calculated m / z value = 339.2; Experimental value 339.2.

[0523] Step 3: 9-(1-Bromoethyl-1-d)-7-methyl-N,N,4-tris(methyl-d) 3 )-5-oxo-4,5-dihydroimidazole [1,5-a]quinazolin-3-carboxamide

[0524] PBr3 (0.33 mL, 3.2 mmol) was added 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]quinazolin-3-carboxamide (1.0 g, 2.96 mmol) in DCM (200 mL) at 0 °C. The resulting mixture was heated to room temperature and stirred for 2 h. The mixture was then quenched with saturated NaHCO3 and extracted with DCM (2x). The combined organic matter was 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.

[0525] Step 4: 9-(1-((2-carbamoyl-6-chloropyridin-3-yl)amino)ethyl-1-d)-7-methyl-N,N,4-trimethyl-1- ...dimethyl-1-ethyl-1-dimethyl-1-ethyl-1-dimethyl-1-ethyl-1-ethyl-2-ethyl-3-ethyl-2-ethyl-2-ethyl-3- (methyl-d) 3 )-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide

[0526] Add 3-amino-6-chloropyridinamide (17 mg, 0.1 mmol) 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]quinazolin-3-carboxamide (20 mg, 0.05 mmol) in DMF (0.3 mL). Heat the mixture to 80 °C for 2 h. After cooling to room temperature, dilute the mixture with MeOH and pass it by preparative HPLC (column: Sunfire prep C18 column, 30 mL). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LCMS C 23 H 15 D 10 ClN7O3 (M+H) + Calculated m / z value = 492.2; Experimental value 492.2.

[0527] Example 48. 9-(1-((2-carbamoyl-6-chloropyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide

[0528] Step 1: 9-(1-Bromoethyl)-N,N,4,7-Tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin- 3-Formamide

[0529] Use and targeting Example 47 The procedure described herein involves replacing 9-acetyl-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid with 9-acetyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid in step 1, replacing bis(methyl-d3)amine with dimethylamine, and replacing NaBD4 with NaBH4 in step 2 to prepare the title compound. LCMS C 17 H 20 BrN4O2 (M+H) + Calculated m / z value = 391.1; Experimental value 391.1.

[0530] Step 2: 9-(1-((2-carbamoyl-6-chloropyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo 4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide

[0531] Add 3-amino-6-chloropyridinamide (17 mg, 0.1 mmol) to a solution of 9-(1-bromoethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide (20 mg, 0.05 mmol) in DMF (0.3 mL). Heat the mixture to 80 °C for 2 h. After cooling to room temperature, dilute the mixture with MeOH and pass it by preparative HPLC (column: Sunfire prep C18 column, 30 mL). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LC-MSC 23 H 25 ClN7O3 (M+H) + Calculated m / z value = 482.2; Experimental value 482.2.

[0532] Examples 49 to 59.

[0533] The following compounds in Table 5 were prepared similarly using appropriate intermediates according to the procedure described for Example 47 or Example 48.

[0534] Table 5.

[0535] Example 60. 2-((1-(3-(1-acetylpiperidin-4-yl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-5-fluorobenzamide

[0536] Step 1: 5-Fluoro-2-((1-(3-iodo-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin- 9-yl)ethyl)amino)benzamide

[0537] Under nitrogen atmosphere and at 0°C, NaHCO3 (768 mg, 9.14 mmol) was added to a mixture of 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid (Example 1, step 11) (1.00 g, 2.29 mmol) in DMF (10 mL). After stirring for 5 min, 1-iodopyrrolidine-2,5-dione (617 mg, 2.74 mmol) was added in a single batch. The resulting mixture was heated to room temperature and stirred for 2 h. After completion, the reactants were quenched with a saturated aqueous solution of Na2S2O3 and diluted with water. The mixture was then extracted with EtOAc. The combined organic matter was 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 hexane and EtOAc (0 to 30%) to give the desired product as a white solid. LCMS C 21 H 20 FIN5O2(M+H) + Calculated m / z value = 520.1; Experimental value 520.1.

[0538] Step 2: 4-(9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5- Dihydroimidazo[1,5-a]quinazolin-3-yl)-3,6-dihydropyridine-1(2H)-tert-butyl formate

[0539] 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), K3PO4 (18 mg, 0.09 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,6-dihydro-2 H A solution of tert-butyl pyridine-1-carboxylate (18 mg, 0.06 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (5 mg, 0.01 mmol) in 1 mL dioxane / H₂O (5:1) was bubbled with N₂ 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 give the desired product. LCMS C 31 H 36 FN6O4 (M+H) + Calculated m / z value = 575.3; experimental value = 575.2.

[0540] Step 3: 2-((1-(4,7-dimethyl-5-oxo-3-(piperidin-4-yl)-4,5-dihydroimidazo[1,5-a]quinoline) (Zazoline-9-yl)ethyl)amino)-5-fluorobenzamide

[0541] Ammonium acetate (2.4 mg, 0.03 mmol) was added to a solution of 4-(9-(1-(((2-carbamoyl-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 (5.0 mg, 0.01 mmol) and 10% palladium supported on activated carbon (1.1 mg, 0.001 mmol) in 1 mL MeOH, and the resulting mixture was stirred at 60 °C for 12 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to dryness. Then, 2 mL of dioxane containing 4 M HCl was added to the residue, 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. LCMSC 26 H 30 FN6O2(M+H) + Calculated m / z value = 477.2; Experimental value 477.2.

[0542] Step 4: 2-((1-(3-(1-acetylpiperidin-4-yl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo) [1,5-a]quinazolin-9-yl)ethyl)amino)-5-fluorobenzamide

[0543] Add 10.0 mg (0.02 mmol) of 2-((1-(4,7-dimethyl-5-oxo-3-(piperidin-4-yl)-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-5-fluorobenzamide (10.0 mg, 0.02 mmol) to a stirred solution of 2-((1-(4,7-dimethyl-5-oxo-3-(piperidin-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. N , N - Diethylethylamine (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 and diluted with MeOH, and then analyzed by preparative HPLC (column: Sunfire prep C18 column, 30). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LCMS C 28 H 32 FN6O3 (M+H) + Calculated m / z value = 519.2; Experimental value = 519.2.

[0544] 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

[0545] 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-dioxaborhexacyclopentan-2-yl)pyrimidin-2-amine (15.3 mg, 0.07 mmol), K3PO4 (22.1 mg, 0.10 mmol), and XPhos Pd G2 (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 a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with MeOH and passed by preparative HPLC (column: Sunfire prep C18 column, 30). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LC-MSC 25 H 24 FN8O2 (M+H) + Calculated m / z value = 487.2; Experimental value 487.2.

[0546] 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-fluorobenzamide

[0547] Step 1: 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl-1-d)-7-methyl-4-(methyl-d3)-5- oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid

[0548] Use and Example 1A similar procedure was described, in which 2-amino-3-bromo-5-methyl-N-(methyl-d3)benzamide (Example 4, step 1) was used instead of 2-amino-3-bromo-N,5-dimethylbenzamide in step 4, and NaBD4 was used instead of NaBH4 in step 8 to prepare the title compound. After completion, the resulting solid was collected to give the desired product as a light gray solid. LCMS C 22 H 17 D4FN5O4 (M+H) + Calculated m / z value = 442.2; Experimental value 442.2.

[0549] Step 2: 5-Fluoro-2-((1-(3-iodo-7-methyl-4-(methyl-d)) 3 )-5-oxo-4,5-dihydroimidazo[1,5- a] Quinazolin-9-yl)ethyl-1-d)amino)benzamide

[0550] Use and targeting Example 60 A similar procedure was described, in which the title compound was prepared in step 1 by replacing 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl-1-d)-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid. The residue was purified by silica gel column chromatography, eluting with hexane and EtOAc (0 to 30%), to give the desired product as a white solid. LCMS C 21 H 16 D4FIN5O2 (M+H) + Calculated m / z value = 524.1; Experimental value 524.1.

[0551] Step 3: 2-((1-(3-(2-aminopyrimidin-5-yl)-7-methyl-4-(methyl-d) 3 )-5-oxo-4,5-dihydroimidazolium Azo[1,5-a]quinazolin-9-yl)ethyl-1-d)amino)-5-fluorobenzamide

[0552] 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-dioxaborhexacyclopentan-2-yl)pyrimidin-2-amine (15.3 mg, 0.07 mmol), K3PO4 (22.1 mg, 0.10 mmol), and XPhos Pd G2 (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 passed by preparative HPLC (column: Sunfire prep C18 column, 30). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LC-MSC 25 H 20 D4FN8O2 (M+H) + Calculated m / z value = 491.2; Experimental value 491.2.

[0553] 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

[0554] Use and targeting Example 61 A similar procedure was described, using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazole instead of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrimidine-2-amine to prepare the title compound. The mixture was diluted with MeOH and subjected to preparative HPLC (column: Sunfire prepC18 column, 30...). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LCMS C 25 H 25 FN7O2 (M+H) + Calculated m / z value = 474.2; Experimental value 474.2.

[0555] Example 64. 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

[0556] Use and targeting Example 62 The procedure described herein involves replacing 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazole with 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrimidine-2-amine in step 3 to prepare the title compound. The mixture was diluted with MeOH and subjected to preparative HPLC (column: Sunfire prep C18 column, 30...). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LC-MSC 25 H 21 D4FN7O2(M+H) + Calculated m / z value = 478.2; Experimental value 478.2.

[0557] 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-fluorobenzamide

[0558] Step 1: 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-7-chloro-4-methyl-5-oxo-4,5-di Hydroimidazole[1,5-a]quinazolin-3-carboxylic acid

[0559] Use and targeting Example 1 The procedure described herein involves replacing 2-amino-5-chlorobenzamide with 2-amino-5-methylbenzamide in step 1 to prepare the title compound. LCMS C 21 H 18 ClFN5O4 (M+H) + Calculated m / z value = 458.1; Experimental value = 458.1.

[0560] Step 2: 2-((1-(7-chloro-3-iodo-4-methyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9- (B-)ethyl)amino)-5-fluorobenzamide

[0561] Use and targeting Example 60 The procedure described herein involves replacing 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-7-chloro-4-methyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid with 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid in step 1 to prepare the title compound. LCMS C 20 H 17 ClFIN5O2(M+H) + Calculated m / z value = 540.0; Experimental value = 540.1.

[0562] 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

[0563] 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-dioxaborhexacyclopentan-2-yl)pyrimidin-2-amine (15 mg, 0.07 mmol), K3PO4 (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 a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with MeOH and passed by preparative HPLC (column: Sunfire prep C18 column, 30). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LCMS C 24 H 21 ClFN8O2 (M+H) + Calculated m / z value = 507.1; experimental value = 507.2.

[0564] 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

[0565] Use and targeting Example 65A similar procedure is described to prepare the title compound. LCMS C 24 H 20 DClFN8O2(M+H) + Calculated m / z value = 508.1; Experimental value = 508.2.

[0566] Example 67. 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-3-(1-(oxecyclobut-3-yl)piperidin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one

[0567] Step 1: 4-(9-acetyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3- tert-butyl 3,6-dihydropyridine-1(2H)-carboxylate

[0568] The title compound was prepared using a procedure similar to that described for step 4 of Example 20.

[0569] Step 2: 4-(9-(1-hydroxyethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidozono[1,5-a]quinazole tert-butyl lin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0570] 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), and then NaBH4 (208 mg, 5.50 mmol) was added in three portions at 0 °C under nitrogen. The resulting mixture was stirred at the same temperature for 10 min and then quenched with saturated NH4Cl. The mixture was diluted with water and extracted with DCM. The combined organic matter was 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 give the desired product (1.4 g, 87%) as a white solid. LC-MSC 24 H 31 N4O4 (M+H) + Calculated m / z value = 439.2; Experimental value 439.2.

[0571] Step 3: 4-(9-(1-hydroxyethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidozono[1,5-a]quinazole tert-butyl lin-3-yl)piperidine-1-carboxylate

[0572] 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 carbon-supported 10% palladium (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 for 16 hours under a nitrogen atmosphere. The mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography, eluting with DCM and EtOAc (0 to 95%), to give the desired product (1.15 g, 82%) as a white solid. LCMS C 24 H 33 N4O4 (M+H) + Calculated m / z value = 441.2; Experimental value = 441.2.

[0573] Step 4: 4-(9-(1-bromoethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin- 3-yl)piperidine-1-carboxylic acid tert-butyl ester

[0574] Pyridine (0.22 mL, 2.72 mmol) and PBr3 (0.13 mL, 1.36 mmol) were added to a mixture of 300 mg (0.68 mmol) of 4-(9-(1-hydroxyethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (20 mL) in THF at 0 °C. The resulting mixture was heated to room temperature and stirred for 2 h. The mixture was then quenched with saturated NaHCO3 and extracted with EtOAc (2x). The combined organic matter was 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.

[0575] Step 5: 4-(9-(1-((6-chloro-2-(2-(methyl-d)) 3 )-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl tert-butyl 4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-yl)piperidine-1-carboxylic acid

[0576] To a solution of tert-butyl piperidine-1-carboxylate (300 mg, 0.60 mmol) in DMF (2 mL), 6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridine-3-amine (intermediate 11) (254 mg, 1.2 mmol) was added to the solution. The mixture was heated to 80 °C for 2 h. The mixture was diluted with water and extracted with EtOAC (2x). The combined organics were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography, eluting with DCM and EtOAc (0 to 95%), to give the desired product (42 mg, 11%) as a white solid. LCMS C 31 H 35 D3ClN 10 O3 (M+H) + Calculated m / z value = 636.3; Experimental value = 636.3.

[0577] Step 6: 9-(1-((6-chloro-2-(2-(methyl-d)) 3 )-2H-tetrazole-5-yl)pyridin-3-yl)amino)ethyl)-4, 7-Dimethyl-3-(piperidin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one

[0578] 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)piperidine-1-carboxylic acid tert-butyl ester (42 mg, 0.066 mmol) was dissolved in dioxane (2 mL) containing 4 M HCl. 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 C 26 H 27 D3ClN 10 O (M+H) + Calculated m / z value = 536.2; Experimental value 536.2.

[0579] Step 7: 9-(1-((6-chloro-2-(2-(methyl-d)) 3 )-2H-tetrazole-5-yl)pyridin-3-yl)amino)ethyl)-4, 7-Dimethyl-3-(1-(oxecyclobut-3-yl)piperidin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one

[0580] Oxycycline-3-one (6.7 mg, 0.1 mmol) was added 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-(piperidin-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). The resulting mixture was heated at 50 °C for 2 hours. After cooling to room temperature, NaBH3CN (2.34 mg, 0.04 mmol) was added, and the mixture was stirred for 30 min. The crude product was diluted with MeOH and analyzed by preparative HPLC (column: Sunfire prep C18 column, 30 min). Purification was performed using a mobile phase of 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LCMS C 29 H 31 D3ClN 10 O2 (M+H) + Calculated m / z value = 592.3; Experimental value 592.3.

[0581] Example 68. 3-(1-acetylpiperidin-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

[0582] Triethylamine (3.0 mg, 0.03 mmol) and acetyl chloride (1.8 mg, 0.02 mmol) were added 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-(piperidin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one (Example 67, step 6) (8 mg, 0.01 mmol) in DCM (1 mL). The resulting mixture was stirred at room temperature for 30 minutes. The crude product was diluted with MeOH and analyzed by preparative HPLC (column: Sunfire prep C18 column, 30 min). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LC-MSC 28 H29 D3ClN 10 O2 (M+H) + Calculated m / z value = 578.3; Experimental value 578.3.

[0583] Example 69. 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2-hydroxyacetyl)piperidin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one

[0584] Add 2-hydroxyacetic acid (2.3 mg, 0.03 mmol), HATU (8.5 mg, 0.02 mmol), and other ingredients 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-(piperidin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one (Example 67, Step 6) (8 mg, 0.01 mmol) in DMF (0.5 mL). N , N -Diisopropylethylamine (13 uL, 0.07 mmol). The resulting mixture was stirred at room temperature for 30 minutes, then diluted with MeOH and passed by preparative HPLC (column: Sunfire prep C18 column, 30 min). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LCMS C 28 H 29 D3ClN 10 O3 (M+H) + Calculated m / z value = 594.3; Experimental value 594.3.

[0585] Example 70. 3-(1-acetylpiperidin-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

[0586] Use and targeting Example 68A similar procedure was described to prepare the title compound. The reaction mixture was diluted with MeOH and then subjected to preparative HPLC (column: Sunfire prep C18 column, 30). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LCMS C 28 H 25 D7ClN 10 O2(M+H) + Calculated m / z value = 582.3; Experimental value 582.3.

[0587] Examples 71 to 75.

[0588] The following compounds in Table 6 were prepared similarly using appropriate intermediates according to the procedure described for Example 68.

[0589] Table 6.

[0590] Example 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

[0591] A mixture of 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]phosphine (4.7 mg, 0.01 mmol), sodium tert-butoxide (7.9 mg, 0.08 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 passed by preparative HPLC (column: Sunfire prep C18 column, 30). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LCMS C 26 H 20 D7N 12 O2 (M+H) + Calculated m / z value = 546.3; experimental value = 546.2.

[0592] 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

[0593] A mixture of 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]phosphine (3.4 mg, 0.001 mmol), K3PO4 (13.9 mg, 0.07 mmol) and methylboronic acid (2.0 mg, 0.03 mmol) in dioxane (0.5 mL) and water (0.1 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 passed by preparative HPLC (column: Sunfire prep C18 column, 30). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LCMS C 26 H 20 D7N 12 O (M+H) + Calculated m / z value = 530.3; Experimental value = 530.3.

[0594] 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

[0595] A solution of ammonium formate (4.13 mg, 0.07 mmol) in 1 mL of MeOH was added to a sealed tube filled with nitrogen containing 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 supported on activated carbon (2.3 mg, 0.002 mmol). The reaction mixture was stirred at 60 °C for 3 h. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated to dryness. The residue was diluted with MeOH and subjected to preparative HPLC (column: Sunfire prep C18 column, 30). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LCMS C 25 H 18 D7N 12 O (M+H) + Calculated m / z value = 516.2; experimental value = 516.3.

[0596] 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]quinazolin-3-carboxamide

[0597] 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]quinazolin-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]phosphine (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 passed by preparative HPLC (column: Sunfire prep C18 column, 30). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LCMS C 25 H 29 N 10 O3 (M+H) + Calculated m / z value = 517.2; Experimental value 517.2.

[0598] 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)-one

[0599] Step 1: 9-(1-bromoethyl)-4,7-dimethyl-3-(pyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)- ketone

[0600] Use and targeting Example 20 The procedure described herein involves replacing 9-acetyl-7-methyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid tert-butyl ester with 9-acetyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid tert-butyl ester with pyridin-3-ylboronic acid in step 4, replacing 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-3,6-dihydropyridin-1(2H)-carboxylic acid tert-butyl ester with NaBH4 in step 7 to prepare the title compound. LCMS C19 H 18 BrN4O (M+H) + Calculated m / z value = 397.1; Experimental value = 397.1.

[0601] Step 2: 9-(1-((4-fluoro-2-(1-(methyl-d)) 3 )-1H-tetrazol-5-yl)phenyl)amino)ethyl)-4,7-di methyl-3-(pyridin-3-yl)imidazo[1,5-a]quinazolin-5(4H)-one

[0602] Add 4-fluoro-2-(1-(methyl-d3)-1H-tetrazol-5-yl)aniline (intermediate 2) (13.3 mg, 0.07 mmol) to a solution of 9-(1-bromoethyl)-4,7-dimethyl-3-(3-pyridyl)imidazo[1,5-a]quinazolin-5-one (18.0 mg, 0.05 mmol) in DMF (0.7 mL). Heat the mixture to 80 °C for 3 h. After cooling to room temperature, dilute the mixture with MeOH and pass it by preparative HPLC (column: Sunfire prep C18 column, 30 mL). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LCMS C 27 H 22 D3FN9O (M+H) + Calculated m / z value = 513.2; Experimental value 513.2.

[0603] 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)-one

[0604] Step 1: 9-[1-[4-fluoro-2-(1-methyl-1,2,4-triazol-3-yl)anilino]ethyl]-3-iodo-4,7-dimethyl α-Imidazolo[1,5-a]quinazolin-5-one

[0605] Use and targeting Example 8 The procedure described herein involves replacing 6-chloro-2-(2-methyl-2H-tetrazol-5-yl)pyridine-3-amine with 4-fluoro-2-(1-methyl-1,2,4-triazol-3-yl)aniline (intermediate 4) in step 5 to prepare the title compound. LCMS C 23 H 22 FIN7O (M+H) + Calculated m / z value = 558.1; Experimental value 558.1.

[0606] Step 2: 3-(2-aminopyrimidin-5-yl)-9-(1-((4-fluoro-2-(1-methyl-1H-1,2,4-triazol-3-yl)benzene) (1,5-a)quinazolin-5(4H)-one (amino)ethyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one

[0607] 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-dioxaborhexacyclopentan-2-yl)pyrimidin-2-amine (10.7 mg, 0.05 mmol), K3PO4 (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 passed by preparative HPLC (column: Sunfire prep C18 column, 30). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LC-MSC 27 H 26 FN 10 Calculated value of O (M+H)+ m / z = 525.2; experimental value 525.2.

[0608] Examples 82 to 84.

[0609] The following compounds in Table 7 were prepared similarly using appropriate intermediates according to the procedure described for Example 81.

[0610] Table 7.

[0611] Example 85. 3-(1-acetylpiperidin-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

[0612] Step 1: 3-(1-acetylpiperidin-4-yl)-9-(1-bromoethyl)-7-methyl-4-(methyl-d3)imidazo[1, [5-a]quinazolin-5(4H)-one

[0613] Use and Example 20A similar procedure is described, in which NaBH4 is used instead of NaBD4 in step 7 to prepare the title compound. LCMS C 21 H 23 D3BrN4O2 (M+H) + Calculated m / z value: 448.1; Experimental value: 448.1; Step 2: 3-(1-acetylpiperidin-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 To a solution of 3-(1-acetylpiperidin-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) at room temperature, 6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (24 mg, 0.14 mmol) was added. The resulting mixture was heated at 80 °C for 4 hours. After completion, the mixture was cooled to room temperature. The crude material was diluted with MeOH and analyzed by preparative HPLC (column: Sunfire prep C18 column, 30). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LC-MSC 28 H 29 D3ClN6O3 (M+H) + Calculated m / z value = 538.2; Experimental value 538.2.

[0614] Example 86. 9-(1-(6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethyl)-3-(1-(2-hydroxyacetyl)piperidin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one

[0615] Step 1: 9-(1-(6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethyl)-4,7-di methyl-3-(piperidin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one

[0616] Use and Example 67 A similar procedure is described in [the document], in which the title compound is prepared by replacing 6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-amine with 6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine in step 5. LCMS C 26 H 30 ClN6O2(M+H)+ Calculated m / z value: 493.2; Experimental value: 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)piperidin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one At 0°C, 9-(1-(6-chloro-2,3-dihydro-1-) H -pyrido[2,3-b][1,4]oxazin-1-yl)ethyl)-4,7-dimethyl-3-(piperidin-4-yl)imidazo[1,5-a]quinazolin-5(4 H )-keto (40 mg, 0.08 mmol) was added to a solution of HATU (40.1 mg, 0.11 mmol) in DMF. N -Ethyl- N -Isopropyl-propyl-2-amine (141 μL, 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 passed through preparative HPLC (column: Sunfire prep C18 column, 30 min). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LCMS C 28 H 32 ClN6O4 (M+H) + Calculated m / z value = 551.2; Experimental value 551.2.

[0617] 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)-one

[0618] Step 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]quinazolin-3-carboxylic acid

[0619] Use and Example 1A similar procedure is described in [the document], in step 8, replacing 9-acetyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid tert-butyl ester (intermediate 13) with 9-formyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid tert-butyl ester, and in step 10, replacing 2-amino-5-fluorobenzamide with 6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine. LCMS C 21 H 19 ClN5O4(M+H) + Calculated m / z value = 440.1; Experimental value 440.1.

[0620] Step 2: 9-((6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)methyl)-3-iodine-4, 7-Dimethylimidazo[1,5-a]quinazolin-5(4H)-one

[0621] Use and Example 8 A similar procedure is described in [the document], in which step 7, 9-(1-(((6-chloro-2,3-dihydro-1H-pyridano[2,3-b][1,4]oxazin-1-yl)methyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylic acid is used instead 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) is used to prepare the title compound. LCMS C 20 H 18 ClIN5O2 (M+H) + Calculated m / z value = 522.0; Experimental value 522.0.

[0622] Step 3: 3-(6-aminopyridin-3-yl)-9-((6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxa (1-azinyl)methyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one

[0623] At room temperature, potassium phosphate (13 mg, 0.06 mmol), Pd(PPh3)4 (5 mg, 0.001 mmol), and (6-amino-3-pyridinyl)boronic acid (4 mg, 0.03 mmol) were added to a mixture of 9-((6-chloro-2,3-dihydro-1H-pyridino[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). 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 passed by preparative HPLC (column: Sunfireprep C18 column, 30). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LCMS C 25 H 23 ClN7O2 (M+H) + Calculated m / z value = 488.2; Experimental value 488.2.

[0624] Examples 88 to 90.

[0625] The following compounds in Table 8 were prepared similarly using appropriate intermediates according to the procedure described for Example 87.

[0626] Table 8.

[0627] Example 91. 9-(1-((6-chloro-2-((3-fluorozacricyclobut-1-yl)methyl)pyridin-3-yl)amino)ethyl)- N,N 4,7-Tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide

[0628] Step 1: 6-Chloro-2-vinylpyridine-3-amine

[0629] 2-Bromo-6-chloro-pyridin-3-amine (5.00 g, 24.10 mmol), tetrakis(triphenylphosphine)palladium(0) (2.79 g, 2.41 mmol), potassium vinyltrifluoroborate (9.69 g, 72.30 mmol), and potassium carbonate (9.99 g, 72.30 mmol) were added to a 5:1 mixture of tetrahydrofuran and water (120 mL) 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, eluting with dichloromethane containing 0-50% ethyl acetate, to give the desired product (3.16 g, 84.8%). LCMSC7H8ClN2 (M+H) + Calculated m / z value = 155.0; Experimental value = 155.0.

[0630] 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]quinazolin-3-carboxamide

[0631] The title compound was prepared in step 2 using a procedure similar to that described in Example 48, with 6-chloro-2-vinylpyridine-3-amine instead of 3-amino-6-chloropyridine amide. LCMS C 24 H 26 ClN6O2 (M+H)+ m / z calculated value = 465.2; experimental value 465.2.

[0632] 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]quinazolin-3-carboxamide

[0633] Sodium hydride (56 mg, 1.40 mmol) was added 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]quinazolin-3-carboxamide (326 mg, 0.70 mmol) in anhydrous DMF at 0 °C. The mixture was stirred for 30 min, and then 1-(bromomethyl)-4-methoxybenzene (202 μL, 1.40 mmol) was added at the same temperature. The resulting mixture was stirred at room temperature for 1 h. After completion, the reaction mixture was diluted with DCM containing 10% MeOH and washed with water (3x). 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 (310 mg, 75.5%) as a yellow solid. LCMS C 32H 34 ClN6O3 (M+H) + Calculated m / z value = 585.2; Experimental value 585.2.

[0634] 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]quinazolin-3-carboxamide

[0635] 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]quinazolin-3-carboxamide (540 mg, 0.92 mmol), OsO4 (4% aqueous solution, 586 μL, 0.09 mmol), 2,6-dimethylpyridine (213 μL, 1.85 mmol), and sodium periodate (987 mg, 4.61 mmol) were successively added to a 5:1 solution of tetrahydrofuran and water 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 C 31 H 32 ClN6O4 (M+H) + Calculated m / z value = 587.2; Experimental value 587.2.

[0636] Step 5: 9-(1-((6-chloro-2-((3-fluorozacricyclobut-1-yl)methyl)pyridin-3-yl)(4-methoxybenzyl) (amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide

[0637] At room temperature, 3-fluorozacriane hydrochloride (12 mg, 0.11 mmol) and sodium triacetoxyborohydride (36 mg, 0.17 mmol) were successively added 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]quinazolin-3-carboxamide (50 mg, 85.17 μmol) in DCM (2 mL). The resulting mixture was stirred for 1 h. After completion, the reaction mixture was diluted with 10% MeOH / DCM and washed with water. The organic layer was separated, dried over sodium sulfate and under reduced pressure. The residue was used directly in the next step. LCMS C 34 H 38 ClFN7O3 (M+H) + Calculated m / z value = 646.3; Experimental value = 646.3.

[0638] Step 6: 9-(1-((6-chloro-2-((3-fluorozacricyclobut-1-yl)methyl)pyridin-3-yl)amino)ethyl)-N, N,4,7-Tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide

[0639] Treatment of 9-(1-((6-chloro-2-((3-fluoroazacyclobut-1-yl)methyl)pyridin-3-yl)(4-methoxybenzyl)amino)ethyl)- in two vials with trifluoroacetic acid at room temperature N,N 4,7-Tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide (10 mg, 0.015 mmol). After stirring for 2 h, the reaction mixture was diluted with methanol and analyzed by preparative HPLC (column: Sunfire prep C18 column, 30). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt, as a white solid. LCMS C 26 H 30 ClFN7O2(M+H) + Calculated m / z value = 526.2; Experimental value 526.2.

[0640] Example 92. 9-(1-((6-chloro-2-((3-fluorozacriane-1-yl)methyl)pyridin-3-yl)amino)ethyl)-N-(2-hydroxyethyl)-N,4,7-trimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide

[0641] Step 1: 9-(1-((6-chloro-2-((3-fluorozacricyclobut-1-yl)methyl)pyridin-3-yl)(4-methoxybenzyl) (amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid tert-butyl ester

[0642] The title compound was prepared in step 2 using a procedure similar to that described in Example 91, with tert-butyl 9-(1-bromoethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylate (Example 1, step 9) instead of 9-(1-bromoethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide. LCMS C 36 H 41 ClFN6O4 (M+H) + Calculated m / z value = 675.3; Experimental value 675.3.

[0643] Step 2: 9-(1-((6-chloro-2-((3-fluorozacricyclobut-1-yl)methyl)pyridin-3-yl)amino)ethyl)-4, 7-Dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid

[0644] 9-(1-((6-chloro-2-((3-fluorozacricyclobut-1-yl)methyl)pyridin-3-yl)(4-methoxybenzyl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid tert-butyl ester (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, and then the solvent was removed under reduced pressure. The residue was azeotropically treated with toluene three times. The resulting crude product was used directly in the next step. LCMS C 24 H 25 ClFN6O3 (M+H) + Calculated m / z value = 499.2; Experimental value 499.2.

[0645] Step 3: 9-(1-((6-chloro-2-((3-fluorozacrianebut-1-yl)methyl)pyridin-3-yl)amino)ethyl)-N- (2-Hydroxyethyl)-N,4,7-trimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide

[0646] HATU (39 mg, 0.10 mmol) was added to a solution of 9-(1-((6-chloro-2-((3-fluorozacricyclobut-1-yl)methyl)pyridin-3-yl)amino)ethyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxylic acid (40 mg, 0.08 mmol) in DMF (0.8 mL) at room temperature. N -Ethyl- N -Isopropyl-propyl-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 passed by preparative HPLC (column: Sunfire prep C18 column, 30). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt. LCMS C 27 H 32 ClFN7O3 (M+H) + Calculated m / z value = 556.2; Experimental value 556.2.

[0647] Example 93. Methyl ((6-chloro-3-((1-(3-(dimethylcarbamoyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)pyridin-2-yl)methyl)carbamate

[0648] Step 1: 9-(1-((6-chloro-2-(((4-methoxybenzyl)amino)methyl)pyridin-3-yl)(4-methoxybenzyl) (N,N,4,7-Tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide)

[0649] The title compound was prepared in step 5 using a procedure similar to that described in Example 91, with 4-methoxybenzylamine used instead of 3-fluorozahexacyclic butane hydrochloride. LCMS C 39 H 43 ClN7O4 (M+H) + Calculated m / z value = 708.3; Experimental value = 708.3.

[0650] Step 2: ((6-chloro-3-((1-(3-(dimethylcarbamoyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazole) [1,5-a]quinazolin-9-yl)ethyl)(4-methoxybenzyl)amino)pyridin-2-yl)methyl)(4-methoxybenzyl)amino Methyl carbamate

[0651] Methyl chloroformate (4 μL, 0.05 mmol) was added dropwise 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]quinazolin-3-carboxamide (30 mg, 0.04 mmol) in dichloromethane (1 mL) at 0 °C. After stirring for 30 min, the mixture was concentrated under reduced pressure. The residue was used directly in the next step. LCMS C 41 H 45 ClN7O6 (M+H) + Calculated m / z value = 766.3; Experimental value 766.3.

[0652] Step 3: ((6-chloro-3-((1-(3-(dimethylcarbamoyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazole) [1,5-a]quinazolin-9-yl)ethyl)amino)pyridin-2-yl)methyl)carbamate

[0653] At 0°C, a 5:1 mixture of trifluoroacetic acid and trifluoromethanesulfonic acid was added dropwise to the crude methyl ((6-chloro-3-((1-(3-(dimethylcarbamoyl)-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 ester from the previous step. After completion, the mixture was diluted with methanol and subjected to preparative HPLC (column: Sunfire prep C18 column, 30 °C). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt. LCMS C 25 H 29 ClN7O4 (M+H)+ Calculated m / z value = 526.2; Experimental value 526.2.

[0654] Example 94. Methyl (6-chloro-3-(((3-(dimethylcarbamoyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)methyl)amino)pyridin-2-yl)carbamate

[0655] Step 1: 9-(bromomethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3- formamide

[0656] Use and Example 1 A similar procedure is described in the paper, in which the title compound is prepared in step 8 by replacing 9-acetyl-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxamide (intermediate 14) with 9-formyl-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazoline-3-carboxylate tert-butyl ester. LCMS C 16 H 18 BrN4O2(M+H) + Calculated m / z value = 377.1; Experimental value 377.1.

[0657] Step 2: (6-chloro-3-(((3-(dimethylcarbamoyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo) [1,5-a]quinazolin-9-yl)methyl)amino)pyridin-2-yl)carbamate methyl ester

[0658] N-(3-amino-6-chloro-2-pyridyl)carbamate (intermediate 5) (10 mg, 0.05 mmol) was added to a solution of 9-(bromomethyl)-N,N,4,7-tetramethyl-5-oxo-imidazo[1,5-a]quinazolin-3-carboxamide (15 mg, 0.04 mmol) in DMF (0.1 mL) at room temperature. The resulting mixture was heated at 80 °C for 1 h. The mixture was then diluted with methanol and analyzed by preparative HPLC (column: Sunfire prep C18 column, 30). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt. LCMS C 23 H 25 ClN7O4(M+H) + Calculated m / z value = 498.2; Experimental value 498.2.

[0659] Examples 95 and 96.

[0660] The following compounds in Table 9 were prepared similarly using appropriate intermediates according to the procedure described for Example 94.

[0661] Table 9.

[0662] Example 97. 9-(1-((6-chloro-2-(2-(1-methylazacyclobut-3-yl)-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

[0663] Step 1: 3-(5-(6-chloro-3-((1-(3-(dimethylcarbamoyl)-4,7-dimethyl-5-oxo-4,5-dihydro) Imidazolo[1,5-a]quinazolin-9-yl)ethyl)amino)pyridin-2-yl)-2H-tetrazol-2-yl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0664] Using a procedure similar to that described in Example 48, the title compound was prepared in step 2 using tert-butyl 3-(5-(3-amino-6-chloropyridin-2-yl)-2H-tetrazol-2-yl)azacyclobutane-1-carboxylate (intermediate 8) instead of 3-amino-6-chloropyridinamide. The resulting mixture was concentrated under reduced pressure. The residue was used directly in the next step. LCMS C 31 H 37 ClN 11 O4(M+H) + Calculated m / z value = 662.3; Experimental value 662.3.

[0665] Step 2: 9-(1-((2-(2-(azacyclobut-3-yl)-2H-tetrazole-5-yl)-6-chloropyridin-3-yl)amino)ethyl (N,N,4,7-Tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide)

[0666] Pure trifluoroacetic acid was added to the crude tert-butyl 3-(5-(6-chloro-3-((1-(3-(dimethylcarbamoyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)pyridin-2-yl)-2H-tetrazol-2-yl)azacyclobutane-1-carboxylate extract from the previous step at 0 °C. After stirring for 20 min, the mixture was diluted with methanol and analyzed by preparative HPLC (column: Sunfire prep C18 column, 30). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt. LC-MSC 26 H 29 ClN11 O2 (M+H) + Calculated m / z value = 562.2; Experimental value 562.2.

[0667] Step 3: 9-(1-((6-chloro-2-(2-(1-methylazacyclobut-3-yl)-2H-tetrazole-5-yl)pyridin-3-yl) (amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide

[0668] At room temperature, formaldehyde (37% aqueous solution) (10 μL), DIEA (20 μL), and sodium triacetoxyborohydride (12 mg, 0.06 mmol) were successively added to a solution of 9-(1-((2-(azacyclobut-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]quinazolin-3-carboxamide TFA salt (10 mg, 0.018 mmol) in DCM (0.5 mL). The resulting mixture was stirred at room temperature for 1 h. The reactants were then diluted with methanol and analyzed by preparative HPLC (column: Sunfire prep C18 column, 30). Purification was performed using a mobile phase of 150 mm and 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min; the eluent fraction was collected and lyophilized to obtain the desired product, TFA salt. LCMS C 27 H 31 ClN 11 O2 (M+H) + Calculated m / z value = 576.2; Experimental value 576.2.

[0669] Examples 98 to 100.

[0670] The following compounds in Table 10 were prepared similarly using appropriate intermediates according to the procedure described for Example 97.

[0671] Table 10.

[0672] Example 101. 3-(2-aminopyrimidin-5-yl)-9-((6-chloro-3,4-dihydro-1,5-naphthidin-1(2H)-yl)methyl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one

[0673] Use and targeting Example 87The procedure described herein involves replacing 6-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine with 6-chloro-1,2,3,4-tetrahydro-1,5-naphthidine (intermediate 10) in step 1, and replacing (6-amino-3-pyridyl)boronic acid with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclop...

Claims

1. A compound of formula I: I Or its pharmaceutically acceptable salt, 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 heterocyclic alkyl or 5-10 membered heteroaryl; L 1 C 1-4 alkylene, wherein the C 1-4 The alkylene group is optionally represented by 1, 2, 3 or 4 independently selected R groups. G Substituent substitution; L 2 Selected from -O- and -N(R) L )-; R L Selected from H, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 1 Selected from H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups and -CN; R 2 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl and C 3-7 cycloalkyl-C 1-4 Alkyl, wherein R 2 The C mentioned 1-6 Alkyl, the C 1-6 Halogenated alkyl groups, the C 3-7 cycloalkyl and the C 3-7 cycloalkyl-C 1-4 Each alkyl group is optionally represented by one, two, three, or four independently selected R groups. G Substituent substitution; R 3 Selected from H, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-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)2R b3 -OS(O)2NR 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)2R b3 -NR c3 S(O)2NR 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)2R b3 -S(O)NR c3 R d3 -S(O)2NR 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)2R b3 -C(O)NR c3 S(O)2NR c3 R d3 -S(O)2NR c3 C(O)R b3 -NR c3 S(O)NR c3 C(O)R b3 and -P(O)R f3 R g3 , where R 3 The C mentioned 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 1-6 Halogenated alkyl groups, the C 3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocyclic alkyl, 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 heterocyclic alkyl)-C 1-4 Alkyl groups and the (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally represented by one, two, three, four, five, or six independently selected R groups. 3A Substituent substitution; Each R a3 R c3 and R d3 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 Alkyl, wherein R a3 R c3 and R d3 The C mentioned 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 1-6 Halogenated alkyl groups, the C 3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocyclic alkyl, 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 heterocyclic alkyl)-C 1-4 Alkyl groups and the (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally represented by one, two, three, four, five, or six independently selected R groups. 3A Substituent substitution; Or, any R connected to the same N atom c3 and R d3 Together with the N atom to which it is attached, a 4-10 membered heterocyclic alkyl group is formed, wherein the 4-10 membered heterocyclic alkyl group is optionally supported by 1, 2, 3, 4, 5 or 6 independently selected R atoms. 3A Substituent substitution; Each R b3 Selected independently from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 Alkyl, wherein R b3 The C mentioned 1-6 Alkyl, the C 1-6 Halogenated alkyl groups, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocyclic alkyl, 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 heterocyclic alkyl)-C 1-4 Alkyl groups and the (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally represented by one, two, three, four, five, or six independently selected R groups. 3A Substituent substitution; Each R e3 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 alkyl; Each R f3 and R g3 Independently selected from H and C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 alkyl; Each R 3A Independently selected from oxo group, H, halogen group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-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)2R b3A -OS(O)2NR 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)2R b3A -NR c3A S(O)2NR 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)2R b3A -S(O)NR c3A R d3A -S(O)2NR 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 c3A S(O)(=NR e3A )R b3A -NR c3A S(O)(=NR e3A )NR c3A R d3A -OS(O)(=NR) e3A )R b3A -S(O)(=NR) e3A )R b3A -S(O)(=NR) e3A )NR c3A R d3A -C(O)NR c3A S(O)2R b3A -C(O)NR c3A S(O)2NR c3A R d3A -S(O)2NR c3A C(O)R b3A -NR c3A S(O)NR c3A C(O)R b3A and -P(O)R f3A R g3A , where R 3A The C mentioned 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 1-6 Halogenated alkyl groups, the C 3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocyclic alkyl, 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 heterocyclic alkyl)-C 1-4 Alkyl groups and the (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally represented by one, two, three, four, five, or six independently selected R groups. G Substituent substitution; Each R a3A R c3A and R d3A Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 Alkyl, wherein R a3A R c3A and R d3A The C mentioned 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 1-6 Halogenated alkyl groups, the C 3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocyclic alkyl, 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 heterocyclic alkyl)-C 1-4 Alkyl groups and the (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally represented by one, two, three, four, five, or six independently selected R groups. G Substituent substitution; Or, any R connected to the same N atom c3A and R d3A Together with the N atom to which it is attached, a 4-10 membered heterocyclic alkyl group is formed, wherein the 4-10 membered heterocyclic alkyl group is optionally supported by 1, 2, 3, 4, 5 or 6 independently selected R atoms. G Substituent substitution; Each R b3A Selected independently from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 Alkyl, wherein R b3A The C mentioned 1-6 Alkyl, the C 1-6 Halogenated alkyl groups, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocyclic alkyl, 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 heterocyclic alkyl)-C 1-4 Alkyl groups and the (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally represented by one, two, three, four, five, or six independently selected R groups. G Substituent substitution; Each R e3A Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 alkyl; Each R f3A and R g3A Independently selected from H and C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 alkyl; R 4 Selected from oxo groups, halogen groups, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-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)2R b4 -OS(O)2NR 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)2R b4 -NR c4 S(O)2NR 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)2R b4 -S(O)NR c4 R d4 -S(O)2NR 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)2R b4 -C(O)NR c4 S(O)2NR c4 R d4 -S(O)2NR c4 C(O)R b4 -NR c4 S(O)NR c4 C(O)R b4 and -P(O)R f4 R g4 , where R 4 The C mentioned 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 1-6 Halogenated alkyl groups, the C 3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocyclic alkyl, 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 heterocyclic alkyl)-C 1-4 Alkyl groups and the (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally represented by one, two, three, four, five, or six independently selected R groups. 4A Substituent substitution; Each R a4 R c4 and R d4 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 Alkyl, wherein R a4 R c4 and R d4 The C mentioned 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 1-6 Halogenated alkyl groups, the C 3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocyclic alkyl, 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 heterocyclic alkyl)-C 1-4 Alkyl groups and the (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally represented by one, two, three, four, five, or six independently selected R groups. 4A Substituent substitution; Or, any R connected to the same N atom c4 and R d4 Together with the N atom to which it is attached, a 4-10 membered heterocyclic alkyl group is formed, wherein the 4-10 membered heterocyclic alkyl group is optionally supported by 1, 2, 3, 4, 5 or 6 independently selected R atoms. 4A Substituent substitution; Each R b4 Selected independently from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 Alkyl, wherein R b4 The C mentioned 1-6 Alkyl, the C 1-6 Halogenated alkyl groups, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocyclic alkyl, 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 heterocyclic alkyl)-C 1-4 Alkyl groups and the (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally represented by one, two, three, four, five, or six independently selected R groups. 4A Substituent substitution; Each R e4 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 alkyl; Each R f4 and R g4 Independently selected from H and C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 alkyl; Each R 4A Independently selected from oxo group, H, halogen group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-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)2R b4A -OS(O)2NR 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)2R b4A -NR c4A S(O)2NR 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)2R b4A -S(O)NR c4A R d4A -S(O)2NR 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)2R b4A -C(O)NR c4A S(O)2NR c4A R d4A -S(O)2NR c4A C(O)R b4A -NR c4A S(O)NR c4A C(O)R b4A and -P(O)R f4A R g4A , where R 4A The C mentioned 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 1-6 Halogenated alkyl groups, the C 3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocyclic alkyl, 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 heterocyclic alkyl)-C 1-4 Alkyl groups and the (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally represented by one, two, three, four, five, or six independently selected R groups. G Substituent substitution; Each R a4A R c4A and R d4A Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 Alkyl, wherein R a4A R c4A and R d4A The C mentioned 1-6 Alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 1-6 Halogenated alkyl groups, the C 3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocyclic alkyl, 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 heterocyclic alkyl)-C 1-4 Alkyl groups and the (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally represented by one, two, three, four, five, or six independently selected R groups. G Substituent substitution; Or, any R connected to the same N atom c4A and R d4A Together with the N atom to which it is attached, a 4-10 membered heterocyclic alkyl group is formed, wherein the 4-10 membered heterocyclic alkyl group is optionally supported by 1, 2, 3, 4, 5 or 6 independently selected R atoms. G Substituent substitution; Each R b4A Selected independently from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 Alkyl, wherein R b4A The C mentioned 1-6 Alkyl, the C 1-6 Halogenated alkyl groups, the C 2-6 alkenyl, the C 2-6 alkynyl group, the C 3-10 cycloalkyl, the C 6-10 aryl, the 4-10 membered heterocyclic alkyl, 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 heterocyclic alkyl)-C 1-4 Alkyl groups and the (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally represented by one, two, three, four, five, or six independently selected R groups. G Substituent substitution; Each R e4A Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 alkyl; Each R f4A and R g4A Independently selected from H and C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocyclic alkyl)-C 1-4 Alkyl and (5-10-membered heteroaryl)-C 1-4 alkyl; Each R G Independently selected from H, D, OH, CN, halogen, oxo group, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Halogenated alkyl, cyano-C 1-4 Alkyl, HO-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 3-7 Cycloalkyl, 4-7 membered heterocyclic alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, amino, C 1-3 Alkylamino, di(C) 1-3 Alkyl)amino, thio, C 1-3 Alkyl thio, C 1-3 alkylsulfinyl, C 1-3 alkylsulfonyl, carbamoyl, C 1-3 Alkyl carbamoyl, di(C 1-3 alkyl) carbamoyl, carboxyl, C 1-3 alkyl carbonyl, C 1-3 alkoxycarbonyl, C 1-3 Alkyl carbonyloxy, C 1-3 Alkyl carbonyl amino, C 1-3 alkoxycarbonylamino, aminocarbonyloxy, C 1-3 Alkylaminocarbonyloxy, di(C 1-3 alkyl)aminocarbonyloxy, C 1-3 Alkylsulfonylamino, aminosulfonyl, C 1-3 alkylaminosulfonyl, di(C 1-3 alkyl)aminosulfonyl, aminosulfonylamino, C 1-3 Alkylaminosulfonylamino, di(C 1-3 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3 Alkylaminocarbonylamino and di(C) 1-3 Alkyl)aminocarbonylamino.

2. The compound of claim 1, wherein the compound of formula I is a compound of formula II: II Or its pharmaceutically acceptable salt, wherein: R 1 Selected from halogen groups, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; R 2 C 1-3 alkyl; R 3 Selected from pyrazolyl, pyrimidinyl, piperidinyl and C(O)NR c3 R d3 , where R 3 The pyrazolyl group, the pyridyl group, and the piperidinyl group are each optionally represented by a group selected from C. 1-3 Alkyl, amino and -C(O)C 1-3 alkyl R 3A Substituent substitution; Each R c3 and R d3 Selected independently from C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; R 4 It is a halogenated group; and R G It can be H or D.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from chloro, methyl and trifluoromethyl.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from methyl and trideuterated methyl.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 3 For C(O)NR c3 R d3 .

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R c3 and R d3 Each is independently selected from methyl and trideuterated methyl.

7. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R c3 and R d3 Each is a methyl group.

8. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R c3 and R d3 Each is a trideuterated methyl group.

9. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from pyrazolyl, pyrimidinyl, and piperidinyl, wherein R 3 The pyrazolyl group, the pyrimidinyl group, and the piperidinyl group are each optionally represented by a group selected from C. 1-3 Alkyl, amino and -C(O)C 1-3 alkyl R 3A Substituent substitution.

10. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from pyrazolyl, pyridyl, pyrimidinyl, and piperidinyl, wherein R 3 The pyrazolyl group, the pyrimidinyl group, and the piperidinyl group are each optionally surrounded by an R group selected from methyl, amino, and methyl carbonyl groups. 3A Substituent substitution.

11. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 3 It is selected from methylpyrazolyl, aminopyrimidinyl and (methylcarbonyl)piperidinyl.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 4 It is either fluorine or chlorine.

13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R G For H.

14. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R G The answer is D.

15. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from chloro, methyl, and trifluoromethyl; R 2 Selected from methyl and trideuterated methyl; R 3 Selected from pyrazolyl, pyridyl, pyrimidinyl, piperidinyl and C(O)NR c3 R d3 , where R 3 The pyrazolyl group, the pyrimidinyl group, and the piperidinyl group are each optionally surrounded by an R group selected from methyl, amino, and methyl carbonyl groups. 3A Substituent substitution; R c3 and R d3 Each is independently selected from methyl and trideuterated methyl groups; R 4 It is either fluorine or chlorine; and R G It can be H or D.

16. The compound of claim 1, wherein the compound of formula I is a compound of formula III: III Or its pharmaceutically acceptable salt, wherein: R 1 Halogenated or C 1-3 alkyl; R 2 C 1-3 alkyl; R 3 Selected from pyrimidinyl, azacyclic butylmethyl, pyrazolyl, pyridinyl, piperidinyl, 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 , where R 3 The pyrimidinyl group, the azacyclobutylmethyl group, the pyrazolyl group, the pyridyl group, the piperidinyl group, the 2H-pyrazolo[3,4-b]pyridyl group, the pyrazolo[1,5-a]pyridyl group, the pyrazolo[1,5-a]pyrimidinyl group, the imidazo[1,5-a]pyridyl group, the imidazoyl group, the thiazolyl group, and the 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl group are each optionally surrounded by one or two R groups. 3A Substituent substitution; Each R 3A Independently selected from halogen groups, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, oxetane, 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 groups and -S(O)2C 1-3 alkyl; R 4 Selected from H, halogen, C 1-3 Alkyl and C 1-3 Alkoxy; R 4A Selected from C 1-3 Alkyl, azacyclic butyl and piperidinyl, wherein R 4 The nitrogen-containing heterocyclic butyl group and the piperidinyl group are each optionally C 1-3 Alkyl substitution; and R G It can be H or D.

17. The compound of claim 1 or 16, or a pharmaceutically acceptable salt thereof, wherein R 1 It can be chlorine or methyl.

18. The compound of any one of claims 1, 16, and 17, or a pharmaceutically acceptable salt thereof, wherein R 2 It is methyl or trideuterated methyl.

19. The compound of any one of claims 1 and 16 to 18, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from pyrimidinyl, azacyclic butylmethyl, pyrazolyl, pyridinyl, piperidinyl, 2H-pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, and imidazo[1,5-a]pyridinyl, wherein R 3 The pyrimidinyl group, the azacyclobutylmethyl group, the pyrazolyl group, the pyridyl group, the piperidinyl group, the 2H-pyrazolo[3,4-b]pyridyl group, the pyrazolo[1,5-a]pyridyl group, the pyrazolo[1,5-a]pyrimidinyl group, and the imidazo[1,5-a]pyridyl group are each optionally surrounded by one or two R groups. 3A Substituent substitution.

20. The compound of any one of claims 1 and 16 to 19, or a pharmaceutically acceptable salt thereof, wherein each R 3A It is independently selected from methyl, fluorine, chlorine, methoxy, amino, methylamino, dimethylamino, hydroxymethyl, hydroxyethyl, oxetane, methyl carbonyl, isopropyl carbonyl, hydroxymethyl carbonyl, cyclopropyl carbonyl, methylsulfonyl, isopropylsulfonyl and cyclopropylsulfonyl.

21. The compound of any one of claims 1 and 16 to 18, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from (difluoroazacyclobutane)methyl, oxacyclobutanepiperidinyl, (methylcarbonyl)piperidinyl, (isopropylcarbonyl)piperidinyl, (hydroxymethylcarbonyl)piperidinyl, (cyclopropylcarbonyl)piperidinyl, (methylsulfonyl)piperidinyl, (isopropylsulfonyl)piperidinyl, (cyclopropylsulfonyl)piperidinyl, pyrazolyl, methylpyrazolyl, (hydroxyethyl)pyrazolyl, pyridinyl, (hydroxymethyl)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, 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.

22. The compound of any one of claims 1 and 16 to 18, or a pharmaceutically acceptable salt thereof, wherein R 3 For C(O)NR c3 R d3 .

23. 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 Each is independently selected from methyl and trideuterated methyl.

24. 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 Each is a methyl group.

25. 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 Each is a trideuterated methyl group.

26. The compound of any one of claims 1 and 16 to 25, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from H, fluorine, chlorine, methyl and methoxy.

27. The compound of any one of claims 1 and 16 to 26, or a pharmaceutically acceptable salt thereof, wherein R 4A Selected from methyl, trideuterated methyl, ethyl, aziridine, and piperidinyl, wherein R 4A The nitrogen-containing heterocyclic butyl group and the piperidinyl group are each optionally substituted with methyl.

28. The compound of any one of claims 1 and 16 to 26, or a pharmaceutically acceptable salt thereof, wherein R 4A It is selected from methyl, trideuterated methyl, ethyl, methylazacyclobutane and methylpiperidinyl.

29. The compound of any one of claims 1 and 16 to 28, or a pharmaceutically acceptable salt thereof, wherein R G For H.

30. The compound of any one of claims 1 and 16 to 28, or a pharmaceutically acceptable salt thereof, wherein R G The answer is D.

31. The compound of claim 1 or 16, or a pharmaceutically acceptable salt thereof, wherein: R 1 It is chlorine or methyl; R 2 It is methyl or trideuterated methyl; R 3 Selected from pyrimidinyl, azacyclic butylmethyl, pyrazolyl, pyridinyl, piperidinyl, 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 , where R 3 The pyrimidinyl group, the azacyclobutylmethyl group, the pyrazolyl group, the pyridyl group, the piperidinyl group, the 2H-pyrazolo[3,4-b]pyridyl group, the pyrazolo[1,5-a]pyridyl group, the pyrazolo[1,5-a]pyrimidinyl group, the imidazo[1,5-a]pyridyl group, the imidazoyl group, the thiazolyl group, and the 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl group are each optionally surrounded by one or two R groups. 3A Substituent substitution; Each R 3A Independently selected from methyl, fluorine, chlorine, methoxy, amino, methylamino, dimethylamino, hydroxymethyl, hydroxyethyl, oxetyl, methylcarbonyl, isopropylcarbonyl, hydroxymethylcarbonyl, cyclopropylcarbonyl, methylsulfonyl, isopropylsulfonyl, and cyclopropylsulfonyl; R c3 and R d3 Each is independently selected from methyl and trideuterated methyl groups; R 4 Selected from H, fluorine, chlorine, methyl, and methoxy; R 4A Selected from methyl, ethyl, trideuterated methyl, aziridine, and piperidinyl, wherein R 4A The aziridine and piperidinyl groups are each optionally substituted with methyl groups; and R G It can be H or D.

32. The compound of claim 1, wherein the compound is selected from: 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; ( R )-9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; ( S )-9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-N,N,7-trimethyl-4-(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl-1-d)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-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; ( 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-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-acetylpiperidin-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-carbamoyl-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-carbamoyl-4-fluorophenyl)amino)ethyl-1-d)-7-chloro-4-methyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-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]quinazolin-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]quinazolin-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]quinazolin-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]quinazolin-3-carboxamide; 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]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl-1-d)-4-methyl-N,N-bis(methyl-d3)-5-oxo-7-(trifluoromethyl)-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 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; 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-carbamoyl-6-chloropyridin-3-yl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-6-chloropyridin-3-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((2-carbamoyl-4-chlorophenyl)amino)ethyl-1-d)-7-methyl-N,N,4-tris(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-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]quinazolin-3-carboxamide; (3-((1-(3-(bis(methyl-d3)carbamoyl)-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-carbamoyl-4-chlorophenyl)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-1H-tetrazol-5-yl)phenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-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]quinazolin-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]quinazolin-3-carboxamide; (6-chloro-3-((1-(3-(dimethylcarbamoyl)-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-aminosulfonylphenyl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((5-chloroquinoline-8-yl)amino)ethyl)-N,N,4,7-tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-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]quinazolin-3-carboxamide; 2-((1-(3-(1-acetylpiperidin-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-(oxecyclobut-3-yl)piperidin-4-yl)imidazo[1,5-a]quinazolin-5(4H)-one; 3-(1-acetylpiperidin-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; 9-(1-((6-chloro-2-(2-(methyl-d3)-2H-tetrazol-5-yl)pyridin-3-yl)amino)ethyl)-3-(1-(2-hydroxyacetyl)piperidin-4-yl)-4,7-dimethylimidazo[1,5-a]quinazolin-5(4H)-one; 3-(1-acetylpiperidin-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-isobutyrylpiperidin-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)piperidin-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)piperidin-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)piperidin-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)piperidin-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-tetrazole-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-pyridyl)-9-[1-[4-fluoro-2-(1-methyltriazol-4-yl)anilino]ethyl]-4,7-dimethyl-imidazo[1,5-a]quinazolin-5-one; 3-(1-acetylpiperidin-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)piperidin-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-fluoroazacyclobut-1-yl)methyl)pyridin-3-yl)amino)ethyl)- N,N ,4,7-Tetramethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((6-chloro-2-((3-fluoroazacyclobut-1-yl)methyl)pyridin-3-yl)amino)ethyl)-N-(2-hydroxyethyl)-N,4,7-trimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide; ((6-chloro-3-((1-(3-(dimethylcarbamoyl)-4,7-dimethyl-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)pyridin-2-yl)methyl)carbamate; (6-chloro-3-(((3-(dimethylcarbamoyl)-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]quinazolin-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(trideuterated methyl)imidazo[1,5-a]quinazolin-3-carboxamide; 9-(1-((6-chloro-2-(2-(1-methylazacyclobut-3-yl)-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-((6-chloro-2-(2-(1-methylpiperidin-4-yl)-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-((6-chloro-2-(2-(1-methylazacyclobut-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]quinazolin-3-carboxamide; 9-(1-((6-chloro-2-(2-(1-methylpiperidin-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]quinazolin-3-carboxamide; 3-(2-aminopyrimidin-5-yl)-9-((6-chloro-3,4-dihydro-1,5-naphthidin-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-difluoroazacyclobut-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-naphthidin-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]quinazolin-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-naphthidin-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; (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-(oxecyclobut-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-hydroxypiperidin-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-morpholinylpyridin-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-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-9-yl)ethyl)amino)-6-chloropyridin-2-yl)-1,2,4-oxadiazol-5(4H)-one; 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; (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-d3)-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-d3)-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 its pharmaceutically acceptable salt.

33. 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-aminothiazolyl-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-methylthiazolyl-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 its pharmaceutically acceptable salt.

34. The compound according to claim 1 or 2, wherein the compound is ( R )-9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide or a pharmaceutically acceptable salt thereof.

35. The compound according to claim 1 or 2, wherein the compound is ( S )-9-(1-((2-carbamoyl-4-fluorophenyl)amino)ethyl)-4,7-dimethyl-N,N-bis(methyl-d3)-5-oxo-4,5-dihydroimidazo[1,5-a]quinazolin-3-carboxamide or a pharmaceutically acceptable salt thereof.

36. 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.

37. 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.

38. A method for inhibiting PI3Kα kinase activity, the method comprising contacting the kinase with a compound of any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof.

39. A method of treating a patient with a PI3Kα-mediated disease or condition, the method comprising administering to the patient a therapeutically effective amount of any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof.

40. The method of claim 39, wherein the disease or condition is cancer.

41. 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.

42. The method of claim 39, wherein the disease or condition is CLOVES syndrome (congenital lipoma overgrowth, vascular malformation, epidermal nevus, scoliosis / skeletal and spinal syndrome) or PIK3CA-associated overgrowth syndrome (PROS).

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