Chemical compounds

Abstract

This disclosure provides novel boron derivatives or salts thereof, compositions containing them, and their use in medicine. These compounds are active as PI3K inhibitors, including PI3K variants, and are useful in the treatment or control of diseases or disorders mediated by PI3K and its variants.

Description

Detailed description of the invention

[0001] [Cross-reference to related applications] This application claims priority to U.S. Provisional Application No. 63 / 452355 filed on 15 March 2023, U.S. Provisional Application No. 63 / 524453 filed on 30 June 2023, U.S. Provisional Application No. 63 / 524489 filed on 30 June 2023, and U.S. Provisional Application No. 63 / 525623 filed on 7 July 2023, all of which are incorporated herein by reference.

[0002] [Technical Field] This disclosure provides novel boron compounds or salts thereof, compositions containing them, and their use in medicine. These compounds exhibit activity as kinase inhibitors.

[0003] [Background technology] Cellular activity can be controlled by external signals that stimulate or inhibit intracellular events. The process by which stimulant or inhibitory signals are transmitted into cells and trigger intracellular responses is called signal transduction. Over the past few decades, the cascade of signal transduction events has been elucidated and revealed to play a central role in various biological responses. Defects in various components of signal transduction pathways have been found to cause a vast number of diseases, including numerous forms of cancer, inflammatory disorders, metabolic disorders, and vascular and neurological diseases (Gaestel et al. Current Medicinal Chemistry (2007) 14:2214-2234).

[0004] Kinases are an important type of signaling molecule. Kinases can generally be classified into protein kinases and lipid kinases, and certain kinases exhibit bispecificity.

[0005] Protein kinases are enzymes that phosphorylate other proteins and / or phosphorylate themselves (i.e., autophosphorylate). Protein kinases can generally be classified into three main groups based on how they utilize their substrates: tyrosine kinases (e.g., erb2, PDGF receptor, EGF receptor, VEGF receptor, src, abl), which primarily phosphorylate substrates on tyrosine residues; serine / threonine kinases (e.g., mTorCl, mTorC2, ATM, ATR, DNA-PK, Akt), which primarily phosphorylate substrates on serine and / or threonine residues; and bispecific kinases, which phosphorylate substrates on tyrosine, serine, and / or threonine residues.

[0006] Lipid kinases are enzymes that catalyze the phosphorylation of lipids within cells. These enzymes, and the resulting phosphorylated lipids and lipid-derived biologically active organic molecules, play roles in many different physiological processes, including cell proliferation, migration, adhesion, and differentiation. A specific group of lipid kinases includes membrane lipid kinases, i.e., kinases that catalyze the phosphorylation of lipids contained in or associated with the cell membrane. Examples of such enzymes include phosphinocitic kinases (PB kinases, PI4 kinases, etc.), diacylglycerol kinases, and sphingosine kinases.

[0007] The PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) gene issues the command to produce the p110 alpha (p110α) protein. This p110α protein is a part (subunit) of an enzyme called phosphatidylinositol 3-kinase (PI3K). The p110α protein is called a catalytic subunit because it carries out the action of PI3K, while other subunits (produced by other genes) regulate the enzyme's activity.

[0008] Phosphatidylinositol 3-kinase (PI3K) is a crucial molecule initiating signaling pathways after the binding of extracellular signals to cell surface receptors. As an intracellular kinase, PI3K activates multiple intracellular signaling pathways that influence cell growth, proliferation, migration, secretion, differentiation, transcription, and translation. Dysregulation of PI3K activity and abnormal PI3K signaling cause a wide range of human diseases, including cancer, immune disorders, diabetes, and cardiovascular diseases. The PI3K signaling pathway is one of the most mutation-prone systems in human cancer.

[0009] PI3K signaling is also involved in many other disease conditions, including allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, psoriasis, multiple sclerosis, asthma, diabetes complications, and cardiovascular inflammatory complications such as acute coronary syndrome.

[0010] PI3Ks are a unique and conserved family of intracellular lipid kinases that phosphorylate the 3'-OH group on phosphatidylinositol or phosphoinositides. Class I PI3Ks are typically activated by tyrosine kinases or G protein-coupled receptors, phosphorylating PIP2 to produce PIP3. PIP3 engages downstream effectors such as the Akt / PDKl pathway, mTOR, Tee family kinases, and Rho family GTPases. Classes II and III play crucial roles in intracellular transport through the synthesis of P1(3)P and P1(3,4)P2.

[0011] PI3K phosphorylates the 3'-hydroxyl group of phosphatidylinositides (PtdIns). Based on their structure and substrate specificity, they are classified into three classes. In mammals, class I PI3K is further classified into subclasses IA and IB based on its regulatory mode. Class IA PI3K is a heterodimer of the p110 catalytic subunit and the p85 regulatory subunit. The genes PIK3CA, PIK3CB, and PIK3CD encode three highly homologous class IA catalytic isoforms: p110α, p110β, and p110δ, respectively. These isoforms are associated with one of five regulatory isoforms: p85α (and its splicing variants p55α and p50α, encoded by PIK3R1), p85β (PIK3R2), and p55γ (PIK3R3), collectively known as the p85 type regulatory subunit. Class IB PI3K is a control isoform of p101 (PIK3R5) or p87 (PIK3R6, which is coded as p84 or p87). PIKAP It is a heterodimer of the p110γ catalytic subunit (encoded by PIK3CG) bound to ). While p110α and p110β are ubiquitously expressed, the expression of p110δ and p110γ is mainly limited to leukocytes. Early PI3K-targeted drug discovery mainly consisted of non-isoform-selective pan-PI3K inhibitors. However, recent studies have shown that different PI3K isoforms play different roles in cell signaling and cancer, suggesting that inhibitors targeting individual isoforms may achieve higher therapeutic efficacy. Currently, isoform-selective inhibitors are emerging. See Thorpe et al., PI3K in Cancer: Divergent Roles of Isoforms, Modes of Activation, and Therapeutic Targeting, Nat. Rev. Cancer, 2015, 15(1): 7-24.

[0012] Hyperactivation of the PI3K pathway is one of the most frequent events in human cancer. PIK3CA mutations are established causative factors in many cancer types. Mutations in the gene encoding the isoform are point mutations concentrated in multiple hotspots within the helical and kinase domains. Missense mutations occur in all domains of p110α, but most concentrate in two hotspots: E542K and E545K in the helical domain and H1047R in the kinase domain. Cell-based analyses have confirmed that these hotspot mutations lead to transformation via constitutive activation of p110α. Due to the high mutation rate, targeting this pathway may offer a valuable therapeutic opportunity.

[0013] Genetic alterations in gene signaling are thought to be involved in various cancers, including 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, fibrous lamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, non-clear renal cell carcinoma, clear renal cell carcinoma, germ cell tumors, thymic tumors, pheochromocytoma, other neuroepithelial tumors, thyroid cancer, leukemia, and capsular glioma (Goncalves MD, Hopkins BD, Cantley LC. Phosphatidylinositol 3-Kinase, Grm.vth Disorders, and Cancer). N Engl J Med.2018 Nov 22;379(21):2052-2062).

[0014] Alpha isoforms are involved in various human cancers, for example. Angiogenesis has been shown to selectively require alpha isoforms in regulating endothelial cell migration (Graupera et al, Nature 2008; 453; 662-6). Mutations in the gene encoding PI3Ka, or mutations leading to overactivation of PI3Ka, are thought to occur in many human cancers, including lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, and skin cancer. Mutations in the encoding gene are point mutations concentrated in multiple hotspots within the helical domain and kinase domain, such as H1047R, E545K, and E542K. Many of these mutations have been shown to be oncogenic gain-of-function mutations. Due to its high mutation rate, targeting this protein may offer valuable therapeutic opportunities, including for cancer. While other isoforms are mainly expressed in hematopoietic cells, PI3Ka is constitutively expressed.

[0015] Because PI3K plays a central role in regulating glucose homeostasis in the body, inhibition of PI3K can cause hyperglycemia and / or hyperinsulinemia in patients (Busaidy NL, et al, Management of metabolic effects associated with anticancer agents targeting the PBK-Akt-mTOR pathway. J Clin Oneal 2012;30:2919-28). High levels of circulating insulin may exert pro-mitotic and / or anti-apoptotic effects on cancer cells, thereby counteracting the antiproliferative effects of inhibitors (Blouin MJ, et al, Abstract 4615: the hyperinsulinemia caused by inhibitors attenuates their antineoplastic efficacy, but can be minimized by co-administration of metformin. Cancer Res 2013; 73 :4615).

[0016] In cancers with mutant PI3Kα, one way to overcome the problem of compensatory insulin and / or glucose production associated with systemic inhibition caused by inhibiting the patient's wild-type PI3K is to develop inhibitors that are more selective to the mutant than to the wild type. This expands the scope for drug administration that selectively inhibits pathological signaling of mutant variants in cancer cells without affecting wild-type host tissues that control systemic metabolism (Okkenhaug K, Graupera M, Vanhaesebroeck B. Targeting PBK in Cancer: Impact on Tumor Cells, Their Protective Strama, Angiogenesis, and Immunotherapy. Cancer Discov. 2016 Oct;6(10): 1090-1105). This limits toxicity, allows for higher doses, and enables more complete inhibition of the drug target (Ariella B. Hanker, et al, Challenges for the clinical development of PBK inhibitors: Strategies to improve their impact in solid tumors. Cancer Discov. 2019 Apr; 9(4): 482-491).

[0017] Currently, PI3K inhibitors exhibit nearly equivalent efficacy against both wild-type and mutant (e.g., PI3Kα) PI3Kα mutations. Because PI3Kα mutations are located far from the active site, mutant-selective PI3Kα inhibitors have been difficult to develop. Therefore, inhibitors that target a second peripheral binding pocket and exhibit activity more specifically against mutants (e.g., H1047R) than against wild-type PI3Kα may offer a pathway to selective PI3Kα inhibition. Thus, targeting mutated peripheral binding pockets of PI3Ka could potentially provide valuable therapeutic targets in drug development.

[0018] Therefore, kinases such as lipid kinases like PI3K are major targets in drug development. This disclosure provides a novel class of kinase inhibitors.

[0019] [Summary of the Invention] One embodiment of this disclosure is formula (A):

[0020] [ka]

[0021] This includes the compounds shown, or their tautomers, enantiomers, diastereomers, mixtures, salts, hydrates, solvates, or deuterated forms. During the ceremony, A1 is

[0022] [ka]

[0023] Selected from the group consisting of,

[0024] [ka]

[0025] In the formula, A' is independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl; Here, each heterocyclyl and heteroaryl may contain one or more heteroatoms selected from N, O, and S; Each A1 is replaced by an optional choice; L 1 This is selected from the group consisting of (i) directly bonded, (ii) optionally substituted arylenes, and (iii) optionally substituted heteroarylenes; L 2 The group consisting of O and NH is selected; R 1a and R 1bare each independently selected from the group consisting of H, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 1-6 alkoxy; Q B is an optionally substituted 8- to 14-member fused ring system optionally containing one or more heteroatoms selected from the group consisting of O, N, and S; Y is H, CR 3c , N, O, or S; when Y is H, R 3a and R 3b each do not exist; when Y is N, R 3a and R 3b are each independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, aryl, C 3-6 cycloalkyl, and 3- to 6-member heterocyclyl; or Y is, as an N atom, bonded to R 3a and R 3b to form a heterocyclic or heteroaromatic monocyclic or spiro ring system or fused ring system, which ring or ring system may additionally contain one or more heteroatoms selected from the group consisting of N, O, and S, and which ring or ring system is optionally substituted; when Y is CR 3c , R 3c does not exist or is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, aryl, C 3-6Selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines; R 3a and R 3b These are H and C, which are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, aryl, C 3-6 Selected from the group consisting of cycloalkyls and 3-6 membered heterocyclines; or Y is a C atom, R 3a and R 3b It combines with to form a cycloalkyl, aryl, heterocyclic, or heterocyclic aromatic monocyclic, spirocyclic, or fused ring system, wherein the heterocyclic ring and heterocyclic aromatic ring contain one or more heteroatoms selected from the group consisting of N, O, and S, and the ring or ring system containing Y is optionally substituted; or If Y is O or S, then R 3a It does not exist, R 3b H, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from a group consisting of alkynnyls.

[0026] In one aspect of this disclosure, A1,

[0027] [ka]

[0028] Selected from, In the formula, each A1 is replaced by any choice from one of the rings in the formula.

[0029] As will be described in more detail herein and recognized by those skilled in the art, embodiments of the present invention may include boron atoms incorporated into the ring. Alternative products (II) or (III) may be formed by metabolic oxidation or hydrolysis. Species (II) may exist in equilibrium with the parent compound (I). The scope of this disclosure is intended to cover all forms. Representative examples are given below:

[0030] [ka]

[0031] As will be described in more detail herein and recognized by those skilled in the art, embodiments of the present invention relate to deuterium or carbon relative to hydrogen. 13 The disclosed compounds may include isotopomers, or isotopic isomers, in which one or more atoms of the compounds are substituted with isotopes, as in the case of C. The scope of the disclosed compounds is intended to capture the isotopic forms of compounds.

[0032] In one aspect of this disclosure, R A1 These are, independently, halogen, OH, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, (CH2) 0-6 CN, (CH2) 1-6 OH, (CH2) 0-6 OC 1-6 Alkyl, (CH2) 0-6 OC 2-6 Alkenyl, (CH2) 0-6 OC 2-6 Alkinyl, (CH2) 0-6 C(O)H, (CH2) 0-6 C(O)(C 1-6 Alkyl, C 2-6 Alkenyl, or C 1-6 Alkinyl), (CH2) 0-6 C(O)OH, (CH2) 0-6 C(O)O(C 1-6Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl), (CH2) 0-6 NH2, (CH2) 0-6 NH(C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl), (CH2) 0-6 N(C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl)2, (CH2) 0-6 C(O)NH2, (CH2) 0-6 C(O)NH(C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl), (CH2) 0-6 C(O)N(C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl)2, (CH2) 0-6 NHC(O)H, (CH2) 0-6 NHC(O)(C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl), and (CH2) 0-6 N(C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl)C(O)(C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl), or R A1 is selected from isotopic forms of.

[0033] The substituents described may be substituted from any of the rings of A1 in the formula, and this concept is extended to more specifically described groups identified at equivalent positions. In this case, the optional substituents may be substituted at any possible position throughout the ring or the entire ring system.

[0034] In one aspect of the present disclosure, A1 is

[0035] [ka]

[0036] Selected from the group consisting of, A1 can be further replaced by any choice.

[0037] In one aspect of this disclosure, R AA These are H, halogen, CN, and C, respectively, independently. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, OH, OC 1-6 Alkyl, OC 2-6 Alkenyl and OC 2-6 Selected from a group consisting of alkynnyls.

[0038] For clarification, R AA If R is hydrogen, then in the formula AA It does not exist, and A1 is not replaced further.

[0039] In one aspect of this disclosure, one or more atoms are in isotopic form.

[0040] In one aspect of this disclosure, the isotope is deuterium.

[0041] In one aspect of this disclosure, R AA It is deuterated.

[0042] In one aspect of this disclosure, R AA C 1-6 Alkyl, OC 1-6 Alkyl, C 1-6 Haloalkyl, deuterated C 1-6 Alkyl, deuterated OC 1-6 alkyl, deuterated C 1-6 Selected from the group consisting of haloalkyls, halogens, and CN.

[0043] In one aspect of this disclosure, R AA These are F, Cl, CH3, OCH3, or CD3.

[0044] In one aspect of this disclosure, Q B teeth:

[0045] [ka]

[0046] JPEG2026510901000009.jpg147169

[0047] Selected from the group consisting of, During the ceremony, Each G that appears is independently selected from carbon or heteroatoms chosen from O, N, or S. Each m, whenever it appears, is independently chosen from 0, 1, 2, 3, 4, 5, and 6. If m is not 0, each R 100 can be substituted by any of the rings in the formula; R 100 If R 100 These are, independently, halogen, OH, oxo, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, (CH2) q -N(H or C 1-6 Alkyl), (CH2) q -OC(O)-(CH2) r -R 140 , (CH2) q -NH-C(O)-(CH2) r -R 140 , (CH2) q -OC(O)-(CH2) r -OR 140 , (CH2) q -NH-C(O)-(CH2) r -OR 140 , (CH2) q-O-(CH2) r -R 140 , (CH2) q -NH-(CH2) r -R 140 , (CH2) q -O-(CH2) r -OR 140 , (CH2) q -NH-(CH2) r -OR 140 , C 3-10 Cycloalkyl, (CH2) q -Hybrid algebra, (CH2)-- q -aryl, and (CH2) q - Selected from the group consisting of heteroaryl groups, the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally selected to be halogen, OH, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, and C 1-6 Substituted with one or more haloalkoxys R 140 It is an E3 ligase-binding ligand, q and r are independently chosen from 0, 1, 2, 3, 4, 5, and 6 each time they appear.

[0048] In one aspect of this disclosure, Q B teeth:

[0049] [ka]

[0050] It is selected from the group consisting of the following.

[0051] In one aspect of this disclosure, Q B teeth:

[0052] [ka]

[0053] And, During the ceremony, X is C(R x )2, O, NR x , or S; R x These are H and C, which are independent of each other. 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkinyls; R 2 H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, C 1-6 Alkoxy, (CH2) 0-6 -R QB1 , (CH2) 0-6 -OR QB1 , (CH2) 0-6 -N(R QB1 )2, (CH2) 0-6 -C(O)R QB1 , (CH2) 0-6 -C(O)OR QB1 , (CH2) 0-6 -C(O)N(R QB1 )2, (CH2) 0-6 -C 3-10 Cycloalkyl, (CH2) 0-6 -Aaryl, (CH2) 0-6 - Complex algebras, and (CH2) 0-6 - Selected from the group consisting of heteroaryls; R 4 H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, C 1-6 Alkoxy, (CH2) 0-6 -R QB1 , (CH2) 0-6 -OR QB1 , (CH2) 0-6 -N(R QB1 )2, (CH2)0-6 -C(O)R QB1 , (CH2) 0-6 -C(O)OR QB1 , (CH2) 0-6 -C(O)N(R QB1 )2, (CH2) 0-6 -C 3-10 Cycloalkyl, (CH2) 0-6 -Aaryl, (CH2) 0-6 - Complex algebras, and (CH2) 0-6 - Selected from the group consisting of heteroaryls; R 5 H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, C 1-6 Alkoxy, (CH2) 0-6 -R QB1 , (CH2) 0-6 -OR QB1 , (CH2) 0-6 -N(R QB1 )2, (CH2) 0-6 -C(O)R QB1 , (CH2) 0-6 -C(O)OR QB1 , (CH2) 0-6 -C(O)N(R QB1 )2, (CH2) 0-6 -C 3-10 Cycloalkyl, (CH2) 0-6 -Aaryl, (CH2) 0-6 - Complex algebras, and (CH2) 0-6 - Selected from the group consisting of heteroaryls; R 6 H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, C 1-6 Alkoxy, (CH2) 0-6 -R QB1 , (CH2)0-6 -OR QB1 , (CH2) 0-6 -N(R QB1 )2, (CH2) 0-6 -C(O)R QB1 , (CH2) 0-6 -C(O)OR QB1 , (CH2) 0-6 -C(O)N(R QB1 )2, (CH2) 0-6 -C 3-10 Cycloalkyl, (CH2) 0-6 -Aaryl, (CH2) 0-6 - Complex algebras, and (CH2) 0-6 - Selected from the group consisting of heteroaryls; R QB1 These are H, halogen, OH, and C, respectively, independently. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, C 1-6 Alkoxy, C 2-6 Alkenoxy, C 2-6 Alkinoxy, C 1-6 Haloalkoxy, C 2-6 Haloalkenoxy and C 2-6 It is alkinoxy.

[0054] In one embodiment of this disclosure, the compound is of formula A(Ia) or A(Ib):

[0055] [ka]

[0056] It is the compound shown.

[0057] In one embodiment of this disclosure, A' is a condensed aryl or heteroaryl.

[0058] In one embodiment of this disclosure, A' is selected from optionally substituted phenyl.

[0059] In one aspect of this disclosure, A' is a substituted phenyl compound.

[0060] In one aspect of this disclosure, L 1 The group consists of directly bonded heteroarylenes, optionally substituted heteroarylenes, or optionally substituted arylenes.

[0061] In one aspect of this disclosure, the optionally substituted arylene is optionally substituted phenylene.

[0062] In one embodiment of this disclosure, the optionally substituted heteroarylene is the optionally substituted pyridylene.

[0063] In one embodiment of this disclosure, optionally substituted arylenes and optionally substituted heteroarylenes are not substituted.

[0064] In one aspect of this disclosure, optionally substituted arylenes and optionally substituted heteroarylenes are, respectively, halogens, C1-C3 alkyls, C1-C3 haloalkyls, C2-C3 alkenyls, C2-C3 haloalkenyls, C2-C3 alkynyls, C2-C3 haloalkynyls, OH, O-(C 1-3 Alkyl, C 2-3 Alkenil, C 2-3 Alkinyl), NH2, NH(C) 1-3 Alkyl, C 2-3 Alkenil, C 2-3 Alkinyl), N(C 1-3 Alkyl, C 2-3 Alkenil, C 2-3 It is substituted with one or two substituents selected from the group consisting of alkynyl)2, C3 cycloalkyl, and C3 halocycloalkyl.

[0065] The compound of claim 22, wherein the optionally substituted arylene and the optionally substituted heteroarylene are each substituted with one or two substituents selected from the group consisting of halogens and C1-C3 alkyl groups.

[0066] In one aspect of this disclosure, L 2 It is NH.

[0067] In one aspect of this disclosure, R 1a and R 1b These are H, halogen, CN, and C, respectively, independently. 1-3 Haloalkyl and C 1-3 Selected from the group consisting of alkyl groups.

[0068] In one aspect of this disclosure, R 1a and R 1b Each is independently selected from the group consisting of H and CH3.

[0069] In one embodiment of this disclosure, the bond shown by the dashed line in the formula is a double bond.

[0070] Parts of one or more embodiments of this disclosure may be incorporated as described herein to produce the compounds of this disclosure. I hereby refer to the teachings and examples of synthesis disclosed in one or more of the following patent publications: WO2024 / 026423, WO2024 / 008122, WO2024 / 000401, WO2023 / 239710, WO2023 / 230262, WO2023 / 207881, WO2023 / 205680, WO2023 / 192416, WO2023 / 159155, WO2023 / 081209, WO2023 / 078401, WO2023 / 060262, WO2024 / 026419, WO2024 / 026424, and WO2021 / 202964. Each of these patent publications is incorporated herein with respect to teachings of synthesis. In certain embodiments, part Q B These may be selected from the listed publications. In a particular embodiment, part Y T The terms may be selected from the listed publications. For example, Y(R) in the formula 3a)(R 3b The part marked with ) may be selected from the published documents.

[0071] As provided in more detail herein and as will be recognized by those skilled in the art, in order to improve molecular properties (e.g., molecular weight, dipole moment, polarizability, van der Waals volume, and surface area) or bulk properties (e.g., acidity or basicity in solution, octanol / water partition coefficient, solubility), Y T You may select and prepare the compounds of this disclosure. T This is chosen to enhance hydrogen bonding ability, thereby improving selectivity for the target.

[0072] In one aspect of this disclosure, Y is N or CR 3 That is the case.

[0073] In one aspect of this disclosure, Y is either replaced or not replaced:

[0074] [ka]

[0075] It is selected from the group consisting of the following.

[0076] In one aspect of this disclosure, Y is CR 3C And CR 3C is hydrogen, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, aryl, C 3-6 Selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines.

[0077] In one aspect of this disclosure, R 3a and R 3b These are H and C, which are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, aryl, C 3-6 Selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines.

[0078] In one aspect of this disclosure, R 2 , R 4 , R 5 , and R 6 These are H, halogen, and C, respectively, independently. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, C3-C6 cycloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, or C 1-6 It is a haloalkyl group.

[0079] In one aspect of this disclosure, R 4 It is either H or CH3.

[0080] In one aspect of this disclosure, R 2 H, C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 It is alkinyl.

[0081] In one aspect of this disclosure, R 4 It is CH3.

[0082] In one aspect of this disclosure, R 5 H is H.

[0083] In one aspect of this disclosure, R 6 H is H.

[0084] One embodiment of the present disclosure is formula (AWH):

[0085] [ka]

[0086] The compound shown, or its tautomers, enantiomers, diastereomers, mixtures, salts, hydrates, solvates, or deuterated forms, WH is the warhead section; L 1 This is selected from the group consisting of directly bonded, optionally substituted cycloalkylene, optionally substituted heterocyclene, optionally substituted arylene, and optionally substituted heteroarylene; L 2 (CH2) 1-6 Selected from the group consisting of O, C(O), S, and NH; R 1a and R 1b These are H, halogen, CN, and C, respectively, independently. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl and C 1-6 Selected from the group consisting of alkoxys; or L 2 -C(R 1a )(R 1b ) combine to form NHC(S), C(S)NH, NHC(O), C(O)NH, NHS(O)2, S(O)2NH, NHC(NH), or C(NH)NH; Q B This is an optionally substituted 8-14 member spiro ring or fused ring system that optionally contains one or more heteroatoms selected from the group consisting of O, N, and S; YT is any part that yields the desired physicochemical properties; It is any E3 ligase-binding ligand.

[0087] In one embodiment of this disclosure, an optional E3 ligase-binding ligand is linked via a linker.

[0088] In one embodiment of this disclosure, WH is a ring system: Q1-Q2 Here, The ring system is L in the formula via either the Q1 or Q2 portion. 1 It is connected, Q1 is an optionally substituted 5 or 6-membered ring having one or more degrees of unsaturation and optionally containing one or more heteroatoms selected from B, N, O, or S; Q2 is a condensed, optionally substituted 5 or 6-membered ring having one or more degrees of unsaturation and optionally containing one or more heteroatoms selected from B, N, O, or S; or Q1 does not exist. Q2 is an optionally substituted 5 or 6-membered ring having one or more degrees of unsaturation and optionally containing one or more heteroatoms selected from B, N, O, or S.

[0089] In one aspect of this disclosure, WH is optionally replaced: Group (a): Cyclohexenone derivatives, alkyl halide derivatives, sulfonyl derivatives, α-cyanoenone derivatives, and epoxide or spiroepoxide derivatives; Group (b):

[0090] [ka]

[0091] and Group (c):

[0092] [ka]

[0093] They are selected from among them.

[0094] In one embodiment of this disclosure, optionally substituted means deuterium, halogen, haloalkyl, R', OR', OH, SH, SR', NO2, CN, C(O)R', NH2, C(O)OR', OC(O)R', CON(R')2, OOC(O)N(R')2, NH2, NHR', N(R')2, NHCOR', NHCOH, NHCONH2, NHCONHR', NHCON(R')2, NRCOR', NRCOH, NHCO2H, NHCO2R', NHC(S)NH2, NHC(S)NHR', NHC(S)N(R')2, CO2R', CO2H, CHO, CONH2, CONHR', CON(R')2 The group is substituted with one or more substituents selected from the group consisting of S(O)2H, S(O)2R', SO2NH2, S(O)H, S(O)R', SO2NHR', SO2N(R')2, NHS(O)2H, NR'S(O)2H, NHS(O)2R', NR'S(O)2R', Si(R')3, =O, =S, =NNHR', =NNH2, =NN(R')2, =N-OR', =N-OH, =NNHCOR', =NNHCOH, =NNHCO2R', =NNHCO2H, =NNHSO2R', =NNHSO2H, =NNHSO2H, =N-CN, =NH, =NR', and each of the aforementioned groups is a divalent alkylene linker (CH2). x (x may be bonded via 1, 2, or 3), and each instance of R' may be identical or different, representing hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, or, if two R's are bonded to a nitrogen atom, they may form a saturated or unsaturated heterocycle containing 4 to 6 ring atoms.

[0095] In one aspect of this disclosure, Q1-Q2 are:

[0096] [ka]

[0097] Selected from,

[0098] [ka]

[0099] In the formula, each A' is a monocyclic cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; Each of the heterocyclyl rings or heteroaryl rings comprises one or more heteroatoms selected from N, O, and S; Each can choose one or more Rs. A1 Replaced with R A1 These are, independently, halogen, OH, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, (CH2) 0-6 CN, (CH2) 1-6 OH, (CH2) 0-6 OC 1-6 Alkyl, (CH2) 0-6 OC 2-6 Alkenyl, (CH2) 0-6 OC 2-6 Alkinyl, (CH2) 0-6 C(O)H, (CH2) 0-6 C(O)(C 1-6 Alkyl, C 2-6 Alkenyl, or C 1-6 Alkinyl), (CH2) 0-6 C(O)OH, (CH2) 0-6 C(O)O(C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkinyl), (CH2) 0-6 NH2, (CH2) 0-6 NH(C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkinyl), (CH2) 0-6 N(C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkinyl)2, (CH2) 0-6 C(O)NH2, (CH2) 0-6 C(O)NH(C1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkinyl), (CH2) 0-6 C(O)N(C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkinyl)2, (CH2) 0-6 NHC(O)H, (CH2) 0-6 NHC(O)(C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkinyl, and (CH2) 0-6 N(C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkinyl)C(O)(C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkinyl) or R A It is selected from the isotopic forms.

[0100] In one aspect of this disclosure, A' is aryl.

[0101] In one aspect of this disclosure, A' is phenyl.

[0102] In one aspect of this disclosure, A' is a heterocyclyl.

[0103] In one embodiment of this disclosure, A' is a heteroaryl.

[0104] In one embodiment of the present disclosure, the heteroaryl is a 5- or 6-membered heteroaryl comprising one or two heteroatoms selected from N, O, and S.

[0105] In one aspect of this disclosure, Q B This is an oxosubstituted 6,6 fused ring containing one or more heteroatoms selected from O, N, or S.

[0106] In one aspect of this disclosure, Q B teeth,

[0107] [ka]

[0108] JPEG2026510901000020.jpg147169

[0109] Selected from, During the ceremony, Each G that appears is independently selected from carbon or heteroatoms chosen from O, N, or S. Each m, whenever it appears, is independently chosen from 0, 1, 2, 3, 4, 5, and 6. R 100 These are, independently, halogen, OH, oxo, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, C 1-6 Alkoxy, (CH2) q -N(H or C 1-6 Alkyl), (CH2) q -OC(O)-(CH2) r -R 140 , (CH2) q -NH-C(O)-(CH2) r -R 140 , (CH2) q -OC(O)-(CH2) r -OR 140 , (CH2) q -NH-C(O)-(CH2) r -OR 140 , (CH2) q -O-(CH2) r -R 140 , (CH2) q -NH-(CH2) r -R 140 , (CH2) q -O-(CH2) r -OR 140 , (CH2) q -NH-(CH2)r -OR 140 , C 3-10 Cycloalkyl, (CH2) q -Hybrid algebra, (CH2)-- q -aryl, and (CH2) q - Selected from the group consisting of heteroaryl groups, the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally selected to be halogen, OH, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, and C 1-6 It may be substituted with one or more haloalkoxys. R 140 It is an E3 ligase-binding ligand, q and r are independently chosen from 0, 1, 2, 3, 4, 5, and 6 each time they appear.

[0110] In one aspect of this disclosure, Q B teeth:

[0111] [ka]

[0112] They are selected from among them.

[0113] In one aspect of this disclosure, at least one R 100 is Q B It is substituted for N in the formula.

[0114] In one aspect of this disclosure, Y T YR 3a R 3b and; Y is H, CR 3c , N, O, or S; If Y is H, then R 3a and R 3b None of them exist. If Y is N, R 3a and R 3b These are H and C, which are independent of each other. 1-6Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, aryl, C 3-6 Selected from the group consisting of cycloalkyls and 3-6 membered heterocyclines; or Y is an N atom, R 3a and R 3b It combines with to form a heterocyclic or heterocyclic aromatic monocyclic, spirocyclic, or fused ring system, the ring or ring system may additionally contain one or more heteroatoms selected from the group consisting of N, O, and S, and the ring or ring system may be optionally substituted; Y is CR 3c If that is the case, R 3c It does not exist, or hydrogen, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, aryl, C 3-6 Selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines; R 3a and R 3b These are H and C, which are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, aryl, C 3-6 Selected from the group consisting of cycloalkyls and 3-6 membered heterocyclines; or Y is a C atom, R 3a and R 3bIt combines with to form a cycloalkyl, aryl, heterocyclic, or heterocyclic aromatic monocyclic, spirocyclic, or fused ring system, wherein the heterocyclic ring and heterocyclic aromatic ring contain one or more heteroatoms selected from the group consisting of N, O, and S, and the ring or ring system containing Y is optionally substituted; or If Y is O or S, then R 3a It does not exist, R 3b H, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from a group consisting of alkynnyls.

[0115] In one aspect of this disclosure, YR 3a R 3b When a ring is formed, the ring consists of deuterium, halogen, haloalkyl, R', OR', OH, SH, SR', NO2, CN, C(O)R', NH2, C(O)OR', OC(O)R', CON(R')2, OC(O)N(R')2, NH2, NHR', N(R')2, NHCOR', NHCOH, NHCONH2, NHCONHR', NHCON(R')2, NRCOR', NRCOH, NHCO2H, NHCO2R', NHC(S)NH2, NHC(S)NHR', NHC(S)N(R')2, CO2R', CO2H, CHO, CONH2, CONHR', CON(R')2, S(O) The group is optionally substituted with one or more substituents selected from the group consisting of 2H, S(O)2R', SO2NH2, S(O)H, S(O)R', SO2NHR', SO2N(R')2, NHS(O)2H, NR'S(O)2H, NHS(O)2R', NR'S(O)2R', Si(R')3, =O, =S, =NNHR', =NNH2, =NN(R')2, =N-OR', =N-OH, =NNHCOR', =NNHCOH, =NNHCO2R', =NNHCO2H, =NNHSO2R', =NNHSO2H, =NNHSO2H, =N-CN, =NH, =NR', and each of the aforementioned groups is a divalent alkylene linker (CH2). x(x may be bonded via 1, 2, or 3), and each instance of R' may be identical or different, representing hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, or, if two R's are each bonded to a nitrogen atom, they may form a saturated or unsaturated heterocycle containing 4 to 6 ring atoms.

[0116] In one embodiment of this disclosure, the compound is (AWH2):

[0117] [ka]

[0118] The compounds shown, or their tautomers, enantiomers, diastereomers, mixtures, salts, hydrates, solvates, or deuterated forms, During the ceremony, X is C(R x )2, O, NR x , or S; R x These are H and C, which are independent of each other. 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkinyls; R 2 H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, (CH2) 0-6 -R AWH2 , (CH2) 0-6 -OR AWH2 , (CH2) 0-6 -N(R AWH2 )2, (CH2) 0-6 -C(O)R AWH2 , (CH2) 0-6 -C(O)OR AWH2 , (CH2) 0-6 -C(O)N(R AWH2 )2, (CH2) 0-6-C 3-10 Cycloalkyl, (CH2) 0-6 -Aaryl, (CH2) 0-6 - Complex algebras, and (CH2) 0-6 - Selected from the group consisting of heteroaryls; R 4 H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, (CH2) 0-6 -R AWH2 , (CH2) 0-6 -OR AWH2 , (CH2) 0-6 -N(R AWH2 )2, (CH2) 0-6 -C(O)R AWH2 , (CH2) 0-6 -C(O)OR AWH2 , (CH2) 0-6 -C(O)N(R AWH2 )2, (CH2) 0-6 -C 3-10 Cycloalkyl, (CH2) 0-6 -Aaryl, (CH2) 0-6 - Complex algebras, and (CH2) 0-6 - Selected from the group consisting of heteroaryls; R 5 H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, (CH2) 0-6 -R AWH2 , (CH2) 0-6 -OR AWH2 , (CH2) 0-6 -N(R AWH2 )2, (CH2) 0-6 -C(O)R AWH2 , (CH2) 0-6 -C(O)OR AWH2 , (CH2) 0-6 -C(O)N(R AWH2 )2, (CH2) 0-6 -C 3-10Cycloalkyl, (CH2) 0-6 -Aaryl, (CH2) 0-6 - Complex algebras, and (CH2) 0-6 - Selected from the group consisting of heteroaryls; R 6 H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, (CH2) 0-6 -R AWH2 , (CH2) 0-6 -OR AWH2 , (CH2) 0-6 -N(R AWH2 )2, (CH2) 0-6 -C(O)R AWH2 , (CH2) 0-6 -C(O)OR AWH2 , (CH2) 0-6 -C(O)N(R AWH2 )2, (CH2) 0-6 -C 3-10 Cycloalkyl, (CH2) 0-6 -Aaryl, (CH2) 0-6 - Complex algebras, and (CH2) 0-6 - Selected from the group consisting of heteroaryls; R AWH2 These are H, halogen, OH, and C, respectively, independently. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, C 1-6 Alkoxy, C 2-6 Alkenoxy, C 2-6 Alkinoxy, C 1-6 Haloalkoxy, C 2-6 Haloalkenoxy and C 2-6 It is alkinoxy.

[0119] In one aspect of this disclosure, Y is N or CR 3C That is the case.

[0120] In one aspect of this disclosure, Y is R 3a and R 3b Combined with: Cycloalkyl groups substituted with B(OH)2; A aryl compound substituted with B(OH)2; Any of the following heterocyclines, The ring or ring system contains a B atom, ii) Substituted with B(OH)2, or iii) A B atom is included, and one or more additional heteroatoms selected from O, N, or S are included, and it is substituted with an optionally substituted 4- to 6-membered ring having one or more degrees of unsaturation; or Any of the following heteroaryls, The ring or ring system contains a B atom, It is replaced by B(OH)2, or It contains a B atom, and is further substituted with an optionally substituted 4- to 6-membered ring that contains one or more heteroatoms selected from O, N, or S, and has one or more degrees of unsaturation; Forming, Each Y-ring or ring system can be optionally substituted.

[0121] In one aspect of this disclosure, Y T It is either replaced or not replaced:

[0122] [ka]

[0123] It is selected from the group consisting of the following.

[0124] In one aspect of this disclosure, Y T teeth,

[0125] [ka]

[0126] It is selected from the group consisting of the following.

[0127] In one aspect of this disclosure, Y is CR 3c And R 3c It does not exist or is H, and R 3a and R 3b These are H and C, which are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, aryl, C 3-6 Selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines.

[0128] As will be described in more detail herein and recognized by those skilled in the art, embodiments of the present invention may be defined in Warhead terms, intended to describe functional groups that enable (offer) the chemical capture of target amino acid residues on target proteins. This includes the formation of covalent or hydrogen bonds with one or more target amino acids. As one aspect of Warhead interactions, the burial of hydrophobic amino acids in the protein core is a driving force for protein folding. The degree to which amino acids interact with the solvent and the protein core is, of course, proportional to the surface area exposed to the solvent environment. The contactable surface area (ASA) or solvent-contactable surface area (SASA) refers to the surface area of ​​a biomolecule that can contact the solvent. The SASA is the surface characterized around the protein by a virtual center of the solvent sphere. As will be described in more detail herein and recognized by those skilled in the art, this disclosure refers to chemical capture, i.e., chemical bonds or other interactions that make an atom more stable by, for example, filling the valence shell of an atom. Chemical capture, i.e., Warhead interactions with target amino acids, include covalent bonds, hydrogen bonds, ionic bonds, and van der Waals interactions.

[0129] In one embodiment of this disclosure, the WH provides chemical capture of a solvent-contactable surface region of a protein.

[0130] In one aspect of this disclosure, the chemical capture is a binding interaction.

[0131] In one aspect of this disclosure, the bond interaction is a covalent bond.

[0132] In one aspect of this disclosure, the bonding interaction is a hydrogen bond.

[0133] In one embodiment of this disclosure, the solvent-contactable surface region of the protein is a contactable amino acid.

[0134] In one aspect of this disclosure, the amino acid is arginine, histidine, lysine, glutamic acid, serine, threonine, or glutamine.

[0135] In one aspect of this disclosure, the amino acid is histidine.

[0136] In one aspect of this disclosure, WH is a boron-containing warhead.

[0137] In one aspect of this disclosure, WH is a boron-free warhead.

[0138] One embodiment of this disclosure is formula (AX):

[0139] [ka]

[0140] This includes the compounds shown, or their tautomers, enantiomers, diastereomers, mixtures, salts, hydrates, solvates, or deuterated forms. During the ceremony, A10 is a 5-14 member monocyclic or fused ring system containing one or more of the following: cycloalkyl, heterocyclyl, aryl, and heteroaryl. Each heterocyclyl ring or heteroaryl ring may contain one or more heteroatoms selected from N, O, S, and B; A10 is an optional choice of one or more R A10 It may be replaced with; R A10 These are, independently, halogen, OH, and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, oxo, (CH2) 0-6 CN, (CH2) 1-6 OH, (CH2) 0-6 OC 1-6 Alkyl, (CH2) 0-6 OC 2-6 Alkenyl, (CH2) 0-6 OC 2-6 Alkinyl, (CH2) 0-6 C(O)H, (CH2) 0-6 C(O)(C 1-6 Alkyl, C 2-6 Alkenyl, or C 1-6 Alkinyl), (CH2) 0-6 C(O)OH, (CH2) 0-6 C(O)O(C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkinyl), (CH2) 0-6 NH2, (CH2) 0-6 NH(C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkinyl), (CH2) 0-6 N(C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkinyl)2, (CH2) 0-6 C(O)NH2, (CH2) 0-6 C(O)NH(C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkinyl), (CH2) 0-6 C(O)N(C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkinyl)2, (CH2) 0-6 NHC(O)H, (CH2) 0-6 NHC(O)(C1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkinyl), (CH2) 0-6 N(C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkinyl)C(O)(C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Selected from alkynyl, B(OH)2, SO2-halogens, and O-SO2-halogens; L 1 This is selected from the group consisting of directly bonded, optionally substituted arylenes, and optionally substituted heteroarylenes; L 2 The group consisting of O and NH is selected; R 1a and R 1b These are H, halogen, CN, and C, respectively, independently. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl and C 1-6 Selected from the group consisting of alkoxys; or L 2 -C(R 1a )(R 1b ) combine to form NHC(O), C(O)NH, NHS(O)2, S(O)2NH, or C(NH)NH2; X is C(R x )2, O, NR x , or S; R x These are H and C, which are independent of each other. 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkinyls; Y is H, CR 3c , N, O, or S; If Y is H, then R 3a and R 3b None of them exist. If Y is N, R 3a and R3b These are H and C, which are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, aryl, C 3-6 Selected from the group consisting of cycloalkyls and 3-6 membered heterocyclines; or Y is an N atom, R 3a and R 3b It combines with to form a heterocyclic or heterocyclic aromatic monocyclic, spirocyclic, or fused ring system, the ring or ring system may additionally contain one or more heteroatoms selected from the group consisting of N, O, and S, and the ring or ring system may be optionally substituted; Y is CR 3c If that is the case, R 3c It does not exist, or hydrogen, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, aryl, C 3-6 Selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines; R 3a and R 3b These are H and C, which are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, aryl, C 3-6 Selected from the group consisting of cycloalkyls and 3-6 membered heterocyclines; or Y is a C atom, R 3a and R 3bIt combines with to form a cycloalkyl, aryl, heterocyclic, or heterocyclic aromatic monocyclic, spirocyclic, or fused ring system, wherein the heterocyclic ring and heterocyclic aromatic ring contain one or more heteroatoms selected from the group consisting of N, O, and S, and the ring or ring system containing Y is optionally substituted; or If Y is O or S, then R 3a It does not exist, R 3b H, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkinyls; R 2 H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, C 1-6 Alkoxy, (CH2) 0-6 -R AX , (CH2) 0-6 -OR AX , (CH2) 0-6 -N(R AX )2, (CH2) 0-6 -C(O)R AX , (CH2) 0-6 -C(O)OR AX , (CH2) 0-6 -C(O)N(R AX )2, (CH2) 0-6 -C 3-10 Cycloalkyl, (CH2) 0-6 -Aaryl, (CH2) 0-6 - Complex algebras, and (CH2) 0-6 - Selected from the group consisting of heteroaryls; R 4 H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, C 1-6 Alkoxy, (CH2)0-6 -R AX , (CH2) 0-6 -OR AX , (CH2) 0-6 -N(R AX )2, (CH2) 0-6 -C(O)R AX , (CH2) 0-6 -C(O)OR AX , (CH2) 0-6 -C(O)N(R AX )2, (CH2) 0-6 -C 3-10 Cycloalkyl, (CH2) 0-6 -Aaryl, (CH2) 0-6 - Complex algebras, and (CH2) 0-6 - Selected from the group consisting of heteroaryls; R 5 H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, C 1-6 Alkoxy, (CH2) 0-6 -R AX , (CH2) 0-6 -OR AX , (CH2) 0-6 -N(R AX )2, (CH2) 0-6 -C(O)R AX , (CH2) 0-6 -C(O)OR AX , (CH2) 0-6 -C(O)N(R AX )2, (CH2) 0-6 -C 3-10 Cycloalkyl, (CH2) 0-6 -Aaryl, (CH2) 0-6 - Complex algebras, and (CH2) 0-6 - Selected from the group consisting of heteroaryls; R 6 H, halogen, CN, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, C 1-6 Alkoxy, (CH2) 0-6 -R AX , (CH2) 0-6 -OR AX , (CH2) 0-6 -N(R AX )2, (CH2) 0-6 -C(O)R AX , (CH2) 0-6 -C(O)OR AX , (CH2) 0-6 -C(O)N(R AX )2, (CH2) 0-6 -C 3-10 Cycloalkyl, (CH2) 0-6 -Aaryl, (CH2) 0-6 - Complex algebras, and (CH2) 0-6 - Selected from the group consisting of heteroaryls; R AX These are H, halogen, OH, and C, respectively, independently. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, C 1-6 Alkoxy, C 2-6 Alkenoxy, C 2-6 Alkinoxy, C 1-6 Haloalkoxy, C 2-6 Haloalkenoxy and C 2-6 It is alkinoxy.

[0141] In one aspect of this disclosure, A10 or Y(R) 3a )(R 3b At least one of the rings or ring systems is (a) having one or more B atoms in the defined ring or ring system; (b) substituted with B(OH)2; or having substituents in the ring or ring system that include B atoms.

[0142] In one aspect of this disclosure, A10 is:

[0143] [ka]

[0144] Selected from the group consisting of,

[0145] [ka]

[0146] In the formula, A' is independently a cycloalkyl, heterocyclyl, aryl, or heteroaryl; Each A10 may optionally have one or more R on any of the rings in the formula. A10 It will be replaced with.

[0147] In one aspect of this disclosure, A10 is:

[0148] [ka]

[0149] And, Each of them can optionally choose one or more Rs on any of the rings in the formula. A10 It will be replaced with.

[0150] In one aspect of this disclosure, A10 is:

[0151] [ka]

[0152] Selected from the group consisting of, R AA10 Each of them is independent of halogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, C3-C6 cycloalkyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6Haloalkynyl, OH, O-C3-C6 cycloalkyl, O-C 1-6 alkyl, O-C 2-6 alkenyl, O-C 2-6 alkynyl, and CN, or their deuterated forms, selected from the group consisting of; Each A10 may be further substituted with one or more R A10 s.

[0153] In one aspect of the present disclosure, R AA10 is F, Cl, CH3, OCH3, or CD3.

[0154] In one aspect of the present disclosure, A10 is not further substituted.

[0155] In one aspect of the present disclosure, A10 is further substituted with one or more R A10 s, and each R A10 is independently selected from the group consisting of halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-C6 cycloalkyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, OH, O-C 1-6 alkyl, O-C 2-6 alkenyl, and O-C 2-6 alkynyl.

[0156] In one aspect of the present disclosure, L 1 is: Substituted or unsubstituted arylene; or, Substituted or unsubstituted heteroarylene.

[0157] L 1 is: Substituted or unsubstituted phenylene; or, The compound of any one of claims 69 to 77, which is a substituted or unsubstituted 5- to 10-member heteroarylene having one or more heteroatoms selected from N, O, and S.

[0158] In one embodiment of the present disclosure, L 1 is substituted or unsubstituted phenylene; or substituted or unsubstituted pyridinylene.

[0159] In one embodiment of the present disclosure, L 1 is halogen, C 1- C3 alkyl, C 1- C3 haloalkyl, C 2- C3 alkenyl, C 2- C3 haloalkenyl, C 2- C3 alkynyl, C 2- C3 haloalkynyl, OH, O-(C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl), NH2, NH(C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl), N(C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl)2, C3 cycloalkyl, and C3 halocycloalkyl, substituted with one or more thereof.

[0160] In one embodiment of the present disclosure, L 1 is substituted with one or more of halogen or C1-C3 alkyl.

[0161] In one embodiment of the present disclosure, X is oxygen.

[0162] In one embodiment of the present disclosure, Y is N or CR 3C is.

[0163] In one embodiment of the present disclosure, Y is CR 3c ; R 3c is H, R 3a and R 3bThese are H and C, which are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, aryl, C 3-6 It is selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines.

[0164] In one aspect of this disclosure, Y is R 3a and R 3b Combined with: Cycloalkyl groups substituted with B(OH)2; A aryl compound substituted with B(OH)2; Any of the following heterocyclines, The ring or ring system contains a B atom, ii) Substituted with B(OH)2, or iii) A B atom is included, and one or more additional heteroatoms selected from O, N, or S are included, and it is substituted with an optionally substituted 4- to 6-membered ring having one or more degrees of unsaturation; or Any of the following heteroaryls, The ring or ring system contains a B atom, It is replaced by B(OH)2, or It contains a B atom, and is further substituted with an optionally substituted 4- to 6-membered ring that contains one or more heteroatoms selected from O, N, or S, and has one or more degrees of unsaturation; Forming, Each Y-ring or ring system can be optionally substituted.

[0165] In one aspect of this disclosure, Y is nitrogen.

[0166] In one aspect of this disclosure, R 1a It is CH3.

[0167] In one aspect of this disclosure, R 1b H is H.

[0168] In one aspect of this disclosure, R 2 , R 4 , R 5 , and R 6 These are H, halogen, and C, respectively, independently. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, C3-C6 cycloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, or C 1-6 It is a haloalkyl group.

[0169] In one aspect of this disclosure, R 2 It is CH3.

[0170] In one aspect of this disclosure, R 4 H, C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 It is alkinyl.

[0171] In one aspect of this disclosure, R 4 It is either H or CH3.

[0172] In one aspect of this disclosure, R 5 H is H.

[0173] In one aspect of this disclosure, R 6 H is H.

[0174] In one embodiment of this disclosure, the bond shown by the dashed line in the formula is a double bond.

[0175] One embodiment of this disclosure is formula Ia or Ib:

[0176] [ka]

[0177] This includes the compounds shown, or their tautomers, enantiomers, diastereomers, mixtures, salts, hydrates, solvates, or deuterated forms. A is an aryl ring or a heteroaryl ring, and together with the boron ring in the formula, forms a fused ring system containing the boron-containing ring in the formula, and this fused ring system is optionally substituted with one or more R A ; R A are each independently halogen, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, (CH2) 0-6 CN, (CH2) 1-6 OH, (CH2) 0-6 O-C 1-6 alkyl, (CH2) 0-6 O-C 2-6 alkenyl, (CH2) 0-6 O-C 2-6 alkynyl, (CH2) 0-6 C(O)H, (CH2) 0-6 C(O)(C 1-6 alkyl, C 2-6 alkenyl, or C 1-6 alkynyl), (CH2) 0-6 C(O)OH, (CH2) 0-6 C(O)O(C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl), (CH2) 0-6 NH2, (CH2) 0-6 NH(C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl), (CH2)​​​​​​​​​​​​​​​​​​​​​​2-6 Alkenyl, or C 2-6 Alkinyl)2, (CH2) 0-6 NHC(O)H, (CH2) 0-6 NHC(O)(C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkinyl, and (CH2) 0-6 N(C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkinyl)C(O)(C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Selected from the alkynyl form or its deuterated form; L 1 This is selected from the group consisting of directly bonded, optionally substituted arylenes, and optionally substituted heteroarylenes; L 2 The group consisting of O and NH is selected; R 1a and R 1b These are H, halogen, CN, and C, respectively, independently. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl and C 1-6 Selected from the group consisting of alkoxys; X is C(R x )2, O, NR x , or S; R x These are H and C, which are independent of each other. 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from the group consisting of alkinyls; R 2 , R 4 , R 5 , and R 6 These are H, halogen, and C, respectively, independently. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, C3-C6 cycloalkyl, C 2-6 Haloalkenil, C 2-6Haloalkynyl, or C 1-6 It is a haloalkyl; Y is N or CR 3a and; If Y is N, R 3a and R 3b These are H and C, which are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, aryl, C 3-6 Selected from the group consisting of cycloalkyls and 3-6 membered heterocyclines; or R 3a and R 3b It bonds with an N atom to form a heterocyclic or heterocyclic aromatic monocyclic, spirocyclic, or fused ring system, which may further contain one or more heteroatoms selected from the group consisting of N, O, and S, and which may be optionally substituted; Y is CR 3c If that is the case, R 3c It does not exist, or hydrogen, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, aryl, C 3-6 Selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines; R 3a and R 3b These are H and C, which are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, aryl, C 3-6 Selected from the group consisting of cycloalkyls and 3-6 membered heterocyclines; or R3a and R 3b It bonds with a C atom to form a cycloalkyl, aryl, heterocyclic, or heterocyclic aromatic monocycle, spirocycle, or fused ring system, and the heterocyclic ring and heterocyclic aromatic ring contain one or more heteroatoms selected from the group consisting of N, O, and S, and the ring or ring system containing Y is optionally substituted.

[0178] If an unbonded valency exists in one or more compounds of this disclosure, such unbonded valency may be considered as hydrogen or an optional substituent as defined herein.

[0179] In one embodiment of this disclosure, A is a phenyl ring.

[0180] In one aspect of this disclosure, R A It does not exist.

[0181] In one aspect of this disclosure, a condensed ring system is one R A It has been replaced with.

[0182] In one aspect of this disclosure, a condensed ring system has two R A It has been replaced with.

[0183] In one aspect of this disclosure, R A Each is independent of C 1-6 Alkyl, OC 1-6 Alkyl, C 1-6 Selected from the group consisting of haloalkyls, halogens, or their deuterated forms.

[0184] In one aspect of this disclosure, R A Each of these is independently selected from the group consisting of halogen, CD3, CH3, OCH3, and CF3.

[0185] In one aspect of this disclosure, L 1 is phenylene that has been optionally substituted.

[0186] In one aspect of this disclosure, L 1is one or more halogens or C 1-6 It is alkyl-substituted phenylene.

[0187] In one aspect of this disclosure, L 1 This is a heteroarylene that has been optionally substituted.

[0188] In one aspect of this disclosure, L 1 This is pyridinylene that has been optionally substituted.

[0189] In one aspect of this disclosure, L 1 is one or more halogens or C 1-6 It is an alkyl-substituted pyridinylene.

[0190] In one aspect of this disclosure, L 1 It is replaced by one or two halogens.

[0191] In one aspect of this disclosure, the pyridinylene is:

[0192] [ka]

[0193] The fused rings are joined as shown, and in either case, the fused rings in the formula can be one or more R of any choice. A It will be replaced with.

[0194] In one embodiment of this disclosure, L in the formula 1 The part is,

[0195] [ka]

[0196] In the fused ring system shown, the B atom in the formula is substituted at the para position.

[0197] In one embodiment of this disclosure, L in the formula 1 The part is,

[0198] [ka]

[0199] In the fused ring system shown, the B atom in the formula is substituted at the meta position.

[0200] In one aspect of this disclosure, L 2 It is NH.

[0201] In one aspect of this disclosure, R 1a H is R 1b These are independently H, halogen, CN, and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl and C 1-6 Selected from the group consisting of alkoxys.

[0202] In one aspect of this disclosure, R 1b is C 1-6 It is alkyl.

[0203] In one aspect of this disclosure, R 1b It is methyl.

[0204] In one embodiment of this disclosure, the chiral center is

[0205] [ka]

[0206] As shown, it is in the R configuration.

[0207] In one aspect of this disclosure, X is O.

[0208] In one aspect of this disclosure, Y is CH, R 3a and R 3b These are C 1-6 Alkyl, C 2-6Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, aryl, C 3-6 Selected from the group consisting of cycloalkyls and 3-6 membered heterocyclines; or Y is CH, R 3a and R 3b It combines with to form a cycloalkyl or heterocyclic monocyclic system containing one heteroatom selected from N and O.

[0209] In one embodiment of this disclosure, Y is CH and R 3a and R 3b These are C 1-3 It is alkyl.

[0210] In one aspect of this disclosure, R 3a and R 3b These are each CH3.

[0211] In one aspect of this disclosure, R 2 It is CH3.

[0212] In one aspect of this disclosure, R 4 H, C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 It is alkinyl.

[0213] In one aspect of this disclosure, R 4 It is either H or CH3.

[0214] In one aspect of this disclosure, R 5 H is H.

[0215] In one aspect of this disclosure, R 6 H is H.

[0216] In one embodiment of this disclosure, the bond shown by the dashed line in the formula is a double bond.

[0217] One embodiment of this disclosure is formula Xa or Xb:

[0218] [ka]

[0219] This includes the compounds shown, or their tautomers, enantiomers, diastereomers, mixtures, salts, hydrates, solvates, or deuterated forms. During the ceremony, m is independently 0, 1, 2, 3, 4, or 5; R XA Each of them is independent of halogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, and C 3-6 Selected from cycloalkyl or their deuterated forms, L 10 This is selected from the group consisting of directly bonded, optionally substituted arylenes, or optionally substituted heteroarylenes; L 20 It is selected from the group consisting of O and NH; R 10 H and C 1-6 Selected from the group consisting of alkyl groups; R 20 These are H, halogens, C1-C6 haloalkyls, and C 1-6 Selected from the group consisting of alkyl groups; R 30 C is replaced by H or of any choice. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Selected from the group consisting of cycloalkyl, N(C1-C6 alkyl), 6-membered aryl, 5- or 6-membered heteroaryl, or 3- to 10-membered heterocyclyl; R 40 H and C 1-6 Selected from the group consisting of alkyl groups.

[0220] In one aspect of this disclosure, L 10 is phenylene that has been optionally substituted.

[0221] In one aspect of this disclosure, L 10 This is phenylene substituted with one or more halogens.

[0222] In one aspect of this disclosure, L 10 This is a heteroarylene that has been optionally substituted.

[0223] In one aspect of this disclosure, L 10 This is pyridinylene that has been optionally substituted.

[0224] In one aspect of this disclosure, L 10 It is a pyridinylene substituted with one or more halogens.

[0225] In one embodiment of this disclosure, the compound is

[0226] [ka]

[0227] It will be replaced by an optional choice.

[0228] In one aspect of this disclosure, L 20 It is NH.

[0229] In one aspect of this disclosure, R 10 is C 1-6 It is alkyl.

[0230] In one aspect of this disclosure, R 10 It is CH3.

[0231] In one aspect of this disclosure, R 20 is C 1-6 It is alkyl.

[0232] In one aspect of this disclosure, R20 It is CH3.

[0233] In one aspect of this disclosure, R 40 is C 1-6 It is alkyl.

[0234] In one aspect of this disclosure, R 40 It is CH3.

[0235] In one aspect of this disclosure, R 30 is an aryl, heteroaryl, or heterocyclyl that has been optionally substituted.

[0236] In one embodiment of the present disclosure, the optionally substituted heterocyclyl comprises 3 to 6 ring atoms, one or two of which are independently selected from the group consisting of nitrogen and oxygen.

[0237] In one aspect of this disclosure, the optionally substituted heterocyclyl is optionally substituted piperidinil.

[0238] In one aspect of this disclosure, the optionally substituted piperidinyl is gem-dimethyl-substituted piperidinyl.

[0239] In one aspect of this disclosure, the optionally substituted heterocyclyl is optionally substituted morpholinil.

[0240] In one embodiment of the present disclosure, the optionally substituted heterocyclyl comprises 3 to 6 ring atoms, one of which is oxygen.

[0241] In one aspect of this disclosure, R 30 is replaced by :C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 It is alkinyl.

[0242] In one embodiment of this disclosure, the compound is of formula XI:

[0243] [ka]

[0244] It is the compound shown.

[0245] In one embodiment of this disclosure, the compound is of formula XII:

[0246] [ka]

[0247] It is the compound shown.

[0248] In one embodiment of this disclosure, the compound is of formula XIII:

[0249] [ka]

[0250] It is the compound shown.

[0251] One embodiment of this disclosure is,

[0252] [ka]

[0253] JPEG2026510901000041.jpg255165

[0254] JPEG2026510901000042.jpg255166

[0255] JPEG2026510901000043.jpg255166

[0256] JPEG2026510901000044.jpg255163

[0257] JPEG2026510901000045.jpg255167

[0258] JPEG2026510901000046.jpg255164

[0259] JPEG2026510901000047.jpg255167

[0260] JPEG2026510901000048.jpg251169

[0261] JPEG2026510901000049.jpg241169

[0262] JPEG2026510901000050.jpg255163

[0263] JPEG2026510901000051.jpg255164

[0264] JPEG2026510901000052.jpg249169

[0265] JPEG2026510901000053.jpg255163

[0266] JPEG2026510901000054.jpg117169

[0267] This includes compounds selected from the group consisting of the following, or their tautomers, enantiomers, diastereomers, mixtures, salts, hydrates, solvates, or deuterated forms.

[0268] In one embodiment of this disclosure, the compound is a racemic mixture.

[0269] In one aspect of this disclosure, the compound is a single stereoisomer that substantially does not include other forms.

[0270] In one aspect of this disclosure, the stereoisomer is R.

[0271] In one aspect of this disclosure, the compound is a preferred equilibrium tautomer.

[0272] One embodiment of the present disclosure includes a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present disclosure and a pharmaceutically acceptable excipient.

[0273] One embodiment of the present disclosure includes a method for inhibiting cell proliferation, which involves contacting cells with an effective amount of the compound of the present disclosure.

[0274] One embodiment of the present disclosure includes a method for treating cancer in a patient, comprising administering a therapeutically effective dose of the compound of the present disclosure to a patient in need thereof.

[0275] One embodiment of the present disclosure includes a method for treating a PI3K-mediated disease or disorder, comprising administering a therapeutically effective dose of the compound of the present disclosure to a patient in need of treatment.

[0276] One embodiment includes a method for treating a disease or disorder mediated by one or more PIK3CA genes, comprising regulating one or more wild-type or mutant PIK3CA genes. The scope of this disclosure includes all other isoforms.

[0277] One embodiment involves regulating a single mutation.

[0278] One embodiment involves regulating two or more mutations.

[0279] One embodiment includes modifying the wild type.

[0280] In one embodiment, the PIK3CA is a PIK3CA mutant.

[0281] In one embodiment, the PIK3CA mediates cancer.

[0282] In one embodiment, the PIK3CA controls the development, progression, or metastasis of cancer.

[0283] In one embodiment, the one or more mutations are any of the p110 mutations.

[0284] In one embodiment, the one or more mutations are selected from one or more mutations of H1047, E545, E542, N345, E726, C420, Q546, G118, E453, Q546, G1049, M1043, K111, E81, N1044, and E110.

[0285] In one embodiment, the one or more mutations are selected from one or more mutations of H1047, E545, and E542.

[0286] In one embodiment, regulation is inhibition.

[0287] In one embodiment, regulation involves selectively inhibiting one or more mutations relative to the wild type.

[0288] In one embodiment, the mutation is selected from H1047X, E545X, and E542X.

[0289] In one embodiment, the mutation is H1047X.

[0290] In one embodiment, the mutation is H1047L.

[0291] In one embodiment, the mutation is H1047R.

[0292] In one embodiment, the mutation is E545X.

[0293] In one embodiment, the mutation is E545K.

[0294] In one embodiment, the mutation is E542X.

[0295] In one embodiment, the mutation is E542K.

[0296] In one embodiment, the method further includes the compound chemically capturing a solvent-contactable surface region of the protein.

[0297] In one embodiment, the solvent-contactable surface region includes one or more amino acid residues.

[0298] In one embodiment, the amino acid residue is selected from one or more of arginine, histidine, lysine, glutamic acid, serine, threonine, or glutamine.

[0299] In one embodiment, the amino acid residue is histidine.

[0300] In one embodiment, the histidine is HIS1048.

[0301] In one embodiment, chemical capture is an interaction.

[0302] In one embodiment, the interaction is a bond.

[0303] In one aspect, the bond is a covalent bond.

[0304] In one embodiment, the bond is a hydrogen bond.

[0305] In one embodiment, the method further comprises administering the compound of the present disclosure.

[0306] One embodiment of the present disclosure includes a method for inhibiting intracellular PI3K activity, which involves modifying the solvent-contactable surface region of a protein using the compounds of the present disclosure.

[0307] In one embodiment, the adjustment is performed in vitro.

[0308] In one embodiment, the adjustment is performed in vivo.

[0309] In one embodiment, the PI3K target gene is PIK3CA.

[0310] In one embodiment, PI3K is PI3Kα.

[0311] In one embodiment, the PI3Kα is a PI3Kα mutant.

[0312] In one embodiment, the PI3Kα is the PI3Kα wild type.

[0313] In one embodiment, the PI3K mediates cancer.

[0314] In one embodiment, the PI3K controls the onset, progression, or metastasis of cancer.

[0315] In one embodiment, the one or more mutations are selected from one or more mutations of H1047, E545, E542, N345, E726, C420, Q546, G118, E453, Q546, G1049, M1043, K111, E81, N1044, and E110.

[0316] In one embodiment, the one or more mutations are selected from one or more mutations of H1047, E545, and E542.

[0317] In one embodiment, regulation is inhibition.

[0318] In one embodiment, regulation means selective inhibition of the wild type, resulting in preferential inhibition at multiple levels: greater than 1, from about 1.5 to about 20 or more, and from about 1.5 to about 100 or more.

[0319] In one embodiment, the mutation is selected from H1047X, E545X, and E542X.

[0320] In one embodiment, the mutation is H1047X.

[0321] In one embodiment, the mutation is H1047L.

[0322] In one embodiment, the mutation is H1047R.

[0323] In one embodiment, the mutation is GLU545X.

[0324] In one embodiment, the mutation is E545K.

[0325] In one embodiment, the mutation is GLU542X.

[0326] In one embodiment, the mutation is E542K.

[0327] One embodiment further includes the compound chemically capturing a solvent-contactable surface region of the protein.

[0328] In one embodiment, the solvent-contactable surface region includes one or more amino acid residues.

[0329] In one embodiment, the amino acid residue is selected from one or more of arginine, histidine, lysine, glutamic acid, serine, threonine, or glutamine.

[0330] In one embodiment, the amino acid residue is histidine.

[0331] In one embodiment, histidine is H1048.

[0332] In one embodiment, chemical capture is an interaction.

[0333] In one embodiment, the interaction is a bond.

[0334] In one aspect, the bond is a covalent bond.

[0335] In one embodiment, the bond is a hydrogen bond.

[0336] One embodiment of the present disclosure includes a method for inhibiting PI3K, which involves chemically capturing a solvent-contactable surface region and modulating a p110 mutant protein subunit.

[0337] In one embodiment, the solvent-contactable surface region includes one or more amino acid residues.

[0338] In one embodiment, the amino acid residue is selected from one or more of arginine, histidine, lysine, glutamic acid, serine, threonine, or glutamine.

[0339] In one embodiment, the amino acid residue is histidine.

[0340] In one embodiment, histidine is H1048.

[0341] In one embodiment, chemical capture is an interaction.

[0342] In one embodiment, the interaction is a bond.

[0343] In one aspect, the bond is a covalent bond.

[0344] In one embodiment, the bond is a hydrogen bond.

[0345] In one embodiment, the p110 mutant protein subunit contains at least one amino acid mutation compared to the wild-type p110 protein subunit.

[0346] In one embodiment, the at least one amino acid mutation is selected from one or more mutations of H1047, E545, E542, N345, E726, C420, Q546, G118, E453, Q546, G1049, M1043, K111, E81, N1044, and E110.

[0347] In one embodiment, the one or more mutations are selected from one or more of H1047, E545, and E542.

[0348] One embodiment includes administering the compounds of the present disclosure.

[0349] One embodiment of the present disclosure includes a method for treating a disease or disorder mediated by PI3Kα, comprising chemically capturing a solvent-contactable amino acid residue and modulating one or more of H1047X, E545X, and E542X.

[0350] In one embodiment, the amino acid residue is selected from one or more of arginine, histidine, lysine, glutamic acid, serine, threonine, or glutamine.

[0351] In one embodiment, the amino acid residue is histidine.

[0352] In one embodiment, the histidine is HIS1048.

[0353] In one embodiment, chemical capture is an interaction.

[0354] In one embodiment, the interaction is a bond.

[0355] In one aspect, the bond is a covalent bond.

[0356] In one embodiment, the bond is a hydrogen bond.

[0357] One embodiment includes adjusting one or more of H1047L and H1047R.

[0358] One embodiment includes adjusting the GLU545K.

[0359] One embodiment includes adjusting the GLU542K.

[0360] One embodiment includes administering the compounds of the present disclosure.

[0361] One embodiment of the present disclosure includes a method for inhibiting PIK3CA gene target protein (PI3K), comprising modulating two or more mutant variants selected from mutations in H1047, E545, E542, N345, E726, C420, Q546, G118, E453, Q546, G1049, M1043, K111, E81, N1044, and E110.

[0362] In one embodiment, the two or more mutant variants are selected from the H1047, E545, and E542 mutations.

[0363] One embodiment of the present disclosure includes a method for treating a disease or disorder mediated by PIK3CA, comprising modulating two or more mutant variants selected from mutations in H1047, E545, E542, N345, E726, C420, Q546, G118, E453, Q546, G1049, M1043, K111, E81, N1044, and E110.

[0364] In one embodiment, the two or more mutant variants are selected from the H1047, E545, and E542 mutations.

[0365] One embodiment includes administering the compounds of the present disclosure.

[0366] One embodiment of the present disclosure includes a method for treating a disease or disorder by modulating PI3K by interacting the compound of the present disclosure with at least two variants.

[0367] In one embodiment, the PI3K gene target is PIK3CA.

[0368] In one embodiment, the PI3K mediates cancer.

[0369] In one embodiment, the PI3K controls the onset, progression, or metastasis of cancer.

[0370] In one embodiment, the mutant variant is selected from mutations of H1047, E545, E542, N345, E726, C420, Q546, G118, E453, Q546, G1049, M1043, K111, E81, N1044, and E110.

[0371] In one embodiment, the mutant variant is selected from one or more mutations of H1047, E545, and E542.

[0372] In one embodiment, regulation is inhibition.

[0373] In one embodiment, the regulation is selective inhibition of the wild type.

[0374] In one embodiment, the mutation is H1047X.

[0375] In one embodiment, the mutation is H1047L.

[0376] In one embodiment, the mutation is H1047R.

[0377] In one embodiment, the mutation is E545X.

[0378] In one embodiment, the mutation is E545K.

[0379] In one embodiment, the mutation is E542.

[0380] In one embodiment, the mutation is E542K.

[0381] One embodiment includes administering the compound of the present disclosure and capturing a solvent-contactable surface region of a protein.

[0382] In one embodiment, the solvent-contactable surface region includes one or more amino acid residues.

[0383] In one embodiment, the amino acid residue is selected from one or more of arginine, histidine, lysine, glutamic acid, serine, threonine, or glutamine.

[0384] In one embodiment, the amino acid residue is histidine.

[0385] In one embodiment, the histidine is HIS1048.

[0386] In one embodiment, chemical capture is an interaction.

[0387] In one embodiment, the interaction is a bond.

[0388] In one aspect, the bond is a covalent bond.

[0389] In one embodiment, the bond is a hydrogen bond.

[0390] In one embodiment, the present disclosure includes a method according to any one of claims 156 to 273, wherein the disease or disorder is cancer.

[0391] In one embodiment, the disease or disorder is a PIK3CA-related overgrowth spectrum (PROS).

[0392] In one embodiment, the disease or disorder is breast cancer, colorectal cancer, uterine cancer, bladder cancer, lung cancer, glioma, head and neck cancer, or other solid tumors.

[0393] In one embodiment, the disease or disorder is breast cancer.

[0394] In one embodiment, the present disclosure includes a method comprising administering one or more additional therapeutic agents.

[0395] In one embodiment, administration involves administering two or more additional therapeutic agents.

[0396] In one embodiment, the additional therapeutic agent is selected from selective estrogen receptor degraders, Protac-mediated estrogen receptor inhibitors, complete estrogen receptor antagonists, sarcoplasmic reticulum calcium ATPase inhibitors, CDK2 / 4 / 6 inhibitors, CDK4 / 6 inhibitors, and aromatase inhibitors.

[0397] In one embodiment, the additional therapeutic agent is selected from fulvestrant, bepdegestrant, parazestrant, imurunestrant, elastrant, giredestrant, camizestrant, palbociclib, ribociclib, abemaciclib, anastrozole, exemestane, and letrozole.

[0398] In one embodiment, each drug is provided in a separate dosage form.

[0399] In one embodiment, one or more drugs are provided in a compound dosage form.

[0400] In one embodiment, the disclosure includes a method for controlling one or more disease onset and progression by modulating one or more PI3K enzymes, comprising interaction with at least one histidine and modification of at least one surface-contactable amino acid or residue.

[0401] In one embodiment, one or more PI3Ks are inhibited.

[0402] In one embodiment, PI3K is PI3Kα.

[0403] In one embodiment, PI3Kα is a mutant variant thereof.

[0404] In one embodiment, the present disclosure includes a method for treating cancer in a patient requiring cancer treatment, the method being: To determine whether cancer is associated with PI3K wild-type or one or more PI3K mutations; and This includes administering a therapeutically effective dose of the compound of this disclosure to a patient.

[0405] In one embodiment, PI3K is a mutant variant thereof.

[0406] In one embodiment, the present disclosure includes compounds of the present disclosure for use in therapy.

[0407] In one embodiment, the Disclosure includes compounds of the Disclosure for use in the treatment of cancer.

[0408] In one embodiment, the present disclosure includes compounds of the present disclosure for use in inhibiting PI3K.

[0409] In one embodiment, PI3K is PI3Kα.

[0410] In one embodiment, the PI3Kα is wild-type.

[0411] In one embodiment, PI3Kα is a mutant variant thereof.

[0412] In one embodiment, the disclosure includes the use of the compounds of the disclosure in the manufacture of a pharmaceutical product for the treatment of cancer.

[0413] In one embodiment, the disclosure includes the use of the compounds of the disclosure in the manufacture of a pharmaceutical product that inhibits the activity of PI3K.

[0414] In one embodiment, the disclosure includes the use of the compounds of the disclosure in the manufacture of a pharmaceutical product for the treatment of a disease or disorder mediated by PI3K.

[0415] In one embodiment, PI3K is PI3Kα.

[0416] In one embodiment, the PI3Kα is wild-type.

[0417] In one embodiment, PI3Kα is a mutant variant thereof.

[0418] One embodiment of the present disclosure includes a process for preparing the compounds of the present disclosure.

[0419] One embodiment of the present disclosure includes a compound obtained by the process of the present disclosure.

[0420] One embodiment of the present disclosure comprises an adduct having a warhead capable of chemically capturing a solvent-contactable surface region (SASA) of a protein. In one embodiment, the SASA comprises one or more residues of available arginine, histidine, lysine, glutamic acid, serine, threonine, and glutamine. In one embodiment, the SASA comprises a histidine residue. In one embodiment, the chemical capture is an interaction. In one embodiment, the interaction is a bond. In one embodiment, the bond is a covalent bond. In one embodiment, the bond is a hydrogen bond. In one embodiment, the warhead comprises at least one boron heteroatom. In one embodiment, the warhead comprises a ring or ring system incorporating at least one boron atom. In one embodiment, the warhead comprises at least one B(OH)2 group as a substituent. In one embodiment, the warhead does not contain a boron heteroatom. In one embodiment, the warhead is selected from cyclohexenone derivatives, alkyl halide derivatives, sulfonyl derivatives, α-cyanoenone derivatives, and epoxide or spiroepoxide derivatives.

[0421] In one embodiment, the present disclosure relates to formula XX:

[0422] [ka]

[0423] This includes the compounds shown, or their tautomers, enantiomers, diastereomers, mixtures, salts, hydrates, solvates, or deuterated forms. Q BThis includes an optionally substituted 8-14 member spiro ring system or fused ring system that optionally contains one or more heteroatoms selected from the group consisting of O, N, or S; Q A teeth XX A1- XX L 1 - XX L 2 -C( XX R 1a-XX R 1b ) and here: XX A1 is a warhead portion that provides chemical capture of the solvent-contactable surface region of the available protein; XX L 1 This is selected from the group consisting of directly bonded, optionally substituted arylenes, and optionally substituted heteroarylenes; XX L 2 It is selected from the group consisting of O and NH; XX R 1a and XX R 1b These are H, halogen, CN, and C, respectively, independently. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl and C 1-6 Selected from the group consisting of alkoxys; or or XX L 2 -C( XX R 1a )( XX R 1b ) combine to form NHC(O), C(O)NH, NHS(O)2, S(O)2NH, or C(NH)NH2; Q C teeth XX Y( XX R 3a - XX R 3b ) and here: XX Y is H, C XX R 3c , N, O, or S; XX If Y is H, XX R 3a and XX R 3b None of them exist; XX If Y is N, XX R 3a and XX R 3b These are H and C, which are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, aryl, C 3-6 Selected from the group consisting of cycloalkyls and 3-6 membered heterocyclines; or Y is represented as an N atom, XX R 3a and XX R 3b It combines with to form a heterocyclic or heterocyclic aromatic monocyclic, spirocyclic, or fused ring system, the ring or ring system may additionally contain one or more heteroatoms selected from the group consisting of N, O, and S, and the ring or ring system may be optionally substituted; Y is C XX R 3c If that is the case, XX R 3c It does not exist, or hydrogen, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, aryl, C 3-6 Selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines; XX R 3a and XX R 3b These are H and C, which are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6Alkinyl, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, aryl, C 3-6 Selected from the group consisting of cycloalkyls and 3-6 membered heterocyclines; or XX Y is a C atom, XX R 3a and XX R 3b It combines with to form a cycloalkyl, aryl, heterocyclic, or heterocyclic aromatic monocyclic, spirocyclic, or fused ring system, wherein the heterocyclic ring and heterocyclic aromatic ring contain one or more heteroatoms selected from the group consisting of N, O, and S. XX A ring or ring system containing Y may be optionally substituted; or XX If Y is O or S, XX R 3a It does not exist. XX R 3b H, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Selected from a group consisting of alkynnyls.

[0424] One embodiment of the present disclosure includes the compounds of Table 1 or their tautomers, enantiomers, diastereomers, mixtures, salts, hydrates, solvates, or deuterated forms.

[0425] [Table 1]

[0426] JPEG2026510901000057.jpg255165

[0427] JPEG2026510901000058.jpg255166

[0428] JPEG2026510901000059.jpg255166

[0429] JPEG2026510901000060.jpg228169

[0430] JPEG2026510901000061.jpg255168

[0431] JPEG2026510901000062.jpg255164

[0432] JPEG2026510901000063.jpg255163

[0433] JPEG2026510901000064.jpg253169

[0434] JPEG2026510901000065.jpg241169

[0435] JPEG2026510901000066.jpg255164

[0436] JPEG2026510901000067.jpg255162

[0437] JPEG2026510901000068.jpg250169

[0438] JPEG2026510901000069.jpg255163

[0439] JPEG2026510901000070.jpg153169

[0440] One aspect of the present disclosure includes the compounds of the present disclosure or their tautomers, enantiomers, diastereomers, mixtures, salts, hydrates, solvates, or deuterated forms, Y T Base, and Y T More specifically described bases that are located in an equivalent position are selected from Table 2.

[0441] [Table 2]

[0442] One aspect of the present disclosure includes the compounds of the present disclosure or their tautomers, enantiomers, diastereomers, mixtures, salts, hydrates, solvates, or deuterated forms, with a linker group and L 1 -L 2 More specifically described bases that are located in an equivalent position are selected from Table 3.

[0443] [Table 3]

[0444] JPEG2026510901000073.jpg249169

[0445] JPEG2026510901000074.jpg255169

[0446] JPEG2026510901000075.jpg198169

[0447] One aspect of the present disclosure includes the compounds of the present disclosure or their tautomers, enantiomers, diastereomers, mixtures, salts, hydrates, solvates, or deuterated forms, Q B Base, and Q B More specifically described bases that are located in an equivalent position are selected from Table 4.

[0448] [Table 4]

[0449] One or more aspects and embodiments may be incorporated into different embodiments, even if not specifically described. That is, all aspects and embodiments may be combined in any way or in any combination.

[0450] [Brief explanation of the drawing] Figure 1 provides tabular biological data relating to the compounds of this disclosure.

[0451] [Detailed explanation] definition When referring to the compounds described herein, unless otherwise specified, the following terms have the meanings set forth below. The following definitions are intended to clarify, not limit, the defined terms. If a particular term used herein is not specifically defined, that term shall not be considered ambiguous. Rather, the term shall be used in the sense that is generally accepted.

[0452] As used herein, “alkyl” refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms. The hydrocarbon chain may be linear or branched. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. Similarly, an “alkenyl” group refers to an alkyl group having one or more double bonds in the chain, and an “alkynyl” group refers to an alkyl group having one or more triple bonds in the chain.

[0453] As used herein, "halogen" or "halo" refers to a halogen. In some embodiments, the halogen is preferably Br, Cl, or F.

[0454] As used herein, “haloalkyl” refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, with at least one hydrogen atom substituted with a halogen. This includes, but is not limited to, perhalo groups in which all hydrogen atoms are substituted with halogen atoms. The haloalkyl chain may be linear or branched. Exemplary alkyl groups include trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, and pentafluoroethyl. Similarly, a “haloalkenyl” group refers to a haloalkyl group having one or more double bonds in the chain, and a “haloalkynyl” group refers to a haloalkyl group having one or more triple bonds in the chain. Furthermore, an “alkylene” linker group refers to a divalent alkyl group, i.e., (CH2) x This refers to x, where x is 1 to 20, preferably 1 to 8, preferably 1 to 6, and more preferably 1 to 3.

[0455] The term "haloalkyloxy" refers to O-haloalkyl groups.

[0456] As used herein, "alkoxy" refers to an O-alkyl group having a specified number of carbon atoms.

[0457] An "alkylene" group is an alkyl group as defined above, which is located between two other chemical groups and plays a role in linking them. Exemplary alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0458] The term "heteroalkyl" refers to an alkyl group as defined above in which one or more carbon atoms in the chain are replaced by heteroatoms selected from the group consisting of O, S, and N.

[0459] As used herein, “hydroxyalkyl” means an alkyl group as defined herein that is substituted with one or more -OH groups. Similarly, “hydroxyalkenyl group” means a hydroxyalkyl group having one or more double bonds in the chain, and “hydroxyalkynyl group” means a hydroxyalkyl group having one or more triple bonds in the chain. Similarly, a “dihydroxyalkyl” group provides two -OH substituents.

[0460] As used herein, "aryl" refers to a suspended or condensed substituted or unsubstituted carbocyclic aromatic ring system, such as phenyl, naphthyl, anthracenyl, phenanthryl, tetrahydronaphthyl, indan, or biphenyl. The preferred aryl group is phenyl.

[0461] An "aralkyl" or "arylalkyl" group consists of an aryl group covalently bonded to an alkyl group as defined above, and each group may be independently and optionally substituted or left unsubstituted. An example of an aralkyl group is (C 1- C6) Alkyl (C6-C 10 Examples of substituted aralkyls include, but are not limited to, benzyl, phenethyl, and naphthylmethyl. Examples of substituted aralkyls include those in which the alkyl group is substituted with a hydroxyalkyl group.

[0462] As will be recognized by those skilled in the art, this disclosure refers to chemical capture, i.e., chemical bonding or other interactions that make an atom more stable by filling its valence shell. Covalent bonds, hydrogen bonds, ionic bonds, and van der Waals interactions differ in strength and properties. A covalent bond can generally be defined as a bond formed by the sharing of electrons between two atoms. Covalent bonds are classified into polar covalent bonds and nonpolar covalent bonds. The properties of a bond are determined by the electronegativity of the atoms in the bond. If their electronegativity is equal, the electrons are shared equally, resulting in a nonpolar covalent bond (e.g., molecular oxygen, O2). If one atom is significantly more electronegative than the other, the electrons are shared unevenly. This is a polar covalent bond (e.g., nitric oxide, NO). A hydrogen bond, as its name suggests, is a bond in which a hydrogen atom is weakly shared between two electronegative atoms. Hydrogen bonding is an example of a readily reversible electrostatic interaction. A hydrogen atom with a weak positive charge is attracted to another atom with a weak negative charge, such as fluorine, oxygen, or nitrogen. The most commonly cited example is water. Ionic bonds are formed by the electrostatic attraction between two ions with opposite charges. In biochemistry and aquatic environments, ionic bonds readily break down into their constituent ions. These ions with opposite charges are still attracted to each other by electrostatic attraction. Finally, van der Waals interactions provide the weakest interaction, resulting from the motion of electrons. Electrons are constantly in motion, which creates transient negatively charged regions (areas where electrons accumulate) or positively charged regions (areas where electrons are absent) on the surface of biomolecules. The next moment, these regions disappear and reappear elsewhere. Occasionally, complementary regions exist on one molecule, causing the two molecules to temporarily attract each other.

[0463] As will be recognized by those skilled in the art, boron can form coordinate bonds with, for example, oxygen or nitrogen under certain circumstances. Coordinate bonds are generally weaker than covalent bonds. In situations where boron forms a covalent bond with at least one oxygen or nitrogen and simultaneously forms coordinate bonds with other oxygen or nitrogen atoms, the coordinate and covalent bonds between the boron and the two identical heteroatoms may be interchangeable or may take the form of resonance hybrids. Furthermore, coordinate bonds may be reversible depending on the chemical structure and biological environment of the parent compound. For example, a reversible coordinate bond formed via a boron atom may lead to the formation of a hydrolysis product (II) or a metabolic oxidation product (III). The hydrolysis product (II) may be in equilibrium with the parent compound (I). The scope of this disclosure is intended to capture all forms. Representative examples are given below:

[0464] [ka]

[0465] There may be uncertainties regarding the exact nature and extent of electron sharing in these situations. The presented structures are intended to include all possible bonding scenarios between the boron atom and the atom bonded to it.

[0466] As used herein, “salt counterion” refers to a positively charged ion that associates with the compound of the present invention when boron is fully negatively charged or partially negatively charged. An example of a salt counterion is H + H3O + Examples include ammonium, lithium, potassium, calcium, magnesium, and sodium. Compounds containing boron bonded to carbon and three heteroatoms (such as the three oxygen atoms described in this section) can optionally contain fully negatively charged or partially negatively charged boron due to the properties of the coordination bond between boron and one of the oxygen atoms. Due to the negative charge, a positively charged counterion may associate with this compound, thereby forming a salt. An example of a positively charged counterion is H+ H3O + Examples include calcium, lithium, sodium, ammonium, potassium, and magnesium. Salts of these compounds are implicitly included in the descriptions of the compounds. The present invention also encompasses compounds that are polyvalent or complex species, such as dimers, trimers, tetramers, and more homologs of the compounds used in the present invention, or reactive analogs thereof.

[0467] As will be recognized by those skilled in the art, certain aspects of this disclosure are defined as adducts. This is intended to describe complexes formed when the compounds of this disclosure bind to biomolecules such as proteins.

[0468] Similarly, certain aspects of this disclosure are defined in Warhead's terms, which are intended to describe functional groups that enable the chemical capture of target amino acid residues on a target protein, including covalent bond formation with one or more target amino acids.

[0469] As used herein, “cycloalkyl” refers to a saturated, unsaturated, or partially saturated hydrocarbon ring containing 3 to 15 cyclic atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and partially saturated forms such as cyclohexenyl and cyclohexadienyl. Crosslinked rings such as adamantane are also included in the definition of “cycloalkyl.”

[0470] As used herein, the term “heterocyclyl” refers to an unsaturated or partially saturated hydrocarbon ring containing 3 to 15 ring atoms, one or more of which carbon atoms are substituted with heteroatoms selected from B, O, N, S, or Si, where N, S, or Si are each oxidizable, and each N is quaternizable. The heterocyclyl group may be bonded to the rest of the molecule via heteroatoms. Heterocyclyls do not include heteroaryls. Examples include, but are not limited to, aziridine, oxirane, thiirane, azetidine, oxetane, thiethane, pyrrolidine, pyrazolidine, imidazolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, thian, morpholine, thiomorpholine, pyrrolizidine, indoline, decahydroquinoline, tetrahydroquinoline, and azaadamantane.

[0471] The term "heterocyclylalkyl" refers to a heterocyclyl group, as defined herein, covalently bonded to an alkyl group, as defined herein above. In this case, the radical is on the alkyl group, and the alkyl group of the heterocyclylalkyl may be optionally substituted.

[0472] As used herein, the terms “heteroaryl” or “heterocyclic aromatic” refer to aromatic ring groups having carbon and 5 to 14 ring atoms selected from at least one (usually 1 to 4, more typically 1 or 2) heteroatoms (e.g., boron, oxygen, nitrogen, sulfur, or silicon). These include monocyclic rings and polycyclic rings in which a monocyclic heterocyclic aromatic ring is fused with one or more other carbocyclic or heterocyclic aromatic rings. Examples of monocyclic heteroaryl groups include furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), and pyrrolyl ( Examples include, but are not limited to, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyridinyl, 4-pyridinyl, 5-pyridinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl), tetrazolyl (e.g., tetrazolyl), and thienyl (e.g., 2-thienyl, 3-thienyl). Examples of monocyclic six-membered nitrogen-containing heteroaryl groups include pyrimidinyl, pyridinyl, and pyridazinyl. Examples of polycyclic aromatic heteroaryl groups include carbazolyl, benzimidazolyl, benzothienyl, benzofuranil, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzisoxazolyl.

[0473] The terms “arylalkyl,” “heteroarylalkyl,” and “heterocyclylalkyl” refer to radicals in which an aryl group, heteroaryl group, or heterocyclyl group is linked via an alkyl group. Examples include benzyl, phenethyl, and pyridylmethyl. These terms also include alkyl linking groups in which a carbon atom (e.g., a methylene group) is substituted, for example, with an oxygen atom. Examples include phenoxymethyl, pyrido-2-yloxymethyl, and 3-(naphtha-1-yloxy)propyl. Similarly, as used herein, the term “benzyl” refers to a radical in which a phenyl group is linked to a CH2 group, i.e., a CH2Ph ​​group. The benzyl group may or may not be substituted. The term substituted benzyl refers to a radical in which the phenyl group or CH2 has one or more substituents. In one embodiment, the phenyl group may have 1 to 5 substituents, and in another embodiment, it may have 2 to 3 substituents.

[0474] A "heteroarylalkyl" group includes a heteroaryl group covalently bonded to an alkyl group, where the radical is on the alkyl group and either is independently or optionally substituted or unsubstituted. Examples of heteroarylalkyl groups include heteroaryl groups having 5, 6, 9, or 10 ring atoms bonded to a C1-C6 alkyl group. Examples of heteroaryl groups include pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, thiazolylmethyl, thiazolylethyl, benzimidazolylmethyl, benzimidazolylethyl, quinazolinylmethyl, quinolinylmethyl, quinolinylethyl, benzofuranylmethyl, indolinylethyl, isoquinolinylmethyl, isoinodylmethyl, synnolinylmethyl, and benzothiophenylethyl. Compounds having adjacent cyclic oxygen and / or sulfur atoms are specifically excluded from the scope of this term.

[0475] As used herein, "optionally substituted" means that a substituent replaces a hydrogen atom that would have otherwise been present. When describing cyclic systems, optional substitutions typically involve one, two, or three substituents replacing the original hydrogen atoms. However, when referring to linear and branched chain portions, the number of substitutions is greater and can occur at any position where hydrogen would otherwise exist. Substitutions may be identical or distinct.

[0476] If there are multiple substituents, they may be the same or different. Exemplary substituents include deuterium, halogen, haloalkyl, R', OR', OH, SH, SR', NO2, CN, C(O)R', NH2, C(O)OR', OC(O)R', CON(R')2, OC(O)N(R')2, NH2, NHR', N(R')2, NHCOR', NHCOH, NHCONH2, NHCONHR', NHCON(R')2, NRCOR', NRCOH, NHCO2H, Examples include NHCO2R', NHC(S)NH2, NHC(S)NHR', NHC(S)N(R')2, CO2R', CO2H, CHO, CONH2, CONHR', CON(R')2, S(O)2H, S(O)2R', SO2NH2, S(O)H, S(O)R', SO2NHR', SO2N(R')2, NHS(O)2H, NR'S(O)2H, NHS(O)2R', NR'S(O)2R', and Si(R')3, where each of the aforementioned groups is a divalent alkylene linker (CH2) x (x may be bonded via 1, 2, or 3). In embodiments in which the saturated carbon atom is optionally substituted with one or more substituents, the substituents may be the same or different, and may include =O, =S, =NNHR', =NNH2, =NN(R')2, =N-OR', =N-OH, =NNHCOR', =NNHCOH, =NNHCO2R', =NNHCO2H, =NNHSO2R', =NNHSO2H, =N-CN, =NH, or =NR'. Each of the aforementioned groups is an alkylene linker (CH2) x(x may be bonded via 1, 2, or 3). R' is either identical or different each time it appears and represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl. Alternatively, if two R's are bonded to a nitrogen atom, they can form a saturated or unsaturated heterocycle containing 4 to 6 ring atoms.

[0477] In some embodiments of this disclosure, the heteroatom may be a boron (B) atom.

[0478] The scope of this disclosure includes isotopic versions of the compounds described herein. For example, one approach to slow the CYP-mediated metabolism of a drug or reduce the formation of undesirable metabolites involves attempting to substitute one or more hydrogen atoms with deuterium atoms. Deuterium is a safe, stable, non-radioactive hydrogen isotope. Compared to hydrogen, deuterium forms stronger bonds with carbon. In certain cases, the increased bond strength due to deuterium may positively impact the ADME properties of a drug, potentially leading to improved efficacy, safety, and / or tolerability. At the same time, because the size and shape of deuterium are essentially identical to those of hydrogen, substituting hydrogen with deuterium is not expected to affect the biochemical potency and selectivity of the drug compared to the original chemical containing only hydrogen.

[0479] Over the past 35 years, the effects of deuterium substitution on metabolic rate have only been reported for a small number of approved drugs (see, for example, Blake, MI et al, J Pharm Sci, 1975, 64:367-91; Foster, AB, Adv Drug Res 1985, 14:1-40 ("Foster"); Kushner, DJ et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, MB et al, Curr Opin Drug Discov Devel, 2006, 9:101-09 ("Fisher")). The results were variable and unpredictable. In some compounds, deuteration reduced in vivo metabolic clearance. In other compounds, no change in metabolism was observed. In yet another compound, metabolic clearance increased. Due to the variability of the deuterium effect, experts have questioned or rejected deuterium modification as a viable drug design strategy for suppressing harmful metabolism (see Foster, p. 35 and Fisher, p. 101).

[0480] The effects of deuterium modification on the metabolic properties of drugs are unpredictable, even when deuterium atoms are introduced into known metabolic sites. Only by actually preparing and testing deuterated drugs can it be determined whether, and to what extent, their metabolic rates differ from those of undeuterated control drugs. See, for example, Fukuto et al. (J. Med. Chem. 1991, 34, 2871-76). Many drugs have multiple metabolic sites. The site requiring deuterium substitution and the degree of deuteration necessary to confirm the metabolic effect (if any) vary from drug to drug.

[0481] In the compounds of this disclosure, an atom specifically designated as "H" or "hydrogen" is understood to have hydrogen at its position in the isotopic composition of its natural abundance. Unless otherwise specified, the position may be specifically designated as "D" or "deuterium," and it is understood that deuterium is present at that position at an abundance at least 3340 times that of deuterium at its natural abundance (0.015%) (i.e., the deuterium introduction rate is at least 50.1%).

[0482] As used herein, the term "isotope enrichment factor" means the ratio of the isotopic abundance to the natural abundance of a given isotope.

[0483] In other embodiments, the compounds of the present invention have an isotopic enrichment factor of at least 3500 (deuterium introduction rate of 52.5% in each of the designated deuterium atoms), at least 4000 (deuterium introduction rate of 60%), at least 4500 (deuterium introduction rate of 67.5%), at least 5000 (deuterium introduction rate of 75%), at least 5500 (deuterium introduction rate of 82.5%), at least 6000 (deuterium introduction rate of 90%), at least 6333.3 (deuterium introduction rate of 95%), at least 6466.7 (deuterium introduction rate of 97%), at least 6600 (deuterium introduction rate of 99%), or at least 6633.3 (deuterium introduction rate of 99.5%) for each of the designated deuterium atoms.

[0484] Compounds represented by a specific chemical structure containing one or more deuterium atoms also include smaller amounts of isotopologs having hydrogen atoms in one or more of the potential deuterium positions. The relative amount of such isotopologs in the compounds of this disclosure depends on a number of factors, including the isotopic purity of the deuterating reagent used in the preparation of the compound and the efficiency of deuterium introduction in the various synthetic steps used in the preparation of the compound. As described above, the relative amount of such isotopologs is less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologs as a whole is less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.

[0485] As used herein, “effective dose” of a compound means an amount sufficient to negatively modulate or inhibit the activity of PI3K or its variants. This amount may be administered as a single dose or according to a drug regimen, thereby becoming effective.

[0486] As used herein, “therapeutic dose” of a compound means an amount sufficient to improve or alleviate symptoms in any way, halt or reverse the progression of a condition, or negatively modulate or inhibit the activity of PI3K or its variants. This amount may be administered as a single dose or according to a drug regimen, thereby proving effective.

[0487] As used herein, treatment means any method by which the symptoms or condition of a state, disorder, or disease are improved or otherwise beneficial changes occur. Treatment also encompasses any pharmaceutical use of the compositions described herein.

[0488] As used herein, improvement of symptoms of a particular disorder by administration of a particular pharmaceutical composition means any relief, whether permanent or temporary, sustained or transient, caused by or related to the administration of the composition.

[0489] Where used herein, the term “about” used to modify numerically defined parameters (e.g., the dosage of a PI3K inhibitor detailed herein, its pharmaceutically acceptable salt, or the duration of treatment described herein) means that the parameter may vary by approximately 10% above or below the numerical value given for that parameter. For example, a dosage of approximately 5 mg / kg may vary in the range of 4.5 mg / kg to 5.5 mg / kg. Where “about” is used at the beginning of a parameter list, it means that “about” modifies each parameter. For example, approximately 0.5 mg, 0.75 mg, or 1.0 mg means approximately 0.5 mg, approximately 0.75 mg, or approximately 1.0 mg. Similarly, approximately 5% or more, 10% or more, 15% or more, 20% or more, and 25% or more means approximately 5% or more, approximately 10% or more, approximately 15% or more, approximately 20% or more, and approximately 25% or more.

[0490] As used herein, "salt" means any salt of any compound described herein that retains its biological properties and is non-toxic or does not have properties undesirable for pharmaceutically acceptable use.

[0491] These salts can be obtained from a variety of organic and inorganic counterions known in the art. These salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, and 2-hydroxyethane. This includes acid addition salts formed from organic or inorganic acids such as sulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphor acid, camphor sulfonic acid, 4-methylbicyclo[2.2.2]octo-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, and muconic acid.

[0492] Salts also include, for illustrative purposes only, salts of non-toxic organic or inorganic acids. For example, halides (chlorides and bromides, etc.), sulfates, phosphates, sulfamates, nitrates, acetates, trifluoroacetates, trichloroacetates, propions, hexanoates, cyclopentylpropions, glycolates, glutarates, pyruvates, lactates, malons, succinates, sorbates, ascorbicates, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoates, picrates, cinnamates, mandelates, phthalates, laurates, methanesulfonates (mesylates), ethanesulfonates, 1,2-ethanes Examples include disulfonates, 2-hydroxyethanesulfonates, benzenesulfonates (vesylates), 4-chlorobenzenesulfonates, 2-naphthalenesulfonates, 4-toluenesulfonates, camphorates, camphor sulfonates, 4-methylbicyclo[2.2.2]octo-2-ene-1-carboxylates, glucoheptonates, 3-phenylpropionates, trimethylacetates, tert-butylacetates, lauryl sulfates, glucons, benzoates, glutamates, hydroxynaphthoates, salicylates, stearates, cyclohexylsulfamates, quinates, muconates, etc.

[0493] Examples of inorganic bases that can be used to form base addition salts include, but are not limited to, metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; metal amides such as lithium amide and sodium amide; metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; and ammonium bases such as ammonium hydroxide and ammonium carbonate.

[0494] Examples of organic bases that can be used to form base addition salts include metal alkoxides such as lithium, sodium, and potassium alkoxides (including lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, and potassium tert-butoxide); quaternary ammonium hydroxides such as choline hydroxide; and amines, including but not limited to aliphatic amines (i.e., alkylamines, alkenylamines, alkynylamines, and alicyclic amines), heterocyclic amines, arylamines, heteroarylamines, basic amino acids, amino sugars, and polyamines. In some embodiments, the salt forms may include lithium salts, sodium salts, potassium salts, and amine salts.

[0495] The base may be a quaternary ammonium hydroxide. In this case, one or more alkyl groups of the quaternary ammonium ion may be optionally substituted with one or more suitable substituents. Preferably, at least one alkyl group is substituted with one or more hydroxyl groups. Non-limiting examples of quaternary ammonium hydroxides usable according to this disclosure include choline hydroxide, trimethylethylammonium hydroxide, and tetramethylammonium hydroxide, preferably choline hydroxide. The alkylamine base may be substituted or unsubstituted. Non-limiting examples of unsubstituted alkylamine bases usable according to this disclosure include methylamine, ethylamine, diethylamine, and triethylamine. The substituted alkylamine base may be substituted with one or more hydroxyl groups, preferably one to three hydroxyl groups. Non-limiting examples of substituted alkylamine bases usable according to this disclosure include 2-(diethylamino)ethanol, N,N-dimethylethanolamine (Deanol), tromethamine, ethanolamine, and diolamine.

[0496] In certain cases, substituents in a formula can contribute to optical isomerism and / or stereoisomerism. Compounds with the same molecular formula but different atomic bonding properties or arrangements, or different spatial arrangements of atoms, are called "isomers." Isomers with different spatial arrangements of atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," while those that are mirror images that cannot be superimposed on each other are called "enantiomers." If a compound has a chiral center, for example, if it is bonded to four different groups, a pair of enantiomers may be formed. Molecules possessing at least one stereocenter are characterized by the absolute configuration of their chiral center, according to the Cahn-Prelog rule (Cahn et al., 1966, Angew. Chem. 78: 413-447, Angew. Chem., Int. Ed. Engl. 5: 385-414 (errata: Angew. Chem., Int. Ed. Engl. 5:511); Prelog and Helmchen, 1982, Angew. Chem. 94: 614-631, Angew. Chem. Internat. Ed. Eng. 21: 567-583; Mata and Lobo, 1993, Tetrahedron: Asymmetry 4: Chiral compounds are designated as (R) or (S) by 657-668), or characterized by the way the molecule rotates its plane of polarization, and are designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal amounts of enantiomers is called a "racemic mixture."

[0497] In certain embodiments, the compounds described herein may have one or more chiral centers. Such compounds may be produced as racemic mixtures, mixtures with an excess of enantiomers, or as individual enantiomers. Unless otherwise specified, the description or naming of specific compounds in the specification and claims is intended to include both individual enantiomers and mixtures thereof, racemic mixtures, or other mixtures, for example, by specifying the stereochemistry at any position in the formula. Methods for determining stereochemistry and separating stereoisomers are known in the art.

[0498] In certain embodiments, the compounds described herein are “stereochemically pure.” A stereochemically pure compound has a level of stereochemical purity that is recognized as “pure” by those skilled in the art. Naturally, this purity level may be less than 100%. In certain embodiments, “stereochemically pure” means a compound in which there are substantially no alternative isomers (i.e., purity of at least about 85% or more relative to alternative isomers). In certain embodiments, the compound has a purity of at least about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or about 99.9% relative to other isomers.

[0499] All isomeric forms of the compounds described herein (in particular, all positional and stereoisomeric forms, e.g., all chiral forms, enantiomeric forms, diastereomeric forms, racemic forms, tautomeric forms, and all geometric isomeric forms, as well as atropisomers (including mutually exchangeable atropisomers)) are intended to be included in the present invention unless a specific isomeric form is specifically indicated. Obviously, the isomer that is pharmacologically most effective and has the fewest side effects is preferred.

[0500] As used herein, the terms “subject” and “patient” may be used interchangeably. In one embodiment, the subject is a human. In one embodiment, the subject is a companion animal such as a dog or cat. In further embodiments, the subject is an animal such as a sheep, cattle, horse, goat, fish, pig, or poultry (e.g., chicken, turkey, duck, or goose). In other embodiments, the subject is a primate such as a monkey (e.g., crab-eating macaque or chimpanzee).

[0501] Furthermore, pharmaceutically acceptable prodrugs of the compounds shown in the formulas are also included in this disclosure. A pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, etc., by solvolysis or under physiological conditions. Examples of groups that form prodrugs are described in Prog. Med., 5, 2157-2161 (1985) or "Pharmaceutical Development" (Hirokawa Shoten, 1990), Vol. 7, Drug Design, 163-198. Throughout this specification, the term prodrug is used to refer to any compound in a pharmaceutically acceptable form that provides an active compound when administered to a patient. A pharmaceutically acceptable prodrug is a compound that is metabolized in the host (e.g., by hydrolysis or oxidation) to form the compounds of this disclosure. Typical examples of prodrugs include compounds having a biologically unstable protecting group on the functional group of the active compound. Prodrugs include compounds that can generate active compounds by oxidation, reduction, amination, deamination, hydroxylation, dehydroxylation, hydrolysis, dehydrolysis, alkylation, dealkylation, acylation, deacylation, phosphorylation, or dephosphorylation.

[0502] This disclosure encompasses all pharmaceutically acceptable isotope-labeled compounds of this disclosure in which one or more atoms are substituted with atoms having the same atomic number but having an atomic mass or mass number different from that which normally exists in nature. Examples of isotopes suitable for inclusion in the compounds of this disclosure include isotopes of hydrogen ( 2 H and 3 H, etc.), carbon isotopes (11 C, 13 C and 14 C, etc., isotopes of chlorine, isotopes of boron ( 10 B and 11 B etc.), 36 Fluorine isotopes such as Cl ( 18 F, etc., isotopes of iodine ( 123 I and 125 I(1), nitrogen isotopes ( 13 N and 15 N, etc., oxygen isotopes ( 15 O, 17 O and 18 O, etc.), phosphorus isotopes ( 32 P, etc.), sulfur isotopes ( 35 Examples include tritium (i.e., S). Certain isotope-labeled compounds (including those containing radioactive isotopes) of this disclosure may be useful in studying the tissue distribution of drugs and substrates. 3 H) and carbon-14 (i.e.) 14 C) is particularly useful for this purpose in terms of its ease of introduction and convenient detection method. Deuterium (i.e.) 2 Substitution with heavier isotopes such as ¹H) may offer certain therapeutic benefits through improved metabolic stability (e.g., extended in vivo half-life or reduced required dose), and is therefore preferable in some situations. Positron-emitting isotopes ( 11 C, 10 B, 18 F, 15 O, and 13 Substitution with N, etc., may be useful in positron emission topography (PET) studies to investigate substrate receptor occupancy. See BNCT (boron neutron capture therapy). The isotope-labeled compounds of this disclosure can generally be prepared by means of prior art known to those skilled in the art, or by processes similar to those described in the following examples, using appropriate isotope-labeling reagents instead of conventionally used unlabeled reagents. [Composition and method of administration] The compounds of the Disclosure used in the methods described herein may be administered in specific embodiments, in which a pharmaceutically acceptable composition comprising at least one compound (in appropriate form, in salt form) is used, which is used alone, in combination with one or more suitable and pharmaceutically acceptable carriers (such as diluents or adjuvants), or in combination with other agents. Compositions comprising the compounds of the Disclosure or derivatives of salts thereof and acceptable excipients, carriers, or diluents are provided. These compositions may take various forms, including, but are not limited to, oral formulations, injectable formulations, and topical formulations, dermal formulations, or subcutaneous formulations.

[0503] The composition may be provided in forms suitable for oral use, such as dietary supplements, lozenges, chewable tablets, tablets, hard or soft capsules, emulsions, aqueous or oily suspensions, aqueous or oily solutions, dispersible powders or granules, syrups, or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, bittering agents, flavoring agents, coloring agents, and preservatives in order to provide a refined and easy-to-administer formulation.

[0504] Lozenges are solid compositions containing one or more active ingredients, intended to dissolve or disintegrate slowly in the oral cavity, either passively held in the mouth or actively sucked or chewed. They may be used for systemic effects when the drug is absorbed through the lining of the cheek or esophagus, or swallowed. Soft lozenges, in particular, may be chewed or allowed to dissolve slowly in the mouth. These dosage forms have the advantage of being easy to administer to both human and animal patients because they can be flavored. They also allow for easy modification of the formulation to suit the patient. Furthermore, they allow for the delivery of the active ingredient in precise amounts to the oral cavity and digestive system. Additionally, they allow the drug to remain in contact with the oral cavity or esophageal lumen for extended periods.

[0505] Tablets may contain the active ingredient in a mixture with non-toxic, pharmaceutically acceptable excipients suitable for tablet manufacturing. These excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; and smoothing agents such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or may be coated using known techniques to slow disintegration and absorption in the gastrointestinal tract, thereby providing a longer-lasting effect.

[0506] Formulations for oral use may be in the form of hard gelatin capsules. In this case, the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin). The capsules may also be in the form of soft gelatin capsules. In this case, the active ingredient is mixed with water, or a miscible solvent such as propylene glycol, PEG, and ethanol, or an oily medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0507] The composition may be in the form of a water-in-oil or oil-in-water emulsion. The oily phase may be a vegetable oil (e.g., olive oil or peanut oil) or a mineral oil (e.g., liquid paraffin or a mixture thereof). Suitable emulsifiers include naturally derived phosphatides (e.g., esters or partial esters derived from soybeans, lecithin, or fatty acids), hexitol anhydride (e.g., sorbitan monooleate), and condensates of the aforementioned partial esters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). These emulsions may also contain sweeteners, bittering agents, flavoring agents, and preservatives.

[0508] In one embodiment of the formulation, the composition is in the form of a microemulsion. Microemulsions are very suitable as liquid carrier vehicles. A microemulsion is a four-component system comprising an aqueous phase, an oily phase, a surfactant, and a co-surfactant. These are translucent, isotropic liquids. A microemulsion consists of stably dispersed microdroplets of the aqueous phase in the oily phase, or conversely, stably dispersed microdroplets of the oily phase in the aqueous phase. The size of these microdroplets is less than 200 nm (1,000 to 100,000 nm in emulsions). An interfacial film is composed of alternating arrangements of surfactant (SA) molecules and co-surfactant (Co-SA) molecules, which reduces interfacial tension, causing the microemulsion to form spontaneously. In one embodiment of the oily phase, the oily phase may be formed from mineral oil or vegetable oil, unsaturated polyglycosylated glycerides, triglycerides, or mixtures of these compounds. In one embodiment of the oily phase, the oily phase contains triglycerides. In another embodiment of the oily phase, the triglyceride is a medium-chain triglyceride, for example, C8-C 10 Caprylic / capric triglyceride is used. In another embodiment, the oily phase represents a range of %v / v in the microemulsion selected from the group consisting of about 2 to about 15%, about 7 to about 10%, and about 8 to about 9% v / v. The aqueous phase includes, for example, water or a glycol derivative (propylene glycol, glycol ether, polyethylene glycol, or glycerol, etc.). In one embodiment of the glycol derivative, the glycol is selected from the group consisting of propylene glycol, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether, and mixtures thereof. Generally, the aqueous phase represents a proportion of about 1 to about 4% v / v in the microemulsion. Surfactants for microemulsions include diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, and polyglycolated C8-C 10This includes glycerides or polyglyceryl-6 dioleate. In addition to these surfactants, auxiliary surfactants include short-chain alcohols such as ethanol and propanol. Some compounds are common to the three components described above (e.g., aqueous phase, surfactant, and auxiliary surfactant). However, using different compounds for each component of the same formulation is within the realm of expert skill. In one embodiment, for example, regarding the surfactant / auxiliary surfactant ratio, the ratio of auxiliary surfactant to surfactant may range from about 1 / 10 to about 1 / 2. In another embodiment, regarding the amount of auxiliary surfactant, the microemulsion contains about 25 to about 75% v / v surfactant and about 10 to about 55% v / v auxiliary surfactant.

[0509] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil (e.g., atatis oil, olive oil, sesame oil, or coconut oil) or mineral oil (e.g., liquid paraffin). The oily suspension may also contain a thickening agent (e.g., beeswax, solid paraffin, or cetyl alcohol). Sweeteners (sucrose, saccharin, or aspartame), bittering agents, and flavoring agents can be added to provide an easily administered oral formulation. These compositions can be preserved by adding antioxidants (e.g., ascorbic acid) or other known preservatives.

[0510] Aqueous suspensions may contain the active substance in a mixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents and include, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum. The dispersant or wetting agent may be a naturally occurring phosphatide (e.g., lecithin), or a condensate of alkylene oxide and fatty acid (e.g., polyoxyethylene stearate), or a condensate of ethylene oxide and long-chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), or a condensate of a fatty acid and a partial ester derived from hexitol and ethylene oxide (e.g., polyoxyethylene sorbitol monooleate), or a condensate of a fatty acid and a partial ester derived from hexitol anhydride and ethylene oxide (e.g., polyethylene sorbitan monooleate). The aqueous suspension may further contain one or more preservatives (e.g., ethyl or n-propyl, p-hydroxybenzoate), one or more colorants, one or more flavoring agents, and one or more sweeteners and / or bittering agents (e.g., those described herein).

[0511] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide the active ingredient in the form of a mixture with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients (e.g., sweeteners, bittering agents, flavoring agents, and coloring agents) may also be present.

[0512] As used herein, the term “dispersion” refers to a dispersion system in which one substance (dispersed phase) is distributed as individual units throughout another substance (continuous phase or vehicle). The size of the dispersed phase can vary greatly (e.g., from nanometer-sized colloidal particles to several microns in size). Generally, the dispersed phase can be a solid, liquid, or gas. In the case of a solid dispersion, both the dispersed phase and the continuous phase are solids. In pharmaceutical applications, a solid dispersion includes a crystalline drug (dispersed phase) in an amorphous polymer (continuous phase); or an amorphous drug (dispersed phase) in an amorphous polymer (continuous phase). In some embodiments, the solid dispersion includes the polymer constituting the dispersed phase and the drug constituting the continuous phase. In other embodiments, the solid dispersion includes the drug constituting the dispersed phase and the polymer constituting the continuous phase. An amorphous solid dispersion (ASD) refers to an amorphous pharmaceutically active ingredient stabilized by a polymer matrix to provide improved properties, including stability, to a solid material that lacks long-range order in molecular positioning. Molecules in amorphous solids generally do not have a distinct arrangement and are randomly positioned. Amorphous solids are generally isotropic, meaning they exhibit similar properties in all directions and do not have a distinct melting point. Amorphous solid dispersions (ASDs) can be used for poorly soluble pharmaceutical compounds. In ASDs, disrupting the crystal lattice of the drug substance generates a high-energy amorphous state, thereby improving the solubility of the drug substance (see Duarte et al., 2015; Elgindy et al., 2011).

[0513] Spray drying converts liquid raw materials into dry particulate matter. Spray drying generally involves contacting a highly dispersed liquid suspension or solution with a sufficient amount of hot air to facilitate the drying of droplets. For example, a liquid solution containing the compound or a salt thereof and at least one polymer may be sprayed into a warm filtered gas stream that evaporates the solvent and carries the dried product to a collector. The evaporated solvent and spent gas are removed from the collector and may be sent to a condenser to capture the solvent. Commercially available spray dryers, for example, are manufactured by Buchi and Niro (e.g., Niro's PSD line spray dryer) (see US2004 / 0105820, US2003 / 0144257). The techniques and methods of spray drying are described in Perry's Chemical Engineering Handbook, 6th Ed., RH Perry, DW Green & JO Maloney, eds.), McGraw-Hill book co. (1984); and Marshall “Atomization and Spray-Drying” 50, Chem. Eng. Prog. Monogr. Series 2 (1954). These three references are incorporated herein by reference in their entirety. Accordingly, compositions comprising the compounds of this disclosure can be prepared as spray-dried dispersions.

[0514] Syrups and elixirs may be prepared using sweeteners (e.g., glycerol, propylene glycol, sorbitol, or sucrose). Such preparations may also contain lubricants, preservatives, flavorings, and colorings.

[0515] The composition may be in the form of an aqueous or oily suspension for sterile injection. This suspension can be prepared according to known techniques using the appropriate dispersants or wetting agents and suspending agents described above. The sterile injection formulation may be a sterile injection solution or suspension as a non-toxic, parenterally acceptable diluent or solvent, such as a solution of 1,3-butanediol. Among the acceptable vehicles and solvents, water, Ringer's solution, and isotonic sodium chloride solution may be used. Cosolvents such as ethanol, propylene glycol, or polyethylene glycol may also be used. Preservatives such as phenol or benzyl alcohol may also be used.

[0516] Furthermore, sterile non-volatile oils have conventionally been used as solvents or suspension media. For this purpose, any non-irritating non-volatile oil, including synthetic monoglycerides or diglycerides, may be used. In addition, fatty acids such as oleic acid are used in the preparation of injectable preparations.

[0517] Topical, cutaneous, and subcutaneous formulations may include emulsions, creams, ointments, gels, or pastes.

[0518] Organic solvents that may be used in this disclosure include, but are not limited to, acetyl tributyl citrate, fatty acid esters such as dimethyl esters, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycol, propylene glycol, 2-pyrrolidone (e.g., N-methylpyrrolidone), diethylene glycol monoethyl ether, ethylene glycol, and diethyl phthalate, or mixtures of at least two of these solvents.

[0519] As a vehicle or diluent, the compositions of the present disclosure include, but are not limited to, vegetable oils (soybean oil, peanut oil, castor oil, corn oil, cottonseed oil, olive oil, grapeseed oil, sunflower oil, etc.); mineral oils (petrolatum, paraffin, silicone, etc., etc.); aliphatic or cyclic hydrocarbons, or, for example, medium-chain (C8-C) hydrocarbons. 12 It may contain triglycerides, etc.

[0520] The dosage form may contain approximately 0.5 mg to 5 g of the active ingredient.

[0521] In one embodiment of this disclosure, the active ingredient is present in the formulation at a concentration of about 0.05 to 10% by weight / volume.

[0522] The compounds of this disclosure can be used in their formulations, either as is or in combination.

[0523] These one or more additional active ingredients may be administered as part of the same or distinct dosage form, by the same or different route of administration, and in the same or different schedule of administration, in accordance with standard pharmaceutical practices known to those skilled in the art.

[0524] Pharmaceutical formulations containing the compounds of this disclosure for delivery to humans or other mammals are preferably in unit dosage forms. In this dosage form, the formulation is divided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form may be a packaged formulation containing individual amounts of the formulation, such as packaged tablets, capsules, and powder in vials or ampoules. Alternatively, the unit dosage form may be a capsule, tablet, or lozenge itself, or an appropriate number of any of these in packaged form.

[0525] The amount of the active ingredient in a unit dose formulation may be varied or adjusted from approximately 0.1 mg to approximately 1000 mg, depending on the specific use and the potency of the active ingredient. Optionally, the composition may also contain other suitable therapeutic agents.

[0526] In therapeutic use for the treatment or relief of one or more symptoms of one or more diseases or disorders, such as cancer, in humans or other mammals, the compound used in the therapeutic method has an initial dose per dosing interval of approximately 0.1 mg / kg to approximately 1,000 mg / kg, approximately 0.1 mg / kg to approximately 500 mg / kg, approximately 0.1 mg / kg to approximately 100 mg / kg, approximately 0.1 mg / kg to approximately 50.0 mg / kg, approximately 0.1 mg / kg to approximately 10.0 mg / kg, approximately 0.1 mg / kg to approximately 5.0 mg / kg, approximately 0.1 mg / kg to approximately 2.5 mg / kg, approximately 0.1 mg / kg to approximately 2.0 mg / kg, approximately 0.1 mg / kg to approximately 1.0 mg / kg, approximately 0.4 mg / kg to approximately 1.0 mg / kg, or approximately 0.4 mg / kg to approximately 0.6 mg / kg. The preferred dosing interval may be once daily, twice daily, three times daily, once weekly, once every two weeks, once monthly, once quarterly, once every six months, or once a year. The dosage may vary depending on the patient's requirements (e.g., the size of the human or mammal being treated, the severity of the condition being treated, the route of administration, and the potency of the compound used). Determining the appropriate dosage and route of administration in a particular situation is within the scope of expert skill. Generally, treatment is started with a small dose less than the optimal dose of the compound and may be increased in small increments until the optimal effect is achieved under the specific circumstances of the condition. For convenience, the total daily dose may be divided and administered in divided doses throughout the day, if desired.

[0527] In therapeutic use, the compounds of this disclosure are useful in the manufacture of pharmaceuticals for methods of treating any indication in which inhibition of PI3K or its variant is desirable.

[0528] One embodiment of the present disclosure provides a compound of the present disclosure introduced into a proteorisis target chimera (PROTAC), i.e., a heterobifunctional molecule comprising two active domains and a linker. The PROTAC may comprise an E3 ubiquitin ligase target site and a compound of the present disclosure, i.e., a target warhead that binds to a target protein to be degraded.

[0529] In yet another embodiment, the Disclosure provides a method for inhibiting the intracellular activity of PI3K or its variants. The method comprises contacting cells in which inhibition of PI3K or its variant activity is desired with an effective amount of the compound of the Disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the contact is carried out in vitro. In one embodiment, the contact is carried out in vivo.

[0530] As used herein, the term “contacting” means bringing specified parts into contact with each other in an in vitro or in vivo system. For example, “contacting” PI3K or its variants with the compounds relating to this specification includes administering the compounds relating to this specification to an individual or patient (e.g., a human) having PI3K or its variants, and introducing the compounds relating to this specification into a sample, for example, a cell preparation or purified preparation containing PI3K or its variants.

[0531] In one embodiment, the activity of PI3K or its variants is negatively regulated by contacting cells in which inhibition of PI3K activity is desired with an effective amount of the compound of the Disclosure. In other embodiments, a pharmaceutically acceptable salt or pharmaceutical composition (containing the compound of the Disclosure) may be used in a therapeutically effective amount.

[0532] By negatively modulating the activity of PI3K or its variants, the methods described herein are designed to inhibit undesirable cell proliferation resulting from enhanced intracellular activity of PI3K or its variants. To obtain the desired negative modulatory effect of PI3K or its variants, cells may be exposed to it in single or multiple doses according to the drug dosing plan in a specific treatment. The degree of modification of PI3K or its variants may be monitored in vitro using well-known methods (including those described below). Furthermore, the efficacy of the treatment may be evaluated by monitoring the inhibitory activity of representative compounds in cells (e.g., by measuring the inhibition of PI3K or its variants), and the dosage may be adjusted by the healthcare provider.

[0533] In another embodiment, a method for treating a patient in need of cancer treatment is provided. The method involves contacting the patient with a therapeutically effective amount of the compound of the Disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof.

[0534] The compositions and methods relating to this specification may be used to treat PI3K-related cancer (or its variants) in patients in need, and include administering to such patients a therapeutically effective dose of the compounds disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing said compound or a pharmaceutically acceptable salt thereof. In one embodiment, the PI3K-related or its variant is cancer.

[0535] The compositions and methods relating to this specification may be used to treat a wide variety of cancers, including tumors of the lung, prostate, breast, brain, skin, cervical, and testicular cancers. More specifically, cancers that may be treated by the compositions and methods relating to this disclosure include, but are not limited to, the following tumor types: astrocytoma, carcinomas and sarcomas of the breast, cervix, colon, endometrium, esophagus, stomach, head and neck, hepatocyte, larynx, lung, oral cavity, ovaries, prostate, and thyroid. More specifically, these compounds may be used to treat the following: heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; lungs: bronchogenic carcinomas (squamous cell carcinoma, anaplastic small cell carcinoma, anaplastic large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrotoxic hamartoma, and mesothelioma; digestive system: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIP-producing tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma) Physioma: Neurofibroma, fibroma; Colon (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma); Urogenital system: Kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia); Bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma); Prostate (adenocarcinoma, sarcoma); Testis (testicular tumor, teratoma, germ cell carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); Liver: Liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: Gallbladder cancer, duodenal papillary carcinoma, cholangiocarcinoma; Bone: Osteogenesis-sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor Chordoma, osteochondroma (osteochondrial exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, giant cell tumor; Nervous system: Skull (osteoma, hemangioma, granuloma, xanthomas, osteoosteitis), Meninges (meningioma, meningiosarcoma, gliosis), Brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal glandoma), glioblastoma multiplex, oligodendroglioma, Schwann cell tumor, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma);Gynecology: Uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia), ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiable cancer), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, budform sarcoma (germ cell rhabdomyosarcoma), fallopian tube (cancer); Hematology: Blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia) Leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus / dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma. In certain embodiments, the cancer is selected from breast cancer, colorectal cancer, uterine cancer, bladder cancer, lung cancer, glioma, head and neck cancer, and other solid tumors. In some embodiments, the cancer is breast cancer.

[0536] The concentration and route of administration to the patient will vary depending on the type of cancer being treated. The compound, its pharmaceutically acceptable salts, and pharmaceutical compositions containing the compound and salts may be administered in combination with other antitumor compounds (e.g., chemotherapy) or used in combination with other treatments (such as radiation therapy or surgical intervention). In this case, they may be used as neoadjuvant therapy or as adjuvant therapy.

[0537] In another embodiment, the diseases / conditions / cancers targeted for treatment / prevention as defined herein (above and below) are selected from the group consisting of pancreatic cancer, colorectal cancer, lung cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular adenoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma, salivary gland cancer, and urinary tract cancer.

[0538] The compounds of this disclosure may be used alone or in combination with one or more other pharmacologically active substances (such as state-of-the-art or standard therapeutic compounds, e.g., cell proliferation inhibitors, anti-angiogenic substances, steroids, or immunomodulators / checkpoint inhibitors, and others). SHP2 (Src homology 2 domain-containing protein tyrosine phosphatase 2) is a non-receptor protein tyrosine phosphatase that removes tyrosine phosphorylation. Functionally, SHP2 acts as a critical hub connecting several intracellular oncogenic signaling pathways (such as Jak / STAT, PI3K / AKT, RAS / Raf / MAPK, and the PD-1 / PD-L1 pathway). Mutations and / or overexpression of SHP2 are associated with hereditary developmental disorders and cancer.

[0539] Pharmacologically active substances that may be administered in combination with the compound pursuant to this disclosure include, but are not limited to, hormones, hormone analogs, and antihormones (e.g., tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), and aromatase inhibitors (e.g., anastrozole). (Letrozole, Rialozol, Borozol, Exemestane, Atamestane), LHRH agonists and antagonists (e.g., goserelin acetate, luprolide), growth factors and / or inhibitors of their corresponding receptors (growth factors include platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER, e.g., HER2, HER3, HER4), and hepatocyte growth factor (HGF) and / or their counterparts) (Responding receptors), inhibitors (e.g., (anti) growth factor antibodies, (anti) growth factor receptor antibodies, and tyrosine kinase inhibitors (such as cetuximab, gefitinib, afatinib, nintedanib, imatinib, lapatinib, bosutinib, bevacizumab, and trastuzumab)); antimetabolites (e.g., antifolic acid agents such as methotrexate and larcitrexed, pyrimidine analogs such as 5-fluorouracil (5-FU), ribonucleosides and deoxyribonucleoside analogs, capecitabine and gemcitabine, mercaptopurine, thioguanine, etc.); Radribine, and purines and adenosine analogs such as pentostatin, cytarabine (ara C), fludarabine); antitumor antibiotics (e.g., doxorubicin, Doxil (pegylated liposomal doxorubicin hydrochloride), Myoseto (non-pegylated liposomal doxorubicin), anthracyclines such as daunorubicin, epirubicin, and idarubicin, mitomycin C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g., cisplatin, oxaliplatin, carboplatin);Alkylating agents (e.g., estramustine, mechloretamine, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosourea compounds (e.g., carmustine, lomustine, etc.), thiotepa); antimitotic agents (e.g., vinca alkaloids (e.g., vinblastine, vindesine, vinorelbine, and vincristine, etc.); and taxanes (paclitaxel, docetaxel, etc.)); angiogenesis inhibitors (e.g., tascinimod), microtubule inhibitors;DNA synthesis inhibitors, PARP inhibitors, topoisomerase inhibitors (e.g., epipodophyllotoxins (e.g., etoposide and etopophos), teniposide, amsacrin, topotecan, irinotecan, mitoxantrone), serine / threonine kinase inhibitors (e.g., PDK1 inhibitors, Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, CRaf inhibitors, mTOR inhibitors, mTORC1 / 2 inhibitors, PI3K inhibitors, PI3Ka inhibitors, dual mTOR / PI3K inhibitors, STK33 inhibitors, AKT inhibitors, PLK 1 inhibitors, CDK inhibitors, Aurora kinase inhibitors), tyrosine kinase inhibitors (e.g., PTK2 / FAK inhibitors), protein-protein interaction inhibitors (e.g., IAP activator, Mcl-1, MDM2 / MDMX), MEK inhibitors, ERK inhibitors, FLT3 inhibitors, BRD4 inhibitors, IGF-1R inhibitors, TRAILR2 agonists, Bcl-xL inhibitors, Bcl-2 inhibitors, Bcl-2 / Bcl-xL inhibitors, ErbB receptor inhibitors, BCR-ABL inhibitors, ABL inhibitors, Src inhibitors, SHP2 inhibitors, rapa Mycin analogs (e.g., everolimus, temsirolimus, ridafolimus, sirolimus), androgen synthesis inhibitors, androgen receptor inhibitors, DNMT inhibitors, HDAC inhibitors, ANG1 / 2 inhibitors, CYP17 inhibitors, radiopharmaceuticals, proteasome inhibitors, immunotherapeutic agents (immune checkpoint inhibitors, etc. (e.g., CTLA4, PD1, PD-L1, PD-L2, LAG3, and TIM3 binding molecules / immunoglobulins (e.g., ipilimumab, nivolumab, pembrolizumab)), ADCC (antibody-dependent cell-mediated cytotoxicity) Enhancers (e.g., anti-CD33 antibodies, anti-CD37 antibodies, anti-CD20 antibodies), T-cell engagers (e.g., bispecific T-cell engagers such as CD3xBCMA, CD3xCD33, CDxCD19 (BiTEs®), PSMAxCD3), tumor vaccines, and various chemotherapeutic agents (amifostine, anagrelide, clodronate, filgrastin, interferon, interferon-α, leucovorin, procarbazine, levamisole, mesna, mitotane, pamidronate, and porfimer, etc.).

[0540] In certain embodiments, the compounds of the present disclosure may be combined with one or more additional therapeutic agents. In other embodiments, the compounds of the present invention may be combined with two or more additional therapeutic agents. In one embodiment, the additional therapeutic agents are selected from selective estrogen receptor degraders, Protac-mediated estrogen receptor inhibitors, complete estrogen receptor antagonists, sarcoplasmic reticulum calcium ATPase inhibitors, CDK2 inhibitors, CDK2 / 4 / 6 inhibitors, CDK4 / 6 inhibitors, aromatase inhibitors, KRAS inhibitors, RAF, MEK, or ERK inhibitors, AKT inhibitors, mTOR inhibitors, tyrosine kinase inhibitors, DNA synthesis inhibitors, SHP2 inhibitors, BCL-2 family inhibitors, immune checkpoint inhibitors, and SRC inhibitors. In another embodiment, the additional therapeutic agent is selected from palbociclib, abemaciclib, ribociclib, letrozole, fulvestrant, parazestrant, camizestrant, elastrant, imurunestrant, exemestane, anastrozole, LSZ102, cetuximab, trastuzumab, pertuzumab, nab-paclitaxel, tucatinib, vinorelbine, everxomostat, eribulin, capecitabine, gedatricib, tamoxifen, zotafinin, neratinib, giredestrant, talazoparib, pembrolizumab, metformin, AMG-510, trametinib, dabrafenib, LY 3214996, PF-07104091, everolimus, and capivacertib. In one embodiment, each drug is provided in a separate dosage form. In one embodiment, one or more drugs are provided in a combined dosage form.

[0541] Furthermore, this specification also provides for the therapeutic use of the compounds disclosed herein, or salts thereof, or pharmaceutical compositions thereof (all as defined herein).

[0542] Furthermore, this specification also provides for the use of the compounds disclosed herein, or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions thereof (all as defined herein) in the treatment of cancer.

[0543] Furthermore, this specification also provides the use of the compounds disclosed herein, or pharmaceutically acceptable salts or solvates thereof (as defined herein), in the inhibition of PI3K or its variants.

[0544] In some embodiments, the variant may be the PI3Kα mutations of H1047, E545, E542, N345, E726, C420, Q546, G118, E453, Q546, G1049, M1043, K111, E81, N1044, and E110. In other embodiments, the variant may be the PI3Kα mutations of H1047, E545, E542, N345, E726, C420, Q546, G118, E453, Q546, G1049, M1043, K111, E81, N1044, E110, R88, I391, R108H, Y1021, R93W, T1025A, R93, V344, R38, P539, E418, and E970.

[0545] Furthermore, this specification also provides for the use of the compounds disclosed herein, or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions thereof (all as defined herein) in the treatment of PI3K-related or mutant diseases / disorders.

[0546] Furthermore, this specification also provides for the use of the compounds disclosed herein, or pharmaceutically acceptable salts or solvates thereof (as defined herein), in the manufacture of pharmaceuticals for the treatment of cancer.

[0547] Furthermore, this specification also provides for the use of the compounds disclosed herein, or pharmaceutically acceptable salts or solvates thereof (as defined herein), in the manufacture of pharmaceuticals for inhibiting the activity of PI3K or its variants.

[0548] Furthermore, this specification also provides for the use of the compounds disclosed herein, or pharmaceutically acceptable salts or solvates thereof (as defined herein), in the manufacture of pharmaceuticals for the treatment of PI3K-related diseases or disorders.

[0549] Furthermore, a method for treating cancer in patients requiring treatment is also provided herein. The method comprises (a) determining that the cancer is associated with a PI3K mutation (e.g., using an approved assay or kit); and (b) administering to the patient a therapeutically effective dose of one of the compounds of the Disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0550] Those skilled in the art will understand that both in vivo and in vitro studies using appropriate, known, and generally accepted cell and / or animal models can predict the ability of a test compound to treat or prevent a particular disorder.

[0551] Those skilled in the art will further understand that human clinical trials (including first-instance human trials, dose-range trials, and efficacy trials) in healthy patients and / or patients with certain disorders may be completed in accordance with methods well known in the clinical and medical fields.

[0552] This disclosure expressly includes the compounds listed below (including their salt forms). This disclosure also includes the compounds listed below (including their stereoisomers). Compositions containing any of these compounds in a therapeutically acceptable amount are also within the scope of this disclosure. Such compositions may further include pharmaceutically acceptable excipients, diluents, carriers, or mixtures thereof. Such compositions may be administered to subjects in need to treat or control diseases or disorders mediated directly or indirectly, in whole or in part, by PI3K or its variants. Such compositions may further include additional active ingredients described herein.

[0553] [Examples of synthesis] The following examples provide a more detailed description of the process conditions for preparing the compounds of this disclosure. However, it should be understood that the present invention is not limited by the following schemes or preparation method details, as fully described herein and as described in the claims.

[0554] Certain abbreviations may be used to describe the embodiments of this disclosure. These abbreviations are intended to be used consistently within the scope of usage generally accepted by those skilled in the art.

[0555] The compounds disclosed herein can be synthesized using the synthesis methods and reaction schemes described herein, or It may also be prepared from commercially available reagents using other reagents and conventional methods well known to those skilled in the art.

[0556] As is evident, certain compounds of this disclosure can not only represent final products having the desired biological effects, but can also function as synthetic intermediates to other final product compounds of this disclosure.

[0557] Compounds of this disclosure that contain one or more chiral centers may be presented, for example, as racemic mixtures or may be characterized as having a specific stereochemical orientation. Stereochemical configurations as used herein are labeled based on prior art information indicating that one enantiomer exhibits preferred biological properties over the other. Absolute configurations are not characterized. All stereoisomers of the illustrated compounds are embodiments of the present invention. Furthermore, the following examples describe characteristic data of specific isomers, but their order is arbitrary and does not imply any suggestion regarding the names of the compounds listed or the order of illustration.

[0558] The following examples illustrate the process conditions for compound preparation in the present invention. However, it should be understood that the present invention is not limited by the following details of the preparation scheme or preparation method, as fully described herein and as described in the claims.

[0559] Certain abbreviations may be used to describe the embodiments of this disclosure. These abbreviations are intended to be used consistently within the scope of usage generally accepted by those skilled in the art.

[0560] In the following schemes, common substituents may be represented by assignments that do not conform to the formulas of this disclosure. The following schemes provide a legend for such substituents, and the schemes should follow this legend, but it should not apply to the formulas of this disclosure.

[0561] The compounds disclosed herein may be prepared according to the synthesis methods described herein, with appropriate modifications so as can be easily understood by those skilled in the art.

[0562] Synthetic support for reference portions of one or more embodiments of this disclosure is provided herein based on the synthetic teachings and examples disclosed in one or more of the following patent publications: WO 2024 / 026423, WO 2024 / 008122, WO 2024 / 000401, WO 2023 / 239710, WO 2023 / 230262, WO 2023 / 207881, WO 2023 / 205680, WO 2023 / 192416, WO 2023 / 159155, WO 2023 / 081209, WO 2023 / 078401, WO 2023 / 060262, WO 2024 / 026419, WO 2024 / 026424, and WO 2021 / 202964.

[0563] The compounds of this disclosure may be synthesized in accordance with the teachings described herein and in the schemes. [Examples] Experimental procedure: Example 1

[0564] [ka]

[0565] Preparation of 8-[1-[4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one A mixture of 4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (258 mg, 1.02 mmol, 1.6 equivalents), 8-(1-bromoethyl)-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (250 mg, 637.22 μmol, 1 equivalent), and TEA (129 mg, 1.27 mmol, 177.39 μL, 2 equivalents) in DMF (2 mL) was degassed and purged three times with N2 at 20°C. The mixture was then stirred at 60°C for 3 hours under an N2 atmosphere. After cooling to room temperature, 5 mL of water at 0°C was added to stop the reaction and form a solid. The reaction mixture was filtered, and the filter cake was collected to obtain the crude product. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to obtain the title compound (228 mg, 403.58 μmol, yield 63.33%) as a brown solid. 1 H NMR (CDCl3, 400 MHz) δ 7.88 (s, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.40 (s, 1H), 7.06 (dd, J = 2.0, 8.4 Hz, 1H), 6.35 (s, 1H), 6.18 (d, J = 8.8 Hz, 1H), 4.98-4.94 (m, 1H), 3.45-3.35 (s, 4H), 2.37 (s, 3H), 2.08 (s, 3H), 1.60 (d, J = 6.4 Hz, 3H), 1.55-1.49 (m, 4H), 1.38 (s, 12H), 1.04 (s, 6H).

[0566] Preparation of [5-chloro-2-[1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromene-8-yl]ethylamino]phenyl]boronic acid To a solution of 8-[1-[4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (180 mg, 318.61 μmol, 1 equivalent) in THF (1.5 mL) / H2O (0.5 mL), NH4OAc (73 mg, 955.84 μmol, 3 equivalents) and NaIO4 (204 mg, 955.84 μmol, 52.97 μL, 3 equivalents) were sequentially added at 20°C, and the reaction mixture was stirred at 50°C for 3 hours. After cooling to room temperature, the reaction mixture was poured into ice water (5 mL), stirred at 20°C for 0.5 hours, and then extracted with ELISA (5 mL x 3). The combined organic phase was washed with saturated saline solution (5 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by prep HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 50% to 80% B over 8.0 mins) to obtain the title compound as an off-white solid (35 mg, 71.85 μmol, yield 22.55%). 1 H NMR (DMSO-d6, 400 MHz) δ 8.52 (s, 2H), 7.62 (s, 1H), 7.57 (d, J = 2.8 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.10 (d, J = 6.0 Hz, 1H), 7.04 (dd, J = 2.8, 8.8 Hz, 1H), 6.20 (d, J = 8.8 Hz, 1H), 4.97-4.89 (m, 1H), 3.42-3.37 (m, 4H), 2.30 (s, 3H), 1.91 (s, 3H), 1.54-1.43 (m, 7H), 0.99 (s, 6H). MS(ESI): Mass calculation value C 26 H 32 BClN2O4 482.21, measured value in m / z: 483.3 [M+H] + . HPLC: 97.98% (220nm), 97.79% (254nm).

[0567] Preparation of [5-chloro-2-[[(1S)-1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromemen-8-yl]ethyl]amino]phenyl]boronic acid and [5-chloro-2-[[(1R)-1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromemen-8-yl]ethyl]amino]phenyl]boronic acid [5-chloro-2-[1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromene-8-yl]ethylamino]phenyl]boronic acid (30.0 mg, 62.14 μmol, 1 equivalent) was separated by SFC (column: REGIS(s,s)WHELK-O1 (250 mm × 30 mm × 5 μm); mobile phase: [CO2-EtOH]; B%: 50%, isocratic elution mode). This yielded isomer 1 (7.9 mg, 16.36 μmol, yield 26.33%), the title compound, as an off-white solid, and isomer 2 (11.1 mg, 22.99 μmol, yield 37.00%), the title compound, as an off-white solid. Isomer 1: 1 H NMR (DMSO-d6, 400 MHz) δ 8.51 (s, 2H), 7.62 (s, 1H), 7.57 (d, J = 2.4 Hz, 1H), 7.36 (s, 1H), 7.12-7.08 (m, 1H), 7.06-7.02 (m, 1H), 6.20 (d, J = 8.8 Hz, 1H), 4.98-4.89 (m, 1H), 3.42-3.37 (m, 4H), 2.30 (s, 3H), 1.91 (s, 3H), 1.54-1.44 (m, 7H), 0.99 (s, 6H). MS(ESI): Mass calculation value C 26 H 32 BClN2O4 482.21, measured value in m / z: 483.3 [M+H] + HPLC: 98.62% (220nm), 98.17% (254nm). Chiral purity: 100%ee. Isomer 2: 1H NMR (DMSO-d6, 400 MHz) δ 8.51 (s, 2H), 7.62 (s, 1H), 7.57 (d, J = 2.4 Hz, 1H), 7.36 (s, 1H), 7.12-7.08 (m, 1H), 7.06-7.02 (m, 1H), 6.20 (d, J = 8.8 Hz, 1H), 4.97-4.90 (m, 1H), 3.42-3.37 (m, 4H), 2.30 (s, 3H), 1.92 (s, 3H), 1.54-1.44 (m, 7H), 0.99 (s, 6H). MS(ESI): Mass calculation value C 26 H 32 BClN2O4 482.21, measured value in m / z: 483.3 [M+H] + HPLC: 97.94% (220nm), 96.63% (254nm). Chiral purity: 90.68%ee.

[0568] Example 2

[0569] [ka]

[0570] Preparation of 2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-8-[1-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]chromen-4-one A solution of 8-(1-bromoethyl)-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (250 mg, 637.22 μmol, 1 equivalent) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (279.21 mg, 1.27 mmol, 2 equivalents) in DMF (2 mL) was stirred at 60°C for 4 hours. The reaction mixture was stopped with water (20 mL) and then extracted with MTBE (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound (300 mg, crude) as a yellow solid. This compound was used in the next step without further purification.

[0571] Preparation of [2-[1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromene-8-yl]ethylamino]phenyl]boronic acid To a solution of 2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-8-[1-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]chromen-4-one (300 mg, 339.30 μmol, 1 equivalent) in THF (2 mL) / H2O (1 mL), NH4OAc (79 mg, 1.02 mmol, 3 equivalents) and NaIO4 (218 mg, 1.02 mmol, 56.40 μL, 3 equivalents) were sequentially added at 20°C, and the reaction mixture was stirred at 50°C for 12 hours. After the reaction mixture was cooled to room temperature, it was poured into ice water (20 mL) and extracted with ELISA (10 mL x 3). The combined organic phase was washed with saturated saline (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 35%~65%B over 8 minutes) to obtain the title compound as an off-white solid (39 mg, 86.54 μmol, yield 25.50%). 1 H NMR (DMSO-d6, 400 MHz) δ 8.28 (s, 2H), 7.61-7.57 (m, 2H), 7.40 (s, 1H), 7.03-7.00 (m, 2H), 6.46 (t, J = 6.8 Hz, 1H), 6.20 (d, J = 8.4 Hz, 1H), 4.97-4.94 (m, 1H), 3.41-3.40 (m, 4H), 2.30 (s, 3H), 1.92 (s, 3H), 1.53 (d, J = 6.4 Hz, 3H), 1.47-1.46 (m, 4H), 0.99 (s, 6H). MS(ESI): Mass calculation value C 26 H 33 BN2O4448.25, measured value in m / z: 449.2 [M+H] +. HPLC: 94.69% (220nm), 96.45% (254nm).

[0572] Preparation of [2-[[(1S)-1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromemen-8-yl]ethyl]amino]phenyl]boronic acid and [2-[[(1R)-1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromemen-8-yl]ethyl]amino]phenyl]boronic acid [2-[1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromene-8-yl]ethylamino]phenyl]boronic acid (36 mg, 80.29 μmol, 1 equivalent) was separated by SFC separation (column: REGIS(s,s)WHELK-O1 (250 mm × 30 mm × 5 μm); mobile phase: [CO2-EtOH]; B%: 50%, isoconcentration elution mode). This yielded isomer 1 (7.5 mg, 16.28 μmol, yield 20.28%) as a white solid, and isomer 2 (10.1 mg, 22.32 μmol, yield 27.80%) as a white solid. Isomer 1: 1 H NMR (DMSO-d6, 400 MHz) δ 8.33 (s, 2H), 7.63 (s, 1H), 7.60 (d, J = 6.8 Hz, 1H), 7.41 (s, 1H), 7.06 (d, J = 6.4 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.48 (t, J = 7.6 Hz, 1H), 6.20 (d, J = 8.0 Hz, 1H), 5.00-4.94 (m, 1H), 3.44-3.42 (m, 4H), 2.32 (s, 3H), 1.93 (s, 3H), 1.53 (d, J = 6.4 Hz, 3H), 1.48-1.47 (m, 4H), 1.00 (s, 6H). MS(ESI): Mass calculation value C 26 H 33 BN2O4448.25, measured value in m / z: 449.2 [M+H] +HPLC: 99.10% (220nm), 98.71% (254nm). Chiral purity: 100%ee. Isomer 2: 1 H NMR (DMSO-d6, 400 MHz) δ 8.32 (s, 2H), 7.61 (s, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.43 (s, 1H), 7.06 (d, J = 6.4 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.48 (t, J = 6.8 Hz, 1H), 6.20 (d, J = 8.0 Hz, 1H), 4.97-4.92 (m, 1H), 3.42-3.40 (m, 4H), 2.30 (s, 3H), 1.92 (s, 3H), 1.53 (d, J = 6.4 Hz, 3H), 1.47-1.46 (m, 4H), 0.99 (s, 6H). MS(ESI): Mass calculation value C 26 H 33 BN2O4448.25, measured value in m / z: 449.2 [M+H] + HPLC: 97.33% (220nm), 97.32% (254nm). Chiral purity: 93.60%ee.

[0573] Example 3

[0574] [ka]

[0575] Preparation of 2-(4,4-dimethylpiperidine-1-yl)-8-(1-((3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)ethyl)-3,6-dimethyl-4H-chromen-4-one 8-(1-bromoethyl)-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (250 mg, 637.22 μmol, 1 equivalent) was added in a 3 mL solution of DMF (350 mg) to 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (250 mg, 1.05 mmol, 1.65 equivalents) at 25°C. The reaction mixture was stirred at 60°C for 4 hours. 10 mL of water at 0°C was added to stop the reaction, and the resulting suspension was filtered directly. The filtered cake was further triturated in water at 0°C for 10 minutes to obtain the title compound (300 mg, crude) as a white solid. This compound was used directly in the next step without further purification.

[0576] Preparation of (2-((1-(2-(4,4-dimethylpiperidine-1-yl)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)amino)-6-fluorophenyl)boronic acid To a solution of 2-(4,4-dimethyl-1-piperidyl)-8-[1-[3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]-3,6-dimethyl-chromen-4-one (250 mg, 455.79 μmol, 1 equivalent) in THF (3 mL) / H2O (1 mL), NaIO4 (293 mg, 1.37 mmol, 75.77 μL, 3 equivalents) and NH4OAc (106 mg, 1.37 mmol, 3 equivalents) were added in one go at 25°C, and the reaction mixture was stirred at 50°C for 3 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with ELISA (10 mL x 3). The combined organic layer was washed with saturated brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by prep HPLC (neutral conditions; column: Waters Xbridge Prep OBD C18 150×40mm×10μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 55%~75%, 8 min) to obtain the title compound (37 mg, 79.34 μmol, yield 17.41%) as a white solid. 1 1H NMR (DMSO-d 6,400 MHz) 8.44 (s, 2H), 7.62-7.61 (d, J = 1.6 Hz, 1H), 7.42-7.41 (d, J = 2.0 Hz, 1H), 6.09-6.99 (d, J = 7.2 Hz, 1H), 6.41-6.40 (d, J = 6.0 Hz, 1H), 6.26-6.22 (t, J = 8.8 Hz, 1H), 6.05-6.03 (d, J = 8.4 Hz, 1H), 4.96-4.93 (m, 1H), 3.41-3.40 (d, J = 2.8 Hz, 4H), 2.31 (s, 3H), 1.91(s, 3H), 1.52-1.51 (d, J = 6.8 Hz, 3H), 1.46-1.45 (d, J = 2.8 Hz, 4H), 0.98 (s, 6H). MS(ESI): Mass calculation value C 26 H 32 BFN2O4 466.36, measured value in m / z: 467.2 [M+H] + . HPLC: 97.09% (220nm), 96.78% (254nm).

[0577] Preparation of (S)-(2-((1-(2-(4,4-dimethylpiperidine-1-yl)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)amino)-6-fluorophenyl)boronic acid and (R)-(2-((1-(2-(4,4-dimethylpiperidine-1-yl)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)amino)-6-fluorophenyl)boronic acid (2-((1-(2-(4,4-dimethylpiperidine-1-yl)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)amino)-6-fluorophenyl)boronic acid (30 mg) was further separated by SFC (conditions: column: REGIS(s,s)WHELK-O1 (250 mm × 30 mm, 5 μm); mobile phase: [CO2-EtOH]; B%: 50%, isoconcentration elution mode). This yielded isomer 1 (6.6 mg, 14.59 μmol, yield 26.67%), the title compound, as a white solid, and isomer 2 (7.8 mg, 16.18 μmol, yield 29.58%), the title compound, as a white solid. Isomer 1: 1 1H NMR (DMSO-d 6, 400 MHz) 8.45 (d, J = 1.2 Hz 2H), 7.62 (s, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.03-6.98 (m, 1H), 6.42-6.40 (d, J = 6.0 Hz, 1H), 6.27-6.22 (t, J = 8.8 Hz, 1H), 6.05-6.03(d, J = 8.0 Hz, 1H), 4.98-4.92 (m, 1H), 3.48-3.40 (m, 4H), 2.32-2.31 (d, J = 4.0 Hz, 3H), 1.92 (s, 3H), 1.53-1.51 (d, J = 6.8 Hz, 3H), 1.48-1.45 (m, 4H), 0.99 (s, 6H). MS(ESI): Mass calculation value C 26 H 32 BFN2O4 466.36, measured value in m / z: 467.2 [M+H] + HPLC: 98.68% (220nm), 97.8% (254nm). Chiral purity: 100%ee. Isomer 2: 1 1H NMR (DMSO-d 6,400 MHz) 8.45 (d, J = 1.2 Hz 2H), 7.62 (s, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.03-6.98 (m, 1H), 6.42-6.40 (d, J = 6.0 Hz, 1H), 6.27-6.22 (t, J = 8.4 Hz, 1H), 6.05-6.03 (d, J = 8.0 Hz, 1H), 4.98-4.92 (t, J = 6.4 Hz, 1H), 3.42-3.40 (m, 4H), 2.33-2.31 (m, 3H), 1.92-1.91 (d, J = 4.0 Hz, 3H), 1.53-1.51 (d, J = 6.4 Hz, 3H), 1.48-1.45 (m, 4H), 0.99 (s, 6H). MS(ESI): Mass calculation value C 26 H 32 BFN2O4 466.36, measured value in m / z: 467.2 [M+H] + HPLC: 95.5% (220nm), 94.5% (254nm). Chiral purity: 99.76%ee.

[0578] Example 4

[0579] [ka]

[0580] Preparation of 2-bromo-3-[1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromene-8-yl]ethylamino]methyl benzoate A solution of 8-(1-bromoethyl)-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (500 mg, 1.3 mmol, 1.0 equivalent) and methyl 3-amino-2-bromobenzoate (587 mg, 2.6 mmol, 2.0 equivalent) in DMF (5 mL) was stirred at 60°C for 2 hours. The reaction mixture was cooled to 25°C, stopped with H₂O (20 mL), and extracted with MTBE (10 mL x 3). The combined organic phase was washed with saturated saline (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (Biotage®; 20 g SepaFlash® Silica Flash Column, eluent: 0-25% petroleum ether / ethyl acetate gradient, flow rate 50 mL / min) to obtain the title compound (400 mg, 738.7 μmol, yield 57.96%) as a pale yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ 7.63 (s, 1H), 7.45 (s, 1H), 7.15-7.11 (m, 1H), 6.84-6.82 (m, 1H), 6.58-6.56 (m, 1H), 5.62-5.60 (m, 1H), 5.08-5.04 (m, 1H), 3.82 (s, 3H), 3.42-3.39 (m, 4H), 2.31 (s, 3H), 1.91 (s, 3H), 1.64-1.63 (m, 3H), 1.47-1.44 (m, 4H), 0.98 (s, 6H).

[0581] Preparation of 3-((1-(2-(4,4-dimethylpiperidine-1-yl)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)amino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl benzoate A mixture of 2-bromo-3-[1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromene-8-yl]ethylamino]methyl benzoate (75 mg, 138.51 μmol, 1 equivalent), B2Pin2 (176 mg, 692.55 μmol, 5 equivalents), KOAc (41 mg, 415.53 μmol, 3 equivalents), and Pd(PPh3)2Cl2 (10 mg, 13.85 μmol, 0.1 equivalents) in dioxane (2 mL) was degassed and purged three times with N2 at 25°C. The mixture was then stirred at 80°C for 12 hours under an N2 atmosphere. For work-up, the two parallel reactions were combined. The reaction mixtures were filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (Biotage®; 12 g SepaFlash® Silica Flash Column, eluent: 0-35% ethyl acetate / petroleum ether radiant, flow rate 45 mL / min) to obtain the title compound (280 mg, crude) as a pale yellow oil. 1 H NMR (CDCl3, 400 MHz) δ 7.86 (s, 1H), 7.41 (s, 1H), 7.15 (d, J = 7.2 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.37 (d, J = 8.0 Hz, 1H), 5.15-5.11 (m, 1H), 5.02-4.97 (m, 1H), 3.88 (s, 3H), 3.41-3.78 (m, 4H), 2.35 (s, 3H), 2.07 (s, 3H), 1.59 (d, J = 6.4 Hz, 3H), 1.51-1.49 (m, 4H), 1.43 (s, 12H), 1.02 (s, 6H).

[0582] Preparation of 2-(4,4-dimethyl-1-piperidyl)-8-[1-[(1-hydroxy-3H-2,1-benzoxabolol-7-yl)amino]ethyl]-3,6-dimethyl-chromen-4-one 3-[1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromene-8-yl]ethylamino]-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl benzoate (180 mg, 305.84 μmol, 1 equivalent) was added in 2 mL of THF to a solution of 58 mg of NaBH4 (1.53 mmol, 5 equivalents) at 0°C. The mixture was heated to 25°C and stirred at 25°C for 1 hour. The reaction mixture was cooled to 0°C and the reaction was stopped by adding 8 mL of H2O at 0°C. The mixture was then adjusted to pH=7 with HCl (2N) and extracted with ELISA (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by prep HPLC (column: Waters Xbridge BEH C18 100×30mm×10μm; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 50%~80%B over 8.0 minutes) to obtain the title compound as a white solid (50 mg, 108.61 μmol, yield 35.51%). 1 H NMR (DMSO-d6, 400 MHz) δ 9.14 (s, 1H), 7.62 (s, 1H), 7.45 (s, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.53 (d, J = 7.2 Hz, 1H), 6.15 (d, J = 8.0 Hz, 1H), 5.53 (d, J = 6.8 Hz, 1H), 5.06 (t, J = 6.8 Hz, 1H), 4.85 (s, 2H), 3.43-3.40 (m, 4H), 2.32 (s, 3H), 1.92 (s, 3H), 1.57 (d, J = 6.8Hz, 3H), 1.47-1.45 (m, 4H), 0.99 (s, 6H). MS(ESI): Mass calculation value C 21 H 33 BN2O4 460.38, measured value in m / z: 461.4 [M+H] + . HPLC: 94.80% (220nm), 95.94% (254nm).

[0583] Preparation of 2-(4,4-dimethyl-1-piperidyl)-8-[(1S)-1-[(1-hydroxy-3H-2,1-benzoxabol-7-yl)amino]ethyl]-3,6-dimethyl-chromen-4-one and 2-(4,4-dimethyl-1-piperidyl)-8-[(1R)-1-[(1-hydroxy-3H-2,1-benzoxabol-7-yl)amino]ethyl]-3,6-dimethyl-chromen-4-one 2-(4,4-dimethyl-1-piperidyl)-8-[1-[(1-hydroxy-3H-2,1-benzoxabolol-7-yl)amino]ethyl]-3,6-dimethyl-chromen-4-one (50 mg, 108.61 μmol, 1 equivalent) was separated by SFC separation (column: ChiralPak IH, 250 × 30 mm × 10 μm; mobile phase: [CO2-MeOH]; B%: 23%, isoconcentration elution mode). This yielded isomer 1 (18.3 mg, 39.6 μmol, yield 36.4%) as a white solid, and isomer 2 (17.3 mg, 37.5 μmol, yield 34.5%) as a white solid. Isomer 1: 1 H NMR (DMSO-d6, 400 MHz) δ 9.16 (s, 1H), 7.62 (s, 1H), 7.45 (s, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.54 (d, J = 7.2 Hz, 1H), 6.16 (t, J = 7.6 Hz, 1H), 5.55 (d, J = 7.2 Hz, 1H), 5.07-5.04 (m, 1H), 4.85 (s, 2H), 3.42-3.40 (m, 4H), 2.31 (s, 3H), 1.91 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H), 1.47-1.46 (m, 4H), 0.99 (s, 6H). MS(ESI): Mass calculation value C 27 H 33 BN2O4 460.25, measured value in m / z: 461.3 [M+H] + HPLC: 99.60% (220nm), 100.00% (254nm). Chiral purity: 99.92%ee. Isomer 2: 1H NMR (DMSO-d6, 400 MHz) δ 9.16 (s, 1H), 7.62 (s, 1H), 7.45 (s, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.54 (d, J = 7.2 Hz, 1H), 6.16 (t, J = 8.0Hz, 1H), 5.55 (d, J = 6.8 Hz, 1H), 5.07-5.04 (m, 1H), 4.85 (s, 2H), 3.43-3.40 (m, 4H), 2.31 (s, 3H), 1.91 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H), 1.47-1.46 (m, 4H), 0.99 (s, 6H). MS(ESI): Mass calculation value C 27 H 33 BN2O4 460.25, measured value in m / z: 461.3 [M+H] + HPLC: 99.75% (220nm), 100.00% (254nm). Chiral purity: 99.22%ee.

[0584] Example 5

[0585] [ka]

[0586] Preparation of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-amine A 10 mL mixture of dioxanes (3-bromopyridine-2-amine (1.00 g, 5.78 mmol, 1 equivalent), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (2.94 g, 11.56 mmol, 2 equivalents), Pd(dppf)Cl2 (211.46 mg, 289.00 μmol, 0.05 equivalents), and KOAc (1.99 g, 20.23 mmol, 3.5 equivalents)) was degassed and purged three times with N2. The reaction mixture was then heated to 100°C and stirred at 100°C for 16 hours under an N2 atmosphere. The reaction mixture was cooled to 20°C and filtered through a Celite pad. The filtration cake was washed with DCM (5 mL x 2), and the filtrate was concentrated under reduced pressure to obtain the residue. The crude product was ground with MTBE / petroleum ether (20 mL, v / v=1:5) at 20°C for 10 minutes, and the resulting precipitate was collected by filtration. This yielded the title compound (750 mg, 3.41 mmol, yield 58.96%) as an off-white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 8.04 (dd, J = 4.8, 2.4 Hz, 1H), 7.67 (dd, J = 7.2, 2.4 Hz, 1H), 6.51 (dd, J = 7.2, 4.8 Hz, 1H), 6.06 (s, 1H), 1.29 (s, 12H).

[0587] Preparation of 2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-8-[1-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]amino]ethyl]chromen-4-one To a CH3CN (5 mL) solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-amine (494 mg, 2.24 mmol, 2.2 equivalents) and 8-(1-bromoethyl)-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (400 mg, 1.02 mmol, 1 equivalent), NaHCO3 (257 mg, 3.06 mmol, 119.01 μL, 3 equivalents) was added in one go. The reaction mixture was heated to 70°C and stirred at 70°C for 12 hours. The reaction mixture was cooled to 25°C, filtered through a Celite pad, and the filter cake was washed with CH3CN (10 mL x 2). The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (Biotage®; 20 g SepaFlash® Silica Flash Column, eluent: 0-100% ethyl acetate / petroleum ether gradient, flow rate 60 mL / min) to obtain the title compound (120 mg, 225.78 μmol, yield 22.14%) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 8.06 (dd, J = 5.2, 2.0 Hz, 1H), 7.69 (dd, J = 7.2, 2.8 Hz, 1H), 7.42 (s, 1H), 6.68 (s, 1H), 6.68 (d, J = 6.8 Hz, 1H), 6.52 (dd, J = 7.2, 5.2 Hz, 1H), 5.67 (t, J = 7.2 Hz, 1H), 3.37 (t, J = 6.8 Hz, 4H), 2.35 (s, 3H), 1.91 (s, 3H), 1.56 (d, J = 6.8 Hz, 3H), 1.47-1.42 (m, 4H), 1.28 (d, J = 13.2 Hz, 12H), 0.97 (s, 6H).

[0588] Preparation of [2-[1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromene-8-yl]ethylamino]-3-pyridyl]boronic acid To a solution of 2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-8-[1-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]amino]ethyl]chromen-4-one (100 mg, 188.15 μmol, 1 equivalent) in THF (2 mL) / H2O (2 mL), NH4OAc (73 mg, 940.75 μmol, 5 equivalents) and NaIO4 (201 mg, 940.75 μmol, 52.13 μL, 5 equivalents) were added in one go at 20°C, and the reaction mixture was stirred at 20°C for 1 hour. The reaction was stopped by adding saturated Na2SO3 aqueous solution (3 mL) at 20°C to the reaction mixture, and then extracted with ELISA (2 mL x 3). The combined organic layers were washed with saturated saline (3 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by prep HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; mobile phase: [H₂O (10 mM NH₄HCO₃)-ACN]; gradient: 35% to 65% B over 8.0 min). The eluent was freeze-dried to obtain the title compound (34.8 mg, 75.30 μmol, yield 40.02%) as an off-white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 8.49 (s, 2H), 7.94 (dd, J = 6.8, 2.0 Hz, 1H), 7.86 (dd, J = 7.2, 2.0 Hz, 1H), 7.61 (s, 1H), 7.43-7.41 (m, 2H), 6.45 (dd, J = 6.8, 4.8 Hz, 1H), 5.64 (q, J = 6.8 Hz, 1H), 3.35 (t, J = 5.2 Hz, 4H), 2.31 (s, 3H), 1.89 (s, 3H), 1.50 (d, J = 6.8 Hz, 3H), 1.42-1.37 (m, 4H), 0.96 (s, 6H). MS(ESI): Mass calculation value C 25 H 32 BN3O4449.25, measured value in m / z: 450.1 [M+H] + . HPLC: 97.23% (220nm), 99.19% (254nm).

[0589] Preparation of [2-[[(1S)-1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromemen-8-yl]ethyl]amino]-3-pyridyl]boronic acid and [2-[[(1R)-1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromemen-8-yl]ethyl]amino]-3-pyridyl]boronic acid [2-[1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromene-8-yl]ethylamino]-3-pyridyl]boronic acid (30 mg, 66.76 μmol, 1 equivalent) was separated by SFC (column: REGIS(s,s)WHELK-O1 (250 mm × 30 mm, 5 μm); mobile phase: [CO2-EtOH]; B%: 50%, isoconcentration elution mode). This yielded isomer 1 (6.0 mg, 13.35 μmol, yield 20.00%), the title compound, as a white solid, and isomer 2 (8.1 mg, 18.03 μmol, yield 27.00%), the title compound, as a white solid. Isomer 1: 1 H NMR (DMSO-d6, 400 MHz) δ 8.48 (s, 2H), 7.94 (d, J = 3.2 Hz, 1H), 7.86 (d, J = 5.6 Hz, 1H), 7.61 (s, 1H), 7.42 (s, 2H), 6.48-6.44 (m, 1H), 5.69-5.61 (m, 1H), 3.52-3.47 (m, 4H), 2.33 (s, 3H), 1.91 (s, 3H), 1.54-1.41 (m, 7H), 0.96 (s, 6H). MS(ESI): Mass calculation value C 25 H 32 BN3O4449.25, measured value in m / z: 450.3 [M+H] + . HPLC: 98.75% (220nm), 99.23% (254nm). Isomer 2: 1H NMR (DMSO-d6, 400 MHz) δ 8.51 (s, 2H), 7.94 (d, J = 3.2 Hz, 1H), 7.86 (d, J = 6.0 Hz, 1H), 7.61 (s, 1H), 7.43-7.40 (m, 2H), 6.48-6.44 (m, 1H), 5.68-5.61 (m, 1H), 3.53-3.46 (m, 4H), 2.33 (s, 3H), 1.90 (s, 3H), 1.54-1.41 (m, 7H), 0.96 (s, 6H). MS(ESI): Mass calculation value C 25 H 32 BN3O4449.25, measured value in m / z: 450.3 [M+H] + . HPLC: 98.52% (220nm), 99.37% (254nm).

[0590] Example 6

[0591] [ka]

[0592] Preparation of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-3-amine A mixture of tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-thienyl]carbamate (276 mg, 848 μmol, 1 equivalent) and HCl / siRNA (3 mL) was stirred at 20°C for 3 hours. The reaction mixture was then concentrated under reduced pressure to obtain the title compound (266 mg, 1.02 mmol, yield 59.92%, HCl) as a white solid. 1 1H NMR (CDCl 3, 400 MHz) δ 7.92 (s, 1H), 7.84 (s, 1H), 1.38-1.36 (s, 12H).

[0593] Preparation of 2-(4,4-dimethylpiperidine-1-yl)-3,6-dimethyl-8-(1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-3-yl)amino)ethyl)-4H-chromen-4one To a 3 mL solution of 2-(4,4-dimethylpiperidine-1-yl)-3,6-dimethyl-8-(1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-3-yl)amino)ethyl)-4H-chromen-4-one (266 mg, 1.02 mmol, 1 equivalent, HCl) in DMF (3 mL), 8-(1-bromoethyl)-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (362 mg, 923 μmol, 0.9 equivalents) and NaHCO3 (152 mg, 1.82 mmol, 70.6 μL, 1.79 equivalents) were added in a single addition, and the reaction mixture was stirred at 40°C for 2 hours. After cooling to room temperature, water (3 mL) was added to the reaction mixture, thereby forming a white solid. The solid was then filtered, and the filtered cake was dried under reduced pressure to obtain the title compound (500 mg, crude). This compound was used directly in the next step without further purification.

[0594] Preparation of [4-[1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromene-8-yl]ethylamino]-3-thienyl]boronic acid To a solution of 2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-8-[1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-thienyl]amino]ethyl]chromen-4-one (500 mg, 931 μmol, 1 equivalent) in THF (4.5 mL) / H2O (1.5 mL), NaIO4 (598 mg, 2.80 mmol, 155 μL, 3 equivalents) and NH4OAc (216 mg, 2.80 mmol, 3 equivalents) were sequentially added at 20°C, and the reaction mixture was stirred at 50°C for 5 hours. After cooling to room temperature, the reaction mixture was diluted with H2O (10 mL) and extracted with ELISA (10 mL x 3). The combined organic layer was washed with saturated brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by prep HPLC (FA conditions, column: Phenomenex luna C18 100×40mm×5μm; mobile phase: [H2O(0.2%FA)-ACN], gradient: 25%~65%B over 8.0 mins) to obtain the title compound (43.2 mg, 92.2 μmol, yield 9.89%) as a yellow solid. 1 1H NMR (DMSO-d 6, 400 MHz) δ 8.33 (s, 2H), 7.84 (d, J =2.8 Hz, 1H), 7.61 (s, 1H), 7.44 (s, 1H), 6.18 (d, J =5.6 Hz, 1H), 5.54 (d, J =3.2 Hz, 1H), 4.78 (t, J =12.8 Hz, 1H), 3.40-3.39 (m, 4H), 2.32 (s, 3H), 1.91 (s, 3H), 1.51 (d, J =6.8 Hz, 3H), 1.45-1.47 (m, 4H),0.98 (s, 6H).

[0595] Example 7

[0596] [ka]

[0597] Preparation of (3-amino-2-bromophenyl)methanol To a 20 mL solution of DCM containing DIBAL-H (1 M in THF, 65.20 mL, 3 equivalents), a 10 mL solution of DCM containing methyl 3-amino-2-bromobenzoate (5.00 g, 21.73 mmol, 1 equivalent) was added dropwise at 0°C, and the mixture was stirred at 0°C for 2 hours. 20 g of Na2SO4·10H2O (at 0°C) was added to stop the reaction, and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The crude product was ground with MTBE (30 mL) at 20°C for 30 minutes, filtered, and the title compound (3.30 g, 16.33 mmol, yield 75.15%) was obtained as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 7.04 (t, J = 7.6 Hz, 1H), 6.71 (t, J = 8.0 Hz, 2H), 5.24 (t, J = 5.6 Hz, 3H), 4.42 (d, J = 5.6 Hz, 2H).

[0598] Preparation of 8-[1-[2-bromo-3-(hydroxymethyl)anilino]ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one To a solution of 8-(1-bromoethyl)-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (500 mg, 1.27 mmol, 1 equivalent) in CH3CN (5 mL) / H2O (1 mL), (3-amino-2-bromophenyl)methanol (515 mg, 2.55 mmol, 2 equivalents) and Cs2CO3 (830 mg, 2.55 mmol, 2 equivalents) were sequentially added at 20°C, and the reaction mixture was stirred at 80°C for 1.5 hours. After cooling to room temperature, the reaction mixture was diluted with H2O (10 mL) and extracted with  (10 mL × 3). The combined organic layers were washed with saturated brine (10 mL × 2), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to obtain the title compound as a yellow oil (460 mg, 895.87 μmol, yield 70.30%). 1H NMR (DMSO-d6, 400 MHz) δ 7.62 (s, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.36 (d, J = 8.0 Hz, 1H), 5.32-5.28 (m, 2H), 5.08-5.00 (m, 1H), 4.46 (d, J = 5.6 Hz, 2H), 3.44-3.40 (m, 4H), 2.31 (s, 3H), 1.92 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H), 1.49-1.45 (m, 4H), 0.99 (s, 6H).

[0599] Preparation of 2-bromo-3-[1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromene-8-yl]ethylamino]benzaldehyde To a solution of 8-[1-[2-bromo-3-(hydroxymethyl)anilino]ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (200 mg, 389.51 μmol, 1 equivalent) in CHCl3 (2 mL), MnO2 (338 mg, 3.90 mmol, 10 equivalents) was added in divided portions at 20 °C, and the reaction mixture was stirred at 50 °C for 12 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound as a yellow oil (190 mg, 371.49 μmol, yield 95.37%). 1 H NMR (DMSO-d6, 400 MHz) δ 10.25 (s, 1H), 7.64 (s, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.08-7.05 (m, 1H), 6.73 (d, J = 7.2 Hz, 1H), 5.72 (d, J = 6.8 Hz, 1H), 5.13-5.06 (m, 1H), 3.43-3.39 (m, 4H), 2.31 (s, 3H), 1.92 (s, 3H), 1.66 (d, J = 6.4 Hz, 3H), 1.47-1.43 (m, 4H), 0.98 (s, 6H).

[0600] Preparation of 3-[1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromene-8-yl]ethylamino]-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde To a 15 mL solution of 2-bromo-3-[1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromene-8-yl]ethylamino]benzaldehyde (480 mg, 938.51 μmol, 1 equivalent) in dioxane (1), B2Pin2 (1.19 g, 4.69 mmol, 5 equivalents), KOAc (276 mg, 2.82 mmol, 3 equivalents), and Pd(PPh3)2Cl2 (66 mg, 93.85 μmol, 0.1 equivalent) were sequentially added at 20°C, and the reaction mixture was stirred at 80°C for 12 hours under N2. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to obtain the title compound (490 mg, 877.33 μmol, yield 93.48%) as a yellow oil. 1 H NMR (DMSO-d6, 400 MHz) δ 10.12 (s, 1H), 7.64 (s, 1H), 7.40 (d, J = 1.6 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 5.74 (d, J = 6.0 Hz, 1H), 5.08-5.01 (m, 1H), 3.38-3.35 (m, 4H), 2.32 (s, 3H), 1.91 (s, 3H), 1.57 (d, J = 6.4 Hz, 3H), 1.44-1.40 (m, 4H), 1.16 (s, 12H), 0.96 (s, 6H).

[0601] Preparation of 2-(4,4-dimethyl-1-piperidyl)-8-[1-[(1-hydroxy-2,3,1-benzoxazavolinin-8-yl)amino]ethyl]-3,6-dimethyl-chromen-4-one To a solution of 3-[1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromene-8-yl]ethylamino]-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (440 mg, 787.80 μmol, 1 equivalent) in EtOH (10 mL), hydroxylamine hydrochloride (109 mg, 1.58 mmol, 2 equivalents) was added in one go at 20°C, and the reaction mixture was stirred at 20°C for 12 hours. The reaction mixture was diluted with H2O (10 mL), and the resulting suspension was filtered directly. The filtered cake was ground with CH3CN (5 mL) and further purified by prep HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 5 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 47% to 77% B over 8.0 mins) to obtain the title compound (120 mg, 253.50 μmol, yield 32.18%) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.78 (s, 1H), 8.44 (s, 1H), 7.64 (s, 1H), 7.44-7.39 (m, 2H), 6.84-6.81 (m, 2H), 6.51 (d, J = 8.4 Hz, 1H), 5.09-5.02 (m, 1H), 3.42-3.38 (m, 4H), 2.31 (s, 3H), 1.92 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H), 1.47-1.43 (m, 4H), 0.97 (s, 6H). MS(ESI): Mass calculation value C 27 H 32 BN3O4473.25, measured value in m / z: 474.3 [M+H] + . HPLC: 96.51% (220nm), 96.06% (254nm).

[0602] Preparation of 2-(4,4-dimethyl-1-piperidyl)-8-[(1S)-1-[(1-hydroxy-2,3,1-benzoxazavolinin-8-yl)amino]ethyl]-3,6-dimethyl-chromen-4-one and 2-(4,4-dimethyl-1-piperidyl)-8-[(1R)-1-[(1-hydroxy-2,3,1-benzoxazavolinin-8-yl)amino]ethyl]-3,6-dimethyl-chromen-4-one 2-(4,4-dimethyl-1-piperidyl)-8-[1-[(1-hydroxy-2,3,1-benzoxazavolinin-8-yl)amino]ethyl]-3,6-dimethyl-chromen-4-one (60 mg, 126.75 μmol, 1 equivalent) was separated by SFC (column: ChiralPak IH, 250 × 30 mm × 10 μm; mobile phase: [CO2-EtOH]; B%: 35%, isoconcentration elution mode), and further separated by prepHPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 5 μm; mobile phase: [H2O (10 mM)]). [NH4HCO3)-ACN]; gradient: Purified by 42%~70% B) over 8.0 mins, isomer 1 (10.4 mg, 21.97 μmol, yield 17.33%), the title compound, was obtained as a white solid, and isomer 2 (10.1 mg, 21.34 μmol, yield 16.83%), the title compound, was obtained as a white solid. Isomer 1: 1 H NMR (DMSO-d6, 400 MHz) δ 9.79 (s, 1H), 8.44 (s, 1H), 7.64 (s, 1H), 7.43-7.39 (m, 2H), 6.84-6.82 (m, 2H), 6.50 (d, J = 8.4 Hz, 1H), 5.07-5.03 (m, 1H), 3.42-3.39 (m, 4H), 2.31 (s, 3H), 1.92 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H), 1.46-1.44 (m, 4H), 0.97 (s, 6H). MS(ESI): Mass calculation value C 27 H 32 BN3O4473.25, measured value in m / z: 474.2 [M+H] +HPLC: 94.77% (220nm), 96.58% (254nm). Chlorine purity: 99.68% ee. Heterogeneous component 2: 1 ¹H NMR (DMSO-d⁶, 400 MHz) δ 9.79 (s, 1H), 8.44 (s, 1H), 7.64 (s, 1H), 7.43–7.39 (m, 2H), 6.84–6.82 (m, 2H), 6.52 (d, J = 8.4 Hz, 1H), 5.07–5.04 (m, 1H), 3.42–3.39 (m, 4H), 2.31 (s, 3H), 1.92 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H), 1.46–1.44 (m, 4H), 0.98 (s, 6H). MS (ESI): Calculated mass value C 27 H 32 BN3O4 473.25, m / z measured value 474.3 [M+H] + HPLC: 93.61% (220nm), 96.02% (254nm). Kiral purity: 97.36% ee.

[0603] Example 8

[0604]

change

[0605] 2-アミノ-6-ブロモbenzoic acid メチルの preparation To a 20 mL solution of 2-amino-6-bromobenzoic acid (1.87 g, 8.66 mmol, 1 equivalent) and K2CO3 (1.44 g, 10.39 mmol, 1.2 equivalents) in DMF (20 mL), MeI (1.47 g, 10.39 mmol, 646.66 μL, 1.2 equivalents) was added dropwise at 25°C, and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was stopped by adding 50 mL of water at 25°C, and extracted with RINKAN (30 mL x 3). The combined organic layers were washed with saturated brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent: 0-3% ethyl acetate / petroleum ether gradient, flow rate 75 mL / min) to obtain the title compound (1.30 g, 5.65 mmol, yield 65.28%) as a yellow oil. 1 1H NMR (DMSO-d 6, 400 MHz) δ 7.02 (t, J = 8.0 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.70 (dd, J = 8.0 Hz, 1H), 5.66 (s, 2H), 3.82 (s, 3H).

[0606] Preparation of 2-bromo-6-[1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromene-8-yl]ethylamino]methyl benzoate To a solution of methyl 2-amino-6-bromobenzoate (500 mg, 2.17 mmol, 2 equivalents) and 8-(1-bromoethyl)-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (426 mg, 1.09 mmol, 1 equivalent) in MeCN (3 mL), Cs2CO3 (708 mg, 2.17 mmol, 2 equivalents) was added in fractions, and the reaction mixture was stirred at 60°C for 5 hours. After cooling to room temperature, the reaction mixture was stopped by adding H2O (10 mL) at 20°C, and then extracted with siRNA (10 mL x 3). The combined organic layer was washed with saturated brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain the title compound (300 mg, crude) as a yellow solid. This compound was used directly in the next step without further purification.

[0607] Preparation of 2-((1-(2-(4,4-dimethylpiperidine-1-yl)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)amino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl benzoate A mixture of 2-bromo-6-[1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromene-8-yl]ethylamino]methyl benzoate (150 mg, 277.02 μmol, 1 equivalent), B2Pin2 (352 mg, 1.39 mmol, 5 equivalents), KOAc (82 mg, 831.06 μmol, 3 equivalents), and Pd(PPh3)2Cl2 (20 mg, 27.70 μmol, 0.1 equivalent) in 3 mL of dioxane was degassed and purged three times with N2. The mixture was then stirred at 80°C for 10 hours under an N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (Biotage®; 4 g SepaFlash® Silica Flash Column, eluent: 0-20% ethyl acetate / petroleum ether gradient, flow rate 75 mL / min) to obtain the title compound (150 mg, 254.87 μmol, yield 92.00%) as a white solid. 1 1H NMR (DMSO-d 6, 400 MHz) δ 7.79 - 7.77 (d, J = 10.8 Hz, 1H), 7.68 (s, 1H), 7.43 (s, 1H), 7.26 (s, 1H), 6.61 - 6.58 (m, 2H), 5.15-5.10 (m, 1H), 3.47 - 3.44 (m, 4H), 2.35 (s, 3H), 1.96 (s, 3H), 1.66 (s, 3H), 1.5 (s, 4H), 1.11 (s, 12H), 1.03 (s, 6H).

[0608] Preparation of 2-(4,4-dimethylpiperidine-1-yl)-8-(1-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-4-yl)amino)ethyl)-3,6-dimethyl-4H-chromen-4one To a solution of 2-[1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromene-8-yl]ethylamino]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl benzoate (230 mg, 390.80 μmol, 1 equivalent) in THF (3 mL), NaBH4 (40 mg, 1.06 mmol, 2.71 equivalents) was added in one go, and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was stopped by adding saturated NH4Cl aqueous solution (15 mL) at 0°C, and extracted with EA (15 mL x 3). The combined organic layer was washed with saturated saline solution (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was subjected to prepHPLC (basic conditions: column: Phenomenex Gemini NXC). 18 The sample was purified using a (75×30mm×3μm) mobile phase [H2O(0.05% NH3H2O+10mM NH4HCO3)-ACN] and a gradient of 30% to 70% B over 8.0 minutes, yielding the title compound (40 mg, 84.95 μmol, yield 21.74%) as a white solid. 1 1H NMR (DMSO-d 6, 400 MHz) δ 8.98 (s, 1H), 7.60 (s, 1H), 7.47 (d, J = 1.9 Hz, 1H), 7.04 - 6.84 (m, 2H), 6.30 (d, J = 7.8 Hz, 1H), 5.68 (d, J = 6.9 Hz, 1H), 5.10 - 4.87 (m, 3H), 3.42 (d, J = 2.0 Hz, 4H), 2.29 (s, 3H), 1.92 (s, 3H), 1.55 (d, J = 6.8 Hz, 3H), 1.47 (d, J = 3.6 Hz, 4H), 0.98 (s, 6H). MS(ESI): Mass calculation value C 27 H 33 BN2O4 460.25, measured value in m / z: 461.3 [M+H] + . HPLC: 97.77% (220nm), 99.24% (254nm).

[0609] Preparation of (S)-2-(4,4-dimethylpiperidine-1-yl)-8-(1-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-4-yl)amino)ethyl)-3,6-dimethyl-4H-chromen-4-one and (R)-2-(4,4-dimethylpiperidine-1-yl)-8-(1-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabolol-4-yl)amino)ethyl)-3,6-dimethyl-4H-chromen-4-one 2-(4,4-dimethyl-1-piperidyl)-8-[1-[(1-hydroxy-3H-2,1-benzoxabolol-4-yl)amino]ethyl]-3,6-dimethylchromen-4-one (40 mg) was separated by SFC (column: ChiralPak IH, 250 × 30 mm × 10 μm; mobile phase: [CO2-EtOH (0.1% NH3.H2O)]; B%: 40%, isoconcentration elution mode). Isomer 1 (18.3 mg, 39.75 μmol, yield 45.75%), the title compound, was obtained as a white solid, and isomer 2 (16.1 mg, 34.97 μmol, yield 40.25%), the title compound, was also obtained as a white solid. Isomer 1: 1 1H NMR (DMSO-d 6, 400 MHz) δ 8.97 (s, 1H), 7.60 (s, 1H), 7.47 (d, J = 2.0 Hz, 1H), 6.98 - 6.96 (m, 1H), 6.93-6.91 (m, 1H), 6.30 (d, J = 7.6 Hz, 1H), 5.67 (d, J = 6.8 Hz, 1H), 5.05 - 4.90 (m, 3H), 3.43 (s, 4H), 2.29 (s, 3H), 1.93 (s, 3H), 1.55 (d, J = 6.8 Hz, 3H), 1.47-1.46 (m, 4H), 0.99 (s, 6H). MS(ESI): Mass calculation value C 27 H 33 BN2O4 460.25, measured value in m / z: 461.2 [M+H] + HPLC: 98.73% (220nm), 100.00% (254nm). Chiral purity: 100%ee. Isomer 2: 1 1H NMR (DMSO-d6, 400 MHz) δ 8.97 (s, 1H), 7.60 (s, 1H), 7.47 (d, J = 1.6 Hz, 1H), 6.98 - 6.96 (m, 1H), 6.93-6.91 (m, 1H), 6.31 (d, J = 7.6 Hz, 1H), 5.67 (d, J = 6.8 Hz, 1H), 5.05 - 4.90 (m, 3H), 3.43-3.41 (s, 4H), 2.29 (s, 3H), 1.93 (s, 3H), 1.55 (d, J = 6.8 Hz, 3H), 1.47-1.46 (m, 4H), 0.99 (s, 6H). MS(ESI): Mass calculation value C 27 H 33 BN2O4 460.25, measured value in m / z: 461.2 [M+H] + HPLC: 99.75% (220nm), 100.00% (254nm). Chiral purity: 99.90%ee.

[0610] Example 9

[0611] [ka]

[0612] Preparation of 7-[1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethylamino]-1-hydroxy-2,1-benzoxabol-3-one A mixture of methyl 3-[1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromene-8-yl]ethylamino]-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (350 mg, 595 μmol, 1 equivalent) and LiOH·H2O (249 mg, 5.95 mmol, 10 equivalents) in THF (2 mL) / H2O (1 mL) was stirred at 20°C for 2 hours. The reaction mixture was concentrated under vacuum, and the residue was poured into ice water (w / w=1 / 1) (10 mL). The aqueous phase was acidified to pH=7 with HCl (2 N) and extracted with ELISA (20 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by prep HPLC (column: Waters Xbridge BEH C18 100×30mm×10μm; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 10%~40%B over 8.0 minutes) to obtain the title compound (80.4 mg, 159.36 μmol, yield 26.80%) as a white solid. 1 H NMR (DMSO+D2O-d6, 400 MHz) δ 7.59 (s, 1H), 7.54 (s, 1H), 6.81-6.77 (m, 1H), 6.72-6.70 (m, 1H), 6.04 (d, J = 7.2 Hz, 1H), 4.95-4.91 (m, 1H), 3.45 (s, 4H), 2.25 (s, 3H), 1.89 (s, 3H), 1.48-1.43 (m, 7H), 0.93 (d, J = 7.2 Hz, 6H). MS(ESI): Mass calculation value C 27 H 31 BN2O5474.23, measured value in m / z: 475.2 [M+H] + . HPLC: 94.17% (220nm), 95.27% (254nm).

[0613] Example 10

[0614] [ka]

[0615] Preparation of 1,4-dibromo-2-(dimethoxymethyl)benzene To a solution of 2,5-dibromobenzaldehyde (100 g, 378.91 mmol, 1 equivalent) and trimethoxymethane (80.42 g, 757.82 mmol, 83.08 mL, 2 equivalents) in MeOH (1000 mL), H2SO4 (1.11 g, 11.37 mmol, 0.03 equivalents) (3 drops) was added dropwise at 20°C, and the mixture was heated to 60°C and stirred at 60°C for 16 hours. For workup, the three parallel reactions were combined. The combined reaction mixture was cooled to 20°C, adjusted to pH=8 with MeONa (30% in MeOH), and concentrated under reduced pressure. The residue was dissolved in siRNA (1500 mL), washed with H2O (1500 mL) and saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. This yielded the title compound (310 g, 1 mol, yield 88.0%) as a pale yellow oil. 1 H NMR (CDCl3, 400 MHz) δ 7.75 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.33 (dd, J = 8.4, 2.4 Hz, 1H), 5.51 (s, 1H), 3.39 (s, 6H).

[0616] Preparation of (4-bromo-2-formylphenyl)boronic acid To a solution of 1,4-dibromo-2-(dimethoxymethyl)benzene (130 g, 419.38 mmol, 1 equivalent) in THF (1300 mL), n-BuLi (2.5 M, 167.8 mL, 1 equivalent) was added dropwise at -78°C, and the mixture was stirred at -78°C for 15 minutes. Then, B(OMe)3 (66 g, 629.07 mmol, 71.05 mL, 1.5 equivalents) was added dropwise at -78°C, and the mixture was stirred at -78°C for 30 minutes. For workup, the two parallel reactions were combined. The combined mixture was heated to 0°C, the reaction was stopped with NH4Cl aqueous solution (600 mL) at 0°C, and extracted with siRNA (1000 mL x 2). The combined organic layer was washed with saturated brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was dissolved in THF (3000 mL) and treated with HCl (4N, 4.08 L, 21 equivalents). The resulting mixture was stirred at 20°C for 15 minutes and then directly extracted with RINKAN (1000 mL x 2). The combined organic layers were washed with saturated brine, dried over Na₂SO₄, and concentrated under reduced pressure to obtain the title compound (150 g, crude) as a pale yellow solid. This product was used directly in the next step without further purification.

[0617] Preparation of 6-bromo-1-hydroxy-2,3,1-benzoxazavolinin To a mixture of (4-bromo-2-formylphenyl)boron (150 g, 655.49 mmol, 1 equivalent) and EtOH (3000 mL), a solution of NH2OH.HCl (91 g, 1.31 mol, 2 equivalents) in H2O (400 mL) was added dropwise at 20°C, and the mixture was stirred at 20°C for 0.5 hours. The mixture was diluted with H2O (400 mL) at 20°C, and the resulting suspension was filtered directly. The filtered cake was washed with H2O (100 mL), dried under reduced pressure, and the title compound (60 g, 265.68 mmol, 31.7% yield in 2 steps) was obtained as an off-white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.55 (s, 1H), 8.64 (s, 1H), 8.04 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.93 (dd, J = 7.6, 1.6 Hz, 1H).

[0618] Preparation of (2-bromo-4-methylphenyl)propanoate To a solution of 2-bromo-4-methylphenol (900.00 g, 4.81 mol, 1 equivalent) and pyridine (570.94 g, 7.22 mol, 582.59 mL, 1.5 equivalents) in DCM (2000 mL), propanoyl chloride (489.74 g, 5.29 mol, 489.74 mL, 1.1 equivalents) was added dropwise at 0°C. The mixture was heated to 20°C and stirred at 20°C for 0.5 hours. The reaction mixture (combined 100 g batches) was poured into water (1000 mL), adjusted to pH=2 with HCl (3N), and then extracted with DCM (1000 mL x 3). The combined organic layer was washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. This yielded the title compound (1300 g, crude) as a pale yellow oil. 1 H NMR (DMSO-d6, 400 MHz) δ 7.52 (s, 1H), 7.22 (dd, J = 1.2, 8.4 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 2.62 (q, J = 7.6 Hz, 2H), 2.30 (s, 3H), 1.17 (t, J = 7.6 Hz, 3H).

[0619] Preparation of 1-(3-bromo-2-hydroxy-5-methylphenyl)propan-1-one A mixture of (2-bromo-4-methylphenyl)propanoate (300 g, 1.23 mol, 1 equivalent) and AlCl3 (329.10 g, 2.47 mol, 2 equivalents) was heated to 140°C and stirred at 140°C for 1 hour. For workup, the five reactions were combined. The combined reaction mixture was cooled to 20°C, poured into ice water (5000 mL), and extracted with ethyl acetate (2000 mL x 3). The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The crude product was ground with PE and ethyl acetate (PE / ethyl acetate = 100 / 1; 2 L) at 20°C for 30 minutes to obtain the title compound (900 g, 3.70 mol, 69.2% yield in 2 steps) as a brown solid. 1H NMR (DMSO-d6, 400 MHz) δ 12.66 (s, 1H), 7.81 (d, J = 1.2 Hz, 1H), 7.71 (d, J = 1.2 Hz, 1H), 3.15 (q, J = 7.2 Hz, 2H), 2.28 (s, 3H), 1.10 (t, J = 7.2 Hz, 3H).

[0620] Preparation of 8-bromo-4-hydroxy-3,6-dimethylchromen-2-thion To a solution of 1-(3-bromo-2-hydroxy-5-methylphenyl)propan-1-one (300 g, 1.23 mol, 1 equivalent) in THF (3000 mL), KOtBu (415 g, 3.70 mol, 3 equivalents) was added in divided portions at 0°C, and the mixture was stirred at 0°C for 10 minutes. Then, CS2 (141 g, 1.85 mol, 111.60 mL, 1.5 equivalents) was added dropwise at 0°C. The resulting mixture was heated to 20°C and stirred at 20°C for 0.5 hours. For workup, the four reactions were combined. The combined mixture was poured into water (5000 mL), adjusted to pH=4 with HCl (2N), and extracted with HCl (1500 mL × 3). The combined organic layer was washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was ground in DCM (6 L) at 20°C for 10 minutes to obtain the title compound (900 g, 3.16 mol, yield 76.7%) as a yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ 7.81 (s, 1H), 7.78 (s, 1H), 2.39 (s, 3H), 2.26 (s, 3H).

[0621] Preparation of 8-bromo-2-ethylsulfanyl-3,6-dimethylchromen-4-one To a mixture of 8-bromo-4-hydroxy-3,6-dimethyl-chromen-2-thion (200 g, 701.37 mmol, 1 equivalent) and K2CO3 (116 g, 841.64 mmol, 1.2 equivalents) in acetone (2500 mL), EtI (459 g, 2.95 mol, 235.6 mL, 4.2 equivalents) was added dropwise at 20°C, and the mixture was heated to 60°C and stirred at 60°C for 2 hours. For workup, the five reactions were combined. The combined reaction mixture was cooled to 20°C, and the resulting suspension was filtered directly. The filtrate was diluted with siRNA (5000 mL), washed with H2O (2500 mL x 2), and then washed with saturated brine (1000 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was ground with PE (2L) to obtain the title compound (900g, 2.87mol, yield 91.0%) as an orange solid. 1 H NMR (DMSO-d6, 400 MHz) δ 7.88 (d, J = 1.6 Hz, 1H), 7.77 (d, J = 1.6 Hz, 1H), 3.30 (q, J = 7.2 Hz, 2H), 2.40 (s, 3H), 1.92 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H).

[0622] Preparation of 8-acetyl-2-ethylsulfanyl-3,6-dimethylchromen-4-one To a solution of 8-bromo-2-ethylsulfanyl-3,6-dimethylchromen-4-one (200 g, 638.55 mmol, 1 equivalent) in dioxane (2000 mL), tributyl(1-ethoxyvinyl) stanane (270 g, 747.10 mmol, 252.40 mL, 1.17 equivalents) was added dropwise at 20°C, and the mixture was stirred at 20°C for 10 minutes. Then, Pd(PPh3)2Cl2 (31.37 g, 44.70 mmol, 0.07 equivalents) was added in portions to the above mixture at 20°C, and the resulting mixture was heated to 95°C and stirred under N2 for 22 hours. The reaction mixture was cooled to 20°C, and HCl (200 mL, 2N) was added dropwise. Then, the mixture was stirred at 50°C for 0.5 hours. Six reactions were combined for workup. The combined reaction mixture was cooled to 20°C and diluted with saturated KF aqueous solution (4000 mL). The resulting suspension was then filtered directly. The filter cake was washed with Depositphotos (1500 mL x 3), and the filtrate was extracted with Depositphotos (1500 mL x 3). The combined organic phase was washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1~2 / 1) to obtain the title compound (700 g, yield 66.1%) as a yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ 8.01 (s, 2H), 3.30 (q, J = 7.2 Hz, 2H), 2.68 (s, 3H), 2.46 (s, 3H), 1.95 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H).

[0623] Preparation of 8-acetyl-2-ethylsulfinyl-3,6-dimethylchromen-4-one To a solution of 8-acetyl-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (200 g, 723.72 mmol, 1 equivalent) in DCM (2000 mL), m-CPBA (161.62 g, 796.09 mmol, 1.1 equivalents) was added in divided portions at 0°C. The mixture was heated to 20°C and stirred at 20°C for 1 hour. For workup, the five reactions were combined. The combined reaction mixture was filtered to obtain a filtrate. The filtrate was poured into a saturated Na2SO3 aqueous solution (6000 mL) and extracted with DCM (2000 mL x 3). The combined organic layer was washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was ground with MTBE (10 L) to obtain the title compound (423 g, yield 48.6%) as a yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ 8.06 (d, J = 1.6 Hz, 1H), 7.99 (d, J = 2.4 Hz, 1H), 3.26 (q, J = 7.6 Hz, 2H), 2.80 (s, 3H), 2.46 (s, 3H), 2.08 (s, 3H), 1.23 (t, J = 7.6 Hz, 3H). MS(ESI): Mass calculation value C 15 H 16 O4S 292.08, measured value in m / z 292.9 [M+H] + . HPLC: 84.94% (220nm), 84.43% (254nm).

[0624] Preparation of 8-acetyl-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one To a solution of 8-acetyl-2-ethylsulfinyl-3,6-dimethyl-chromen-4-one (130.00 g, 444.67 mmol, 1.0 equivalent) and 4,4-dimethylpiperidine hydrochloride (99.83 g, 667.01 mmol, 1.5 equivalents) in MeCN (1300 mL), DIPEA (172.41 g, 1.33 mol, 232.36 mL, 3 equivalents) was added dropwise at 20°C, and the mixture was stirred under reflux for 16 hours. For workup, the two parallel reactions were combined. The reaction mixture was cooled to 20°C and filtered directly. The filtered cake was washed with MeCN (300 mL) and dried in vacuum. The crude product was ground with MTBE (500 mL) at 20°C to obtain the title compound as a yellow solid (230 g, 702.47 mmol, yield 79.0%). 1 H NMR (CDCl3, 400 MHz) δ 8.16 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 3.44-3.41 (m, 4H), 2.71 (s, 3H), 2.45 (s, 3H), 2.04 (s, 3H), 1.53-1.50 (m, 4H), 1.03 (s, 6H).

[0625] Preparation of 2-(4,4-dimethyl-1-piperidyl)-8-(1-hydroxyethyl)-3,6-dimethyl-chromen-4-one To a solution of 8-acetyl-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (20.00 g, 61.1 mmol, 1 equivalent) in EtOH (200 mL), NaBH4 (2.68 g, 70.8 mmol, 1.16 equivalents) was added in divided portions over 20 minutes at 10°C under N2. The reaction mixture was heated to 20°C and stirred at 20°C for 15 hours. The reaction mixture was poured into 0°C ice water (300 mL) and extracted with DCM (120 mL x 3). The combined organic phase was washed with saturated saline (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. This yielded the title compound (20.0 g, 60.71 mmol, yield 99.39%) as a yellow solid. This compound was used in the next step without further purification. 1 1H NMR (DMSO-d6, 400 MHz) δ 7.62 (s, 1H), 7.57 (d, J = 2.0 Hz, 1H), 5.32 (d, J = 4.4 Hz, 1H), 5.25-5.18 (m, 1H), 3.40-3.34 (m, 4H), 2.39 (s, 3H), 1.89 (s, 3H), 1.46 (t, J = 5.6 Hz, 4H), 1.40 (d, J = 6.4 Hz, 3H), 0.99 (s, 6H).

[0626] Preparation of 8-(1-bromoethyl)-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one To a 100 mL solution of 2-(4,4-dimethyl-1-piperidyl)-8-(1-hydroxyethyl)-3,6-dimethyl-chromen-4-one (10.00 g, 30.4 mmol, 1 equivalent) in DCM (100 mL), PBr3 (9.86 g, 36.4 mmol, 3.46 mL, 1.2 equivalents) was added dropwise at 0°C under N2. The reaction mixture was then heated to 20°C and stirred at 20°C for 1 hour. For workup, the two parallel reactions were combined. The reaction mixture was stopped with 200 mL of saturated NaHCO3 aqueous solution at 0°C, the pH was adjusted to 7 with saturated NaHCO3 aqueous solution, and extracted with DCM (150 mL x 3). The combined organic layer was washed with saturated brine (200 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (Biotage®; 220 g SepaFlash® Silica Flash Column, eluent: 0-20% ethyl acetate / petroleum ether gradient, flow rate 100 mL / min) to obtain the title compound (11.20 g, 28.55 mmol, yield 47.02%) as a white solid. 1 1H NMR (CDCl3, 400 MHz) δ 7.95 (s, 1H), 7.52 (d, J = 2.0 Hz, 1H), 5.68 (q, J = 7.2 Hz, 1H), 3.49-3.45 (m, 4H), 2.45 (s, 3H), 2.15 (d, J =7.2 H, 3H), 2.05 (s, 3H), 1.57-1.53 ​​(m, 4H), 1.06 (s, 6H).

[0627] Preparation of 2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-8-[1-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]chromen-4-one A solution of 8-(1-bromoethyl)-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (0.50 g, 1.27 mmol, 1.00 equivalent) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (558 mg, 2.55 mmol, 2.00 equivalent) in DMF (5 mL) was stirred at 60°C for 4 hours. The reaction mixture was cooled to 20°C, diluted with water (20 mL), and extracted with MTBE (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. This yielded the title compound (0.70 g, crude) as a brown solid. This compound was used directly in the next step without further purification.

[0628] Preparation of 2-(4,4-dimethyl-1-piperidyl)-8-[1-[2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)anilino]ethyl]-3,6-dimethyl-chromen-4-one A mixture of 6-bromo-1-hydroxy-2,3,1-benzoxazavolinin (250 mg, 1.11 mmol, 1.00 equivalent), 2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-8-[1-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]chromen-4-one (587 mg, 1.11 mmol, 1.00 equivalent), K2CO3 (306 mg, 2.21 mmol, 2.00 equivalent), and Pd(dppf)Cl2 (81 mg, 110.70 μmol, 0.10 equivalent) in EtOH (5 mL) / H2O (2 mL) was degassed and purged three times with N2. The mixture was then stirred at 80°C for 2 hours under an N2 atmosphere. The reaction mixture was cooled to 20°C and filtered through a Celite pad. The filtered cake was washed with EtOH (10 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 250 × 50 mm × 10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 30% to 60% B over 8.0 mins) to obtain the title compound (180 mg, 312.88 μmol, yield 28.26%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 9.37 (s, 1H), 8.65 (s, 1H), 8.15 (d, J = 7.6 Hz, 1H), 7.84-7.82 (m, 2H), 7.61 (s, 1H), 7.48 (s, 1H), 7.11-7.04 (s, 1H), 6.71 (t, J = 7.2 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 5.05 (d, J = 6.4 Hz, 1H), 4.95-4.91 (m, 1H), 3.31-3.27 (m, 4H), 2.32 (s, 3H), 1.90 (s, 3H), 1.47 (d, J = 6.0 Hz, 3H), 1.39-1.35 (m, 4H), 0.95 (s, 6H). MS(ESI): Mass calculation value C 33 H 36 BN3O4549.28, measured value in m / z: 550.2 [M+H] + . HPLC: 95.51% (220nm), 96.98% (254nm).

[0629] Preparation of 2-(4,4-dimethyl-1-piperidyl)-8-[(1R)-1-[2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)anilino]ethyl]-3,6-dimethyl-chromen-4-one and 2-(4,4-dimethyl-1-piperidyl)-8-[(1S)-1-[2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)anilino]ethyl]-3,6-dimethyl-chromen-4-one 2-(4,4-dimethyl-1-piperidyl)-8-[1-[2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)anilino]ethyl]-3,6-dimethyl-chromen-4-one (180 mg, 309.39 μmol, 1.00 equivalent) was separated by SFC (column: DAIEL CHIRALCEL OD (250 mm × 30 mm × 10 μm); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 50%, isoconcentration elution mode). This yielded isomer 1 (61.9 mg, 111.30 μmol, yield 35.97%) as a white solid, and isomer 2 (77.6 mg, 140.38 μmol, yield 45.37%) as a white solid. Isomer 1: 1 H NMR (DMSO-d6, 400 MHz) δ 9.43 (s, 1H), 8.66 (s, 1H), 8.15 (d, J = 7.6 Hz, 1H), 7.85-7.82 (m, 2H), 7.60 (s, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.09-7.07 (m, 1H), 7.04 (d, J = 1.2 Hz, 1H), 6.71 (t, J = 7.6 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 5.06 (d, J = 6.8 Hz, 1H), 4.96-4.91 (m, 1H), 3.31-3.22 (m, 4H), 2.32 (s, 3H), 1.90 (s, 3H), 1.47 (d, J = 6.8 Hz, 3H), 1.40-1.38 (m, 4H), 0.95 (s, 6H). MS(ESI): Mass calculation value C 33H 36 BN3O4549.28, measured value in m / z: 550.2 [M+H] + HPLC: 98.80% (220nm), 100.00% (254nm). Chiral purity: 100%ee. Isomer 2: 1 H NMR (DMSO-d6, 400 MHz) δ 9.43 (s, 1H), 8.66 (s, 1H), 8.15 (d, J = 7.6 Hz, 1H), 7.85-7.82 (m, 2H), 7.60 (s, 1H), 7.48 (d, J = 1.2 Hz, 1H), 7.09-7.06 (m, 1H), 7.04 (d, J = 1.2 Hz, 1H), 6.71 (t, J = 7.6 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 5.06 (d, J = 6.8 Hz, 1H), 4.96-4.90 (m, 1H), 3.31-3.27 (m, 4H), 2.32 (s, 3H), 1.90 (s, 3H), 1.47 (d, J = 6.8 Hz, 3H), 1.40-1.35 (m, 4H), 0.95 (s, 6H). MS(ESI): Mass calculation value C 33 H 36 BN3O4549.28, measured value in m / z: 550.3 [M+H] + HPLC: 99.41% (220nm), 100.00% (254nm). Chiral purity: 99.16%ee.

[0630] Example 11

[0631] [ka]

[0632] Preparation of 2-bromo-3-[1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromene-8-yl]ethylamino]methyl benzoate To a 5 mL solution of 8-(1-bromoethyl)-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (500 mg, 1.27 mmol, 1 equivalent) in DMF (5 mL), methyl 3-amino-2-bromobenzoate (498 mg, 2.17 mmol, 1.7 equivalents) was added in one batch at 25 °C, and the reaction mixture was stirred at 60 °C for 4 hours. The reaction mixture was cooled to 0 °C, water (10 mL) was added to stop the reaction, and then extracted with siRNA (10 mL x 3). The combined organic layers were washed with saturated brine (10 mL x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (Biotage®; 20 g SepaFlash® Silica Flash Column, eluent: 0-40% ethyl acetate / petroleum ether gradient, flow rate 50 mL / min) to obtain the title compound (450 mg, 831.06 μmol, yield 65.21%) as a pale yellow solid. 1 1H NMR (CDCl 3, 400 MHz) δ 7.88 (s, 1H), 7.32 (s, 1H), 7.07-7.03 (m, 1H), 7.00-6.98 (m, 1H), 6.41 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 5.11 (d, J = 5.6 Hz, 1H), 5.02-4.98 (m, 1H), 3.93 (s, 3H), 3.42-3.39 (m, 4H), 2.36 (s, 3H), 2.06 (s, 3H), 1.68 (d, J = 6.8 Hz, 3H), 1.58 (s, 1H), 1.54-1.51 (m, 4H), 1.04 (s, 6H).

[0633] Preparation of 3-[1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromene-8-yl]ethylamino]-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl benzoate A mixture of 2-bromo-3-[1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromene-8-yl]ethylamino]methyl benzoate (450 mg, 831.06 μmol, 1 equivalent), B2Pin2 (1.06 g, 4.16 mmol, 5 equivalents), KOAc (245 mg, 2.49 mmol, 3 equivalents), and Pd(PPh3)2Cl2 (58 mg, 83.11 μmol, 0.1 equivalent) in 10 mL of dioxane was degassed and purged three times at 25°C with N2. The mixture was then heated to 80°C and stirred at 80°C for 12 hours under an N2 atmosphere. The reaction mixture was cooled to 25°C and filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (Biotage®; 20 g SepaFlash® Silica Flash Column, eluent: 0-35% ethyl acetate / petroleum ether gradient, flow rate 60 mL / min). The eluent was concentrated under reduced pressure to obtain the residue. The residue was purified by prep HPLC (column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 50%-90% B over 8.0 mins) to obtain the title compound (250 mg, crude) as a pale yellow oil. 1 1H NMR (DMSO-d 6, 400 MHz) δ 7.64 (s, 1H), 7.39 (s, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.55 (d, J = 8.4 Hz, 1H), 5.21 (d, J = 6.0 Hz, 1H), 5.04-5.01 (m, 1H), 3.78 (s, 3H), 3.37-3.34 (m, 4H), 2.31 (s, 3H), 1.91 (s, 3H), 1.55 (d, J = 6.4 Hz, 3H), 1.43-1.40 (m, 4H), 1.30 (s, 12H), 0.96 (s, 6H).

[0634] Preparation of 3-[[(1S)-1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl benzoate and 3-[[(1R)-1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]amino]-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl benzoate The residue was separated by SFC (column: DAIEL CHIRALPAKAD (250 mm × 30 mm × 10 μm); mobile phase: [CO2-IPA (0.1% NH3H2O)]; B%: 24%, isoconcentration elution mode). This yielded isomer 1 (80 mg, 132.05 μmol, yield 38.86%), the title compound, as a pale yellow oil, and isomer 2 (70 mg, 116.75 μmol, yield 34.36%), the title compound, as a white solid. Isomer 1: 1 1H NMR (DMSO-d 6, 400 MHz) δ 7.64 (s, 1H), 7.39 (s, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.55 (d, J = 8.0 Hz, 1H), 5.21 (d, J = 6.0 Hz, 1H), 5.04-5.01 (m, 1H), 3.78 (s, 3H), 3.38-3.35 (m, 4H), 2.32 (s, 3H), 1.91 (s, 3H), 1.55 (d, J = 6.4 Hz, 3H), 1.44-1.41 (m, 4H), 1.30 (s, 12H), 0.96 (s, 6H). Isomer 2: 1 1H NMR (DMSO-d 6,400 MHz) δ 7.64 (s, 1H), 7.39 (s, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.55 (d, J = 8.0 Hz, 1H), 5.21 (d, J = 6.4 Hz, 1H), 5.04-5.01 (m, 1H), 3.78 (s, 3H), 3.38-3.35 (m, 4H), 2.32 (s, 3H), 1.91 (s, 3H), 1.55 (d, J = 6.4 Hz, 3H), 1.44-1.41 (m, 4H), 1.30 (s, 12H), 0.96 (s, 6H).

[0635] Preparation of (S)-2-(4,4-dimethylpiperidine-1-yl)-8-(1-((1-hydroxy-3-oxo-1,3-dihydrobenzo[c][1,2]oxabolol-7-yl)amino)ethyl)-3,6-dimethyl-4H-chromen-4one 3-[[(1S)-1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromene-8-yl]ethyl]amino]-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl benzoate (30 mg, 50.97 μmol, 1 equivalent) in a THF (0.5 mL) / H2O (0.3 mL) solution, LiOH . H2O (6.42 mg, 152.92 μmol, 3 equivalents) was added in fractions at 0°C. The reaction mixture was then heated to 20°C and stirred at 20°C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 15%~45% B over 8.0 mins) to obtain isomer 1 (22.0 mg, 44.77 μmol, yield 87.84%), the title compound, as a white solid. 1 1H NMR (MeOD ,400 MHz) δ 7.79 (s, 1H), 7.69 (s, 1H), 7.23 (d, J = 7.2 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.45 (d, J = 8.0 Hz, 1H), 5.33-5.28 (m, 1H), 3.50-3.47 (m, 4H), 2.41 (s, 3H), 2.02 (s, 3H), 1.70 (d, J = 6.8 Hz, 3H), 1.55-1.52 (m, 4H), 1.05 (s, 6H). MS(ESI): Mass calculation value C 27 H 31 BN2O5474.23, measured value in m / z: 475.2 [M+H] + HPLC: 96.54% (220nm), 97.21% (254nm). Chiral purity: 100%ee.

[0636] Preparation of (R)-2-(4,4-dimethylpiperidine-1-yl)-8-(1-((1-hydroxy-3-oxo-1,3-dihydrobenzo[c][1,2]oxabolol-7-yl)amino)ethyl)-3,6-dimethyl-4H-chromen-4-one To a solution of 3-[[(1R)-1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromene-8-yl]ethyl]amino]-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl benzoate (50 mg, 84.96 μmol, 1 equivalent) in THF (0.5 mL) / H2O (0.3 mL), LiOH·H2O (11 mg, 254.87 μmol, 3 equivalents) was added in divided portions at 0°C, the reaction mixture was heated to 20°C, and stirred at 20°C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10μm; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 15%~45%B over 8.0 mins). The title compound, isomer 2 (34.5 mg, 69.75 μmol, yield 82.10%), was obtained as a white solid. 1 1H NMR (MeOD ,400 MHz) δ 7.80 (s, 1H), 7.69 (s, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.46 (d, J = 7.6 Hz, 1H), 5.33-5.31 (m, 1H), 3.49-3.47 (m, 4H), 2.41 (s, 3H), 2.02 (s, 3H), 1.70 (d, J = 6.8 Hz, 3H), 1.55-1.52 (m, 4H), 1.05 (s, 6H). MS(ESI): Mass calculation value C 27 H 31 BN2O5474.23, measured value in m / z: 475.2 [M+H] + HPLC: 95.90% (220nm), 96.84% (254nm). Chiral purity: 97.76%ee.

[0637] Example 12

[0638] [ka]

[0639] Preparation of 8-(1-hydroxyethyl)-3,6-dimethyl-4H-chromen-4-one To a solution of 8-acetyl-2-ethylsulfanyl-3,6-dimethyl-chromen-4-one (4.00 g, 14.47 mmol, 1 equivalent) in EtOH (100 mL), Raney nickel (1.24 g, 14.47 mmol, 1 equivalent) was added under N2 conditions. The suspension was degassed under vacuum and purged several times with N2. The resulting reaction mixture was stirred under N2 conditions at 20°C for 32 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain the title compound (4.00 g, crude) as a yellow solid. This compound was used directly in the next step without further purification. 1 H NMR (CDCl3, 400 MHz) δ 7.89 (s, 1H), 7.79 (s, 1H), 7.63 (s, 1H), 5.43-5.39 (m, 1H), 2.44 (s, 3H), 2.03 (s, 3H), 1.55 (d, J = 6.4Hz, 3H).

[0640] Preparation of 8-(1-bromoethyl)-3,6-dimethylchromen-4-one To a solution of 8-(1-hydroxyethyl)-3,6-dimethyl-chromen-4-one (1.00 g, 3.67 mmol, 1 equivalent) in DCM (10 mL) / DMF (2.68 mg, 36.7 μmol, 2.82 μL, 0.01 equivalent), thionyl bromide (991 mg, 4.77 mmol, 369.2 μL, 1.3 equivalents) was added dropwise at 0°C. The reaction mixture was heated to 20°C and stirred at 20°C for 20 minutes. The reaction mixture was poured into ice H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with saturated NaHCO3 aqueous solution until the pH was 8, washed with saturated saline solution (30 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and the residue was obtained. The residue was purified by flash silica gel chromatography (Biotage®; 12 g SepaFlash® Silica Flash Column, eluent: 0-11% ethyl acetate / petroleum ether gradient, flow rate 40 mL / min) to obtain the title compound (700 mg, 2.49 mmol, yield 67.92%) as a yellow solid. 1 1H NMR (CDCl3, 400 MHz) δ 8.00 (s, 1H), 7.86 (s, 1H), 7.66 (d, J = 2.0 Hz, 1H), 5.75 (q, J = 6.8 Hz, 1H), 2.47 (s, 3H), 2.12 (d, J = 6.8 Hz, 3H), 2.05 (s, 3H).

[0641] Preparation of 3,6-dimethyl-8-[1-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]chromen-4-one To a 5 mL solution of 8-(1-bromoethyl)-3,6-dimethyl-chromen-4-one (500 mg, 1.78 mmol, 1.00 equivalent) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (428.60 mg, 1.96 mmol, 1.10 equivalents) in DMF, NaHCO3 (149.40 mg, 1.78 mmol, 69.20 μL, 1.00 equivalent) was added in one go at 20°C, and the resulting reaction mixture was stirred at 60°C for 4 hours. After cooling to 25°C, the reaction mixture was diluted with water (20 mL) and extracted with MTBE (10 mL x 3). The combined organic phase was washed with saturated saline (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (Biotage®; 12 g SepaFlash® Silica Flash Column, eluent: 0-23% petroleum ether / ethyl acetate gradient, flow rate 40 mL / min) to obtain the title compound (580 mg, crude) as a white solid. This compound was used directly in the next step without further purification.

[0642] Preparation of 8-[1-[2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)anilino]ethyl]-3,6-dimethylchromen-4-one A mixture of 6-bromo-1-hydroxy-2,3,1-benzoxazavolinin (250 mg, 1.11 mmol, 1.00 equivalent), 3,6-dimethyl-8-[1-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]chromen-4-one (557 mg, 1.33 mmol, 1.20 equivalent), K2CO3 (306.00 mg, 2.21 mmol, 2 equivalents), and Pd(dppf)Cl2 (81 mg, 110.70 μmol, 0.10 equivalent) in EtOH (2 mL) / H2O (0.2 mL) was degassed and purged three times with N2. The mixture was then stirred at 80°C for 2 hours under an N2 atmosphere. The reaction mixture was cooled to 25°C, filtered through a Celite pad, and the filtered cake was further washed with EtOH (10 mL). The filtrate was concentrated under reduced pressure, and the crude product was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; mobile phase: [H2O (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; gradient: 10% to 40% B over 8.0 mins) to obtain the title compound (150 mg, 342.25 μmol, yield 30.92%) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.34 (s, 1H), 8.67 (s, 1H), 8.17-8.15 (m, 2H), 7.84 (d, J = 7.6 Hz, 1H), 7.80 (s, 1H), 7.70 (s, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.08-7.04 (m, 2H), 6.69 (t, J = 7.2 Hz, 1H), 6.51 (d, J = 8.4 Hz, 1H), 5.12 (d, J = 7.2 Hz, 1H), 5.00-4.93 (m, 1H), 2.35 (s, 3H), 1.91 (s, 3H), 1.40 (d, J = 8.0 Hz, 3H). MS(ESI): Mass calculation value C 26 H 23 BN2O4438.18, measured value in m / z: 439.1 [M+H] + . HPLC: 98.67% (220nm), 100.00% (254nm).

[0643] Preparation of 8-[(1S)-1-[2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)anilino]ethyl]-3,6-dimethylchromen-4-one and 8-[(1R)-1-[2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)anilino]ethyl]-3,6-dimethylchromen-4-one 8-[1-[2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)anilino]ethyl]-3,6-dimethyl-chromen-4-one (0.18 g, 410.69 μmol, 1.00 equivalent) was separated by SFC (column: ChiralPak IH, 250 × 30 mm × 10 μm; mobile phase: [CO2-IPA]; B%: 32%, isoconcentration elution mode). This yielded isomer 1 (77.3 mg, 175.67 μmol, yield 42.77%), the title compound, as a white solid, and isomer 2 (78.6 mg, 177.74 μmol, yield 43.28%), the title compound, as a white solid. Isomer 1: 1 H NMR (DMSO-d6, 400 MHz) δ 9.43 (s, 1H), 8.68 (s, 1H), 8.17-8.16 (m, 2H), 7.84 (d, J = 7.6 Hz, 1H), 7.81 (s, 1H), 7.70 (s, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.08-7.04 (m, 2H), 6.70 (t, J = 7.2 Hz, 1H), 6.51 (d, J = 8.0 Hz, 1H), 5.12 (d, J = 7.2 Hz, 1H), 5.00-4.93 (m, 1H), 2.35 (s, 3H), 1.91 (s, 3H), 1.40 (d, J = 6.8 Hz, 3H). MS(ESI): Mass calculation value C 26 H 23 BN2O4438.18, measured value in m / z: 439.1 [M+H] + HPLC: 99.60% (220nm), 98.68% (254nm). Chiral purity: 100%ee. Isomer 2: 1H NMR (DMSO-d6, 400 MHz) δ 9.43 (s, 1H), 8.68 (s, 1H), 8.17-8.16 (m, 2H), 7.84 (d, J = 8.0 Hz, 1H), 7.81 (s, 1H), 7.70 (s, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.07-7.04 (m, 2H), 6.70 (t, J = 7.2 Hz, 1H), 6.51 (d, J = 8.4 Hz, 1H), 5.12 (d, J = 7.6 Hz, 1H), 5.00-4.93 (m, 1H), 2.35 (s, 3H), 1.91 (s, 3H), 1.40 (d, J = 6.8 Hz, 3H). MS(ESI): Mass calculation value C 26 H 23 BN2O4438.18, measured value in m / z: 439.2 [M+H] + HPLC: 99.11% (220nm), 99.28% (254nm). Chiral purity: 98.1%ee.

[0644] Example 13

[0645] [ka]

[0646] Preparation of 2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-8-[1-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]chromen-4-one 8-(1-bromoethyl)-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (5.00 g, 12.7 mmol, 1 equivalent) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (3.37 g, 15.3 mmol, 1.2 equivalents) were added in a single addition of CS2CO3 (6.23 g, 19.12 mmol, 1.5 equivalents) under N2 at 20°C, and the reaction mixture was stirred at 20°C for 15 hours. For workup, the three parallel reactions were combined. The combined reaction mixture was poured into H2O (1500 mL) at 0°C and extracted with MTBE (500 mL x 3). The combined organic phase was washed with saturated brine (600 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. This yielded the title compound (25.00 g, 47.04 mmol, 97.13% yield) as an off-white solid. This compound was used in the next step without further purification. 1 1H NMR (DMSO-d6, 400 MHz) δ 7.88 (s, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.67 (dd, J = 1.6, 6.0 Hz, 1H), 7.29-7.27 (m, 1H), 6.94 (t, J = 7.2 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 5.83 (q, J = 6.4 Hz, 1H), 3.40-3.32 (m, 4H), 2.42 (s, 3H), 2.04 (s, 3H), 1.68 (d, J = 6.0 Hz, 3H), 1.53-1.49 (m, 4H), 1.37 (s, 12H), 1.04 (s, 6H).

[0647] Preparation of 2-(4,4-dimethyl-1-piperidyl)-8-[1-[2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)phenoxy]ethyl]-3,6-dimethyl-chromen-4-one To a mixture of 2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-8-[1-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]chromen-4-one (3.20 g, 4.82 mmol, 1 equivalent) and 6-bromo-1-hydroxy-2,3,1-benzoxazavolinin (1.20 g, 5.30 mmol, 1.1 equivalents) in EtOH (64 mL) / H2O (8 mL), K2CO3 (1.33 g, 9.63 mmol, 2 equivalents) and di-tert-butyl(cyclopentyl)phosphine; dichloropalladium; iron (314 mg, 482 μmol, 0.1 equivalents) were sequentially added under N2 conditions at 20°C. The reaction suspension was degassed under vacuum and purged three times with N2. The reaction mixture was then stirred directly under N2 at 80°C (oil bath preheated to 80°C) for 2 hours. The reaction mixture was cooled to 25°C, filtered, and concentrated under vacuum to remove EtOH. The residue was diluted with H2O (100 mL), adjusted to pH=7 using 2N HCl at 0°C, and the aqueous phase was extracted with siRNA (80 mL x 3). The combined organic layers were washed with saturated brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by prep HPLC (column: Welch Ultimate C18 250 × 70 mm × 10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 50%~80% B over 0.1 min) to obtain the title compound (700 mg, 1.27 mmol, yield 28.07%) as a yellow solid. 1 1H NMR (DMSO-d6, 400 MHz) δ 9.40 (s, 1H), 8.59 (s, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.88-7.83 (m, 2H), 7.64 (s, 1H), 7.40-7.33(m, 3H), 7.11-7.07 (m, 2H), 5.83 (q, J = 6.4 Hz, 1H), 3.24-3.22 (m, 4H), 2.27 (s, 3H), 1.87 (s, 3H), 1.63 (d, J = 6.4 Hz, 3H), 1.36-1.28 (m, 4H), 0.92 (s, 6H). MS(ESI): Mass calculation value C 33 H35 BN2O5550.26, measured value in m / z: 549.1 [M+H] + . HPLC: 99.46(220nm), 99.64(240nm).

[0648] Preparation of 2-(4,4-dimethyl-1-piperidyl)-8-[(1R)-1-[2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)phenoxy]ethyl]-3,6-dimethyl-chromen-4-one and 2-(4,4-dimethyl-1-piperidyl)-8-[(1S)-1-[2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)phenoxy]ethyl]-3,6-dimethyl-chromen-4-one The crude product (260 mg, purity 90%) was further separated by SFC (column: DAIEL CHIRALCEL OD (250 mm × 30 mm × 10 μm); mobile phase: [CO2-IPA]; B%: 45%, isoconcentration elution mode). This yielded isomer 1 (35.0 mg, 62.88 μmol, yield 1.54%), the title compound, as a white solid, and isomer 2 (35.0 mg, 62.58 μmol, yield 1.54%), the title compound, as a white solid. Isomer 1: 1 1H NMR (DMSO-d6, 400 MHz) δ 9.40 (s, 1H), 8.59 (s, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.88-7.83 (m, 2H), 7.64 (s, 1H), 7.39 (dd, J = 1.6, 6.0 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.34-7.31 (m, 1H), 7.12-7.03 (m, 2H), 5.83 (q, J = 6.4 Hz, 1H), 3.28-3.17 (m, 4H), 2.27 (s, 3H), 1.87 (s, 3H), 1.63 (d, J = 6.4 Hz, 3H), 1.36-1.28 (m, 4H), 0.93 (s, 6H). MS(ESI): Mass calculation value C 33 H 35 BN2O5550.26, measured value in m / z: 551.3 [M+H] +. HPLC:98.89(220nm), 99.72(240nm). Isomer 2: 1 1H NMR (DMSO-d6, 400 MHz) δ 9.40 (s, 1H), 8.59 (s, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.89-7.81 (m, 2H), 7.64 (s, 1H), 7.39 (dd, J = 1.6, 6.0 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.34-7.30 (m, 1H), 7.13-7.03 (m, 2H), 5.83 (q, J = 6.4 Hz, 1H), 3.27-3.18 (m, 4H), 2.27 (s, 3H), 1.87 (s, 3H), 1.63 (d, J = 6.4 Hz, 3H), 1.35-1.29 (m, 4H), 0.92 (s, 6H). MS(ESI): Mass calculation value C 33 H 35 BN2O5550.26, measured value in m / z: 551.3 [M+H] + . HPLC: 98.42(220nm), 96.57(240nm).

[0649] Example 14

[0650] [ka]

[0651] Preparation of 3,6-dimethyl-8-[1-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]chromen-4-one 8-(1-bromoethyl)-3,6-dimethyl-chromen-4-one (500 mg, 1.78 mmol, 1.00 equivalent) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (509 mg, 2.31 mmol, 1.30 equivalents) were dissolved in DMF (5 mL), to which CS2CO3 (927 mg, 2.85 mmol, 1.6 equivalents) was added in one step at 20°C. The reaction mixture was stirred at 20°C for 12 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with MTBE (10 mL x 3). The combined organic phase was washed with saturated saline (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (Biotage®; 12 g SepaFlash® Silica Flash Column, eluent: 0-23% petroleum ether / ethyl acetate gradient, flow rate 40 mL / min) to obtain the title compound (450 mg, 1.07 mmol, yield 60.20%) as a yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ 8.30 (s, 1H), 7.97 (s, 1H), 7.77 (s, 1H), 7.52 (dd, J = 7.2 Hz, 1.6 Hz, 1H), 7.34-7.32 (m, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.91 (t, J = 7.4 Hz, 1H), 5.98 (q, J = 6.0 Hz, 1H), 2.41 (s, 3H), 1.93 (s, 3H), 1.56 (d, J = 6.0 Hz, 3H), 1.33 (s, 12H). Preparation of 8-[1-[2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)phenoxy]ethyl]-3,6-dimethyl-chromen-4-one A mixture of 6-bromo-1-hydroxy-2,3,1-benzoxazavolinin (180 mg, 797.04 μmol, 1.00 equivalent), 3,6-dimethyl-8-[1-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]chromen-4-one (402 mg, 956.45 μmol, 1.20 equivalent), K2CO3 (221 mg, 1.59 mmol, 2.00 equivalent), and Pd(dppf)Cl2 (59 mg, 79.70 μmol, 0.10 equivalent) in EtOH (2 mL) / H2O (0.2 mL) was degassed and purged three times with N2 at 20°C. The mixture was then stirred at 80°C for 2 hours under an N2 atmosphere. The reaction mixture was cooled to 25°C, filtered through a Celite pad, and the filtrate cake was washed with EtOH (10 mL). The filtrate was concentrated under reduced pressure, and the crude product was further purified by reverse-phase HPLC (column: Waters Xbridge BEH C18 100 × 25 mm × 10 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 25% to 55% B over 8.0 mins) to obtain the title compound (180 mg, 405.14 μmol, yield 50.83%) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 9.40 (s, 1H), 8.67 (s, 1H), 8.21 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.93-7.90 (m, 2H), 7.74-7.73 (m, 1H), 7.41-7.38(m, 2H), 7.37-7.36 (m, 1H), 7.09-7.06 (m, 2H), 5.91-5.86 (m, 1H), 2.26 (s, 3H), 1.90 (s, 3H), 1.57 (d, J = 6.4 Hz, 3H). MS(ESI): Mass calculation value C 26 H 22 BNO5439.16, measured value in m / z: 440.2 [M+H] + . HPLC: 98.87% (220nm), 99.26% (254nm).

[0652] Preparation of 8-[(1S)-1-[2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)phenoxy]ethyl]-3,6-dimethylchromen-4-one and 8-[(1R)-1-[2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)phenoxy]ethyl]-3,6-dimethylchromen-4-one 8-[1-[2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)phenoxy]ethyl]-3,6-dimethyl-chromen-4-one (180 mg, 409.77 μmol, 1.00 equivalent) was separated by SFC (column: ChiralPak IH, 250 × 30 mm × 10 μm; mobile phase: [CO2-IPA]; B%: 29%, isoconcentration elution mode). This yielded isomer 1 (67.50 mg, 151.58 μmol, yield 36.99%), the title compound, as a white solid, and isomer 2 (77.80 mg, 177.11 μmol, yield 43.22%), the title compound, as a white solid. Isomer 1: 1 H NMR (DMSO-d6, 400 MHz) δ 9.41 (s, 1H), 8.67 (s, 1H), 8.20 (d, J = 1.2 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.93-7.90 (m, 2H), 7.74-7.73 (m, 1H), 7.39-7.38 (m, 2H), 7.37-7.36 (m, 1H), 7.08-7.06 (m, 2H), 5.89 (q, J = 6.4 Hz, 1H), 2.26 (s, 3H), 1.90 (s, 3H), 1.57 (d, J = 6.0 Hz, 3H). MS(ESI): Mass calculation value C 26 H 22 BNO5439.16, measured value in m / z: 440.1 [M+H] + HPLC: 98.64% (220nm), 99.41% (254nm). Chiral purity: 97.86%ee. Isomer 2: 1H NMR (DMSO-d6, 400 MHz) δ 9.41 (s, 1H), 8.67 (s, 1H), 8.20 (d, J = 1.2 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.93-7.90 (m, 2H), 7.74-7.73 (m, 1H), 7.39-7.38 (m, 2H), 7.37-7.36 (m, 1H), 7.08-7.06 (m, 2H), 5.89 (q, J = 6.4 Hz, 1H), 2.26 (s, 3H), 1.90 (s, 3H), 1.57 (d, J = 6.0 Hz, 3H). MS(ESI): Mass calculation value C 26 H 22 BNO5439.16, measured value in m / z: 440.1 [M+H] + HPLC: 100.00% (220nm), 100.00% (254nm). Chiral purity: 98.9%ee.

[0653] Example 16

[0654] [ka]

[0655] Preparation of (NZ,S)-N-[1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromene-8-yl]ethylidene]-2-methyl-propane-2-sulfinamide To a solution of acetyl-2-(4,4-dimethylpiperidine-1-yl)-3,6-dimethyl-4H-chromen-4-one (50 g, 152.71 mmol) and (S)-2-methylpropan-2-sulfinamide (37 g, 305.42 mmol, 2 equivalents) in THF (500 mL), Ti(i-PrO)4 (196 g, 687.20 mmol, 202.8 mL, 4.5 equivalents) was added in one go at 25 °C, the mixture was heated to 80 °C, and stirred at 80 °C for 36 hours. Three parallel reactions were combined for workup. The reaction mixture was cooled to 20 °C, The mixture was poured into H2O (2 L) and filtered. The filtered cake was washed with RINKAN (500 mL x 3), and the filtrate was extracted with RINKAN (2 L x 3). The combined organic layers were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0~3:1), then ground with PE and RINKAN (PE:RINKAN = 5:1, 1200 mL) to obtain the title compound (170 g, 394.80 mmol, yield 86.2%) as a pale yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ 7.85-7.76 (m, 1H), 7.55-7.39 (m, 1H), 3.36-3.34 (m, 4H), 2.76 (s, 2H), 2.54 (s, 1H), 2.41-2.40 (s, 3H), 1.91 (s, 3H), 1.43-1.41 (m, 4H), 1.21-1.09 (m, 9H), 0.98 (s, 6H).

[0656] Preparation of (S)-N-((R)-1-(2-(4,4-dimethylpiperidine-1-yl)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)-2-methylpropane-2-sulfinamide (NZ,S)-N-[1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethylidene]-2-methyl-propane-2-sulfinamide (56 g, 130.05 mmol, 1 equivalent) was added dropwise to a solution of THF (600 mL) with L-selectride (1 M, 260.10 mL, 2 equivalents) under N2 at -78°C, and the mixture was stirred at -78°C for 1 hour. The reaction mixture was then heated to -20°C and stirred at -20°C for 2 hours. Three parallel reactions were combined for workup. The reaction mixture was heated to 0°C and stopped with saturated NH4Cl aqueous solution (500 mL) at 0°C. The reaction mixture was then diluted with water (300 mL) and extracted with ELISA (600 mL x 3). The combined organic phases were washed with saturated saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was further ground with RINKAN (1000 mL) to obtain isomer 1 (94 g, 75.69 mmol, yield 55.7%), the title compound, as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 7.65 (s, 1H), 7.53 (s, 1H), 5.50 (d, J = 5.6 Hz, 1H), 4.95 (m, 1H), 3.41-3.39 (m, 4H), 2.37 (s, 3H), 1.90 (s, 3H), 1.55 (d, J = 6.8 Hz, 3H), 1.48-1.46 (m, 4H), 1.08 (s, 9H), 1.00 (m, 6H).

[0657] Preparation of (R)-8-(1-aminoethyl)-2-(4,4-dimethylpiperidine-1-yl)-3,6-dimethyl-4H-chromen-4-one (S)-N-[(1R)-1-[2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-4-oxo-chromene-8-yl]ethyl]-2-methyl-propane-2-sulfinamide (42 g, 97.08 mmol, 1 equivalent) was dissolved in HCl / siRNA (4N, 300 mL) at 25°C and the mixture was stirred at 25°C for 2 hours. For work-up, the two parallel reactions were combined. The resulting suspension was filtered directly. The filtered cake was dissolved in H₂O (400 mL), adjusted to pH=12 with NH₃·H₂O, and extracted with siRNA (300 mL x 3). The combined organic phase was washed with saturated brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. This yielded isomer 2, the title compound, as a pale yellow solid (50.7 g, 154.36 mmol, 79.5% yield). 1 H NMR (DMSO-d6, 400 MHz) δ 7.63 (s, 1H), 7.59 (s, 1H), 4.53-4.48 (m, 1H), 3.39-3.36 (m, 4H), 2.38 (s, 3H), 1.94-1.93 (br s, 2H), 1.89 (s, 3H), 1.47-1.45 (m, 4H), 1.31 (d, J = 6.8 Hz, 3H), 1.00 (s, 6H).

[0658] Preparation of (R)-8-(1-((2-bromo-4-chlorophenyl)amino)ethyl)-2-(4,4-dimethylpiperidine-1-yl)-3,6-dimethyl-4H-chromen-4-one Using 8-[(1R)-1-aminoethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (300 mg, 913.39 μmol, 1 equivalent) and 2-bromo-4-chloro-1-iodobenzene (580 mg, 1.83 mmol, 2 equivalents), the title compound (330 mg, 637.21 μmol, yield 69.76%) was prepared as a pale yellow gum by the same procedure as in Example 78. ¹H NMR (CDCl) 3,400 MHz) δ 7.88 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.31 (s, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 4.96-4.91 (m, 1H), 4.71-4.70 (m, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.41-3.38 (m, 4H), 2.37 (s, 3H), 2.06 (s, 3H), 1.66 (d, J = 6.8 Hz, 3H), 1.53-1.51 (m, 4H), 1.04 (s, 6H).

[0659] Preparation of (R)-8-(1-((4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)ethyl)-2-(4,4-dimethylpiperidine-1-yl)-3,6-dimethyl-4H-chromen-4-one Using 8-[(1R)-1-(2-bromo-4-chloroanilino)ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (330 mg, 637.21 μmol, 1 equivalent) and B2Pin2 (324 mg, 1.27 mmol, 2 equivalents), the title compound (350 mg, 619.52 μmol, 97.22% yield) was prepared as a yellow solid according to the procedure and synthetic scheme described herein. This product was used directly in the next step without further purification.

[0660] Preparation of (R)-8-(1-((4-chloro-2-(1-hydroxy-1H-benzo[d][1,2,6]oxazavolinin-6-yl)phenyl)amino)ethyl)-2-(4,4-dimethylpiperidine-1-yl)-3,6-dimethyl-4H-chromen-4-one Using 8-[(1R)-1-[4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (225 mg, 398.52 μmol, 1.5 equivalents) and 6-bromo-1-hydroxy-2,3,1-benzoxazavolinin (60 mg, 265.68 μmol, 1 equivalent), the title compound (25.6 mg, 42.03 μmol, yield 15.82%) was prepared as a white solid by the procedure and synthesis scheme described herein. 1 1H NMR (DMSO-d6) , 400 MHz) δ 9.46 (br s, 1H), 8.65 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.87-7.84 (m, 2H), 7.60 (s, 1H), 7.44 (s, 1H), 7.15-7.12 (m, 1H), 7.08 (s, 1H), 6.53 (d, J = 8.8 Hz, 1H), 5.25-5.24 (m, 1H), 4.91-4.88 (m, 1H), 3.32-3.24 (m, 4H), 2.32 (s, 3H), 1.89 (s, 3H), 1.46-1.44 (m, 3H), 1.40-1.37 (m, 4H), 0.95 (s, 6H). MS(ESI): Calculated mass C33H35BClN3O4 583.24, measured m / z value 584.3[M+H] + HPLC: 95.87% (220nm), 96.33% (254nm). Chiral purity: 98.02%ee.

[0661] Example 17

[0662] [ka]

[0663] Preparation of 8-[1-[4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]-3,6-dimethylchromen-4-one To a solution of 8-(1-bromoethyl)-3,6-dimethyl-chromen-4-one (500 mg, 1.78 mmol, 1.00 equivalent) and 4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.42 g, 1.96 mmol, 1.10 equivalents) in DMF (5 mL), NaHCO3 (150 mg, 1.78 mmol, 69.20 μL, 1.00 equivalent) was added in fractions at 20 °C. The reaction mixture was heated to 60 °C and stirred at 60 °C for 4 hours. The mixture was cooled to 25 °C, diluted with water (20 mL), and extracted with MTBE (10 mL x 3). The combined organic phase was washed with saturated saline (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (Biotage®; 12 g SepaFlash® Silica Flash Column, eluent: 0-23% petroleum ether / ethyl acetate gradient, flow rate 40 mL / min) to obtain the title compound (400 mg, 881.51 μmol, yield 49.57%) as a yellow solid. 1 H NMR (DMSO-d6, 400 MHz) δ 8.31 (s, 1H), 7.74 (s, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.33 (d, J = 2.8 Hz, 1H), 7.15 (dd, J = 8.8, 2.8 Hz, 1H), 6.41 (d, J = 7.2 Hz, 1H), 6.35 (d, J = 9.2 Hz, 1H), 5.07-5.00 (m, 1H), 2.35 (s, 3H), 1.93 (s, 3H), 1.54 (d, J = 6.8 Hz, 3H), 1.35 (s, 12H).

[0664] Preparation of ethyl 8-[1-[4-chloro-2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)anilino]ethyl]-3,6-dimethylchromen-4-one A mixture of 6-bromo-1-hydroxy-2,3,1-benzoxazavolinin (150 mg, 664.20 μmol, 1.00 equivalent), 8-[1-[4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]-3,6-dimethyl-chromen-4-one (332 mg, 730.62 μmol, 1.10 equivalent), Pd(dppf)Cl2 (49 mg, 66.42 μmol, 0.10 equivalent), and K2CO3 (184 mg, 1.33 mmol, 2.00 equivalent) in EtOH (3 mL) / H2O (0.3 mL) was degassed and purged three times with N2 at 20°C. The reaction mixture was then heated to 80°C and stirred at 80°C for 2 hours under an N2 atmosphere. The reaction mixture was cooled to 20°C and filtered through a Celite pad. The filtered cake was washed with EtOH (10 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by prep HPLC (column: Phenomenex Gemini NX-C18 (75 × 30 mm × 3 μm); mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 25% to 55% B over 8.0 mins) to obtain the title compound (40 mg, 77.24 μmol, yield 11.63%) as a yellow solid.

[0665] Preparation of 8-[(1S)-1-[4-chloro-2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)anilino]ethyl]-3,6-dimethyl-chromen-4-one and 8-[(1R)-1-[4-chloro-2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)anilino]ethyl]-3,6-dimethyl-chromen-4-one 8-[1-[4-chloro-2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)anilino]ethyl]-3,6-dimethyl-chromen-4-one (40.00 mg, 84.62 μmol, 1.00 equivalent) was separated by SFC (column: ChiralPak IH, 250 × 30 mm, 10 μm; mobile phase: [CO2-IPA]; B%: 25%, isoconcentration elution mode). This yielded isomer 1 (10.2 mg, 20.75 μmol, yield 24.53%), the title compound, as an off-white solid, and isomer 2 (11.3 mg, 22.85 μmol, yield 27.00%), the title compound, as an off-white solid. Isomer 1: 1 H NMR (DMSO-d6, 400 MHz) δ 9.47 (s, 1H), 8.68 (s, 1H), 8.18-8.16 (m, 2H), 7.86-7.83 (m, 2H), 7.71 (d, J = 1.2 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.11 (dd, J = 8.4, 2.8 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.49 (d, J = 8.8 Hz, 1H), 5.31 (d, J = 7.2 Hz, 1H), 4.97-4.90 (m, 1H), 2.35 (s, 3H), 1.91 (s, 3H), 1.42 (d, J = 6.8 Hz, 3H). MS(ESI): Mass calculation value C 26 H 22 BClN2O4 472.14, measured value in m / z: 473.2 [M+H] + HPLC: 96.19% (220nm), 96.79% (254nm). Chiral purity: 97.98%ee. Isomer 2: 1H NMR (DMSO-d6, 400 MHz) δ 9.47 (s, 1H), 8.68 (s, 1H), 8.18-8.16 (m, 2H), 7.86-7.83 (m, 2H), 7.71 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.11 (dd, J = 8.4, 2.8 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.49 (d, J = 8.8 Hz, 1H), 5.31 (d, J = 7.2 Hz, 1H), 4.97-4.90 (m, 1H), 2.35 (s, 3H), 1.91 (s, 3H), 1.42 (d, J = 6.8 Hz, 3H). MS(ESI): Mass calculation value C 26 H 22 BClN2O4 472.14, measured value in m / z: 473.2 [M+H] + HPLC: 95.58% (220nm), 95.98% (254nm). Chiral purity: 97.96%ee.

[0666] Example 18

[0667] [ka]

[0668] Preparation of 8-[(1R)-1-(2-bromo-4-chloroanilino)ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one Using 8-[(1R)-1-aminoethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (200 mg, 608.93 μmol, 1 equivalent) and 2-bromo-4-chloro-1-iodobenzene (387 mg, 1.22 mmol, 2 equivalents), the title compound (350 mg, crude) was prepared as a pale yellow oil by the same procedure as in Example 78. 1 1H NMR (DMSO-d 6,400 MHz) δ 7.63 (s, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.42 (s, 1H), 7.10 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 6.43 (d, J = 8.8 Hz, 1H), 5.46 (d, J = 6.8 Hz, 1H), 5.03-5.00 (m, 1H), 3.41-3.38 (m, 4H), 2.31 (s, 3H), 1.91 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H), 1.47-1.44 (m, 4H), 0.98 (s, 6H).

[0669] Preparation of 8-[(1R)-1-[4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one Using 8-[(1R)-1-(2-bromo-4-chloroanilino)ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (320 mg, 617.90 μmol, 1 equivalent) and B2Pin2 (314 mg, 1.24 mmol, 2 equivalents), the title compound (270 mg, 477.92 μmol, yield 77.35%) was prepared as a pale yellow oil according to the procedure and synthesis scheme described herein. 1 1H NMR (DMSO-d 6, 400 MHz) δ 7.93 (s, 1H), 7.64 (s, 1H), 7.35-7.33 (m, 2H), 7.17 (dd, J = 8.8 Hz, J = 2.8 Hz, 1H), 6.37 (d, J = 2.4 Hz, 1H), 5.01-4.98 (m, 1H), 3.39-3.37 (m, 4H), 2.32 (s, 3H), 1.91 (s, 3H), 1.55 (d, J = 6.8 Hz, 3H), 1.46-1.43 (m, 4H), 1.32 (s, 12H), 0.98 (s, 6H).

[0670] Preparation of 8-[(1R)-1-[4-chloro-2-(1-hydroxy-2,3,1-benzoxazavolinin-7-yl)anilino]ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one Using 7-bromo-1-hydroxy-2,3,1-benzoxazavolinin (53.5 mg, 236.90 μmol, 1 equivalent) and 8-[(1R)-1-[4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (268 mg, 473.80 μmol, 2 equivalents), the title compound (29.4 mg, 49.10 μmol, yield 20.73%) was prepared as a white solid according to the procedure and synthesis scheme described herein. 1 1H NMR (DMSO-d 6, 400 MHz) δ 9.42 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 7.95-7.93 (m, 1H), 7.84-7.82 (m, 1H), 7.60 (s, 1H), 7.43 (s, 1H), 7.14-7.12 (m, 1H), 7.07 (s, 1H), 6.51 (d, J = 8.8 Hz, 1H), 5.22 (d, J = 6.8 Hz, 1H), 4.93-4.89 (m, 1H), 3.30-3.28 (m, 4H), 2.32 (s, 3H), 1.90 (s, 3H), 1.44 (d, J = 6.8 Hz, 3H), 1.41-1.38 (m, 4H), 0.96 (s, 6H). MS(ESI): Mass calculation value C 33 H 35 BClN3O4583.24, measured value in m / z: 584.1 [M+H] + HPLC: 97.52% (220nm), 98.281% (254nm). Chiral purity: 100%ee.

[0671] Example 19

[0672] [ka]

[0673] Preparation of (R)-8-(1-((2-bromo-3-fluorophenyl)amino)ethyl)-2-(4,4-dimethylpiperidine-1-yl)-3,6-dimethyl-4H-chromen-4-one Using (R)-8-(1-aminoethyl)-2-(4,4-dimethylpiperidine-1-yl)-3,6-dimethyl-4H-chromen-4-one (200 mg) and 2-bromo-1-fluoro-3-iodobenzene (366 mg, 1.22 mmol, 2 equivalents), the title compound (300 mg, 538.46 μmol, yield 88.43%) was prepared as a yellow solid according to the procedure and synthesis scheme described herein. 1 H NMR (CDCl3, 400 MHz) δ 7.88 (s, 1H), 7.35 (d, J = 2.0 Hz, 1H), 6.97 (dd, J =14.4 Hz 8.0 Hz, 1H), 6.46 (t, J = 7.6 Hz, 1H), 6.11 (d, J = 8.4 Hz, 1H), 5.03-4.95 (m, 1H), 4.85-4.84 (m, 1H), 3.41-3.38 (m, 4H), 2.37 (s, 3H), 2.05 (s, 3H), 1.67 (d, J = 6.8 Hz, 3H), 1.53-1.50 (m, 4H), 1.03 (s, 6H).

[0674] Preparation of (R)-8-(1-((2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-fluorophenyl)amino)ethyl)-2-(4,4-dimethylpiperidine-1-yl)-3,6-dimethyl-4H-chromen-4-one Using (R)-8-(1-((2-bromo-3-fluorophenyl)amino)ethyl)-2-(4,4-dimethylpiperidine-1-yl)-3,6-dimethyl-4H-chromen-4-one (50 mg) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (113 mg, 498.57 μmol, 5 equivalents), the title compound (50 mg, 74.84 μmol, yield 75.05%) was prepared as a yellow solid according to the procedure and synthesis scheme described herein. 1 H NMR (CDCl3, 400 MHz) δ 7.87-7.86 (m, 1H), 7.40-7.39 (m, 1H), 7.04-6.98 (m, 1H), 6.32-6.28 (m, 1H), 6.01 (d, J = 8.4 Hz, 1H), 5.00-4.95 (m, 1H), 3.68-3.66 (m, 4H), 3.40-3.37 (m, 4H), 2.36 (s, 3H), 2.06 (s, 3H), 1.57 (d, J = 6.8 Hz, 3H), 1.52-1.49 (m, 4H), 1.03 (d, J = 2.4 Hz, 6H), 0.99 (s, 6H).

[0675] Preparation of (R)-2-(4,4-dimethylpiperidine-1-yl)-8-(1-((3-fluoro-2-(1-hydroxy-1H-benzo[d][1,2,6]oxazavolinin-6-yl)phenyl)amino)ethyl)-3,6-dimethyl-4H-chromen-4-one Using (R)-8-(1-((2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-fluorophenyl)amino)ethyl)-2-(4,4-dimethylpiperidine-1-yl)-3,6-dimethyl-4H-chromen-4-one (46 mg), the title compound (16.7 mg, 28.97 μmol, yield 43.62%) was prepared as a white solid according to the procedure and synthesis scheme described herein. 1H NMR (DMSO-d6, 400 MHz) δ 8.50 (s, 1H), 8.07 (d, J = 7.2 Hz, 1H), 7.64-7.61 (m, 3H), 7.38 (d, J = 1.6 Hz, 1H), 7.13-7.07 (m, 1H), 6.53-6.49 (m, 1H), 6.35 (d, J = 8.0 Hz, 1H), 6.07-6.00 (m, 2H), 4.99-4.92 (m, 1H), 4.87-4.86 (m, 1H), 3.13-3.07 (m, 4H), 2.32 (s, 3H), 1.90 (s, 3H), 1.43-1.41 (m, 7H), 0.96 (s, 6H). MS(ESI): Mass calculation value C33H35BFN3O4 567.27, m / z actual value 568.3[M+H] + . HPLC: 98.45% (220nm), 98.61% (254nm).

[0676] Example 20

[0677] [ka]

[0678] Preparation of 8-[(1R)-1-(2-bromo-4-fluoroanilino)ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one Using 8-[(1R)-1-aminoethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (200 mg, 609 μmol, 1 equivalent) and 2-bromo-4-fluoro-1-iodobenzene (366 mg, 1.22 mmol, 2 equivalents), the title compound (225 mg, 448.72 μmol, yield 73.69%) was prepared as a yellow solid by the same procedure as in Example 78. 1 1H NMR (DMSO-d6, 400 MHz) δ 7.63 (s, 1H), 7.43 (s, 1H), 7.41 (d, J = 2.8 Hz, 1H), 6.98-6.93 (m, 1H), 6.44-6.40 (m, 1H), 5.03-4.96 (m, 1H), 3.41 (t, J = 5.6 Hz, 4H), 2.31 (s, 3H), 1.91 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H), 1.46 (t, J = 5.6 Hz, 4H), 0.99 (s, 6H).

[0679] Preparation of 2-(4,4-dimethyl-1-piperidyl)-8-[(1R)-1-[4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]-3,6-dimethyl-chromen-4-one Using 8-[(1R)-1-(2-bromo-4-fluoroanilino)ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (200 mg, 399 μmol, 1 equivalent) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (304 mg, 1.20 mmol, 3 equivalents), the title compound (250 mg, 364.63 μmol, yield 91.42%) was prepared as a yellow oil by the procedure and synthesis scheme described herein. 1 1H NMR (DMSO-d6, 400 MHz) δ 7.93 (s, 1H), 7.63 (s, 1H), 7.36 (s, 1H), 7.13-7.10 (m, 1H), 7.02-6.99 (m, 1H), 6.33 (dd, J = 9.2, 4.4 Hz, 1H), 4.98 (t, J = 6.4 Hz, 1H), 3.38 (t, J = 5.6 Hz, 4H), 2.32 (s, 3H), 1.91 (s, 3H), 1.54 (d, J = 6.4 Hz, 3H), 1.45 (t, J = 5.2 Hz, 4H), 1.07 (s, 12H), 0.98 (s, 6H).

[0680] Preparation of 2-(4,4-dimethyl-1-piperidyl)-8-[(1R)-1-[4-fluoro-2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)anilino]ethyl]-3,6-dimethyl-chromen-4-one Using 2-(4,4-dimethyl-1-piperidyl)-8-[(1R)-1-[4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]-3,6-dimethyl-chromen-4-one (200.0 mg, 292 μmol, 1 equivalent) and 6-bromo-1-hydroxy-2,3,1-benzoxazavolinin (79.1 mg, 350 μmol, 1.2 equivalents), the title compound (26.8 mg, 36.77 μmol, yield 12.61%) was prepared as an off-white solid according to the procedure and synthesis scheme described herein. 1 1H NMR (DMSO-d6, 6.96 (d, J = 9.2 Hz, 2H), 6.54 (q, J = 4.4 Hz, 1H), 5.04-5.02 (m, 1H), 4.85-4.82 (m, 1H), 3.30-3.22 (m, 4H), 2.32 (s, 3H), 1.89 (s, 3H), 1.43 (d, J = 6.4 Hz, 3H), 1.38 (t, J = 5.2 Hz, 4H), 0.95 (s, 6H). MS(ESI): Mass calculation value C 33 H 35 BFN3O4275.11, measured value in m / z: 276.2 [M+H] + . HPLC: 93.52 (220nm), 94.91 (240nm).

[0681] Example 21

[0682] [ka]

[0683] Preparation of 8-[(1R)-1-(2-bromo-5-fluoroanilino)ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one Using 1-bromo-4-fluoro-2-iodobenzene (366 mg, 1.22 mmol, 2 equivalents) and 8-[(1R)-1-aminoethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (200 mg, 608 μmol, 1 equivalent), the title compound (280 mg, 558 μmol, yield 91.7%) was prepared as a yellow solid by the same procedure as in Example 78. 1 1H NMR (CDCl 3, 400 MHz) δ 7.90 (d, J = 1.2 Hz, 1H), 7.39-7.33 (m, 2H), 6.29 (dt, J = 2.8, 8.4 Hz, 1H), 6.09 (dd, J = 2.8, 11.2 Hz, 1H), 4.97-4.91 (m, 1H), 4.82 (br d, J = 5.2 Hz, 1H), 3.46-3.37 (m, 4H), 2.39 (s, 3H), 2.06 (s, 3H), 1.67 (d, J = 6.8 Hz, 3H), 1.57-1.48 (m, 4H), 1.04 (s, 6H).

[0684] Preparation of 8-[(1R)-1-[2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluoroanilino]ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one Using 8-[(1R)-1-(2-bromo-5-fluoroanilino)ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (200 mg, 398 μmol, 1 equivalent) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (450 mg, 1.99 mmol, 5 equivalents), the title compound (200 mg, 374.20 μmol, yield 93.82%) was prepared as a yellow solid according to the procedure and synthetic scheme described herein. This product was used directly in the next step without further purification.

[0685] Preparation of 2-(4,4-dimethyl-1-piperidyl)-8-[(1R)-1-[5-fluoro-2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)anilino]ethyl]-3,6-dimethyl-chromen-4-one Using 8-[(1R)-1-[2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluoroanilino]ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (150 mg, 280 μmol, 1.5 equivalents), 6-bromo-1-hydroxy-2,3,1-benzoxazavolinin (42.2 mg, 187 μmol, 1 equivalent), and K2CO3 (51.7 mg, 374 μmol, 2 equivalents), the title compound (28.1 mg, 49.52 μmol, yield 26.47%) was prepared as a white solid according to the procedure and synthesis scheme described herein. 1 1H NMR (DMSO-d 6,400 MHz) δ 9.51-9.34 (m, 1H), 8.64 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.87-7.73 (m, 2H), 7.62 (d, J = 1.6 Hz, 1H), 7.48 (d, J = 1.6 Hz, 1H), 7.12-6.96 (m, 1H), 6.49 (dt, J = 2.4, 8.4 Hz, 1H), 6.33 (dd, J = 2.4, 12.0 Hz, 1H), 5.37 (br d, J = 7.2 Hz, 1H), 5.02-4.89 (m, 1H), 3.42-3.33 (m, 2H), 3.29-3.22 (m, 2H), 2.33 (s, 3H), 1.90 (s, 3H), 1.52-1.45 (m, 3H), 1.44-1.31 (m, 4H), 0.95 (s, 6H). MS(ESI): Mass calculation value C 33 H 35 BFN3O4567.27, measured value in m / z: 568.3 [M+H] + HPLC: 96.65% (220nm), 95.61% (254nm). Chiral purity: 96.3%ee.

[0686] Example 22

[0687] [ka]

[0688] Preparation of 8-[(1R)-1-(2-bromo-6-fluoroanilino)ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one Using 8-[(1R)-1-aminoethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (250 mg, 761.16 μmol, 1 equivalent) and 1-bromo-3-fluoro-2-iodobenzene (458.06 mg, 1.52 mmol, 2 equivalents), the title compound (0.32 g, 638.18 μmol, yield 83.84%) was prepared as a pale yellow oil by the same procedure as in Example 78. 1H NMR (CDCl3, 400 MHz) δ 7.84 (s, 1H), 7.31 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.85-6.82 (m, 1H), 6.61-6.58 (m, 1H), 5.49-5.46 (m, 1H), 4.43-4.40 (m, 1H), 3.41-3.38 (m, 4H), 2.37 (s, 3H), 2.04 (s, 3H), 1.62 (s, J = 6.8 Hz, 3H), 1.54-1.52 (m, 4H), 1.05 (s, 6H).

[0689] Preparation of 2-(4,4-dimethyl-1-piperidyl)-8-[(1R)-1-[2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]-3,6-dimethyl-chromen-4-one Using 8-[(1R)-1-(2-bromo-6-fluoroanilino)ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (300 mg, 598.29 μmol, 1 equivalent) and B2Pin2 (379.82 mg, 1.50 mmol, 2.5 equivalents), the title compound (340 mg, crude) was prepared as a pale yellow oil according to the procedure described in the above examples.

[0690] This product was used directly in the next step without further purification. 1 H NMR (CDCl3, 400 MHz) δ 7.84 (s, 1H), 7.44-7.41 (m, 2H), 6.99-6.93 (m, 1H), 6.66-6.62 (m, 1H), 5.96-5.94 (m, 1H), 5.54-5.50 (m, 1H), 3.39-3.36 (m, 4H), 2.38 (s, 3H), 2.04 (s, 3H), 1.55 (d, J = 6.4 Hz, 3H), 1.53-1.50 (m, 4H), 1.35 (d, J = 8.0 Hz, 12H), 1.04 (s, 6H).

[0691] Preparation of 2-(4,4-dimethyl-1-piperidyl)-8-[(1R)-1-[2-fluoro-6-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)anilino]ethyl]-3,6-dimethyl-chromen-4-one Using 2-(4,4-dimethyl-1-piperidyl)-8-[(1R)-1-[2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]-3,6-dimethyl-chromen-4-one (320 mg, 583.42 μmol, 1 equivalent) and 6-bromo-1-hydroxy-2,3,1-benzoxazavolinin (119 mg, 525.07 μmol, 0.9 equivalents), the title compound (49.3 mg, 84.49 μmol, yield 14.48%) was prepared as a white solid according to the procedure and synthesis scheme described herein. 1 H NMR (DMSO-d6, 400 MHz) δ 9.30 (s, 1H), 8.31 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.50 (s, 1H), 7.41 (s, 1H), 7.23-7.21 (m, 1H), 6.93-6.86 (m, 2H), 5.17-5.13 (m, 1H), 4.47-4.43 (m, 1H), 3.04-3.00 (m, 4H), 2.30 (s, 3H), 1.80 (s, 3H), 1.34-1.28 (m, 7H), 0.95 (s, 6H). MS(ESI): Mass calculation value C 33 H 35 BFN3O4567.27, measured value in m / z: 568.1 [M+H] + HPLC: 97.25% (220nm), 97.32% (254nm). Chiral purity: 96.72%ee.

[0692] Example 23

[0693] [ka]

[0694] Preparation of 8-(1-(2-bromo-3-fluorophenoxy)ethyl)-2-(4,4-dimethylpiperidine-1-yl)-3,6-dimethyl-4H-chromen-4-one A mixture of 8-(1-bromoethyl)-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (1.00 g, 2.55 mmol, 1.0 equivalent), 2-bromo-3-fluorophenol (535 mg, 2.80 mmol, 1.1 equivalent), and CS2CO3 (1.33 g, 4.08 mmol, 1.6 equivalent) in 15 mL of DMF was degassed and purged three times with N2 at 25°C. The reaction mixture was then stirred at 25°C for 4 hours under an N2 atmosphere. After stopping the reaction by adding water (30 mL) to the reaction mixture, it was extracted with RINKAN (30 mL x 3). The combined organic layers were washed with saturated brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (Biotage®; 12 g Sepa Flash® Silica Flash Column, eluent: 0-30% ethyl acetate / petroleum ether gradient, flow rate 40 mL / min) to obtain the title compound (900 mg, 1.79 mmol, yield 70.28%) as an off-white solid. 1 1H NMR (DMSO-d 6, 400 MHz) δ 7.70 (s, 1H), 7.52 (s, 1H), 7.29 (q, J = 6.8 Hz, 1H), 6.94 (t, J = 6.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 5.98 (t, J = 6.4 Hz, 1H), 3.35-3.33 (m, 4H), 2.36 (s, 3H), 1.90 (s, 3H), 1.43-1.40 (m, 4H), 0.97 (s, 6H).

[0695] 1.2.2 Preparation of 8-[1-[2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-fluorophenoxy]ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one Using 8-[1-(2-bromo-3-fluorophenoxy)ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (300 mg, 600 μmol, 1 equivalent) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxaborinan (270 mg, 1200 μmol, 2 equivalents), the title compound (300 mg, 560 μmol, yield 93.83%) was prepared as an off-white solid according to the procedure and synthesis scheme described herein.

[0696] 1 1H NMR (DMSO-d 6, 400 MHz) δ 7.67 (s, 1H), 7.53 (s, 1H), 7.24-7.21 (m, 1H), 6.70-6.64 (m, 1H), 5.90-5.88 (m, 1H), 4.32 (t, J = 5.2 Hz, 1H), 3.10 (s, 4H), 3.14-3.13 (m, 4H), 1.91 (s, 1H), 1.65 (d, J = 6.4 Hz, 3H), 1.41 (t, J = 5.2 Hz, 4H), 0.95 (d, J = 7.2 Hz, 4H).

[0697] Preparation of 2-(4,4-dimethyl-1-piperidyl)-8-[1-[3-fluoro-2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)phenoxy]ethyl]-3,6-dimethyl-chromen-4-one Using 6-bromo-1-hydroxy-2,3,1-benzoxazavolinin (112 mg, 498.02 μmol, 1 equivalent) and 8-[1-[2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-fluorophenoxy]ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (400 mg, 747 μmol, 1.5 equivalents), the title compound (60 mg, 105 μmol, yield 21.19%) was prepared as a white solid according to the procedure and synthesis scheme described herein. 1 1H NMR (DMSO-d 6,400 MHz) δ 9.42 (s, 1H), 8.59 (s, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.72-7.70 (m, 2H), 7.65 (s, 1H), 7.39-7.37 (m, 1H), 7.24 (s, 1H), 6.98 (t, J = 7.6 Hz, 2H), 5.84 (d, J = 6.4 Hz, 1H), 3.26-3.22 (m, 4H), 2.26 (s, 3H), 1.88 (s, 3H), 1.59 (d, J = 6.0 Hz, 3H), 1.35-1.31 (m, 4H), 0.94 (s, 6H). MS(ESI): Mass calculation value C 33 H 34 BFN2O5568.25, measured value in m / z: 569.2 [M+H] + . HPLC: 97.61% (220nm), 97.66% (254nm).

[0698] Preparation of 2-(4,4-dimethyl-1-piperidyl)-8-[(1S)-1-[3-fluoro-2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)phenoxy]ethyl]-3,6-dimethyl-chromen-4-one and 2-(4,4-dimethyl-1-piperidyl)-8-[(1R)-1-[3-fluoro-2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)phenoxy]ethyl]-3,6-dimethyl-chromen-4-one 2-(4,4-dimethyl-1-piperidyl)-8-[1-[3-fluoro-2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)phenoxy]ethyl]-3,6-dimethyl-chromen-4-one (60 mg, purity 97.61%) was separated by SFC (column: ChiralPak IH, 250 × 30 mm, 10 μm; mobile phase: [CO2-EtOH]; B%: 25%, isoconcentration elution mode). This yielded isomer 1 (23 mg, 40 μmol, yield 38.15%), the title compound, as a white solid, and isomer 2 (23 mg, 40 μmol, yield 37.67%), the title compound, as a white solid. Isomer 1: 1 1H NMR (DMSO-d 6,400 MHz) δ 9.45 (s, 1H), 8.60 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.73-7.70 (m, 2H), 7.65 (s, 1H), 7.39-7.35 (m, 1H), 7.24 (s, 1H), 6.98 (q, J = 8.4 Hz, 2H), 5.84 (q, J = 6.4 Hz, 1H), 3.27-3.21 (m, 4H), 2.26 (s, 3H), 1.88 (s, 3H), 1.59 (d, J = 6.4 Hz, 3H), 1.35-1.31 (m, 4H), 0.93 (s, 6H). MS(ESI): Mass Calculation Value 33 H 34 BFN2O5 568.25, m / z measured value 569.2 [M+H] + HPLC: 98.27% (220nm), 98.15% (254nm). Chlorine purity: 96.36% ee. Heterogeneous component 2: 1 H NMR (DMSO-d 6, 400 MHz) δ 9.45 (s, 1H), 8.60 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.73-7.70 (m, 2H), 7.64 (s, 1H), 7.39-7.35 (m, 1H), 7.24 (s, 1H), 6.97 (q, J = 8.4 Hz, 2H), 5.84 (q, J = 6.4 Hz, 1H), 3.27-3.21 (m, 4H), 2.26 (s, 3H), 1.88 (s, 3H), 1.59 (d, J = 6.4 Hz, 3H), 1.35-1.31 (m, 4H), 0.93 (s, 6H). MS(ESI): Mass Calculation Value 33 H 34 BFN2O5 568.25, m / z measured value 569.2 [M+H] + HPLC: 99.52% (220nm), 100.00% (254nm). Kiral purity: 98.96% ee.

[0699] Example 24

[0700]

change

[0701] JPEG2026510901000101.jpg93169

[0702] Preparation of 8-acetyl-2-(5-fluoroisoindolin-2-yl)-3,6-dimethylchromen-4-one To a 40 mL solution of 8-acetyl-2-ethylsulfinyl-3,6-dimethyl-chromen-4-one (4.00 g, 13.68 mmol, 1.00 equivalent) and 5-fluoroisoindoline (2.61 g, 15.05 mmol, 1.10 equivalents, HCl) in MeCN, DIEA (5.31 g, 41.05 mmol, 7.15 mL, 3.00 equivalent) was added dropwise at 20°C. The reaction mixture was heated to 100°C and stirred at 100°C for 12 hours. The reaction mixture was cooled to 25°C and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (Biotage®, 40 g SepaFlash® Silica Flash Column, eluent: 0-87% petroleum ether / ethyl acetate gradient, flow rate 40 mL / min) to obtain 8-acetyl-2-(5-fluoroisoindorin-2-yl)-3,6-dimethylchromen-4-one (2.8 g, 7.97 mmol, yield 58.24%) as a brown solid. 1 H NMR (DMSO-d6, 400 MHz) δ 7.96 (s, 1H), 7.87 (s, 1H), 7.46-7.43 (m, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.19-7.15 (m, 1H), 5.15-5.12 (m, 4H), 2.73 (s, 3H), 2.42 (s, 3H), 2.22 (s, 3H).

[0703] Preparation of (NZ,S)-N-[1-[2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-4-oxochromen-8-yl]ethylidene]-2-methylpropane-2-sulfinamide To a solution of 8-acetyl-2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-chromen-4-one (2.80 g, 7.97 mmol, 1.00 equivalent) and (S)-2-methylpropan-2-sulfinamide (1.93 g, 15.94 mmol, 2.00 equivalent) in THF (28 mL), Ti(i-PrO)4 (9.06 g, 31.88 mmol, 9.41 mL, 4.00 equivalent) was added dropwise at 20 °C. The reaction mixture was heated to 80 °C and stirred at 80 °C for 36 hours. The reaction mixture was cooled to 20 °C, diluted with water (60 mL), and filtered. The filtered cake was washed with siRNA (25 mL x 3), and the filtrate was extracted with siRNA (25 mL x 3). The combined organic layers were washed with saturated brine (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (Biotage®; 40 g SepaFlash® Silica Flash Column, eluent: 0-70% petroleum ether / ethyl acetate gradient, flow rate 80 mL / min) to obtain (NZ,S)-N-[1-[2-(5-fluoroisoindorin-2-yl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethylidene]-2-methyl-propane-2-sulfinamide (3.20 g, 7.04 mmol, yield 88.34%) as a brown solid. 1 H NMR (DMSO-d6, 400 MHz) δ 7.87-7.77 (m, 1H), 7.58-7.38 (m, 2H), 7.29-7.24 (m, 1H), 7.19-7.17 (m, 1H), 5.20-5.02 (m, 4H), 2.80-2.60 (m, 3H), 2.42-2.40 (m, 3H), 2.24-2.22 (m, 3H), 1.09-1.07 (s, 9H).

[0704] Preparation of (S)-N-[(1R)-1-[2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-4-oxo-chromemen-8-yl]ethyl]-2-methyl-propane-2-sulfinamide and (S)-N-[(1S)-1-[2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-4-oxo-chromemen-8-yl]ethyl]-2-methyl-propane-2-sulfinamide (NZ,S)-N-[1-[2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-4-oxochromen-8-yl]ethylidene]-2-methyl-propane-2-sulfinamide (3.20 g, 7.04 mmol, 1.00 equivalent) was added in an EtOH (16 mL) / THF (16 mL) solution to NaBH4 (0.40 g, 10.57 mmol, 1.50 equivalent) in divided portions at -78 °C. The reaction mixture was warmed to 20 °C and stirred at 20 °C for 1 hour. The mixture was poured in divided portions into ice water (50 mL) at 0 °C and extracted with DCM (20 mL x 3). The combined organic phase was washed with saturated saline (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by prep HPLC (column: Agela DuraShell C18 250×70mm×10μm; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 37%~58%B over 17.0 mins). Isomer 1 (0.49 g, 1.06 mmol, yield 15.04%), the title compound, was obtained as a white solid, and isomer 2 (1.70 g, 3.48 mmol, yield 49.41%), the title compound, was also obtained as a white solid. Isomer 1: 1 H NMR (DMSO-d6, 400 MHz) δ 7.66 (s, 1H), 7.52 (s, 1H), 7.47-7.47 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.20-7.16 (m, 1H), 5.54 (d, J = 4.8 Hz, 1H), 5.24-5.11 (m, 4H), 5.03 (q, J = 6.8 Hz, 1H), 2.37 (s, 3H), 2.22 (s, 3H), 1.60 (d, J = 7.2 Hz, 3H), 1.07 (s, 9H). Isomer 2: 1H NMR (DMSO-d6, 400 MHz) δ 7.66 (s, 1H), 7.58 (s, 1H), 7.45-7.43 (m, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.18-7.15 (m, 1H), 5.80 (d, J = 7.2 Hz, 1H), 5.23-5.13 (m, 4H), 4.99 (q, J = 6.8 Hz, 1H), 2.39 (s, 3H), 2.22 (s, 3H), 1.55 (d, J = 6.8 Hz, 3H), 1.09 (s, 9H).

[0705] Preparation of 8-[(1S)-1-aminoethyl]-2-(5-fluoroisoindolin-2-yl)-3,6-dimethylchromen-4-one (S)-N-[(1S)-1-[2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]-2-methyl-propane-2-sulfinamide (1.70 g, 3.72 mmol, 1.00 equivalent) was dissolved in 0.5 mL of ELISA, to which HCl / EtOA (4N, 25.50 mL) was added dropwise at 20°C. The reaction mixture was stirred at 20°C for 1 hour. The resulting suspension was filtered directly, and the filtered cake was dissolved in 10 mL of water, adjusted to pH=9 with concentrated NH3·H2O, and filtered again. The filtered cake was dried under vacuum to obtain 8-[(1S)-1-aminoethyl]-2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-chromen-4-one (1.00 g, 2.70 mmol, yield 72.63%) as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 7.67 (s, 1H), 7.64 (s, 1H), 7.47-7.44 (m, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.21-7.18 (m, 1H), 5.22-5.13 (m, 4H), 4.74 (q, J = 6.0 Hz, 1H), 2.40 (s, 3H), 2.23 (s, 3H), 1.48 (d, J = 6.8 Hz, 3H).

[0706] Preparation of 8-[(1S)-1-(2-bromo-4-chloroanilino)ethyl-2-(5-fluoroisoindorin-2-yl)-3,6-dimethylchromen-4-one] Using 8-[(1S)-1-aminoethyl]-2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-chromen-4-one (300 mg, 851.30 μmol, 1.00 equivalent) and 2-bromo-4-chloro-1-iodobenzene (405 mg, 1.28 mmol, 1.50 equivalent), the title compound (360 mg, 664.40 μmol, yield 78.05%) was prepared as a yellow solid according to the procedure and synthesis scheme described herein. 1 H NMR (DMSO-d6, 400 MHz) δ 7.64-7.62 (m, 1H), 7.44-7.42 (m, 1H), 7.38- 7.37 (m, 1H), 7.30-7.26 (m, 2H), 7.17-7.16 (m, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.52-6.48 (m, 2H), 5.22-5.10 (m, 5H), 2.31 (s, 3H), 2.25 (s, 3H), 1.54 (d, J = 2.8 Hz, 3H).

[0707] Preparation of 8-[(1S)-1-[4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]-2-(5-fluoroisoindorin-2-yl)-3,6-dimethyl-chromen-4-one Using 8-[(1S)-1-(2-bromo-4-chloroanilino)ethyl]-2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-chromen-4-one (360 mg, 664.40 μmol, 1.00 equivalent) and B2Pin2 (675 mg, 2.66 mmol, 4.00 equivalent), the title compound (260 mg, 441.50 μmol, yield 66.45%) was prepared as a yellow solid according to the procedure and synthesis scheme described herein. 1H NMR (DMSO-d6, 400 MHz) δ 7.64 (s, 1H), 7.44-7.42 (m, 1H), 7.34 (d, J = 2.8 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.28-7.26 (m, 1H), 7.19-7.16 (m, 2H), 6.39-6.36 (m, 2H), 5.19-5.10 (m, 5H), 2.31 (s, 3H), 2.25 (s, 3H), 1.59 (d, J = 6.4 Hz, 3H), 1.33 (s, 12H).

[0708] Preparation of 8-[(1S)-1-[4-chloro-2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)anilino]ethyl]-2-(5-fluoroisoindorin-2-yl)-3,6-dimethyl-chromen-4-one Using 8-[(1S)-1-[4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]-2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-chromen-4-one (260 mg, 441.50 μmol, 1.00 equivalent) and 6-bromo-1-hydroxy-2,3,1-benzoxazavolinin (200 mg, 883.00 μmol, 2.00 equivalent), the title compound (22.40 mg, 36.19 μmol, yield 8.20%) was prepared as a white solid according to the procedure and synthesis scheme described herein. 1H NMR (DMSO-d6, 400 MHz) δ 9.40 (s, 1H), 8.61 (s, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.82-7.81 (m, 2H), 7.62 (d, J = 1.2 Hz, 1H), 7.40-7.39 (m, 2H), 7.25-7.23 (m, 1H), 7.16-7.13 (m, 2H), 7.07 (d, J = 2.8 Hz, 1H), 6.58 (d, J = 9.2 Hz, 1H), 5.33-5.31 (m, 1H), 5.13-4.97 (m, 5H), 2.32 (s, 3H), 2.24 (s, 3H), 1.48 (d, J = 6.8 Hz, 3H). MS(ESI): Mass calculation value C 34 H 28 BClFN3O4607.18, measured value in m / z: 608.3 [M+H] + HPLC: 98.21% (220nm), 99.51% (254nm). Chiral purity: 100%ee.

[0709] Preparation of Methyl(R)-8-(1-aminoethyl)-2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-4H-chromen-4-one (S)-N-[(1R)-1-[2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-4-oxo-chromen-8-yl]ethyl]-2-methyl-propane-2-sulfinamide (480 mg, 1.05 mmol, 1 equivalent) was dissolved in HCl / HCl (4N, 5 mL) in HCl (3 mL) at 25°C. The mixture was stirred at 25°C for 1 hour. The resulting suspension was filtered directly, and the filtered cake was dissolved in water (10 mL), adjusted to pH=9 with concentrated NH3·H2O, and filtered again. The filtered cake was dried under vacuum to obtain 8-[(1R)-1-aminoethyl]-2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-chromen-4-one (300 mg, 851.30 μmol, yield 80.98%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 7.61 (d, J = 7.6 Hz, 2H), 7.45-7.44 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.17 (t, J = 8.8 Hz, 1H), 5.16-5.10 (m, 4H), 4.59-4.54 (m, 1H), 2.38 (s, 3H), 2.22 (s, 3H), 1.35 (d, J = 6.4 Hz, 3H).

[0710] Preparation of (R)-8-(1-((2-bromo-4-chlorophenyl)amino)ethyl)-2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-4H-chromen-4-one Using 8-[(1R)-1-aminoethyl]-2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-chromen-4-one (300 mg, 851.30 μmol, 1 equivalent) and 2-bromo-4-chloro-1-iodobenzene (405 mg, 1.28 mmol, 1.5 equivalents), the title compound (400 mg, 738.23 μmol, yield 86.72%) was prepared as a yellow solid by the same procedure as in Example 78. 1 H NMR (DMSO-d6, 400 MHz) δ 7.63 (d, J = 1.2 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.45-7.42 (m, 1H), 7.38-7.37 (m, 1H), 7.32-7.31 (m, 1H), 7.27-7.25 (m, 1H), 7.19-7.17 (m, 1H), 7.12-7.01 (m, 1H), 5.51 (d, J = 6.8 Hz, 1H), 5.20-5.10 (m, 4H), 2.31 (s, 3H), 2.25 (s, 3H), 1.64 (d, J = 9.2 Hz, 1H).

[0711] Preparation of (R)-8-(1-((4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)ethyl)-2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-4H-chromen-4one Using 8-[(1R)-1-(2-bromo-4-chloroanilino)ethyl]-2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-chromen-4-one (400 mg, 738.23 μmol, 1 equivalent) and B2Pin2 (375 mg, 1.48 mmol, 2 equivalents), the title compound (400 mg, crude) was prepared as a yellow solid according to the procedure described in the above examples. This product was used directly in the next step without further purification.

[0712] Preparation of (R)-8-(1-((4-chloro-2-(1-hydroxy-1H-benzo[d][1,2,6]oxazavolinin-6-yl)phenyl)amino)ethyl)-2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-4H-chromen-4-one Using 8-[(1R)-1-[4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]-2-(5-fluoroisoindolin-2-yl)-3,6-dimethyl-chromen-4-one (150 mg, 254.71 μmol, 1 equivalent) and 6-bromo-1-hydroxy-2,3,1-benzoxazavolinin (115 mg, 509.42 μmol, 2 equivalents), the title compound (2.14 mg, 3.52 μmol, yield 1.38%) was prepared as a white solid according to the procedure and synthesis scheme described herein. 1 1H NMR (DMSO-d 6,400 MHz) δ 9.39 (s, 1H), 8.61 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.82-7.80 (m, 2H), 7.61 (s, 1H), 7.42-7.39 (m, 2H), 7.19-7.16 (m, 1H), 7.14-7.13 (m, 2H), 7.07-7.06 (m, 1H), 8.58 (d, J = 8.8 Hz, 1H), 5.32-5.30 (m, 1H), 5.13-4.97 (m, 5H), 2.32 (s, 3H), 2.24 (s, 3H), 1.48 (d, J = 4.4 Hz, 3H). MS(ESI): Mass calculation value C 34 H 28 BClFN3O4607.87, measured value in m / z: 608.2 [M+H] + HPLC: 98.03% (220nm), 99.73% (254nm). Chiral purity: 97.14%ee.

[0713] Example 25

[0714] [ka]

[0715] Preparation of 8-[(1R)-1-(2-bromo-5-methyl-anilino)ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one Using 8-[(1R)-1-aminoethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (0.5 g, 1.52 mmol, 1 equivalent) and 1-bromo-2-iodo-4-methylbenzene (904 mg, 3.04 mmol, 2 equivalents), the title compound (600 mg, 1.21 mmol, yield 79.23%) was prepared as a yellow solid by the same procedure as in Example 78. 1H NMR (CDCl3, 400 MHz) δ 7.89 (d, J = 1.2 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.38 (dd, J = 1.2, 8.0 Hz, 1H), 6.19 (d, J = 1.2 Hz, 1H), 5.00-4.98 (m, 1H), 4.67-4.66 (s, 1H), 3.42-3.39 (m, 4H), 2.38 (s, 3H), 2.12 (s, 3H), 2.07 (s, 3H), 1.66 (d, J = 6.8 Hz, 3H), 1.53-1.50 (m, 4H), 1.03 (s, 6H).

[0716] Preparation of (R)-8-(1-((2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-methylphenyl)amino)ethyl)-2-(4,4-dimethylpiperidine-1-yl)-3,6-dimethyl-4H-chromen-4-one Using 8-[(1R)-1-(2-bromo-5-methylanilino)ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (500 mg, 1.01 mmol, 1 equivalent) and B2neop2 (1.14 g, 5.03 mmol, 5 equivalents), the title compound (500 mg, crude) was prepared as a yellow solid according to the procedure described in the above examples.

[0717] This product was used directly in the next step without further purification.

[0718] Preparation of 2-(4,4-dimethyl-1-piperidyl)-8-[(1R)-1-[2-(1-hydroxy-2,1-benzoxaporinin-6-yl)-5-methyl-anilino]ethyl]-3,6-dimethyl-chromen-4-one Using 8-[(1R)-1-[2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-methyl-anilino]ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (400 mg, 754 μmol, 1 equivalent) and 6-bromo-1-hydroxy-2,3,1-benzoxazavolinin (170 mg, 754 μmol, 1 equivalent), the title compound (31.4 mg, 55.72 μmol, yield 20.93%) was prepared as a white solid according to the procedure and synthesis scheme described herein. 1 1H NMR (DMSO-d6, 6.93 (d, J = 7.2 Hz, 1H), 6.53 (d, J = 7.6 Hz, 1H), 6.44 (s, 1H), 5.02-5.00 (m, 1H), 4.98-4.91 (m, 1H), 3.29-3.20 (m, 4H), 2.33 (s, 3H), 2.14 (s, 3H), 1.89 (s, 3H), 1.45 (d, J = 6.8 Hz, 3H), 1.44-1.38 (m, 4H), 0.95 (s, 6H). MS(ESI): Mass calculation value C 34 H 38 BN3O4563.51, measured value in m / z: 564.3 [M+H] + HPLC: 98.73% (220nm), 99.05% (254nm). Chiral purity: 100%ee.

[0719] Example 26

[0720] [ka]

[0721] Preparation of 8-[(1R)-1-(2-bromo-4-methyl-anilino)ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one Using 2-bromo-1-iodo-4-methylbenzene (361 mg, 1.22 mmol, 2 equivalents) and 8-[(1R)-1-aminoethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (200 mg, 608 μmol, 1 equivalent), the title compound (200 mg, 402 μmol, yield 66.0%) was prepared as a yellow solid by the same procedure as in Example 78. 1 1H NMR (CDCl3, 400 MHz) δ 7.87 (d, J = 1.2 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.29-7.27 (m, 1H), 6.82 (dd, J = 1.2, 8.4 Hz, 1H), 6.23 (d, J = 8.4 Hz, 1H), 4.96 (d, J = 6.4 Hz, 1H), 4.59 (s, 1H), 3.43-3.35 (m, 4H), 2.36 (s, 3H), 2.18 (s, 3H), 2.06 (s, 3H), 1.67-1.63 (m, 3H), 1.55-1.50 (m, 4H), 1.04 (s, 6H).

[0722] Preparation of 8-[(1R)-1-[2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-methyl-anilino]ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one Using 8-[(1R)-1-(2-bromo-4-methyl-anilino)ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (200 mg, 402 μmol, 1 equivalent) and B2neop2 (454 mg, 2.01 mmol, 5 equivalents), the title compound (200 mg, 377 μmol, yield 93.7%) was prepared as a yellow oil according to the procedure and synthesis scheme described herein. 1 1H NMR (CDCl3, 400 MHz) δ 7.84 (s, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.45 (s, 1H), 6.93 (d, J = 7.2 Hz, 1H), 6.38 (s, 1H), 6.16 (s, 1H), 5.05-4.83 (m, 1H), 3.83 (s, 2H), 3.66 (s, 2H), 3.43-3.34 (m, 4H), 2.35 (s, 3H), 2.18 (s, 3H), 2.06 (d, J = 1.2 Hz, 3H), 1.59 (s, 3H), 1.54-1.48 (m, 4H), 1.07 (s, 6H), 1.03 (s, 6H).

[0723] Preparation of 2-(4,4-dimethyl-1-piperidyl)-8-[(1R)-1-[2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)-4-methyl-anilino]ethyl]-3,6-dimethyl-chromen-4-one and by-product 2-hydroxy-8-[(1R)-1-[2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)-4-methyl-anilino]ethyl]-3,6-dimethyl-chromen-4-one Using 8-[(1R)-1-[2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-methyl-anilino]ethyl]-2-(4,4-dimethyl-1-piperidyl)-3,6-dimethyl-chromen-4-one (200 mg, 377 μmol, 1.5 equivalents) and 6-bromo-1-hydroxy-2,3,1-benzoxazavolinin (56.7 mg, 251 μmol, 1 equivalent) in H2O (0.4 mL), the title compound (18 mg, 31.9 μmol, yield 12.7%) was prepared as a white solid according to the procedure and synthesis scheme described herein. 1H NMR (DMSO-d6,400 MHz) δ 9.43 (s, 1H), 8.64 (s, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.83-7.80 (m, 2H), 7.59 (s, 1H), 7.45 (d, J = 1.6 Hz, 1H), 6.91-6.82 (m, 2H), 6.49 (d, J = 8.4 Hz, 1H), 4.94-4.85 (m, 2H), 3.27-3.20 (m, 4H), 2.32 (s, 3H), 2.10 (s, 3H), 1.89 (s, 3H), 1.49-1.41 (m, 3H), 1.41-1.33 (m, 4H), 0.95 (s, 6H). MS(ESI): Mass calculation value C 34 H 38 BN3O4563.30, measured value in m / z: 564.3 [M+H] + HPLC: 97.62% (220 nm), 98.10% (254 nm). Chiral purity: 97.14% ee. The by-product, 2-hydroxy-8-[(1R)-1-[2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)-4-methyl-anilino]ethyl]-3,6-dimethyl-chromen-4-one, was also isolated as a yellow solid (6.5 mg, 13.8 μmol, yield 5.5%). 1 H NMR (DMSO-d6, 400 MHz) δ 9.41 (s, 1H), 8.69 (s, 1H), 8.15 (d, J = 7.6 Hz, 1H), 7.83 (dd, J = 1.6, 7.6 Hz, 1H), 7.80 (s, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 6.90-6.85 (m, 2H), 6.40 (d, J = 8.4 Hz, 1H), 4.93-4.78 (m, 2H), 2.30 (s, 3H), 2.14 (s, 3H), 1.98 (s, 3H), 1.37 (d, J = 6.4Hz, 3H). MS(ESI): Mass calculation value C 27 H 25 BN2O5468.19, measured value in m / z: 469.3 [M+H] +. HPLC: 93.30% (220nm), 93.19% (254nm).

[0724] Example 27

[0725] [ka]

[0726] Preparation of 8-acetyl-3,6-dimethyl-2-morpholino-chromen-4-one 8-acetyl-2-ethylsulfinyl-3,6-dimethyl-chromen-4-one (1.00 g, 3.42 mmol, 1 equivalent) and morpholine (745 mg, 8.55 mmol, 2.5 equivalents) were dissolved in MeCN (20 mL). DIEA (1.33 g, 10.3 mmol, 1.79 mL, 3 equivalents) was added in a single addition at 20 °C. The reaction mixture was heated to 100 °C and stirred at 100 °C for 18 hours. After cooling the reaction to 25 °C, some solid was formed. The solid was filtered, ground with MTBE (10 mL), and dried in vacuum. This yielded the title compound (700 mg, 2.32 mmol, 67.91% yield) as a yellow solid. 1 1H NMR (DMSO-d 6, 400 MHz) δ 7.98 (d, J = 1.6 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 3.75 - 3.72 (m, 4H), 3.46 - 3.42 (m, 4H), 2.70 (s, 3H), 2.43 (s, 3H), 1.93 (s, 3H).

[0727] Preparation of 8-(1-hydroxyethyl)-3,6-dimethyl-2-morpholino-chromen-4-one To a solution of 8-acetyl-3,6-dimethyl-2-morpholino-chromen-4-one (1.15 g, 3.82 mmol, 1 equivalent) in EtOH (10 mL) / DCM (10 mL), NaBH4 (320 mg, 8.46 mmol, 2.2 equivalents) was added in 20°C fractions under N2. The reaction mixture was heated to 20°C and stirred at 20°C for 1 hour. The mixture was poured into 0°C ice water (35 mL) and protected under a nitrogen atmosphere. The mixture was heated to 20°C and extracted with DCM (20 mL x 3). The combined organic phase was washed with saturated saline solution (25 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. This yielded the title compound (1.1 g, 3.63 mmol, yield 95.02%) as a yellow solid. 1 1H NMR (DMSO-d 6, 400 MHz) δ 7.63 (s, 1H), 7.59 (d, J = 2.0 Hz, 1H), 5.34 (d, J = 4.4 Hz, 1H), 5.24 - 5.18 (m, 1H), 3.74 (t, J = 4.4 Hz, 4H), 3.41 - 3.37 (m, 4H), 2.39 (s, 3H), 1.91 (s, 3H), 1.40 (d, J = 6.4 Hz, 3H).

[0728] Preparation of 8-(1-bromoethyl)-3,6-dimethyl-2-morpholino-chromen-4-one To a 20 mL solution of 8-(1-hydroxyethyl)-3,6-dimethyl-2-morpholino-chromen-4-one (1.50 g, 4.94 mmol, 1 equivalent) in DCM, PBr3 (1.61 g, 5.93 mmol, 1.2 equivalents) was added dropwise at 0°C under N2 conditions, and the reaction mixture was stirred at 0°C for 30 minutes. The reaction mixture was poured onto 20 g of ice, adjusted to pH=7 with saturated NaHCO3 aqueous solution at 0°C, and extracted with DCM (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (BIOTAGE®; 20 g SepaFlash® Silica Flash Column, eluent: 0-100% ethyl acetate / petroleum ether, flow rate 60 mL / min) to obtain the title compound (450 mg, 1.23 mmol, yield 24.85%) as a pale yellow solid. 1 1H NMR (CDCl 3, 400 MHz) δ 7.97 (s, 1H), 7.53 (s, 1H), 5.64 (q, J = 3.2 Hz, 1H), 3.89 (t, J = 4.4 Hz, 4H), 3.51 (t, J = 4.4 Hz, 4H), 2.46 (s, 3H), 2.17 (d, J = 6.8 Hz, 1H), 2.07 (s, 3H).

[0729] Preparation of 3,6-dimethyl-2-morpholino-8-[1-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]chromen-4-one To a 10 mL solution of 8-(1-bromoethyl)-3,6-dimethyl-2-morpholino-chromen-4-one (450 mg, 1.23 mmol, 1 equivalent) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (450 mg, 2.05 mmol, 1.67 equivalents), NaHCO3 (155 mg, 1.84 mmol, 1.5 equivalents) was added at 25°C. The reaction mixture was heated to 60°C and stirred at 60°C for 2 hours. The reaction mixture was cooled to 0°C, poured into 40 mL of ice water, diluted with DCM (15 mL), and extracted with DCM (15 mL x 3). The combined organic layers were washed with saturated brine (25 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (BIOTAGE®; 20 g SepaFlash® Silica Flash Column, eluent: 0-100% ethyl acetate / petroleum ether gradient, flow rate 75 mL / min) to obtain the title compound (500 mg, 991.23 μmol, yield 80.67%) as a pale yellow solid. 1 1H NMR (CDCl 3, 400 MHz) δ 7.87 (s, 1H), 7.66 (dd, J = 1.6, 7.2 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.17 - 7.12 (m, 1H), 6.64 (t, J = 7.2 Hz, 1H), 6.36 (br s, 1H), 6.25 (d, J = 8.0 Hz, 1H), 5.02 - 4.95 (m, 1H), 3.87 - 3.82 (m, 4H), 3.43 - 3.40 (m, 4H), 2.38 (s, 3H), 2.07 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H), 1.38 (s, 12H).

[0730] Preparation of 8-[1-[2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)anilino]ethyl]-3,6-dimethyl-2-morpholino-chromen-4-one To a solution of 3,6-dimethyl-2-morpholino-8-[1-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilino]ethyl]chromen-4-one (180 mg, 357 μmol, 1 equivalent) and 6-bromo-1-hydroxy-2,3,1-benzoxazavolinin (105 mg, 464 μmol, 1.3 equivalents) in dioxane (3.2 mL) / H2O (0.4 mL), Pd(dppf)Cl2 (26 mg, 35.7 μmol, 0.1 equivalent) and K2CO3 (99 mg, 713 μmol, 2 equivalents) were sequentially added at 25 °C. The reaction mixture was degassed, purged three times with N2, and then stirred at 80 °C (oil bath preheated to 80 °C) for 2 hours under an N2 atmosphere. The reaction mixture was cooled to 25°C and filtered. The filtrate was directly purified by prep HPLC (column: Waters Xbridge BEH C18 100×30mm×10μm; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 22%~50%B over 8.0 minutes) to obtain the title compound (38.1 mg, yield 20.20%) as a white solid. 1 1H NMR (DMSO-d 6, 400 MHz) δ 9.39 (s, 1H), 8.66 (s, 1H), 8.15 (d, J = 7.6 Hz, 1H), 7.87 - 7.83 (m, 1H), 7.82 (s, 1H), 7.62 (d, J = 1.2 Hz, 1H), 7.49 (d, J = 1.2 Hz, 1H), 7.10 (t, J = 7.2 Hz, 1H), 7.07 - 7.03 (m, 1H), 6.71 (t, J = 7.6 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 5.05 (d, J = 7.2 Hz, 1H), 4.97 - 4.90 (m, 1H), 3.66 (t, J = 4.8 Hz, 4H), 3.28 - 3.19 (m, 4H), 2.33 (s, 3H), 1.91 (s, 3H), 1.45 (d, J = 6.8 Hz, 3H). MS(ESI): Mass calculation value C 30 H 30 BN3O5523.23, measured value in m / z: 524.2 [M+H] +. HPLC: 99.02% (220nm), 99.55% (254nm).

[0731] Preparation of 8-[(1S)-1-[2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)anilino]ethyl]-3,6-dimethyl-2-morpholino-chromen-4-one and 8-[(1R)-1-[2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)anilino]ethyl]-3,6-dimethyl-2-morpholino-chromen-4-one 8-[1-[2-(1-hydroxy-2,3,1-benzoxazavolinin-6-yl)anilino]ethyl]-3,6-dimethyl-2-morpholino-chromen-4-one (111 mg) was separated by SFC (column: DAIEL CHIRALPAK IG (250 mm × 30 mm, 10 μm); mobile phase: [CO2-IPA]; B%: 50%, isoconcentration elution mode). This yielded isomer 1 (41.6 mg, yield 36.74%), the title compound, as a white solid, and isomer 2 (40.5 mg, yield 36.24%), the title compound, as a white solid. Isomer 1: 1 1H NMR (DMSO-d 6, 400 MHz) δ 9.41 (s, 1H), 8.66 (s, 1H), 8.15 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.82 (s, 1H), 7.61 (d, J = 1.2 Hz, 1H), 7.49 (d, J = 1.2 Hz, 1H), 7.10 - 7.03 (m, 2H), 6.71 (t, J = 7.2 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 5.05 (d, J = 7.2 Hz, 1H), 4.97 - 4.90 (m, 1H), 3.70 - 3.65 (m, 4H), 3.28 - 3.18 (m, 4H), 2.33 (s, 3H), 1.90 (s, 3H), 1.45 (d, J = 6.4 Hz, 3H). MS(ESI): Mass calculation value C 30 H 30BN3O5523.23, measured value in m / z: 524.3 [M+H] + HPLC: 98.04% (220nm), 98.79% (254nm). Chiral purity: 100%ee. Isomer 2: 1 1H NMR (DMSO-d 6, 400 MHz) δ 9.40 (s, 1H), 8.66 (s, 1H), 8.15 (d, J = 7.6 Hz, 1H), 7.87 - 7.83 (m, 1H), 7.82 (s, 1H), 7.62 (s, 1H), 7.49 (d, J = 1.2 Hz, 1H), 7.15 - 7.03 (m, 2H), 6.71 (t, J = 7.2 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 5.05 (d, J = 7.6 Hz, 1H), 4.97 - 4.90 (m, 1H), 3.66 (t, J = 4.8 Hz, 4H), 3.28 - 3.19 (m, 4H), 2.33 (s, 3H), 1.91 (s, 3H), 1.45 (d, J = 6.8 Hz, 3H). MS(ESI): Mass calculation value C 30 H 30 BN3O5523.23, measured value in m / z: 524.3 [M+H] + HPLC: 99.33% (220nm), 99.62% (254nm). Chiral purity: 98.46%ee.

[0732] Example 28

[0733] [ka]

[0734] Preparation of 3,6-dimethyl-2-(piperidine-1-yl)-8-(1-((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)ethyl)-4H-chromen-4one A mixture of 8-(1-bromoethyl)-3,6-dimethyl-2-(1-piperidyl)chromen-4-one (500 mg, 1.37 mmol, 1 equivalent), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (601 mg, 2.75 mmol, 2 equivalents), and NaHCO3 (172 mg, 2.06 mmol, 80 μL, 1.5 equivalents) in DMF (10 mL) was degassed and purged three times with N2 at 20°C. The mixture was then heated to 60°C and stirred at 60°C for 2 hours under an N2 atmosphere. The reaction mixture was cooled to 20°C, poured into H2O (50 mL), and filtered. The filtered cake was collected and dried under vacuum to obtain the title compound (1.0 g, crude) as a ye...

Claims

1. Formula (A): 【Chemistry 1】 (A) The compounds shown, or their tautomers, enantiomers, diastereomers, mixtures, salts, hydrates, solvates, or deuterated forms, During the ceremony, A1 is, 【Chemistry 2】 Selected from the group consisting of, 【Transformation 3】 In the formula, A' is independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl; Here, each heterocyclyl and heteroaryl may contain one or more heteroatoms selected from N, O, and S; Each A1 is replaced by an optional choice; L １ This is selected from the group consisting of (i) directly bonded, (ii) optionally substituted arylene, and (iii) optionally substituted heteroarylene; L ２ The group consisting of O and NH is selected; R １ａ and R １ｂ are each independently selected from the group consisting of H, halogen, CN, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, and C １－６ alkoxy; Q Ｂ This is an optionally substituted 8-14 member fused ring system that optionally contains one or more heteroatoms selected from the group consisting of O, N, and S; Y is H, CR ３ｃ , N, O, or S; a) If Y is H, R ３ａ and R ３ｂ None of them exist; b) If Y is N, R ３ａ and R ３ｂ These are H and C, which are independent of each other. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, aryl, C ３－６ Selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines; or Y is an N atom, R ３ａ and R ３ｂ It combines with to form a heterocyclic or heterocyclic aromatic monocyclic, spirocyclic, or fused ring system, the ring or ring system may additionally contain one or more heteroatoms selected from the group consisting of N, O, and S, and the ring or ring system may be optionally substituted; c) Y is CR ３ｃ If that is the case, R ３ｃ It does not exist, or hydrogen, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, aryl, C ３－６ Selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines; R ３ａ and R ３ｂ These are H and C, which are independent of each other. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, aryl, C ３－６ Selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines; or Y is a C atom, R ３ａ and R ３ｂ It combines with to form a cycloalkyl, aryl, heterocyclic, or heterocyclic aromatic monocyclic, spirocyclic, or fused ring system, wherein the heterocyclic ring and heterocyclic aromatic ring contain one or more heteroatoms selected from the group consisting of N, O, and S, and the ring or ring system containing Y is optionally substituted; or d) If Y is O or S, R ３ａ It does not exist, R ３ｂ H, C １－６ Alkyl, C ２－６ Alkenyl and C ２－６ Selected from the group consisting of alkinyls, Compounds, their tautomers, enantiomers, diastereomers, mixtures, salts, hydrates, solvates, or deuterated forms.

2. A1 is, 【Chemistry 4】 Selected from, The compound of claim 1, wherein each A1 is optionally substituted from any of the rings in the formula.

3. Each A1 is one or more R Ａ１ Replaced by optional selection, R Ａ１ is each independently halogen, OH, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ２－６ haloalkenyl, C ２－６ haloalkynyl, (CH ２ ) ０－６ CN, (CH ２ ) １－６ OH, (CH ２ ) ０－６ O - C １－６ alkyl, (CH ２ ) ０－６ O - C ２－６ alkenyl, (CH ２ ) ０－６ O - C ２－６ alkynyl, (CH ２ ) ０－６ C(O)H, (CH ２ ) ０－６ C(O)(C １－６ alkyl, C ２－６ alkenyl, or C １－６ alkynyl), (CH ２ ) ０－６ C(O)OH, (CH ２ [[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​Alkyl, C ２－６ Alkenyl, or C ２－６ (Alkinyl), (CH ２ ) ０－６ C(O)N(C １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ Alkinyl) ２ , (CH ２ ) ０－６ NHC(O)H, (CH ２ ) ０－６ NHC(O)(C) １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ (Alkinyl), and (CH ２ ) ０－６ N(C) １－６ Alkyl, C ２－６ Alkenyl and C ２－６ Alkinyl) C(O) (C １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ Alkinyl), or R Ａ１ Selected from the isotopic forms, The compound according to claim 1 or 2.

4. A1 is, 【Transformation 5】 Selected from the group consisting of, A1 is further replaced by any choice. A compound according to any one of claims 1 to 3.

5. R ＡＡ These are H, halogen, CN, and C, respectively, independently. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, OH, O-C １－６ Alkyl, O-C ２－６ Alkenyl and O-C ２－６ A compound according to claim 4, selected from the group consisting of alkynyl compounds.

6. A compound according to any one of claims 1 to 5, wherein one or more atoms are in isotopic form.

7. The compound according to claim 6, wherein the isotope is deuterium.

8. R ＡＡ The compound of claim 7, wherein it is deuterated.

9. R ＡＡ C １－６ Alkyl, O-C １－６ Alkyl, C １－６ Haloalkyl, deuterated C １－６ Alkyl, deuterated O-C １－６ Alkyl, deuterated C １－６ A compound according to any one of claims 4 to 8, selected from the group consisting of haloalkyl, halogen, and CN.

10. R ＡＡ F, Cl, CH ３ , OCH ３ , or CD ３ A compound according to any one of claims 1 to 9.

11. Q Ｂ teeth: 【Transformation 6】 【change】 Selected from the group consisting of, During the ceremony, Each G, as it appears, is independently selected from carbon or a heteroatom chosen from O, N, or S. Each m, whenever it appears, is independently chosen from 0, 1, 2, 3, 4, 5, and 6. If m is not 0, each R １００ may be substituted by any of the rings in the formula; R １００ If R exists, １００ These are, independently, halogen, OH, oxo, and C. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C １－６ Alkoxy, (CH ２ ) ｑ -N(H or C １－６ (alkyl), (CH ２ ) ｑ -O-C(O)-(CH ２ ) ｒ -R １４０ , (CH ２ ) ｑ -NH-C(O)-(CH ２ ) ｒ -R １４０ , (CH ２ ) ｑ -O-C(O)-(CH ２ ) ｒ -OR １４０ , (CH ２ ) ｑ -NH-C(O)-(CH ２ ) ｒ -OR １４０ , (CH ２ ) ｑ -O-(CH ２ ) ｒ -R １４０ , (CH ２ ) ｑ -NH-(CH ２ ) ｒ -R １４０ , (CH ２ ) ｑ -O-(CH ２ ) ｒ -OR １４０ , (CH ２ ) ｑ -NH-(CH ２ ) ｒ -OR １４０ , C ３－１０ Cycloalkyl, (CH ２ ) ｑ - Heterogene, (CH ２ )-- ｑ - Aryl, and (CH ２ ) ｑ - Selected from the group consisting of heteroaryls, the cycloalkyl, heterocyclic, aryl, and heteroaryl are each optionally selected to be halogen, OH, and C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, and C １－６ Substituted with one or more haloalkoxys R １４０ It is an E3 ligase-binding ligand, q and r are independently selected from 0, 1, 2, 3, 4, 5, and 6 each time they appear. A compound according to any one of claims 1 to 10.

12. Q Ｂ teeth: 【Transformation 7】 A compound according to any one of claims 1 to 11, selected from the group consisting of the following.

13. Q Ｂ teeth: 【Transformation 8】 And, During the ceremony, X is C(R ｘ ) ２ , O, NR ｘ , or S; R ｘ These are H and C, which are independent of each other. １－６ Alkyl, C ２－６ Alkenyl and C ２－６ Selected from the group consisting of alkinyls; R ２ H, halogen, CN, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, C １－６ Alkoxy, (CH ２ ) ０－６ -R ＱＢ１ , (CH ２ ) ０－６ -OR ＱＢ１ , (CH ２ ) ０－６ -N(R) ＱＢ１ ) ２ , (CH ２ ) ０－６ -C(O)R ＱＢ１ , (CH ２ ) ０－６ -C(O)OR ＱＢ１ , (CH ２ ) ０－６ -C(O)N(R) ＱＢ１ ) ２ , (CH ２ ) ０－６ -C ３－１０ Cycloalkyl, (CH ２ ) ０－６ - Aryl, (CH ２ ) ０－６ - Heterogenes, and (CH ２ ) ０－６ - Selected from the group consisting of heteroaryls; R ４ H, halogen, CN, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, C １－６ Alkoxy, (CH ２ ) ０－６ -R ＱＢ１ , (CH ２ ) ０－６ -OR ＱＢ１ , (CH ２ ) ０－６ -N(R) ＱＢ１ ) ２ , (CH ２ ) ０－６ -C(O)R ＱＢ１ , (CH ２ ) ０－６ -C(O)OR ＱＢ１ , (CH ２ ) ０－６ -C(O)N(R) ＱＢ１ ) ２ , (CH ２ ) ０－６ -C ３－１０ Cycloalkyl, (CH ２ ) ０－６ - Aryl, (CH ２ ) ０－６ - Heterogenes, and (CH ２ ) ０－６ - Selected from the group consisting of heteroaryls; R ５ H, halogen, CN, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, C １－６ Alkoxy, (CH ２ ) ０－６ -R ＱＢ１ , (CH ２ ) ０－６ -OR ＱＢ１ , (CH ２ ) ０－６ -N(R) ＱＢ１ ) ２ , (CH ２ ) ０－６ -C(O)R ＱＢ１ , (CH ２ ) ０－６ -C(O)OR ＱＢ１ , (CH ２ ) ０－６ -C(O)N(R) ＱＢ１ ) ２ , (CH ２ ) ０－６ -C ３－１０ Cycloalkyl, (CH ２ ) ０－６ - Aryl, (CH ２ ) ０－６ - Heterogenes, and (CH ２ ) ０－６ - Selected from the group consisting of heteroaryls; R ６ H, halogen, CN, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, C １－６ Alkoxy, (CH ２ ) ０－６ -R ＱＢ１ , (CH ２ ) ０－６ -OR ＱＢ１ , (CH ２ ) ０－６ -N(R) ＱＢ１ ) ２ , (CH ２ ) ０－６ -C(O)R ＱＢ１ , (CH ２ ) ０－６ -C(O)OR ＱＢ１ , (CH ２ ) ０－６ -C(O)N(R) ＱＢ１ ) ２ , (CH ２ ) ０－６ -C ３－１０ Cycloalkyl, (CH ２ ) ０－６ - Aryl, (CH ２ ) ０－６ - Heterogenes, and (CH ２ ) ０－６ - Selected from the group consisting of heteroaryls; R ＱＢ１ These are H, halogen, OH, and C, respectively, independently. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, C １－６ Alkoxy, C ２－６ Alkenoxy, C ２－６ Alkinoxy, C １－６ Haloalkoxy, C ２－６ Haloalkenoxy and C ２－６ It is an alkinoxy. A compound according to any one of claims 1 to 12.

14. Formula A(Ia) or A(Ib): 【Chemistry 9】 A compound according to any one of claims 1 to 13, which is a compound shown in the image.

15. The compound of claim 14, wherein A' is a condensed aryl or heteroaryl compound.

16. The compound of claim 15, wherein A' is selected from optionally substituted phenyl compounds.

17. The compound of claim 16, wherein A' is a substituted phenyl compound.

18. L １ The compound according to any one of claims 1 to 17, wherein is selected from the group consisting of directly bonded, optionally substituted heteroarylene, or optionally substituted arylene.

19. The compound according to any one of claims 1 to 18, wherein the optionally substituted arylene is optionally substituted phenylene.

20. The compound according to any one of claims 1 to 18, wherein the optionally substituted heteroarylene is optionally substituted pyridylene.

21. The compound according to any one of claims 1 to 20, wherein the optionally substituted arylene and the optionally substituted heteroarylene are each unsubstituted.

22. Optionally substituted arylenes and optionally substituted heteroarylenes are halogens and C, respectively. １ -C ３ Alkyl, C １ -C ３ Haloalkyl, C ２ -C ３ Alkenil, C ２ -C ３ Haloalkenil, C ２ -C ３ Alkinyl, C ２ -C ３ Haloalkynyl, OH, O-(C) １－３ Alkyl, C ２－３ Alkenil, C ２－３ Alkinyl), NH ２ NH(C １－３ Alkyl, C ２－３ Alkenil, C ２－３ Alkinyl), N(C) １－３ Alkyl, C ２－３ Alkenil, C ２－３ Alkinyl) ２ , C ３ Cycloalkyl, and C ３ A compound according to any one of claims 1 to 20, which is substituted with one or two substituents selected from the group consisting of halocycloalkyls.

23. Optionally substituted arylenes and optionally substituted heteroarylenes are halogens and C, respectively. １ -C ３ The compound according to claim 22, which is substituted with one or two substituents selected from the group consisting of alkyl groups.

24. L ２ A compound according to any one of claims 1 to 23, wherein is NH.

25. R １ａ and R １ｂ These are H, halogen, CN, and C, respectively, independently. １－３ Haloalkyl and C １－３ A compound according to any one of claims 1 to 24, selected from the group consisting of alkyl groups.

26. R １ａ and R １ｂ These are H and CH, respectively, independently. ３ A compound according to claim 25, selected from the group consisting of the following.

27. The compound according to any one of claims 1 to 26, wherein the bond indicated by the dashed line in the formula is a double bond.

28. Y is N or CR ３ A compound according to any one of claims 1 to 27.

29. Y is either replaced or not replaced: 【Chemistry 10】 A compound according to any one of claims 1 to 28, selected from the group consisting of the following.

30. Y is CR ３Ｃ And CR ３Ｃ is hydrogen, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, aryl, C ３－６ A compound according to any one of claims 1 to 27, selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines.

31. R ３ａ and R ３ｂ These are H and C, which are independent of each other. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, aryl, C ３－６ The compound according to claim 30, selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclines.

32. R ２ , R ４ , R ５ , and R ６ These are H, halogen, and C, respectively, independently. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３ -C ６ Cycloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, or C １－６ A compound according to any one of claims 13 to 31, which is a haloalkyl compound.

33. R ４ is H or CH ３ The compound according to any one of claims 13 to 32.

34. R ２ H, C １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ A compound according to any one of claims 13 to 33, wherein the compound is an alkynyl.

35. R ４ CH ３ The compound according to any one of claims 13 to 34.

36. R ５ A compound according to any one of claims 13 to 35, wherein is H.

37. R ６ A compound according to any one of claims 13 to 36, wherein is H.

38. Formula (AWH): 【Chemistry 11】 The compounds shown, or their tautomers, enantiomers, diastereomers, mixtures, salts, hydrates, solvates, or deuterated forms, During the ceremony, WH is the warhead part; L １ This is selected from the group consisting of directly bonded, optionally substituted cycloalkylene, optionally substituted heterocyclene, optionally substituted arylene, and optionally substituted heteroarylene; L ２ (CH ２ ) １－６ Selected from the group consisting of O, C(O), S, and NH; R １ａ and R １ｂ These are H, halogen, CN, and C, respectively, independently. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl and C １－６ Selected from the group consisting of alkoxys; or L ２ -C(R １ａ ) (Caution １ｂ ) combine to form NHC(S), C(S)NH, NHC(O), C(O)NH, NHS(O) ２ , S(O) ２ Forming NH, NHC(NH), or C(NH)NH; Q Ｂ This is an optionally substituted 8-14 member spiro ring system or fused ring system that optionally contains one or more heteroatoms selected from the group consisting of O, N, and S; YT is any part that yields the desired physicochemical properties; Any E3 ligase-binding ligand, Compounds, their tautomers, enantiomers, diastereomers, mixtures, salts, hydrates, solvates, or deuterated forms.

39. WH is a ring system: Q1 - Q2, Here, The ring system is L in the formula via either the Q1 or Q2 portion. １ It is connected, a) Q1 is an optionally substituted 5 or 6-membered ring having one or more degrees of unsaturation and optionally containing one or more heteroatoms selected from B, N, O, or S; Q2 is condensed with Q1 and is an optionally substituted 5 or 6-membered ring having one or more degrees of unsaturation and optionally containing one or more heteroatoms selected from B, N, O, or S; or b) Q1 does not exist, Q2 is an optionally substituted 5 or 6-membered ring having one or more degrees of unsaturation and optionally containing one or more heteroatoms selected from B, N, O, or S; The compound according to claim 38.

40. WH was replaced by choice: Group (a): Cyclohexenone derivatives, alkyl halide derivatives, sulfonyl derivatives, α-cyanoenone derivatives, and epoxide or spiroepoxide derivatives; Group (b): 【Chemistry 12】 A compound according to claim 39, selected from the above.

41. Optional substitutions include deuterium, halogens, haloalkyls, R', OR', OH, SH, SR', and NO. ２ , CN, C(O)R', NH ２ , C(O)OR', OC(O)R', CON(R') ２ ,OC(O)N(R') ２ NH ２ , NHR', N(R') ２ , NHCOR', NHCOH, NHCONH ２ , NHCONHR', NHCON(R') ２ , NRCOR', NRCOH, NHCO ２ H, NHCO ２ R',NHC(S)NH ２ , NHC(S)NHR', NHC(S)N(R') ２ CO ２ R', CO ２ H, CHO, CONH ２ , CONHR', CON(R') ２ , S(O) ２ H, S(O) ２ R', SO ２ NH ２ , S(O)H, S(O)R', SO ２ NHR', SO ２ N(R') ２ NHS (O) ２ H, NR'S (O) ２ H, NHS(O) ２ R', NR'S (O) ２ R', Si(R') ３ , =O, =S, =NNHR', =NNH ２ , = NN(R') ２ , =N-OR', =N-OH, =NNHCOR', =NNHCOH, =NNHCO ２ R', = NNHCO ２ H, = NNHSO ２ R', = NNHSO ２ It is substituted with one or more substituents selected from the group consisting of H, =N-CN, =NH, and =NR', and each of the aforementioned groups is a divalent alkylene linker (CH ２ ) ｘ The compound of any one of claims 38 to 40, wherein the bonds may be formed via (x is 1, 2, or 3), and each time R' appears, it may be the same or different, and represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, or, if two R's are each bonded to a nitrogen atom, they may form a saturated or unsaturated heterocycle containing 4 to 6 ring atoms.

42. Q1-Q2 are: 【Chemistry 13】 Selected from, 【Chemistry 14】 In the formula, each A' is a monocycle of a cycloalkyl, heterocyclyl, aryl, or heteroaryl group; Each of the heterocyclyl rings or heteroaryl rings comprises one or more heteroatoms selected from N, O, and S; Each can choose one or more Rs. Ａ１ Replaced with R Ａ１ These are, independently, halogen, OH, and C. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, (CH ２ ) ０－６ CN, (CH ２ ) １－６ OH, (CH ２ ) ０－６ O-C １－６ Alkyl, (CH ２ ) ０－６ O-C ２－６ Alkenil, (CH ２ ) ０－６ O-C ２－６ Alkinyl, (CH ２ ) ０－６ C(O)H, (CH ２ ) ０－６ C(O)(C １－６ Alkyl, C ２－６ Alkenyl, or C １－６ (Alkinyl), (CH ２ ) ０－６ C(O)OH, (CH ２ ) ０－６ C(O)O(C １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ (Alkinyl), (CH ２ ) ０－６ NH ２ , (CH ２ ) ０－６ NH(C) １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ (Alkinyl), (CH ２ ) ０－６ N(C) １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ Alkinyl) ２ , (CH ２ ) ０－６ C(O)NH ２ , (CH ２ ) ０－６ C(O)NH(C １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ (Alkinyl), (CH ２ ) ０－６ C(O)N(C １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ Alkinyl) ２ , (CH ２ ) ０－６ NHC(O)H, (CH ２ ) ０－６ NHC(O)(C) １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ (Alkinyl), and (CH ２ ) ０－６ N(C) １－６ Alkyl, C ２－６ Alkenyl and C ２－６ Alkinyl) C(O) (C １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ Alkinyl), or R Ａ Selected from the isotopic forms, A compound according to any one of claims 39 to 41.

43. The compound of claim 42, wherein A' is an aryl compound.

44. The compound of claim 43, wherein A' is phenyl.

45. The compound of claim 42, wherein A' is a heterocyclyl.

46. The compound of claim 42, wherein A' is a heteroaryl compound.

47. The compound of claim 46, wherein the heteroaryl is a five- or six-membered heteroaryl comprising one or two heteroatoms selected from N, O, and S.

48. Q Ｂ The compound according to any one of claims 37 to 47, wherein is an oxosubstituted 6,6 fused ring containing one or more heteroatoms selected from O, N, or S.

49. Q Ｂ teeth: 【Chemistry 15】 【change】 Selected from, During the ceremony, Each G, as it appears, is independently selected from carbon or a heteroatom chosen from O, N, or S. Each m, whenever it appears, is independently chosen from 0, 1, 2, 3, 4, 5, and 6. R １００ These are, independently, halogen, OH, oxo, and C. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, C １－６ Alkoxy, (CH ２ ) ｑ -N(H or C １－６ (alkyl), (CH ２ ) ｑ -O-C(O)-(CH ２ ) ｒ -R １４０ , (CH ２ ) ｑ -NH-C(O)-(CH ２ ) ｒ -R １４０ , (CH ２ ) ｑ -O-C(O)-(CH ２ ) ｒ -OR １４０ , (CH ２ ) ｑ -NH-C(O)-(CH ２ ) ｒ -OR １４０ , (CH ２ ) ｑ -O-(CH ２ ) ｒ -R １４０ , (CH ２ ) ｑ -NH-(CH ２ ) ｒ -R １４０ , (CH ２ ) ｑ -O-(CH ２ ) ｒ -OR １４０ , (CH ２ ) ｑ -NH-(CH ２ ) ｒ -OR １４０ , C ３－１０ Cycloalkyl, (CH ２ ) ｑ - Heterogene, (CH ２ )-- ｑ - Aryl, and (CH ２ ) ｑ - Selected from the group consisting of heteroaryls, the cycloalkyl, heterocyclic, aryl, and heteroaryl are each optionally selected to be halogen, OH, and C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, and C １－６ It may be substituted with one or more haloalkoxys. R １４０ It is an E3 ligase-binding ligand, q and r are independently selected from 0, 1, 2, 3, 4, 5, and 6 each time they appear. A compound according to any one of claims 37 to 47.

50. Q Ｂ teeth: 【Chemistry 16】 A compound according to any one of claims 37 to 49, selected from the above.

51. At least one R １００ Q Ｂ The compound of claim 50, wherein N in the formula is substituted.

52. Y Ｔ YR ３ａ R ３ｂ And; Y is H, CR ３ｃ , N, O, or S; a) If Y is H, R ３ａ and R ３ｂ None of them exist. b) If Y is N, R ３ａ and R ３ｂ These are H and C, which are independent of each other. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, aryl, C ３－６ Selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines; or Y is an N atom, R ３ａ and R ３ｂ It combines with to form a heterocyclic or heterocyclic aromatic monocyclic, spirocyclic, or fused ring system, the ring or ring system may additionally contain one or more heteroatoms selected from the group consisting of N, O, and S, and the ring or ring system may be optionally substituted; c) Y is CR ３ｃ If that is the case, R ３ｃ It does not exist, or hydrogen, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, aryl, C ３－６ Selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines; R ３ａ and R ３ｂ These are H and C, which are independent of each other. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, aryl, C ３－６ Selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines; or Y is a C atom, R ３ａ and R ３ｂ It combines with to form a cycloalkyl, aryl, heterocyclic, or heterocyclic aromatic monocyclic, spirocyclic, or fused ring system, wherein the heterocyclic ring and heterocyclic aromatic ring contain one or more heteroatoms selected from the group consisting of N, O, and S, and the ring or ring system containing Y is optionally substituted; or d) If Y is O or S, R ３ａ It does not exist, R ３ｂ H, C １－６ Alkyl, C ２－６ Alkenyl and C ２－６ Selected from the group consisting of alkinyls, A compound according to any one of claims 38 to 51.

53. YR ３ａ R ３ｂ When a ring is formed, the ring consists of deuterium, halogen, haloalkyl, R', OR', OH, SH, SR', NO ２ , CN, C(O)R', NH ２ , C(O)OR', OC(O)R', CON(R') ２ ,OC(O)N(R') ２ NH ２ , NHR', N(R') ２ , NHCOR', NHCOH, NHCONH ２ , NHCONHR', NHCON(R') ２ , NRCOR', NRCOH, NHCO ２ H, NHCO ２ R',NHC(S)NH ２ , NHC(S)NHR', NHC(S)N(R') ２ CO ２ R', CO ２ H, CHO, CONH ２ , CONHR', CON(R') ２ , S(O) ２ H, S(O) ２ R', SO ２ NH ２ , S(O)H, S(O)R', SO ２ NHR', SO ２ N(R') ２ NHS (O) ２ H, NR'S (O) ２ H, NHS(O) ２ R', NR'S (O) ２ R', Si(R') ３ , =O, =S, =NNHR', =NNH ２ , = NN(R') ２ , =N-OR', =N-OH, =NNHCOR', =NNHCOH, =NNHCO ２ R', = NNHCO ２ H, = NNHSO ２ R', = NNHSO ２ It is optionally substituted with one or more substituents selected from the group consisting of H, =N-CN, =NH, and =NR', and each of the aforementioned groups is a divalent alkylene linker (CH ２ ) ｘ The compound of claim 52, wherein the bonds may be formed via (x is 1, 2, or 3), and each time R' appears, it may be the same or different, and represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, or, if two R's are each bonded to a nitrogen atom, they may form a saturated or unsaturated heterocycle containing 4 to 6 ring atoms.

54. (AWH2): 【Chemistry 17】 The compound shown, or its tautomers, enantiomers, diastereomers, mixtures, salts, hydrates, solvates, or deuterated forms, During the ceremony, X is C(R ｘ ) ２ , O, NR ｘ , or S; R ｘ These are H and C, which are independent of each other. １－６ Alkyl, C ２－６ Alkenyl and C ２－６ Selected from the group consisting of alkinyls; R ２ H, halogen, CN, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C １－６ Alkoxy, (CH ２ ) ０－６ -R ＡＷＨ２ , (CH ２ ) ０－６ -OR ＡＷＨ２ , (CH ２ ) ０－６ -N(R) ＡＷＨ２ ) ２ , (CH ２ ) ０－６ -C(O)R ＡＷＨ２ , (CH ２ ) ０－６ -C(O)OR ＡＷＨ２ , (CH ２ ) ０－６ -C(O)N(R) ＡＷＨ２ ) ２ , (CH ２ ) ０－６ -C ３－１０ Cycloalkyl, (CH ２ ) ０－６ - Aryl, (CH ２ ) ０－６ - Heterogenes, and (CH ２ ) ０－６ - Selected from the group consisting of heteroaryls; R ４ H, halogen, CN, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C １－６ Alkoxy, (CH ２ ) ０－６ -R ＡＷＨ２ , (CH ２ ) ０－６ -OR ＡＷＨ２ , (CH ２ ) ０－６ -N(R) ＡＷＨ２ ) ２ , (CH ２ ) ０－６ -C(O)R ＡＷＨ２ , (CH ２ ) ０－６ -C(O)OR ＡＷＨ２ , (CH ２ ) ０－６ -C(O)N(R) ＡＷＨ２ ) ２ , (CH ２ ) ０－６ -C ３－１０ Cycloalkyl, (CH ２ ) ０－６ - Aryl, (CH ２ ) ０－６ - Heterogenes, and (CH ２ ) ０－６ - Selected from the group consisting of heteroaryls; R ５ H, halogen, CN, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C １－６ Alkoxy, (CH ２ ) ０－６ -R ＡＷＨ２ , (CH ２ ) ０－６ -OR ＡＷＨ２ , (CH ２ ) ０－６ -N(R) ＡＷＨ２ ) ２ , (CH ２ ) ０－６ -C(O)R ＡＷＨ２ , (CH ２ ) ０－６ -C(O)OR ＡＷＨ２ , (CH ２ ) ０－６ -C(O)N(R) ＡＷＨ２ ) ２ , (CH ２ ) ０－６ -C ３－１０ Cycloalkyl, (CH ２ ) ０－６ - Aryl, (CH ２ ) ０－６ - Heterogenes, and (CH ２ ) ０－６ - Selected from the group consisting of heteroaryls; R ６ H, halogen, CN, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C １－６ Alkoxy, (CH ２ ) ０－６ -R ＡＷＨ２ , (CH ２ ) ０－６ -OR ＡＷＨ２ , (CH ２ ) ０－６ -N(R) ＡＷＨ２ ) ２ , (CH ２ ) ０－６ -C(O)R ＡＷＨ２ , (CH ２ ) ０－６ -C(O)OR ＡＷＨ２ , (CH ２ ) ０－６ -C(O)N(R) ＡＷＨ２ ) ２ , (CH ２ ) ０－６ -C ３－１０ Cycloalkyl, (CH ２ ) ０－６ - Aryl, (CH ２ ) ０－６ - Heterogenes, and (CH ２ ) ０－６ - Selected from the group consisting of heteroaryls; R ＡＷＨ２ is each independently H, halogen, OH, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ２－６ haloalkenyl, C ２－６ haloalkynyl, C １－６ alkoxy, C ２－６ alkenoxy, C ２－６ alkynoxy, C １－６ haloalkoxy, C ２－６ haloalkenoxy, and C ２－６ alkynoxy, A compound according to any one of claims 38 to 53.

55. Y is N or CR ３Ｃ The compound according to any one of claims 38 to 54.

56. Y is R ３ａ and R ３ｂ Combined with: a) B(OH) ２ Cycloalkyl substituted with; b) an aryl substituted with B(OH) ２ ; c) Any of the following heterocyclines, i) The ring or ring system contains a B atom, ii) B (OH) ２ It is replaced by, or iii) A B atom is included, and one or more heteroatoms selected from O, N, or S are additionally included, and the ring is substituted with an optionally substituted 4- to 6-membered ring having one or more degrees of unsaturation; or d) Any of the following heteroaryls, i) The ring or ring system contains a B atom, ii) B (OH) ２ It is replaced by, or iii) A B atom is included, and one or more heteroatoms selected from O, N, or S are additionally included, and the ring is substituted with an optionally substituted 4- to 6-membered ring having one or more degrees of unsaturation; Forming, Each Y-ring or ring system can be optionally substituted. The compound according to claim 55.

57. Y Ｔ It is either replaced or not replaced: [Chemistry 18] A compound according to any one of claims 38 to 56, selected from the group consisting of the following.

58. Y Ｔ teeth: 【Chemistry 19】 A compound according to any one of claims 38 to 56, selected from the group consisting of the following.

59. Y is CR ３ｃ And R ３ｃ It does not exist or is H, R ３ａ and R ３ｂ These are H and C, which are independent of each other. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, aryl, C ３－６ A compound according to any one of claims 38 to 55, selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines.

60. WH is a compound according to any one of claims 38 to 59, which provides chemical capture of a solvent-contactable surface region of a protein.

61. The compound of claim 60, wherein the chemical capture is a bonding interaction.

62. The compound according to claim 61, wherein the bond interaction is a covalent bond.

63. The compound according to claim 61, wherein the bond interaction is a hydrogen bond.

64. The compound according to any one of claims 60 to 63, wherein the solvent-contactable surface region of the protein is a contactable amino acid.

65. The compound of claim 64, wherein the amino acid is arginine, histidine, lysine, glutamic acid, serine, threonine, or glutamine.

66. The compound of claim 65, wherein the amino acid is histidine.

67. A compound according to any one of claims 60 to 66, wherein WH is a boron-containing warhead.

68. The compound according to any one of claims 60 to 66, wherein WH is a boron-free warhead.

69. Formula (AX): 【Chemistry 20】 The compounds shown, or their tautomers, enantiomers, diastereomers, mixtures, salts, hydrates, solvates, or deuterated forms, During the ceremony, A10 is a 5-14 member monocyclic or fused ring system containing one or more cycloalkyl, heterocyclyl, aryl, and heteroaryl groups. Each heterocyclyl ring or heteroaryl ring may contain one or more heteroatoms selected from N, O, S, and B; A10 is an optional selection of one or more R Ａ１０ It may be replaced with; R Ａ１０ is each independently halogen, OH, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ２－６ haloalkenyl, C ２－６ haloalkynyl, oxo, (CH ２ ) ０－６ CN, (CH ２ ) １－６ OH, (CH ２ ) ０－６ O - C １－６ alkyl, (CH ２ ) ０－６ O - C ２－６ alkenyl, (CH ２ ) ０－６ O - C ２－６ alkynyl, (CH ２ ) ０－６ C(O)H, (CH ２ )]]) ０－６ C(O)(C １－６ alkyl, C ２－６ alkenyl, or C １－６ alkynyl), (CH ２ ) ０－６ C(O)OH, (CH ２ ) ０－６ C(O)O(C １－６ alkyl, C ２－６ alkenyl, or C ２－６ alkynyl), (CH ２ ) ０－６ NH ２ , (CH ２ ) ０－６ NH(C １－６ alkyl, C ２－６ alkenyl, or C ２－６ alkynyl), (CH ２ ) ０－６ N(C １－６ alkyl, C ２－６ alkenyl, or C ２－６ alkynyl) ２ , (CH ２ ) ０－６ C(O)NH ２ , (CH ２ ) ０－６ C(O)NH(C １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ (Alkinyl), (CH ２ ) ０－６ C(O)N(C １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ Alkinyl) ２ , (CH ２ ) ０－６ NHC(O)H, (CH ２ ) ０－６ NHC(O)(C) １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ (Alkinyl), (CH ２ ) ０－６ N(C) １－６ Alkyl, C ２－６ Alkenyl and C ２－６ Alkinyl) C(O) (C １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ Alkinyl), B(OH) ２ SO ２ - Halogens, and O-SO ２ - Selected from halogens; L １ This is selected from the group consisting of directly bonded, optionally substituted arylenes, and optionally substituted heteroarylenes; L ２ The group consisting of O and NH is selected; R １ａ and R １ｂ These are H, halogen, CN, and C, respectively, independently. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl and C １－６ Selected from the group consisting of alkoxys; or L ２ -C(R １ａ ) (Caution １ｂ ) combine to form NHC(O), C(O)NH, and NHS(O). ２ , S(O) ２ NH, or C(NH)NH ２ Forming; X is C(R ｘ ) ２ , O, NR ｘ , or S; R ｘ These are H and C, which are independent of each other. １－６ Alkyl, C ２－６ Alkenyl and C ２－６ Selected from the group consisting of alkinyls; Y is H, CR ３ｃ , N, O, or S; a) If Y is H, R ３ａ and R ３ｂ None of them exist. b) If Y is N, R ３ａ and R ３ｂ These are H and C, which are independent of each other. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, aryl, C ３－６ Selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines; or Y is an N atom, R ３ａ and R ３ｂ It combines with to form a heterocyclic or heterocyclic aromatic monocyclic, spirocyclic, or fused ring system, the ring or ring system may additionally contain one or more heteroatoms selected from the group consisting of N, O, and S, and the ring or ring system may be optionally substituted; c) Y is CR ３ｃ If that is the case, R ３ｃ It does not exist, or hydrogen, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, aryl, C ３－６ Selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines; R ３ａ and R ３ｂ These are H and C, which are independent of each other. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, aryl, C ３－６ Selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines; or Y is a C atom, R ３ａ and R ３ｂ It combines with to form a cycloalkyl, aryl, heterocyclic, or heterocyclic aromatic monocyclic, spirocyclic, or fused ring system, wherein the heterocyclic ring and heterocyclic aromatic ring contain one or more heteroatoms selected from the group consisting of N, O, and S, and the ring or ring system containing Y is optionally substituted; or d) If Y is O or S, R ３ａ It does not exist, R ３ｂ H, C １－６ Alkyl, C ２－６ Alkenyl and C ２－６ Selected from the group consisting of alkinyls; R ２ H, halogen, CN, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, C １－６ Alkoxy, (CH ２ ) ０－６ -R ＡＸ , (CH ２ ) ０－６ -OR ＡＸ , (CH ２ ) ０－６ -N(R) ＡＸ ) ２ , (CH ２ ) ０－６ -C(O)R ＡＸ , (CH ２ ) ０－６ -C(O)OR ＡＸ , (CH ２ ) ０－６ -C(O)N(R) ＡＸ ) ２ , (CH ２ ) ０－６ -C ３－１０ Cycloalkyl, (CH ２ ) ０－６ - Aryl, (CH ２ ) ０－６ - Heterogenes, and (CH ２ ) ０－６ - Selected from the group consisting of heteroaryls; R ４ H, halogen, CN, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, C １－６ Alkoxy, (CH ２ ) ０－６ -R ＡＸ , (CH ２ ) ０－６ -OR ＡＸ , (CH ２ ) ０－６ -N(R) ＡＸ ) ２ , (CH ２ ) ０－６ -C(O)R ＡＸ , (CH ２ ) ０－６ -C(O)OR ＡＸ , (CH ２ ) ０－６ -C(O)N(R) ＡＸ ) ２ , (CH ２ ) ０－６ -C ３－１０ Cycloalkyl, (CH ２ ) ０－６ - Aryl, (CH ２ ) ０－６ - Heterogenes, and (CH ２ ) ０－６ - Selected from the group consisting of heteroaryls; R ５ H, halogen, CN, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, C １－６ Alkoxy, (CH ２ ) ０－６ -R ＡＸ , (CH ２ ) ０－６ -OR ＡＸ , (CH ２ ) ０－６ -N(R) ＡＸ ) ２ , (CH ２ ) ０－６ -C(O)R ＡＸ , (CH ２ ) ０－６ -C(O)OR ＡＸ , (CH ２ ) ０－６ -C(O)N(R) ＡＸ ) ２ , (CH ２ ) ０－６ -C ３－１０ Cycloalkyl, (CH ２ ) ０－６ - Aryl, (CH ２ ) ０－６ - Heterogenes, and (CH ２ ) ０－６ - Selected from the group consisting of heteroaryls; R ６ H, halogen, CN, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, C １－６ Alkoxy, (CH ２ ) ０－６ -R ＡＸ , (CH ２ ) ０－６ -OR ＡＸ , (CH ２ ) ０－６ -N(R) ＡＸ ) ２ , (CH ２ ) ０－６ -C(O)R ＡＸ , (CH ２ ) ０－６ -C(O)OR ＡＸ , (CH ２ ) ０－６ -C(O)N(R) ＡＸ ) ２ , (CH ２ ) ０－６ -C ３－１０ Cycloalkyl, (CH ２ ) ０－６ - Aryl, (CH ２ ) ０－６ - Heterogenes, and (CH ２ ) ０－６ - Selected from the group consisting of heteroaryls; R ＡＸ These are H, halogen, OH, and C, respectively, independently. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, C １－６ Alkoxy, C ２－６ Alkenoxy, C ２－６ Alkinoxy, C １－６ Haloalkoxy, C ２－６ Haloalkenoxy and C ２－６ It is an alkinoxy. Compounds, their tautomers, enantiomers, diastereomers, mixtures, salts, hydrates, solvates, or deuterated forms.

70. A10 or Y(R) ３ａ ) (Caution ３ｂ At least one of the following is (a) having one or more B atoms in the defined ring or ring system; (b) B(OH) ２ The compound of claim 69, which is substituted with; or has a substituent in the ring or ring system that includes a B atom in the ring or ring system.

71. A10 is: 【Chemistry 21】 Selected from the group consisting of, 【Chemistry 22】 In the formula, A' is independently a cycloalkyl, heterocyclyl, aryl, or heteroaryl; Each A10 is optionally selected to have one or more R on any of the rings in the formula. Ａ１０ Replaced by, The compound of claim 69 or 70.

72. A10 is: 【Chemistry 23】 And, Each of these can optionally include one or more R on any of the rings in the formula. Ａ１０ Replaced by, A compound according to any one of claims 69 to 71.

73. A10 is: 【Chemistry 24】 Selected from the group consisting of, R ＡＡ１０ These are halogen and C, respectively, independently. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３ -C ６ Cycloalkyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, OH, O-C ３ -C ６ Cycloalkyl, O-C １－６ Alkyl, O-C ２－６ Alkenyl, O-C ２－６ Selected from the group consisting of alkynyls and CN, or their deuterated forms; Each A10 has one or more R Ａ１０ It may be further replaced with A compound according to any one of claims 69 to 72.

74. R ＡＡ１０ F, Cl, CH ３ , OCH ３ , or CD ３ The compound according to claim 73.

75. A10 is an unsubstituted compound of claim 73 or 74.

76. A10 is one or more R Ａ１０ Further substitution occurs with R Ａ１０ These are, independently, halogen, CN, and C. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３ -C ６ Cycloalkyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, OH, O-C １－６ Alkyl, O-C ２－６ Alkenyl and O-C ２－６ A compound according to claim 73 or 74, selected from the group consisting of alkynyl compounds.

77. L １ teeth: It is a substituted or unsubstituted arrine; or, These are substituted or unsubstituted heteroarylenes. A compound according to any one of claims 69 to 76.

78. L １ teeth: substituted or unsubstituted phenylene; or, A substituted or unsubstituted 5-10 member heteroarylene having one or more heteroatoms selected from N, O, and S. A compound according to any one of claims 69 to 77.

79. L １ teeth: substituted or unsubstituted phenylene; or, Substituted or unsubstituted pyridinylene, A compound according to any one of claims 69 to 78.

80. L １ is halogen, C １－ C ３ Alkyl, C １－ C ３ Haloalkyl, C ２－ C ３ Alkenil, C ２－ C ３ Haloalkenil, C ２－ C ３ Alkinyl, C ２－ C ３ Haloalkynyl, OH, O-(C) １－３ Alkyl, C ２－３ Alkenil, C ２－３ Alkinyl), NH ２ NH(C １－３ Alkyl, C ２－３ Alkenil, C ２－３ Alkinyl), N(C) １－３ Alkyl, C ２－３ Alkenil, C ２－３ Alkinyl) ２ , C ３ Cycloalkyl, and C ３ A compound according to any one of claims 76 to 79, substituted with one or more halocycloalkyl groups.

81. L １ is halogen or C １ -C ３ The compound according to claim 80, which is substituted with one or more alkyl groups.

82. A compound according to any one of claims 69 to 81, wherein X is oxygen.

83. Y is N or CR ３Ｃ The compound according to any one of claims 69 to 82.

84. Y is CR ３ｃ And; R ３ｃ H is R ３ａ and R ３ｂ These are H and C, which are independent of each other. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, aryl, C ３－６ Selected from the group consisting of cycloalkyls and 3-6 membered heterocyclines, A compound according to any one of claims 69 to 82.

85. Y is R ３ａ and R ３ｂ Combined with: a) B(OH) ２ Cycloalkyl substituted with; b) B(OH) ２ The aryl replaced by; c) Any of the following heterocyclines, i) The ring or ring system contains a B atom, ii) B (OH) ２ It is replaced by, or iii) A B atom is included, and one or more heteroatoms selected from O, N, or S are additionally included, and the ring is substituted with an optionally substituted 4- to 6-membered ring having one or more degrees of unsaturation; or d) Any of the following heteroaryls, iv) A ring or ring system containing a B atom, v) B(OH) ２ It is replaced by, or vi) A B atom is included, and an optional substituted 4- to 6-membered ring is included, further comprising one or more heteroatoms selected from O, N, or S, and having one or more degrees of unsaturation; Forming, Each Y-ring or ring system can be optionally substituted. Compounds according to claims 69 to 84.

86. The compound of claim 85, wherein Y is nitrogen.

87. R １ａ CH ３ The compound according to any one of claims 69 to 86.

88. R １ｂ A compound according to any one of claims 69 to 87, wherein is H.

89. R ２ , R ４ , R ５ , and R ６ These are H, halogen, and C, respectively, independently. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３ -C ６ Cycloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, or C １－６ A compound according to any one of claims 69 to 88, which is a haloalkyl compound.

90. R ２ CH ３ The compound according to any one of claims 69 to 89.

91. R ４ H, C １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ A compound according to any one of claims 69 to 90, which is an alkynyl.

92. R ４ is H or CH ３ A compound according to any one of claims 69 to 91.

93. R ５ A compound according to any one of claims 69 to 92, wherein is H.

94. R ６ A compound according to any one of claims 69 to 93, wherein is H.

95. The compound according to any one of claims 69 to 94, wherein the bond indicated by the dashed line in the formula is a double bond.

96. Formula Ia or Ib: 【Chemistry 25】 The compounds shown, or their tautomers, enantiomers, diastereomers, mixtures, salts, hydrates, solvates, or deuterated forms, A is an aryl ring or heteroaryl ring, and together with the boron ring in the formula, forms a fused ring system containing the boron-containing ring in the formula, and this fused ring system optionally contains one or more R Ａ Replaced by; R Ａ These are, independently, halogen, OH, and C. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, (CH ２ ) ０－６ CN, (CH ２ ) １－６ OH, (CH ２ ) ０－６ O-C １－６ Alkyl, (CH ２ ) ０－６ O-C ２－６ Alkenil, (CH ２ ) ０－６ O-C ２－６ Alkinyl, (CH ２ ) ０－６ C(O)H, (CH ２ ) ０－６ C(O)(C １－６ Alkyl, C ２－６ Alkenyl, or C １－６ (Alkinyl), (CH ２ ) ０－６ C(O)OH, (CH ２ ) ０－６ C(O)O(C １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ (Alkinyl), (CH ２ ) ０－６ NH ２ , (CH ２ ) ０－６ NH(C) １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ (Alkinyl), (CH ２ ) ０－６ N(C) １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ Alkinyl) ２ , (CH ２ ) ０－６ C(O)NH ２ , (CH ２ ) ０－６ C(O)NH(C １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ (Alkinyl), (CH ２ ) ０－６ C(O)N(C １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ Alkinyl) ２ , (CH ２ ) ０－６ NHC(O)H, (CH ２ ) ０－６ NHC(O)(C) １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ (Alkinyl), and (CH ２ ) ０－６ N(C) １－６ Alkyl, C ２－６ Alkenyl and C ２－６ Alkinyl) C(O) (C １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ Selected from alkynyl, or its deuterated form; L １ This is selected from the group consisting of directly bonded, optionally substituted arylenes, and optionally substituted heteroarylenes; L ２ The group consisting of O and NH is selected; R １ａ and R １ｂ These are H, halogen, CN, and C, respectively, independently. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl and C １－６ Selected from the group consisting of alkoxys; X is C(R ｘ ) ２ , O, NR ｘ , or S; R ｘ These are H and C, which are independent of each other. １－６ Alkyl, C ２－６ Alkenyl and C ２－６ Selected from the group consisting of alkinyls; R ２ , R ４ , R ５ , and R ６ These are H, halogen, and C, respectively, independently. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３ -C ６ Cycloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, or C １－６ It is a haloalkyl; Y is N or CR ３ａ And; a) If Y is N, R ３ａ and R ３ｂ These are H and C, which are independent of each other. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, aryl, C ３－６ Selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines; or R ３ａ and R ３ｂ It bonds with an N atom to form a heterocyclic or heterocyclic aromatic monocyclic, spirocyclic, or fused ring system, which may further contain one or more heteroatoms selected from the group consisting of N, O, and S, and which may be optionally substituted; b) Y is CR ３ｃ If that is the case, R ３ｃ It does not exist, or hydrogen, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, aryl, C ３－６ Selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines; R ３ａ and R ３ｂ These are H and C, which are independent of each other. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, aryl, C ３－６ Selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines; or R ３ａ and R ３ｂ It bonds with a C atom to form a cycloalkyl, aryl, heterocyclic, or heterocyclic aromatic monocycle, spirocycle, or fused ring system, and the heterocyclic ring and heterocyclic aromatic ring contain one or more heteroatoms selected from the group consisting of N, O, and S, and the ring or ring system containing Y is optionally substituted. Compounds, their tautomers, enantiomers, diastereomers, mixtures, salts, hydrates, solvates, or deuterated forms.

97. The compound of claim 96, wherein A is a phenyl ring.

98. R Ａ The compound of claim 96 or 97 does not exist.

99. The aforementioned fused ring system is one R Ａ The compound of claim 96 or 97, which is substituted with

100. The aforementioned fused ring system consists of two R Ａ The compound of claim 96 or 97, which is substituted with

101. R Ａ Each is independent of C １－６ Alkyl, O-C １－６ Alkyl, C １－６ A compound according to claim 99 or 100, selected from the group consisting of haloalkyls, halogens, or deuterated forms thereof.

102. R Ａ These are halogen and CD, respectively, and are independent of each other. ３ ,CH ３ , OCH ３ , and CF ３ A compound according to claim 101, selected from the group consisting of the following.

103. L １ A compound according to any one of claims 96 to 102, wherein is optionally substituted phenylene.

104. L １ is one or more halogens or C １－６ The compound of claim 103, wherein the phenylene is alkyl-substituted.

105. L １ A compound according to any one of claims 96 to 102, wherein is an optionally substituted heteroarylene.

106. L １ The compound of claim 105, wherein is optionally substituted pyridinylene.

107. L １ is one or more halogens or C １－６ The compound of claim 106, wherein the pyridinylene is alkyl-substituted.

108. L １ The compound according to any one of claims 96 to 107, wherein is substituted with one or two halogens.

109. The aforementioned pyridinylene is: 【Chemistry 26】 Combined as follows, In either case, the fused ring in the formula can be one or more R rings of any choice. Ａ Replaced by, A compound according to any one of claims 106 to 108.

110. L in the above formula １ The part is, 【Chemistry 27】 In the fused ring system shown, the B atom in the formula is substituted at the para position. A compound according to any one of claims 96 to 109.

111. L in the above formula １ The part is, 【Chemistry 28】 In the fused ring system shown, the B atom in the formula is substituted at the meta position. A compound according to any one of claims 96 to 109.

112. L ２ A compound according to any one of claims 96 to 111, wherein is NH.

113. R １ａ is H; R １ｂ These are independently H, halogen, CN, and C. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl and C １－６ Selected from the group consisting of alkoxys, A compound according to any one of claims 96 to 112.

114. R １ｂ is C １－６ The compound of claim 113, which is alkyl.

115. R １ｂ The compound of claim 114, wherein is methyl.

116. The chiral center is 【Chemistry 29】 As shown in the R configuration, A compound according to any one of claims 113 to 115.

117. A compound according to any one of claims 96 to 116, wherein X is O.

118. Y is CH, R ３ａ and R ３ｂ These are C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ２－６ Haloalkenil, C ２－６ Haloalkynyl, aryl, C ３－６ Selected from the group consisting of cycloalkyls and 3- to 6-membered heterocyclines; or Y is CH, R ３ａ and R ３ｂ It combines with to form a cycloalkyl or heterocyclic monocyclic system containing one heteroatom selected from N and O. A compound according to any one of claims 96 to 117.

119. Y is CH, R ３ａ and R ３ｂ These are C １－３ A compound according to any one of claims 96 to 118, wherein the compound is alkyl.

120. R ３ａ and R ３ｂ These are CH ３ The compound according to claim 119.

121. R ２ CH ３ A compound according to any one of claims 96 to 120.

122. R ４ H, C １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ A compound according to any one of claims 96 to 121, wherein the compound is an alkynyl.

123. R ４ is H or CH ３ A compound according to any one of claims 96 to 122.

124. R ５ A compound according to any one of claims 96 to 123, wherein is H.

125. R ６ A compound according to any one of claims 96 to 124, wherein is H.

126. The compound according to any one of claims 96 to 125, wherein the bond indicated by the dashed line in the formula is a double bond.

127. Formula Xa or Xb: 【Transformation 30】 The compounds shown, or their tautomers, enantiomers, diastereomers, mixtures, salts, hydrates, solvates, or deuterated forms, During the ceremony, m is independently 0, 1, 2, 3, 4, or 5; R ＸＡ These are halogen and C, respectively, independently. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C １－６ Alkoxy, and C ３－６ Selected from cycloalkyl or their deuterated forms, L １０ This is selected from the group consisting of directly bonded, optionally substituted arylenes, or optionally substituted heteroarylenes; L ２０ It is selected from the group consisting of O and NH; R １０ H and C １－６ Selected from the group consisting of alkyl groups; R ２０ H, halogen, C １ -C ６ Haloalkyl and C １－６ Selected from the group consisting of alkyl groups; R ３０ C is replaced by H or of any choice. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Cycloalkyl, N(C) １ -C ６ Selected from the group consisting of alkyl, 6-membered aryl, 5 or 6-membered heteroaryl, or 3- to 10-membered heterocycline; R ４０ H and C １－６ Selected from the group consisting of alkyl groups, Compounds, their tautomers, enantiomers, diastereomers, mixtures, salts, hydrates, solvates, or deuterated forms.

128. L １０ The compound of claim 127, wherein is optionally substituted phenylene.

129. L １０ The compound of claim 128, wherein is phenylene substituted with one or more halogens.

130. L １０ The compound of claim 127, wherein is an optionally substituted heteroarylene.

131. L １０ The compound of claim 130, wherein is optionally substituted pyridinylene.

132. L １０ The compound of claim 131, wherein is a pyridinylene substituted with one or more halogens.

133. Replaced by choice, 【Chemistry 31】 A compound as shown in claim 131 or 132.

134. L ２０ A compound according to any one of claims 127 to 133, wherein is NH.

135. R １０ is C １－６ A compound according to any one of claims 127 to 134, wherein the compound is alkyl.

136. R １０ CH ３ The compound according to claim 135.

137. R ２０ is C １－６ A compound according to any one of claims 127 to 136, wherein it is alkyl.

138. R ２０ CH ３ The compound according to claim 137.

139. R ４０ is C １－６ A compound according to any one of claims 127 to 138, wherein the compound is alkyl.

140. R ４０ CH ３ The compound according to claim 139.

141. R ３０ A compound according to any one of claims 127 to 140, wherein is optionally substituted with an aryl, heteroaryl, or heterocyclyl.

142. The compound of claim 141, wherein the optionally substituted heterocyclyl comprises 3 to 6 ring atoms, and one or two of the ring atoms are independently selected from the group consisting of nitrogen and oxygen.

143. The compound of claim 142, wherein the optionally substituted heterocyclyl is optionally substituted piperidinyl.

144. The compound of claim 143, wherein the optionally substituted piperidinyl is gem-dimethyl substituted piperidinyl.

145. The compound of claim 142, wherein the optionally substituted heterocyclyl is optionally substituted morpholinyl.

146. The compound of claim 142, wherein the optionally substituted heterocyclyl contains 3 to 6 ring atoms, one of which is oxygen.

147. R ３０ This was replaced by choice: C １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ A compound according to any one of claims 124 to 143, wherein the compound is an alkynyl.

148. Formula XI: 【Chemistry 32】 The compounds shown in claims 127 to 147.

149. Equation XII: 【Transformation 33】 The compounds of claims 124 to 144 shown in [the relevant document].

150. Equation XIII: 【Transformation 34】 The compounds of claims 124 to 144 shown in [the relevant document]. 【Request Item 151】 【Chemistry 35】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 A compound selected from the group consisting of the following, or its tautomers, enantiomers, diastereomers, mixtures, salts, hydrates, solvates, or deuterated forms.

152. A compound according to any one of claims 1 to 151, as a racemate.

153. A compound according to any one of claims 1 to 152, as a single stereoisomer substantially free from other forms.

154. The compound of claim 153, wherein the stereoisomer is R.

155. A compound according to any one of claims 1 to 154 as a preferred equilibrium tautomer form.

156. A pharmaceutical composition comprising a therapeutically effective amount of any one of claims 1 to 155 and a pharmaceutically acceptable excipient.

157. A method for inhibiting cell proliferation, comprising contacting cells with an effective amount of a compound according to any one of claims 1 to 155.

158. A method for treating cancer in a patient, comprising administering a therapeutically effective dose of a compound according to any one of claims 1 to 155 to a patient in need thereof.

159. A method for treating a PI3K-mediated disease or disorder, comprising administering a therapeutically effective dose of any one of the compounds according to claims 1 to 155 to a patient in need of treatment.

160. A method for treating a disease or disorder mediated by one or more PIK3CA genes, comprising regulating one or more of the wild-type or mutant versions of one or more PIK3CA genes.

161. The method of claim 160, comprising regulating a single mutation.

162. The method of claim 160, comprising regulating two or more mutations.

163. A method according to any one of claims 160 to 162, comprising modifying the wild type.

164. The method according to any one of claims 160 to 163, wherein the PIK3CA is a PIK3CA variant.

165. The method according to any one of claims 160 to 164, wherein the PIK3CA mediates cancer.

166. The method according to any one of claims 160 to 165, wherein the PIK3CA controls the development, progression, or metastasis of cancer.

167. The method according to any one of claims 160 to 166, wherein the one or more mutations are any of the p110 mutations.

168. The method according to any one of claims 160 to 167, wherein the one or more mutations are selected from one or more mutations of H1047, E545, E542, N345, E726, C420, Q546, G118, E453, Q546, G1049, M1043, K111, E81, N1044, and E110.

169. The method according to any one of claims 160 to 168, wherein the one or more mutations are selected from one or more mutations of H1047, E545, and E542.

170. The method of any one of claims 160 to 169, wherein regulation is inhibiting.

171. The method according to any one of claims 160 to 170, wherein regulation is the selective inhibition of one or more mutations relative to the wild type.

172. The method according to any one of claims 160 to 171, wherein the mutation is selected from H1047X, E545X, and E542X.

173. The method according to any one of claims 160 to 172, wherein the mutation is H1047X.

174. The method of claim 173, wherein the mutation is H1047L.

175. The method of claim 173, wherein the mutation is H1047R.

176. The method according to any one of claims 160 to 175, wherein the mutation is E545X.

177. The method of claim 176, wherein the mutation is E545K.

178. The method according to any one of claims 160 to 177, wherein the mutation is E542X.

179. The method of claim 178, wherein the mutation is E542K.

180. The method according to any one of claims 160 to 179, further comprising the compound chemically capturing a solvent-contactable surface region of the protein.

181. The method of claim 180, wherein the solvent-contactable surface region comprises one or more amino acid residues.

182. The method of claim 181, wherein the amino acid residue is selected from one or more of arginine, histidine, lysine, glutamic acid, serine, threonine, or glutamine.

183. The method of claim 182, wherein the amino acid residue is histidine.

184. The method of claim 183, wherein the histidine is HIS1048.

185. The method according to any one of claims 180 to 184, wherein the chemical capture is an interaction.

186. The method of claim 185, wherein the interaction is a bond.

187. The method of claim 186, wherein the bond is a covalent bond.

188. The method of claim 186, wherein the bond is a hydrogen bond.

189. A method according to any one of claims 160 to 188, comprising administering a compound according to any one of claims 1 to 155.

190. A method for inhibiting intracellular PI3K activity, comprising modifying the solvent-contactable surface region of a protein using a compound according to any one of claims 1 to 155.

191. The method of claim 190, wherein the adjustment is performed in vitro.

192. The method of claim 190, wherein the adjustment is performed in vivo.

193. The method according to any one of claims 190 to 192, wherein the PI3K target gene is PIK3CA.

194. The method of claim 193, wherein the PI3K is PI3Kα.

195. The method according to any one of claims 190 to 194, wherein the PI3Kα is a PI3Kα mutant.

196. The method according to any one of claims 190 to 194, wherein the PI3Kα is PI3Kα wild type.

197. The method according to any one of claims 190 to 196, wherein the PI3K mediates cancer.

198. The method according to any one of claims 190 to 197, wherein the PI3K controls the development, progression, or metastasis of cancer.

199. The method according to any one of claims 190 to 198, wherein the one or more mutations are selected from one or more mutations of H1047, E545, E542, N345, E726, C420, Q546, G118, E453, Q546, G1049, M1043, K111, E81, N1044, and E110.

200. The method according to any one of claims 190 to 198, wherein the one or more mutations are selected from one or more mutations of H1047, E545, and E542.

201. The method of any one of claims 190 to 200, wherein regulation is inhibiting.

202. The method according to any one of claims 190 to 201, wherein the regulation is selective inhibition relative to the wild type, resulting in preferential inhibition at multiple levels: greater than 1, about 1.5 to about 20 or more, and about 1.5 to about 100 or more.

203. The method according to any one of claims 190 to 202, wherein the mutation is selected from H1047X, E545X, and E542X.

204. The method according to any one of claims 190 to 203, wherein the mutation is H1047X.

205. The method of claim 204, wherein the mutation is H1047L.

206. The method of claim 204, wherein the mutation is H1047R.

207. The method according to any one of claims 190 to 206, wherein the mutation is GLU545X.

208. The method of claim 207, wherein the mutation is E545K.

209. The method according to any one of claims 190 to 208, wherein the mutation is GLU542X.

210. The method of claim 209, wherein the mutation is E542K.

211. The method according to any one of claims 190 to 210, further comprising the compound chemically capturing a solvent-contactable surface region of the protein.

212. The method of claim 211, wherein the solvent-contactable surface region comprises one or more amino acid residues.

213. The method of claim 212, wherein the amino acid residue is selected from one or more of arginine, histidine, lysine, glutamic acid, serine, threonine, or glutamine.

214. The method of claim 213, wherein the amino acid residue is histidine.

215. The method of claim 214, wherein the histidine is H1048.

216. The method according to any one of claims 211 to 215, wherein the chemical capture is an interaction.

217. The method of claim 216, wherein the interaction is a bond.

218. The method of claim 217, wherein the bond is a covalent bond.

219. The method of claim 216, wherein the bond is a hydrogen bond.

220. A method for inhibiting PI3K, comprising chemically capturing a solvent-contactable surface region and modulating a p110 mutant protein subunit.

221. The method of claim 220, wherein the solvent-contactable surface region comprises one or more amino acid residues.

222. The method of claim 221, wherein the amino acid residue is selected from one or more of arginine, histidine, lysine, glutamic acid, serine, threonine, or glutamine.

223. The method of claim 222, wherein the amino acid residue is histidine.

224. The method of claim 223, wherein the histidine is H1048.

225. The method according to any one of claims 220 to 224, wherein the chemical capture is an interaction.

226. The method of claim 225, wherein the interaction is a bond.

227. The method of claim 226, wherein the bond is a covalent bond.

228. The method of claim 226, wherein the bond is a hydrogen bond.

229. The method according to any one of claims 220 to 228, wherein the p110 mutant protein subunit comprises at least one amino acid mutation compared to the wild-type p110 protein subunit.

230. The method of claim 229, wherein the at least one amino acid mutation is selected from one or more mutations of H1047, E545, E542, N345, E726, C420, Q546, G118, E453, Q546, G1049, M1043, K111, E81, N1044, and E110.

231. The method of claim 230, wherein the one or more mutations are selected from one or more of H1047, E545, and E542.

232. The method of claims 220 to 231, comprising administering a compound according to any one of claims 1 to 155.

233. A method for treating a disease or disorder mediated by PI3Kα, comprising chemically capturing a solvent-contactable amino acid residue and modifying one or more of H1047X, E545X, and E542X.

234. The method of claim 233, wherein the amino acid residue is selected from one or more of arginine, histidine, lysine, glutamic acid, serine, threonine, or glutamine.

235. The method of claim 234, wherein the amino acid residue is histidine.

236. The method of claim 235, wherein the histidine is HIS1048.

237. The method according to any one of claims 233 to 236, wherein chemical capture is an interaction.

238. The method of claim 237, wherein the interaction is a bond.

239. The method of claim 238, wherein the bond is a covalent bond.

240. The method of claim 238, wherein the bond is a hydrogen bond.

241. A method according to any one of claims 233 to 240, comprising adjusting one or more of H1047L and H1047R.

242. A method according to any one of claims 233 to 241, comprising adjusting GLU545K.

243. A method according to any one of claims 233 to 242, comprising adjusting GLU542K.

244. A method according to any one of claims 233 to 243, comprising administering a compound according to any one of claims 1 to 155.

245. A method for inhibiting the PIK3CA gene target protein (PI3K), comprising modulating two or more mutant variants selected from mutations in H1047, E545, E542, N345, E726, C420, Q546, G118, E453, Q546, G1049, M1043, K111, E81, N1044, and E110.

246. The method of claim 245, wherein the two or more mutant variants are selected from the H1047, E545, and E542 mutations.

247. A method for treating a disease or disorder mediated by PIK3CA, comprising modulating two or more mutant variants selected from mutations in H1047, E545, E542, N345, E726, C420, Q546, G118, E453, Q546, G1049, M1043, K111, E81, N1044, and E110.

248. The method of claim 247, wherein the two or more mutant variants are selected from the H1047, E545, and E542 mutations.

249. A method according to any one of claims 245 to 248, comprising administering a compound according to any one of claims 1 to 155.

250. A method for treating a disease or disorder by regulating PI3K by interacting a compound according to any one of claims 1 to 155 with at least two mutant variants.

251. The method of claim 250, wherein the PI3K gene target is PIK3CA.

252. The method according to claim 250 or 251, wherein the PI3K mediates cancer.

253. The method according to any one of claims 250 to 252, wherein the PI3K controls the development, progression, or metastasis of cancer.

254. The method according to any one of claims 250 to 253, wherein the mutant variant is selected from the mutations of H1047, E545, E542, N345, E726, C420, Q546, G118, E453, Q546, G1049, M1043, K111, E81, N1044, and E110.

255. The method of claim 254, wherein the mutant variant is selected from one or more mutations of H1047, E545, and E542.

256. The method of any one of claims 250 to 255, wherein regulation is inhibition.

257. The method of claim 256, wherein the regulation is selective inhibition of the wild type.

258. The method according to any one of claims 250 to 257, wherein the mutation is H1047X.

259. The method of claim 258, wherein the mutation is H1047L.

260. The method of claim 258, wherein the mutation is H1047R.

261. The method according to any one of claims 250 to 260, wherein the mutation is E545X.

262. The method of claim 261, wherein the mutation is E545K.

263. The method according to any one of claims 250 to 262, wherein the mutation is GLU542.

264. The method of claim 263, wherein the mutation is E542K.

265. The method according to any one of claims 250 to 264, further comprising chemically capturing a solvent-contactable surface region of a protein with a compound according to any one of claims 1 to 155.

266. The method of claim 265, wherein the solvent-contactable surface region comprises one or more amino acid residues.

267. The method of claim 266, wherein the amino acid residue is selected from one or more of arginine, histidine, lysine, glutamic acid, serine, threonine, or glutamine.

268. The method of claim 267, wherein the amino acid residue is histidine.

269. The method of claim 268, wherein the histidine is HIS1048.

270. The method according to any one of claims 265 to 269, wherein the chemical capture is an interaction.

271. The method of claim 270, wherein the interaction is a bond.

272. The method of claim 271, wherein the bond is a covalent bond.

273. The method of claim 271, wherein the bond is a hydrogen bond.

274. The method according to any one of claims 156 to 273, wherein the disease or disorder is cancer.

275. The method according to any one of claims 156 to 274, wherein the disease or disorder is PIK3CA-related hypergrowth spectrum (PROS).

276. The method according to any one of claims 156 to 275, wherein the disease or disorder is breast cancer, colorectal cancer, uterine cancer, bladder cancer, lung cancer, glioma, head and neck cancer, or other solid tumor.

277. The method of claim 276, wherein the disease or disorder is breast cancer.

278. The method according to any one of claims 156 to 277, further comprising administering one or more additional therapeutic agents.

279. The method of claim 278, further comprising administering two or more additional therapeutic agents.

280. The method of claim 278 or 279, wherein the additional therapeutic agent is selected from selective estrogen receptor degraders, Protac-mediated estrogen receptor inhibitors, complete estrogen receptor antagonists, sarcoplasmic reticulum calcium ATPase inhibitors, CDK2 / 4 / 6 inhibitors, CDK4 / 6 inhibitors, and aromatase inhibitors.

281. The method of any one of claims 278 to 280, wherein the additional therapeutic agent is selected from fulvestrant, bepdegestrant, parazestrant, imurunestrant, elastrant, giredestrant, camizestrant, palbociclib, ribociclib, abemaciclib, anastrozole, exemestane, and letrozole.

282. The method according to any one of claims 278 to 281, wherein each drug is provided in a separate dosage form.

283. The method according to any one of claims 278 to 281, wherein one or more drugs are provided in a compound dosage form.

284. A method for controlling one or more disease onset and progression by regulating one or more PI3K enzymes, comprising interaction with at least one histidine and regulation of at least one surface-contactable amino acid or residue.

285. The method of claim 284, wherein one or more PI3Ks are inhibited.

286. The method of claim 285, wherein the PI3K is PI3Kα.

287. The method of claim 286, wherein PI3Kα is a mutant variant thereof.

288. The method of claims 284 to 287, comprising administering a compound according to any one of claims 1 to 155.

289. (a) determining whether the cancer is associated with PI3K wild-type or one or more PI3K mutations; and (b) administering to the patient a therapeutically effective dose of any one of the compounds according to claims 1 to 155, Methods of treating cancer in patients who require cancer treatment, including [specific examples of cancer treatment methods].

290. The method of claim 289, wherein PI3K is a variant thereof.

291. A compound according to any one of claims 1 to 155 for use in therapy.

292. A compound according to any one of claims 1 to 155 for use in the treatment of cancer.

293. A compound according to any one of claims 1 to 155 for use in inhibiting PI3K.

294. The compound of claim 293, wherein PI3K is PI3Kα.

295. The compound of claim 294, wherein the PI3Kα is wild-type.

296. The compound of claim 294, wherein PI3Kα is a mutant variant thereof.

297. Use of any one compound according to claim 1 to 155 in the manufacture of a pharmaceutical product for the treatment of cancer.

298. Use of any one compound according to claim 1 to 155 in the manufacture of a pharmaceutical product that inhibits the activity of PI3K.

299. Use of any one compound according to claim 1 to 155 in the manufacture of a pharmaceutical product for treating a disease or disorder mediated by PI3K.

300. The use of claim 298 or 299, wherein the PI3K is PI3Kα.

301. The use of claim 300, wherein the PI3Kα is wild-type.

302. The use of claim 300, wherein PI3Kα is a mutant variant thereof.

303. A process for preparing a compound according to any one of claims 1 to 155.

304. A compound according to any one of claims 1 to 155, obtained by the process of claim 303.

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