Degradation of Bruton's Tyrosine Kinase (BTK) by Conjugating BTK Inhibitors to E3 Ligase Ligands and Methods of Use

Abstract

Disclosed herein are novel bifunctional compounds formed by conjugating a BTK inhibitor moiety with an E3 ligase ligand moiety for recruiting target proteins to an E3 ubiquitin ligase for degradation, as well as methods for their preparation and use.

Description

[Technical Field]

[0001] Disclosed herein are novel bifunctional compounds formed by conjugating a BTK inhibitor moiety with an E3 ligase ligand moiety for recruiting target proteins to an E3 ubiquitin ligase for degradation, as well as methods for their preparation and use. [Background technology]

[0002] Targeted protein degradation compounds (PROTACs) are a novel strategy for selectively knocking down target proteins using small molecules (Sakamoto KM et al., Proc Natl Acad Sci 2001, 98:8554-9; Sakamoto KM et al., Methods Enzymol. 2005;399:833-847). PROTACs utilize the ubiquitin-protease system to target specific proteins and induce their degradation in cells (Zhou P. et al., Mol Cell. 2000;6(3):751-756; Neklesa TK et al., Pharmacol Ther. 2017;174:138-144; Lu M. et al., Eur J Med Chem. 2018;146:251-259). The normal physiological function of the ubiquitin-protease system is responsible for the removal of degenerated, mutated, or harmful proteins in cells. The normal physiological function of the ubiquitin-protease system is responsible for the removal of degenerated, mutated, or harmful proteins in cells. The ubiquitin-proteasome system (UPS), also known as the ubiquitin-proteasome pathway (UPP), is a common post-translational modification mechanism involved in protein degradation in normal and pathological conditions (Ardley H. et al., Essays Biochem. 2005, 41, 15-30; Komander D. et al., Biochem. 2012, 81, 203-229; Grice G. L. et al., Cell Rep. 2015, 12, 545-553; Swatek KN et al., Cell Res. 2016, 26, 399-422). Ubiquitin, a 76-amino acid modification molecule highly conserved in eukaryotic cells, covalently attaches to and labels target substrates through a series of enzymatic reactions involving E1, E2, and E3 enzymes. The modified substrate is then recognized by the 26S proteasome complex, which carries out ubiquitination-mediated degradation. To date, two E1 enzymes, designated UBA1 and UBA6, have been discovered. Meanwhile, there are approximately 40 E2 enzymes and over 600 E3 enzymes, providing functional diversity for regulating the activity of many downstream protein substrates.However, only a limited number of E3 ubiquitin ligases have been successfully utilized in small molecule PROTAC technology: Von Hippel-Lindau disease tumor suppressor protein (VHL), mouse double minute 2 (MDM2), inhibitor of apoptosis (cIAP), and cereblon (Philipp O. et al., Chem. Biol. 2017, 12, 2570-2578).

[0003] Bifunctional compounds consisting of a target protein-binding moiety and an E3 ubiquitin ligase-binding moiety have been shown to be able to induce proteasome-mediated degradation of selected proteins. These drug-like molecules offer the possibility of temporal control of protein expression and can be used as biochemical reagents to treat diseases. In recent years, this newly developed method has been widely used in anti-tumor research (Lu J. et al., Chem Biol. 2015;22(6):755-763; Ottis P. et al., Chem Biol. 2017;12(4):892-898; Crews CM et al., J Med Chem. 2018;61(2):403-404; Neklesa TK et al., Pharmacol Ther. 2017,174:138-144; Cermakova K. et al., Molecules, 2018.23(8); An S. et al., BioMedicine, 2018; Lebraud H. et al., Essays Biochem. 2017;61(5):517-527; Sun YH et al., Cell Res. 2018;28:779-81; Toure M. et al., Angew Chem Int Ed Engl. 2016;55(6):1966-1973; Yonghui Sun et al., Leukemia, Vol. 33, pp. 2105-2110 (2019); Shaodong Liu et al., Medicinal Chemistry Research, Vol. 29, pp. 802-808 (2020); Shenxin Z. et al., European Journal of Medicinal Chemistry, 2020, doi.org / 10.1016 / j.ejmech.2020.112981), e.g., US20160045607, US20170008904, US20180050021, US20180072711, WO2002020740, WO2014108452, WO2016146985, WO2016149668, WO2016149989, WO2016197032, WO2016197114, WO201 These techniques are disclosed or discussed in published patent applications such as WO 7011590, WO2017030814, WO2017079267, WO2017182418, WO2017197036, WO2017197046, WO2017197051, WO2017197056, WO2017201449, WO2017211924, WO2018033556, WO2018071606, US 20200297725, US20200239430, WO 2020142228, WO2020163823, WO2020198711, and WO2020201080.

[0004] Bruton's tyrosine kinase (Btk) belongs to the Tec tyrosine kinase family (Vetrie et al., Nature 361: 226-233, 1993; Bradshaw, Cell Signal. 22: 1175-84, 2010). Btk is primarily expressed in most hematopoietic cells, such as B cells, mast cells, and macrophages (Smith et al., J. Immunol. 152: 557-565, 1994), and is localized in bone marrow, spleen, and lymph node tissues. Btk plays an important role in the B cell receptor (BCR) and FcR signaling pathways involved in B cell development and differentiation (Khan, Immunol. Res. 23: 147, 2001). Btk is activated by upstream Src family kinases. Once activated, Btk phosphorylates PLC gamma, affecting B cell function and viability (Humphries et al., J. Biol. Chem. 279: 37651, 2004). These signaling pathways must be precisely regulated. Mutations in the gene encoding Btk result in a human inherited B cell-specific immunodeficiency disorder called X-linked agammaglobulinemia (XLA) (Conley et al., Annu. Rev. Immunol. 27: 199-227, 2009). Aberrant BCR-mediated signaling can lead to dysregulated B cell activation and various autoimmune and inflammatory diseases. Preclinical studies have shown that Btk-deficient mice are resistant to the development of collagen-induced arthritis. Furthermore, clinical studies of Rituxan (a CD20 antibody for depleting mature B cells) have revealed the important involvement of B cells in various inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis (Gurcan et al., Int. Immunopharmacol. 9: 10-25, 2009). Therefore, Btk inhibitors may be useful for the treatment of autoimmune and / or inflammatory diseases.

[0005] BTK inhibition has been shown to affect cancer progression (B-cell malignancies) and cell viability, and to ameliorate autoimmune diseases (e.g., rheumatoid arthritis and lupus). Alternative strategies, such as BTK degradation, have also been reported (Alexandru D. et al., Biochemistry 2018, 57, 26, 3564-3575; Adelajda Z. et al., PNAS 2018, 115 (31); Dennis D. et al., Blood, 2019, 133:952-961; Yonghui S. et al., Cell Research, 2018, 28, 779-781; Yonghui S. et al., Leukemia, 2019, Degradation of Bruton's tyrosine kinase mutants by PROTACs for potential treatment of ibrutinib-resistant non-Hodgkin's disease). lymphomas) and are disclosed or discussed in the following published patents: US20190276459, WO2019186343, WO2019186358, WO2019148150, WO2019177902, WO2019127008, and WO2020239103. Summary of the Invention [Problem to be solved by the invention]

[0006] There is a need for new BTK inhibitors or degraders that are more effective than known BTK inhibitors and that inhibit BTK by alternative strategies, e.g., by degrading BTK. The present application meets this need. [Means for solving the problem]

[0007] The following aspects or embodiments are part of the present invention, but the present invention is not limited thereto.

[0008] Aspect 1. A compound of formula (I): TIFF2025501082000001.tif55161 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0009] During the ceremony, The TIFF2025501082000002.tif818 part is an E3 ubiquitin ligase portion selected from TIFF2025501082000003.tif59161;

[0010] Cy1a, Cy1b, and Cy1c each independently represent a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered saturated or unsaturated ring containing 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur as ring members; Cy2 is a 5- or 6-membered saturated or unsaturated ring (preferably an aromatic ring) containing 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur as ring members; Cy3 is a 5- or 6-membered saturated or unsaturated ring containing no additional heteroatoms; L a , L b , L c and L d are each independently a single bond, -O-, -S-, -C(O)-, -(CR a R b ) n -or-NR c - and L 1 and L 2 are each independently a single bond, -O-, -S-, -C(O)-, or -(CR a R b ) n -or-NR c - and Z 1 and Z 2 are independently CH, CR 14 or N, X e are each independently 14 or N,

[0011] R 1 , R2 , R 3 , R 4 , R 8 , R 9 , R 10 , R 11 , R 13 and R 14 Each occurrence of is independently hydrogen, halogen, or -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -NO2, -OR c , -SO2R c , -COR c , -CO2R c , -CONR c R d , -C(=NR c )NR d R e , -NR c R d , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NR c SONR d R e , -NR c SO2NR d R e , or -NR c SO2R d and -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally halogen, hydroxy, -haloC 1-8 Alkyl, -C 1-8 substituted with alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; R 6 , R 7 and R 12 are each independently hydrogen, -C1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally halogen, hydroxy, -haloC 1-8 Alkyl, -C 1-8 substituted with alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0012] R 5 is a 5- or 6-membered aromatic ring containing 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur as ring members, and the aromatic ring may optionally contain halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR c , -SO2R c , -COR c , -CO2R c , -CONR c R d , -C(=NR c )NR d R e , -NR c R d , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NR c SONR d R e , -NR c SO2NR d R e , or -NR c SO2R d and -C 1-8 Alkyl, -C 2-8Alkenyl, -C 2-8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally -C 1-8 Alkyl, halogen, hydroxy, -haloC 1-8 Alkyl, -C 1-8 substituted with alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0013] p1, p2, p3, p4, p5, and p6 are each independently 0, 1, 2, 3, or 4; s1, s2, and s3 are each independently 0 or 1; n is 0, 1, 2, 3, 4, 5, or 6; R a and R b are each independently hydrogen, halogen, or -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -NO2, -OR c , -SO2R c , -COR c , -CO2R c , -CONR c R d , -C(=NR c )NR d R e , -NR c R d , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NR c SONR d R e , -NR c SO2NR d R e , or -NR c SO2R d and -C 1-8 Alkyl, -C 2-8Alkenyl, -C 2-8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally halogen, hydroxy, -haloC 1-8 Alkyl, -C 1-8 substituted with alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0014] R a and R b are taken together with the atoms to which they are attached to form a 3- to 12-membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, and said ring optionally contains halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 substituted with at least one substituent independently selected from alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, or —NO; R c , R d and R e are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or (R c and R d ) or (R d and R e ) together with the atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, and said ring optionally containing halogen, —C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Substituted with at least one substituent independently selected from alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, or -NO2.

[0015] Aspect 2. The TIFF2025501082000004.tif818 part is Selected from TIFF2025501082000005.tif2747, Cy3 is a 6-membered saturated or unsaturated ring containing no additional heteroatoms; L 1 , X e , R 12 , R 13 and p6 is as defined in embodiment 1.

[0016] Aspect 3. The TIFF2025501082000006.tif818 part is Selected from TIFF2025501082000007.tif23161, L 1 , X e , R 12 , R 13 and p6 is as defined in aspect 1.

[0017] Aspect 4. The TIFF2025501082000008.tif818 part is Selected from TIFF2025501082000009.tif84161, L 1 , L 2 , Z 1 , Z 2 , X e , R 12 , R 13 and p6 is as defined in embodiment 1.

[0018] Aspect 5. The TIFF2025501082000010.tif818 part is Selected from TIFF2025501082000011.tif144161TIFF2025501082000012.tif153161, L 1 , L 2 , X e , R 12 , R 13and p6 is as defined in embodiment 1.

[0019] Aspect 6. A compound according to any one of Aspects 1 to 5, L 1 and L 2 are each independently a single bond, -O-, -S-, -C(O)-, or -(CR a R b ) n -or-NR c - and n is 1, 2, 3, 4, 5, or 6; R a and R b are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl, or R a and R b are taken together with the atoms to which they are attached to form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, and said ring optionally containing halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 substituted with at least one substituent independently selected from alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, or —NO; R c are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 It is alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl.

[0020] Aspect 7. A compound according to any one of Aspects 1 to 6, p6 is independently 0, 1, 2, 3 or 4; X e are each independently 14 or N, R 13 and R 14 are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, heterocyclyl, phenyl, heteroaryl, oxo (=O), -CN, -NO2, -OR c , -SO2R c , -COR c , -CO2R c , -CONR c R d , -C(=NR c )NR d R e , -NR c R d , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NR c SONR d R e , -NR c SO2NR d R e , or -NR c SO2R d and wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8Alkenyl, -C 2-8 Each of alkynyl, heterocyclyl, phenyl, or heteroaryl is optionally F, Cl, Br, I, hydroxy, -haloC 1-8 Alkyl, -C 1-8 substituted with alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; R c , R d and R e are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl, or

[0021] (R c and R d ) or (R d and R e ) together with the atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, said ring optionally containing halogen, —C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 substituted with at least one substituent independently selected from alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, or —NO; R 12 are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; and the methyl, ethyl, propyl, butyl, pentyl, hexyl, -C 2-8 Alkenyl, -C 2-8Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, and heteroaryl is optionally F, Cl, Br, I, hydroxy, -haloC 1-8 Alkyl, -C 1-8 It is substituted with alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl.

[0022] Aspect 8. A compound according to any one of aspects 1 to 8, L a , L b , L c and L d are each independently a single bond, -O-, -CO-, -(CR a R b ) n -or-NR c - selected from n is 1, 2, 3, 4 or 5; R a and R b are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -NO2, -OR c , -SO2R c , -COR c , -CO2R c , -CONR c R d , -C(=NR c )NR d R e , -NR c R d , -NR c COR d , -NR c CONR d R e , -NRc CO2R d , -NR c SONR d R e , -NR c SO2NR d R e or -NR c SO2R d and wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl is optionally F, Cl, Br, I, hydroxy, -haloC 1-8 substituted with alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl;

[0023] R a and R b are taken together with the atoms to which they are attached to form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, said ring optionally containing F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Substituted with at least one substituent independently selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, or -NO2.

[0024] Aspect 9. A compound according to any one of aspects 1 to 8, L a, L b , L c and L d are each independently a single bond, -O-, -CO-, -(CR a R b ) n -or-NR c - selected from n is 1, 2, 3, 4 or 5; R a and R b are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -NO2, -OR c , -SO2R c , -COR c , -CO2R c , -CONR c R d , -C(=NR c )NR d R e , -NR c R d , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NR c SONR d R e , -NR c SO2NR d R e or -NR c SO2R d is.

[0025] Aspect 10.L a , L b , L c and L dare each independently a single bond, -O-, -CO-, -N(CH3)-, -NH-, or -(CH2) n -, -[CH(CH3)] n -, -[C(CH3)2] n -, where n is 1, 2, 3, 4 or 5, preferably L a , L b , L c and L d are each independently selected from a single bond, —O—, —CO—, —N(CH3)—, —NH—, —CH2—, —CH2CH2—, —CH2CH2CH2—, and —CH2CH2CH2CH2—.

[0026] Embodiment 11. Each Cy1a independently represents: TIFF2025501082000013.tif45161, Each of TIFF2025501082000014.tif45161 is selectively R 9 is replaced by

[0027] n1, n2, n3, n4, and n5 each independently represent 0, 1, 2, 3, or 4; X 3 and X 4 are each independently -CR a or N; X 5 , X 6 and X 7 are each independently -NR c -, -O-, -S- and -CR a R b - selected from R a , R b R c A compound according to any one of aspects 1 to 10, wherein is as defined in aspect 1. *1a is TIFF2025501082000015.tif4244 indicates the position where the molecule binds, and **1a indicates the position where the molecule binds to the molecule. TIFF2025501082000016.tif1855 indicates the position where it binds to the part.

[0028] Embodiment 12. Each Cy1a independently represents: TIFF2025501082000017.tif61161, Each of TIFF2025501082000018.tif61161 is selectively R 9 is replaced by

[0029] X 3 and X 4 are each independently -CR a or N; X 5 , X 6 and X 7 are each independently -NR c -, -O-, -S- and -CR a R b - selected from R a and R b are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -NO2, -OR c , -SO2R c , -COR c , -CO2R c , -CONR c R d , -C(=NR c )NR d R e , -NR c R d , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NRc SONR d R e , -NR c SO2NR d R e or -NR c SO2R d and wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl is optionally F, Cl, Br, I, hydroxy, -haloC 1-8 substituted with alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; R c are independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 12. The compound according to any one of aspects 1 to 11, wherein the aryl group is selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl.

[0030] Embodiment 13. Each Cy1a is independently 12. The compound of any one of aspects 1 to 11, wherein the compound is TIFF2025501082000019.tif74161.

[0031] Embodiment 14. Each Cy1b is independently TIFF2025501082000020.tif45161, Each of TIFF2025501082000021.tif45161 is selectively R 10is replaced by n1, n2, n3, n4, and n5 each independently represent 0, 1, 2, 3, or 4; X 3 and X 4 are each independently -CR a or N; X 5 , X 6 and X 7 are each independently -NR c -, -O-, -S- and -CR a R b - selected from R a , R b R c is as defined in aspect 1; *1b is TIFF2025501082000022.tif4261 indicates the position where the molecule binds to the target molecule, and **1b indicates the position where the molecule binds to the target molecule. 14. The compound of any one of embodiments 1 to 13, wherein the TIFF2025501082000023.tif1738 moiety is linked to the compound.

[0032] Embodiment 15. Each Cy1b is independently TIFF2025501082000024.tif57161, Each of TIFF2025501082000025.tif57161 is selectively R 10 is replaced by X 3 and X 4 are each independently -CR a or N; X 5 , X 6 and X 7 are each independently -NR c -, -O-, -S- and -CR a R b - selected from

[0033] R a and R bare each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -NO2, -OR c , -SO2R c , -COR c , -CO2R c , -CONR c R d , -C(=NR c )NR d R e , -NR c R d , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NR c SONR d R e , -NR c SO2NR d R e or -NR c SO2R d and wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl is optionally F, Cl, Br, I, hydroxy, -haloC 1-8substituted with alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; R c are independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 15. The compound according to any one of aspects 1 to 14, wherein the aryl group is selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl.

[0034] Embodiment 16. Each Cy1b is independently 16. The compound of any one of aspects 1 to 15, wherein the compound is TIFF2025501082000026.tif74161.

[0035] Embodiment 17. Cy1c independently comprises: TIFF2025501082000027.tif45161, Each of TIFF2025501082000028.tif45161 is selectively R 11 is replaced by

[0036] n1, n2, n3, n4, and n5 each independently represent 0, 1, 2, 3, or 4; X 3 and X 4 are each independently -CR a or N; X 5 , X 6 and X 7 are each independently -NR c -, -O-, -S- and -CR a R b - selected from R a , R b R cis as defined in aspect 1; *1c is TIFF2025501082000029.tif4074 indicates the position where the molecule binds to the target molecule, and **1c indicates the position where the molecule binds to the target molecule. 17. The compound of any one of embodiments 1 to 16, wherein the TIFF2025501082000030.tif621 moiety is linked to the compound.

[0037] Embodiment 18. Cy1c independently comprises: TIFF2025501082000031.tif61161, Each of TIFF2025501082000032.tif61161 is selectively R 11 is replaced by X 3 and X 4 are each independently -CR a or N; X 5 , X 6 and X 7 are each independently -NR c -, -O-, -S- and -CR a R b - selected from

[0038] R a and R b are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, oxo, (=O), -CN, -NO2, -OR c , -SO2R c , -COR c , -CO2R c , -CONR c R d , -C(=NR c )NR d Re , -NR c R d , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NR c SONR d R e , -NR c SO2NR d R e or -NR c SO2R d and wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl is optionally F, Cl, Br, I, hydroxy, -haloC 1-8 substituted with alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; R c are independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 18. The compound according to any one of aspects 1 to 17, wherein the aryl group is selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl.

[0039] Embodiment 19. Cy1c independently comprises: 19. The compound of any one of aspects 1 to 18, wherein the compound is TIFF2025501082000033.tif75161.

[0040] Aspect 20. The TIFF2025501082000034.tif2688 part is TIFF2025501082000035.tif133161TIFF2025501082000036.tif124161

[0041] and *La is TIFF2025501082000037.tif4844 indicates the position where the molecule binds to the target molecule, and *Lb indicates the position where the molecule binds to the target molecule. 20. The compound of any one of embodiments 1 to 19, wherein the TIFF2025501082000038.tif718 moiety is linked to the compound.

[0042] Aspect 21.R 1 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR c , -SO2R c , -COR c , -CO2R c , -CONR c R d , -C(=NR c )NR d R e , -NR c R d , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NR c SONR d R e , -NR c SO2NR d R e, or -NR c SO2R d and wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, and heteroaryl is optionally F, Cl, Br, I, hydroxy, -haloC 1-8 substituted with alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl;

[0043] R c , R d and R e are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl, or (R c and R d ) or (R d and R e ) together with the atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, said ring optionally containing halogen, —C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8A compound according to any one of aspects 1 to 20, substituted with at least one substituent independently selected from alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, or -NO2.

[0044] Aspect 22.R 1 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN or -NO2, preferably R 1 22. The compound of any one of aspects 1-21, wherein is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl. Aspect 23.R 2 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR c , -SO2R c , -COR c , -CO2R c , -CONR c R d , -C(=NR c )NR d R e , -NR c R d , -NR c COR d , -NR c CONR d R e , -NR cCO2R d , -NR c SONR d R e , -NR c SO2NR d R e , or -NR c SO2R d and wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, and heteroaryl is optionally F, Cl, Br, I, hydroxy, -haloC 1-8 substituted with alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl;

[0045] R c , R d and R e are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl, or (R c and R d ) or (R d and R e ) together with the atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, said ring optionally containing halogen, —C 1-8 Alkyl, -C 2-8Alkenyl, -C 2-8 A compound according to any one of aspects 1 to 22, substituted with at least one substituent independently selected from alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, or -NO2.

[0046] Aspect 24.R 2 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN or -NO2, preferably R 2 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, —CN, or —NO 2 .

[0047] Aspect 25.R 3 and R 4 are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR c , -SO2R c , -COR c , -CO2R c , -CONR c R d , -C(=NR c )NR d R e , -NR c Rd , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NR c SONR d R e , -NR c SO2NR d R e , or -NR c SO2R d and wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, and heteroaryl is optionally F, Cl, Br, I, hydroxy, -haloC 1-8 substituted with alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl;

[0048] R c , R d and R e are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl, or (R c and R d ) or (R d and R e) together with the atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, said ring optionally containing halogen, —C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 A compound according to any one of aspects 1 to 24, substituted with at least one substituent independently selected from alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, or -NO2.

[0049] Aspect 26.R 3 and R 4 are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, or —CN, preferably R 3 and R 4 A compound according to any one of aspects 1 to 25, wherein each independently is hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0050] Aspect 27. The TIFF2025501082000039.tif2819 part is TIFF2025501082000040.tif27161, and *3 is TIFF2025501082000041.tif2320 indicates the position where the sequence binds to the fragment, and **3 indicates the position where the sequence binds to the fragment. 27. The compound of any one of embodiments 1 to 26, wherein the TIFF2025501082000042.tif30101 moiety is attached to the compound.

[0051] Aspect 28.R 6 and R 7are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, and heteroaryl is optionally F, Cl, Br, I, hydroxy, -haloC 1-8 substituted with alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl, preferably R 6 and R 7 is each independently H, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0052] Aspect 29.R 5 teeth, TIFF2025501082000043.tif2326, Y 1 , Y 2 , Y 3 and Y 4 are each independently selected from CH, O, S, or N; R 15 are independently hydrogen, halogen, -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR c , -SO2R c , -CORc , -CO2R c , -CONR c R d , -C(=NR c )NR d R e , -NR c R d , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NR c SONR d R e , -NR c SO2NR d R e , or -NR c SO2R d -C is selected from 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally halogen, hydroxy, -haloC 1-8 Alkyl, -C 1-8 substituted with alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R c , R d , and R e are each independently as defined in aspect 1; and p7 is 0, 1, 2, 3, or 4.

[0053] Aspect 30.Y 1 is CH, S, N or O, and Y 2 is CH, S, O or N, and Y 3 is CH, O, S or N, and Y 4 is CH, O, S, or N.

[0054] Aspect 31. TIFF2025501082000044.tif2326 29. The compound of embodiment 28, selected from TIFF2025501082000045.tif20161.

[0055] Aspect 32.R 15 -H, -F, -Cl, -Br, -I, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 , -CH 13 , methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, -CH(OH)CH2CH3, -CH2CH(OH)CH3, -CH2OCH3, -CFH2, -CF2H, -CF3, -CH2CF3, -CH2CH2CF3, and is selected from said -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 , -CH 13 , methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C 2-8 Alkenyl, -C 2-8 Each alkynyl may optionally be selected from the group consisting of at least one of F, Cl, Br, I, hydroxy, -haloC 1-8 Alkyl, -C 1-8 30. The compound according to embodiment 29, wherein the compound is substituted with alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0056] Aspect 33.R 15 teeth, 30. The compound of embodiment 29, selected from TIFF2025501082000046.tif14161.

[0057] Aspect 34. The TIFF2025501082000047.tif1720 part is 34. The compound of any one of embodiments 1 to 33, wherein the compound is TIFF2025501082000048.tif18161.

[0058] Aspect 35. A compound according to any one of aspects 1 to 34, wherein Cy2 is a 5- or 6-membered aromatic ring containing from 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur as ring members.

[0059] Aspect 36. TIFF2025501082000049.tif2042 TIFF2025501082000050.tif59161, Y 1 , Y 2 , Y 3 and Y 4 are each independently as defined in embodiment 29; *Cy2 is TIFF2025501082000051.tif4426 indicates the position where the fragment binds, and **3 indicates the position where the fragment binds to the fragment. 36. The compound of any one of embodiments 1 to 35, wherein the TIFF2025501082000052.tif2285 moiety is linked to the compound.

[0060] Aspect 37. TIFF2025501082000053.tif2042 37. The compound of any one of embodiments 1 to 36, wherein the compound is TIFF2025501082000054.tif179161.

[0061] Aspect 38.R 8 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR c , -SO2R c , -COR c , -CO2R c , -CONRc R d , -C(=NR c )NR d R e , -NR c R d , -NR c COR d , -NR c CONR d R e , -NR c CO2R d , -NR c SONR d R e , -NR c SO2NR d R e , or -NR c SO2R d and wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, and heteroaryl is optionally F, Cl, Br, I, hydroxy, -haloC 1-8 substituted with alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl; R c , R d and R e are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl, or (R c and R d ) or (Rd and R e ) together with the atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, said ring optionally containing halogen, —C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 A compound according to any one of aspects 1 to 36, substituted with at least one substituent independently selected from alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, or -NO2.

[0062] Aspect 39.R 8 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN or -NO2, preferably R 2 is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, —CN, or —NO 2 .

[0063] Aspect 40. TIFF2025501082000055.tif2042 39. The compound of any one of embodiments 1 to 38, wherein the compound is TIFF2025501082000056.tif90161.

[0064] Aspect 41. The TIFF2025501082000057.tif4238 part is 41. The compound of any one of embodiments 1 to 40, selected from: TIFF2025501082000058.tif127161TIFF2025501082000059.tif196161.

[0065] Embodiment 42. The compound of any one of embodiments 1 to 41, selected from: TIFF2025501082000060.tif213161TIFF2025501082000061.tif224161TIFF2025501082000062.tif227161TIFF20255010820 00063.tif247161TIFF2025501082000064.tif231161TIFF2025501082000065.tif219161TIFF2025501082000066.tif226161

[0066] Aspect 43. A pharmaceutical composition comprising a compound according to any one of Aspects 1 to 42, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient. Aspect 44. A method of inhibiting BTK activity, comprising administering to a subject a compound according to any one of Aspects 1 to 42, including a compound of Formula (I) or any of the specific compounds exemplified herein, or a pharmaceutically acceptable salt thereof.

[0067] Aspect 45. A method of treating a disease or disorder in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of Aspects 1-42, or a pharmaceutically acceptable salt thereof, as a BTK kinase inhibitor, wherein the disease or disorder is associated with inhibition of BTK, and preferably, the disease or disorder is cancer. DETAILED DESCRIPTION OF THE INVENTION

[0068] definition The following terms have the meanings indicated throughout this specification. As used in this specification (including the appended claims), the singular forms of words such as "a / an" and "said" include their corresponding plural forms unless the context clearly dictates otherwise. The term "or" is used to mean, and is used interchangeably with, the term "and / or," unless context clearly indicates otherwise.

[0069] The term "alkyl" refers to a hydrocarbon group selected from straight-chain and branched saturated hydrocarbon groups containing 1 to 18 (e.g., 1 to 12, further such as 1 to 10, further such as 1 to 8, or 1 to 6, or 1 to 4) carbon atoms. Alkyl groups containing 1 to 6 carbon atoms (i.e., C 1-6 Examples of alkyl include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), 1,1-dimethylethyl or tert-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0070] The term "propyl" refers to 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"). The term "butyl" refers to 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), 1,1-dimethylethyl or tert-butyl ("t-Bu"). The term "pentyl" refers to 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl. The term "hexyl" means 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl and 3,3-dimethyl-2-butyl.

[0071] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). The term "haloalkyl" refers to an alkyl group in which one or more hydrogens have been replaced with one or more halogen atoms, such as fluorine, chlorine, bromine, and iodine. Examples of haloalkyl include haloC 1-8 Alkyl, HaloC 1-6 Alkyl or haloC 1-4 Alkyl, such as, but not limited to, -CF3, -CH2Cl, -CH2CF3, -CHCl2, -CF3, and the like. The term "alkenyl" refers to a hydrocarbon group selected from straight-chain and branched hydrocarbon groups containing at least one C=C double bond and 2 to 18 (e.g., 2 to 8, further e.g., 2 to 6) carbon atoms. 2-6 Examples of alkenyl include, but are not limited to, ethenyl (ethenyl or vinyl), prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl.

[0072] The term "alkynyl" refers to a hydrocarbon group selected from straight-chain and branched hydrocarbon groups containing at least one C≡C triple bond and 2 to 18 (e.g., 2 to 8, further e.g., 2 to 6) carbon atoms. 2-6 Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl. The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused, bridged, or spiro-linked cycloalkyl groups. For example, cycloalkyl may contain 3 to 12 (e.g., 3 to 10, further for example, 3 to 8, further for example, 3 to 6, 3 to 5, or 3 to 4) carbon atoms. Further for example, cycloalkyl groups may be selected from monocyclic groups containing 3 to 12 (e.g., 3 to 10, further for example, 3 to 8, 3 to 6) carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. In particular, saturated monocyclic cycloalkyl groups (e.g., C 3-8 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In preferred embodiments, cycloalkyl is a monocyclic ring (C 3-6Bicyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyls include those having 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or arranged as a bridged bicyclic ring selected from bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, and bicyclic [3.2.2]nonane. Other examples of bicyclic cycloalkyls include those arranged as a bicyclic ring selected from [5,6] and [6,6] ring systems.

[0073] The term "spirocycloalkyl" refers to a ring structure containing carbon atoms and formed by at least two rings that share one atom. The term "7-12 membered spirocycloalkyl" refers to a ring structure containing 7-12 carbon atoms and formed by at least two rings that share one atom. The term "fused cycloalkyl" refers to a bicyclic cycloalkyl, as defined herein, that is saturated and formed by two or more rings that share two adjacent atoms. The term "bridged cycloalkyl" refers to a cyclic structure formed by two rings containing 7 to 12 carbon atoms and sharing two non-adjacent atoms. The term "7-10-membered bridged cycloalkyl" refers to a cyclic structure formed by two rings containing 7 to 12 carbon atoms and sharing two non-adjacent atoms. The term "cycloalkenyl" refers to a non-aromatic cyclic alkyl group of 3 to 10 carbon atoms, monocyclic or polycyclic, having at least one double bond, preferably 1 to 2 double bonds. In one embodiment, cycloalkenyl is cyclopentenyl or cyclohexenyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, preferably cyclohexenyl.

[0074] The term "fused cycloalkyl" refers to a bicyclic cycloalkyl, as defined herein, that contains at least one double bond and is formed by two or more rings that share two adjacent atoms. The term "cycloalkynyl" refers to a non-aromatic cycloalkyl group of 5 to 10 carbon atoms, which may be monocyclic or polycyclic and which has at least one triple bond. The term "fused cycloalkynyl" refers to a bicyclic cycloalkyl, as defined herein, that contains at least one triple bond and is formed by two or more rings that share two adjacent atoms. The term "benzofused cycloalkyl" refers to a bicyclic fused cycloalkyl in which a 4- to 8-membered monocyclic cycloalkyl ring is fused to a benzene ring. For example, a benzofused cycloalkyl is TIFF2025501082000067.tif14161, and the wavy lines indicate the connection points. The term "benzofused cycloalkenyl" refers to a bicyclic fused cycloalkenyl in which a 4- to 8-membered monocyclic cycloalkenyl ring is fused to a benzene ring. The term "benzofused cycloalkynyl" refers to a bicyclic fused cycloalkynyl in which a 4- to 8-membered monocyclic cycloalkynyl ring is fused to a benzene ring.

[0075] Examples of fused cycloalkyl, fused cycloalkenyl, or fused cycloalkynyl include bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decalin, and benzo 3- to 8-membered cycloalkyl, benzo C 4-6 Examples include, but are not limited to, cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, etc. Preferred embodiments are 8-9 membered fused rings, which in the above examples refer to ring structures containing 8-9 ring atoms. The term "aryl" used alone or in combination with other terms means a) 5- and 6-membered carbocyclic aromatic rings such as phenyl; b) bicyclic ring systems, such as 7-12 membered bicyclic ring systems in which at least one ring is carbocyclic and aromatic, such as naphthyl and indanyl, and c) Tricyclic ring systems, such as 10-15 membered tricyclic ring systems, in which at least one ring is carbocyclic and aromatic, such as fluorenyl.

[0076] The terms "heteroaromatic ring" and "heteroaryl" are used interchangeably throughout this disclosure. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10 (aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring. The term "bicyclic fused aryl" refers to a bicyclic aryl ring as defined herein. An exemplary bicyclic fused aryl is naphthalene.

[0077] The term "heteroaryl" refers to a) a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom selected from nitrogen (N), sulfur (S), and oxygen (O), for example, 1 to 4 (or in some embodiments 1 to 3, in some embodiments 1 to 2) heteroatoms, with the remaining ring atoms being carbon; b) 7-12 membered bicyclic rings containing at least one heteroatom selected from N, O, and S, for example 1-4 (or 1-3 in some embodiments, or 1 or 2 in other embodiments) heteroatoms, the remaining ring atoms being carbon, and at least one ring being aromatic, with at least one heteroatom being in the aromatic ring; and c) refers to groups selected from 11-14 membered tricyclic rings containing at least one heteroatom selected from N, O, and S, for example, 1-4 (or 1-3 in some embodiments, or 1 or 2 in other embodiments) heteroatoms, the remaining ring atoms being carbon, and at least one ring being aromatic, with at least one heteroatom being present in the aromatic ring.

[0078] When the total number of S and O atoms in a heteroaryl exceeds 1, the heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in a heteroaryl is 2 or less. In some embodiments, the total number of S and O atoms in an aromatic heterocycle is 1 or less. When a heteroaryl contains more than one heteroatom ring member, the heteroatoms can be the same or different. Nitrogen atoms in one or more rings of a heteroaryl group can be oxidized to form an N-oxide. In particular, the term "bicyclic fused heteroaryl" refers to a 7- to 12-membered, preferably 7- to 10-membered, and more preferably 9- or 10-membered fused bicyclic heteroaryl ring, as defined herein. Typically, a bicyclic fused heteroaryl is a 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered, or 6-membered / 7-membered bicyclic ring. Such groups may be attached to the remainder of the molecule via either ring.

[0079] Representative examples of bicyclic fused heteroaryls include, but are not limited to, the following groups: benzisoxazolyl, benzoxadiazolyl, benzofuranyl, benzofurazanyl, benzofuranyl, benzimidazolyl, benzisothiazolyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxadiazolyl, benzoxazolyl, furopyridinyl, furopyrrolyl, imidazopyridinyl, imidazothiazolyl, indazolyl, indolizinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolinyl (also isoquinolyl, naphthyridinyl, phthalazinyl, pteridinyl, purinyl, pyrazinopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, pyrazolotriazinyl, pyrazolopyridinyl, pyrrolopyridinyl, quinazolinyl, quinolinyl (or quinolyl), quinoxalinyl, thiazolopyridinyl, thienopyrazinyl, thienopyrazolyl, thienopyridinyl, thienopyrrolyl, thienothienyl or triazolopyridinyl. The term "benzofused heteroaryl" refers to a bicyclic fused heteroaryl in which a 5- to 7-membered (preferably 5- or 6-membered) monocyclic heteroaryl ring, as defined herein, is fused to a benzene ring.

[0080] The terms "heteroaromatic ring" and "heteroaryl" are used interchangeably throughout this disclosure. In some embodiments, a monocyclic or bicyclic heteroaromatic ring has 5, 6, 7, 8, 9, or 10 ring members, with 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O), and the remaining ring members are carbon. In some embodiments, a monocyclic or bicyclic heteroaromatic ring is a monocyclic or bicyclic ring containing 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, a monocyclic or bicyclic heteroaromatic ring is a monocyclic 5-6 membered heteroaryl ring having 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a bicyclic 8-10 membered heteroaryl ring having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

[0081] Examples of heteroaryl or monocyclic or bicyclic heteroaromatic rings include (numbered from the bonding position of priority 1) pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl), tetrahydropyridinyl, ... zolyl, thienyl (e.g., thiophen-2-yl, thiophen-3-yl), triazinyl, benzothienyl, furanyl or furanyl, benzofuranyl, benzimidazolyl, indolyl, isoindolyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl, or 1,3,4-triazolyl). , quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (e.g., benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-oxadiazolyl, 1-oxa-2,4-oxadiazolyl, 1-oxa-2,5-oxadiazolyl, 1-oxa-3,4-oxadiazolyl, 1-thia-2,3-oxadiazolyl Indazolyl (e.g., 1H-indazol-5-yl) and benzothiazolyl (e.g., benzo[d]thiazolyl-6-yl). "Aromatic ring" refers to aromatic carbocycles (eg, aryl as defined above) and aromatic heterocycles (eg, heteroaryl as defined above).

[0082] "Heterocyclyl," "heterocycle," or "heterocyclic" are interchangeable and include non-aromatic heterocyclic groups containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spirocyclic rings, i.e., monocyclic heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, and fused heterocyclyl. As used herein, the term "optionally oxidized sulfur" refers to S, SO, or SO.

[0083] The term "monocyclic heterocyclyl" refers to a monocyclic group in which at least one ring member (e.g., 1 to 3 heteroatoms, 1 or 2 heteroatoms) is a heteroatom selected from nitrogen, oxygen, or optionally oxidized sulfur. The heterocycle may be saturated or partially saturated. Exemplary monocyclic 4- to 9-membered heterocyclyls include pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, oxiranyl, aziridine- 1-yl, aziridin-2-yl, azocyclooctan-1-yl, azocyclooctan-2-yl, azocyclooctan-3-yl, azocyclooctan-4-yl, azocyclooctan-5-yl, thiiranyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, oxetanyl, thietanyl, 1,2-dithianyl, 1,3-dithianyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl yl, homopiperidinyl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxepanyl, thiepanyl, 1,4-oxathiepanyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1-4-oxazepanyl, 1,4-dithianyl, 1,4-thiazepan and 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathiepanyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothiophenyl, dihydropyran ... Examples include, but are not limited to, furanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl, or 1,1-dioxo-thiomorpholinyl.

[0084] The term "spiroheterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl having rings joined by one common carbon atom (referred to as a spiroatom), containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings of a spiroheterocyclyl may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. Preferably, the spiroheterocyclyl has 6 to 14 members, more preferably 7 to 12 members. Depending on the number of common spiro atoms, the spiroheterocyclyl may be a monospiroheterocyclyl, dispiroheterocyclyl, or polyspiroheterocyclyl, preferably a monospiroheterocyclyl or dispiroheterocyclyl, more preferably a 4-membered / 3-membered, 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl. Representative examples of spiroheterocyclyl include, but are not limited to, the following groups: 2,3-dihydrospiro[indene-1,2'-pyrrolidine] (e.g., 2,3-dihydrospiro[indene-1,2'-pyrrolidine]-1'-yl), 1,3-dihydrospiro[indene-2,2'-pyrrolidine] (e.g., 1,3-dihydrospiro[indene-2,2'-pyrrolidine]-1'-yl), azaspiro[2.4]heptane (e.g., 5-azaspiro[2.4]heptan-5-yl), 2-oxa-6-azaspiro[3.3]heptane (e.g., 2-oxa-6-azaspiro[3.3]heptan-6-yl), azaspiro[3.4]octane (e.g., 6-azaspiro[3.4] ]octan-6-yl), 2-oxa-6-azaspiro[3.4]octane (e.g., 2-oxa-6-azaspiro[3.4]octan-6-yl), azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]octan-6-yl), azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]octan-6-yl), 1,7-dioxaspiro[4.5]decane, 2-oxa-7-aza-spiro[4.4]nonane (e.g., 2-oxa-7-aza-spiro[4.4]nonan-7-yl), 7-oxa-spiro[3.5]nonyl, and 5-oxa-spiro[2.4]heptyl.

[0085] The term "fused heterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl in which each ring contains one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, and shares adjacent atom pairs (carbon and carbon atoms or carbon and nitrogen atoms) with another ring. One or more rings of a fused heterocyclyl may contain one or more double bonds, but the fused heterocyclyl does not have a completely conjugated π-electron system. Preferably, the fused heterocyclyl has 6 to 14 members, more preferably 7 to 12 members, or 7 to 10 members. Depending on the number of constituent rings, the fused heterocyclyl may be bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl. Such groups may be attached to the remainder of the molecule via any ring.

[0086] In particular, the term "bicyclic fused heterocyclyl" refers to a 7- to 12-membered, preferably 7- to 10-membered, more preferably 9- or 10-membered fused heterocyclyl as defined herein, containing two fused rings and containing 1 to 4 heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members. Typically, a bicyclic fused heterocyclyl is a 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered, or 6-membered / 7-membered bicyclic fused heterocyclyl. Representative examples of (bicyclic) fused heterocycles include, but are not limited to, the following groups: Octahydrocyclopenta[c]pyrrole, octahydropyrrolo[3,4-c]pyrrolyl, octahydroisoindolyl, isoindolinyl, octahydrobenzo[b][1,4]dioxin, indolinyl, isoindolinyl, benzopyranyl, dihydrothiazolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl (or tetrahydroisoquinolinyl), dihydrobenzofuranyl, dihydrobenzoxazinyl, dihydrobenzimidazolyl, tetrahydro dihydrobenzothiophenyl, tetrahydrobenzofuranyl, benzodioxolyl, benzodioxepinyl, chromanyl, chromenyl, dihydrobenzoxapinyl, dihydrobenzoxazinyl, dihydrobenzodioxepinyl, dihydrothienodioxepinyl, dihydrobenzoxazepinyl, tetrahydrobenzoxazepinyl, dihydrobenzazepinyl, tetrahydrobenzazepinyl, isochromanyl, chromanyl, or tetrahydropyrazopyrimidinyl (e.g., 4,5,6,7-tetrahydropyrazo[1,5-a]pyrimidin-3-yl). The term "benzofused heterocyclyl" refers to a bicyclic fused heterocyclyl in which a monocyclic 4- to 9-membered heterocyclyl (preferably 5- or 6-membered), as defined herein, is fused to a benzene ring.

[0087] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocycloalkyl group in which two rings in the system each share two non-linking atoms containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, and the remaining ring members are carbon. One or more rings of a bridged heterocyclyl may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. Preferably, the bridged heterocyclyl has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of ring members, the bridged heterocyclyl may be a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl, and is preferably a bicyclic, tricyclic, or tetracyclic bridged heterocyclyl, more preferably a bicyclic or tricyclic bridged heterocyclyl. Representative example groups of bridged heterocyclyl include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.2]octyl, and 2-azabicyclo[3.3.2]decyl.

[0088] The term "at least one substituent" as disclosed herein includes, for example, 1 to 4 (e.g., 1 to 3, or even 1 or 2) substituents, provided that valence theory is satisfied. For example, "at least one substituent R" as disclosed herein 6d " is an R 6d and 1 to 4 (eg 1 to 3, or even 1 or 2) substituents selected from the list below.

[0089] The compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. When a compound disclosed herein has two or more asymmetric centers, it may additionally exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. All possible stereoisomers are intended to be included, such as substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and / or pharmaceutically acceptable salts thereof are intended to be included. A reference to one isomer applies to any possible isomer unless otherwise specified. Unless the isomeric composition is specified, all possible isomers are included.

[0090] As used herein, the term "substantially pure" means that the target stereoisomer contains 35% or less, such as 30% or less, further such as 25% or less, and even further such as 20% or less, calculated by weight, of any other stereoisomer. In some embodiments, the term "substantially pure" means that the target stereoisomer contains 10% or less, such as 5% or less, such as 1% or less, calculated by weight, of any other stereoisomer.

[0091] When compounds disclosed herein contain olefinic double bonds, such double bond, unless otherwise specified, is intended to include both E and Z geometric isomers.

[0092] When the compound disclosed herein contains a bisubstituted cyclic ring system, the substituents found on such ring system can adopt cis and trans form.Cis form means that both two substituents are located above the position of the two substituents on carbon, and trans means that they are located on both sides relative to each other.For example, bisubstituted cyclic ring system can be a cyclohexyl ring or a cyclobutyl ring. It may be advantageous to separate reaction products from one another and / or from starting materials. The desired products of each step or series of steps are separated and / or purified (hereinafter "separated") to the desired degree of homogeneity by techniques commonly used in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography may include any number of methods, including, for example, reverse-phase and normal-phase chromatography, size-exclusion chromatography, ion-exchange chromatography, high-, medium-, and low-pressure liquid chromatography methods and apparatus, small-scale analytical chromatography, simulated moving bed ("SMB") chromatography, and preparative thin- or thick-layer chromatography, as well as small-scale thin-layer and flash chromatography techniques. Those skilled in the art will use the technique most likely to achieve the desired separation.

[0093] "Diastereomers" refer to stereoisomers of compounds that have two or more chiral centers but are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, for example, via chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers to the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers and diastereomers can also be separated using a chiral HPLC column. Single stereoisomers (e.g., substantially pure enantiomers) can be obtained by resolving racemic mixtures using methods such as (e.g., formation of diastereomers using optically active resolving agents) (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C.H. et al. "Chromatographic resolution of enantiomers: Selective review." J. Chromatogr., 113(3)(1975): pp. 283-302). Racemic mixtures of chiral compounds of the present invention can be separated and isolated by any suitable method, including (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing agents, separation of the diastereomers, and conversion to pure stereoisomers, or (3) direct separation of substantially pure or enriched stereoisomers under chiral conditions. See Wainer, Irving W., ed., Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0094] "Pharmaceutically acceptable salts" refers to salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, and the like, and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting a free base function with a suitable organic acid, or an acidic group with a suitable base. Furthermore, if the compound disclosed herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional methods for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation. As defined herein, "a pharmaceutically acceptable salt thereof" includes at least one salt of a compound of formula (I) and salts of stereoisomers, such as salts of enantiomers and / or diastereomers of a compound of formula (I).

[0095] As used herein, the terms "administration," "administering," "treating," and "treatment," when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refer to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent with a cell, and contact of a reagent with a fluid, which is in contact with the cell. The terms "administration" and "treatment" further refer to in vitro and ex vivo treatment of a cell, for example, with a reagent, diagnostic agent, binding compound, or with another cell. A "subject" herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human. The term "effective amount" or "therapeutically effective amount" refers to the amount of an active ingredient (e.g., a compound) sufficient to affect treatment of a disease, disorder, or condition when administered to a subject for treating at least one clinical symptom of the disease, disorder, or condition. The term "therapeutically effective amount" may vary depending on the compound, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age and / or weight of the subject being treated. The appropriate amount in any given case may be readily apparent to one of ordinary skill in the art or may be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound disclosed herein and / or at least one stereoisomer thereof and / or at least one pharmaceutically acceptable salt thereof effective to "treat" a disease or disorder, as defined herein, in a subject. In the case of combination therapy, the term "therapeutically effective amount" refers to the total amount of the combined components for effective treatment of the disease, disorder, or condition.

[0096] Pharmaceutical compositions containing the compounds disclosed herein can be administered to a subject in need thereof by oral, inhalation, rectal, parenteral, or topical administration. For oral administration, the pharmaceutical composition may be a conventional solid formulation such as a tablet, powder, granules, or capsule; a liquid formulation such as an aqueous or oily suspension; or other liquid formulations such as a syrup, solution, or suspension. For parenteral administration, the pharmaceutical composition may be a solution, aqueous solution, oily suspension concentrate, lyophilized powder, or the like. Preferably, the dosage form of the pharmaceutical composition is selected from tablets, coated tablets, capsules, suppositories, nasal sprays, or injections, more preferably tablets or capsules. The pharmaceutical composition may be a single-unit administration using a precise dose. Furthermore, the pharmaceutical composition may contain additional active ingredients.

[0097] All formulations of the pharmaceutical compositions disclosed herein can be prepared by conventional methods in the pharmaceutical arts. For example, the active ingredient can be mixed with one or more excipients, followed by preparation of the desired formulation. The term "pharmaceutically acceptable excipient" refers to conventional pharmaceutical carriers appropriate for the desired drug dosage form, such as diluents, carriers such as water and various organic solvents, fillers such as starch and sucrose, binders such as cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone (PVP), humectants such as glycerin, disintegrants such as agar, calcium carbonate, and sodium bicarbonate, absorption enhancers such as quaternary ammonium compounds, surfactants such as cetyl alcohol, absorbent carriers such as kaolin and bentonite clay, and lubricants such as talc, calcium stearate, magnesium stearate, and polyethylene glycol. Pharmaceutical compositions may also contain other pharmaceutically acceptable excipients, such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, flavors, sweeteners, and dyes.

[0098] The term "disease" refers to any disease, ailment, illness, symptom, or indication, and is interchangeable with the terms "disorder" or "condition." Throughout the specification and the appended claims, unless the context requires otherwise, the term "comprise" and variations thereof, such as "comprises" and "comprising," are intended to specify the presence of the subsequent feature and do not exclude the presence or addition of one or more other features. As used herein, the term "comprises" may be substituted with "contain," "include," or sometimes "have."

[0099] Throughout the specification and in the appended claims, "C n-m " denotes a range inclusive of the endpoints, where n and m are integers and indicate the number of carbons. For example, C 1-8 , C 1-6 etc. Unless expressly defined elsewhere herein, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. [Example]

[0100] The following examples are intended to be illustrative only and should not be construed as limiting in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Temperatures are in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI and used without further purification unless otherwise indicated. Unless otherwise indicated, reactions described below were carried out under a positive pressure of nitrogen or argon or in anhydrous solvents using drying tubes; reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe; and glassware was oven-dried and / or heat-dried.

[0101] 1 1 H NMR spectra were recorded on an Agilent instrument operating at a frequency of 400 MHz. 1 H NMR spectra were acquired using CDCl3, CD2Cl2, CD3OD, DO, d6-DMSO, d6-acetone, or (CD3)2CO as solvents, with tetramethylsilane (0.00 ppm) or residual solvent as the reference standard (CDCl3: 7.25 ppm; CD3OD: 3.31 ppm; DO: 4.79 ppm; d6-DMSO: 2.50 ppm; d6-acetone: 2.05; (CD3)3CO: 2.05). When reporting peak multiplicities, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextet), m (multiplet), br (broad), dd (doublet of doublets), and dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz).

[0102] LCMS-1: LC-MS spectrometer (Agilent 1260 Infinity), detector: MWD (190-400 nm), mass detector: 6120 SQ, mobile phase: A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid, column: Poroshell 120 EC-C18, 4.6 x 50 mm, 2.7 pm, gradient method: flow rate: 1.8 mL / min, time (min) A (%) B (%) TIFF2025501082000068.tif50161LCMS, LCMS-3: LC-MS spectrometer (Agilent 1260 Infinity II), detector: MWD (190-400 nm), mass detector: G6125C SQ, mobile phase: A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid, column: Poroshell 120 EC-C18, 4.6 x 50 mm, 2.7 pm, gradient method: flow rate: 1.8 mL / min, time (min) A (%) B (%)

[0103] TIFF2025501082000069.tif50161LCMS-2: LC-MS spectrometer (Agilent 1290 Infinity II), detector: MWD (190-400 nm), mass detector: G6125C SQ, mobile phase: A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid, column: Poroshell 120 EC-C18, 4.6 x 50 mm, 2.7 pm, gradient method: flow rate: 1.2 mL / min, time (min) A (%) B (%) TIFF2025501082000070.tif50161

[0104] Preparative HPLC was performed on any commercially available column (e.g., 150 x 21.2 mm ID, 5 pm, Gemini NXC 18, Waters Xselect CSH C18, or Waters Xbridge C18) at a flow rate of 20 mL / min, a 2 mL injection volume, room temperature, and UV detection at 214 nm and 254 nm. Mobile phase A was ACN (optionally containing 0.1% FA), and mobile phase B was water (optionally containing 0.1% FA or 0.03% NH₃·H₂O). Gradient table: Mobile phase A (20% to 90%, 30% to 90%, 40% to 90%, or 50% to 90%), time (min): 0 to 15 min, 0 to 17 min, or 0 to 20 min.

[0105] In the examples below, the following abbreviations are used: TIFF2025501082000071.tif196161TIFF2025501082000072.tif196161TIFF2025501082000073.tif190161

[0106] Example 1: (R)-3-(tert-butyl)-N-(1-(4-(6-((4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0107] Step 1: (R)-3-(tert-butyl)-N-(1-(5-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide A mixture of (R)-1-(5-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-amine hydrochloride (2 g, 6.3 mmol), 3-(tert-butyl)-1,2,4-oxadiazol-5-carboxylate (2.5 g, 12.6 mmol), and K2CO3 (2.6 g, 18.9 mmol) in EtOH (50 mL) was stirred at 80 °C for 16 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (1:1) to give the product (660 mg, 24%). [M+H] + = 432.3.

[0108] Step 2: tert-butyl 4-(4-((6-chloropyrimidin-4-yl)amino)phenyl)piperazine-1-carboxylate TIFF2025501082000075.tif2038 A mixture of 4,6-dichloropyrimidine (1 g, 6.76 mmol), tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (1.87 g, 6.76 mmol), and DIEA (1.74 g, 13.52 mmol) in dioxane (25 mL) was stirred at 102 °C for 16 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10:1) to give the product (2.2 g, 84%). [M+H] + = 390.2.

[0109] Step 3: (R)-tert-butyl 4-(4-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-2-fluoro-5-methylphenyl)pyrimidin-4-yl)amino)phenyl)piperazine-1-carboxylate TIFF2025501082000076.tif4256 tert-Butyl 4-(4-((6-chloropyrimidin-4-yl)amino)phenyl)piperazine-1-carboxylate (500 mg, 1.28 mmol), (R)-3-(tert-butyl)-N-(1-(5-fluoro-2-methyl-4-(4, A mixture of 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (660 mg, 1.54 mmol), Pd(dppf)Cl2 (93.6 mg, 0.128 mmol), and K2CO3 (530 mg, 3.84 mmol) was stirred at 100 °C under N2 atmosphere for 16 h. The mixture was cooled. Water (25 mL) was added to the resulting mixture, and it was extracted with DCM (3 × 20 mL). The combined organic layers were washed with saturated NaCl (25 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10:1) to give the product (0.8 g, 95%). [M+H] + = 659.5.

[0110] Step 4: (R)-3-(tert-butyl)-N-(1-(5-fluoro-2-methyl-4-(6-((4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide 2,2,2-trifluoroacetate salt To a stirred solution of (R)-tert-butyl 4-(4-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-2-fluoro-5-methylphenyl)pyrimidin-4-yl)amino)phenyl)piperazine-1-carboxylate (800 mg, 1.21 mmol) in DCM (10 mL) was added TFA (10 mL) at room temperature. The resulting solution was stirred at room temperature for 2 h and concentrated in vacuo to give the product (800 mg, 100%). [M+H] + = 559.6.

[0111] Step 5: (R)-3-(tert-butyl)-N-(1-(4-(6-((4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide TIFF2025501082000078.tif4585To a stirred solution of (R)-3-(tert-butyl)-N-(1-(5-fluoro-2-methyl-4-(6-((4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide 2,2,2-trifluoroacetate salt (100 mg, 0.149 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (67.4 mg, 0.224 mmol) in THF / DMF (2:1, 6 mL), titanium tetraisopropoxide (1.0 mL) was added portionwise. The resulting mixture was stirred at room temperature for 16 h. The mixture was then cooled. Sodium triacetoxyborohydride (158 mg, 0.745 mmol) was added and stirred at room temperature for 2 h. The mixture was concentrated and purified on a SiO2-gel column (DCM:MeOH = 10:1). The residue was purified by reverse-phase flash chromatography using the following conditions: Column: C18, Mobile phase A: 0.1% FA in water, Mobile phase B: ACN, 10% to 50% gradient in 25 min, Detector: UV 214 nm. This gave the product (17 mg, 14%). 1H NMR (500MHz, DMSO) δ 10.19 (s, 1H), 9.79 (d, J = 7.9Hz, 1H), 9.44 (s, 1H), 8.56 (s, 1H), 7.81 (d, J = 8.0Hz, 1H), 7.42 (d, J = 6.5Hz, 2H), 7.35 (d, J = 13.0Hz, 1H), 7.06 (d, J = 9.0Hz, 3H), 6.86 (dd, J = 8.8, 3.8Hz, 4H), 5.21-5.25 (m, 1H), 3.63-3.59 (m, 4H), 3.11-2.94 (m, 4H), 2.62-2.56 (m, 4H), 2.48-2.43 (m, 3H), 2.34 (s, 3H), 2.18-2.11 (m, 2H), 1.76-1.70 (m, 2H), 1.69-1.57 (m, 1H), 1.44-1.42 (d, J = 7.0Hz, 3H), 1.30 (s, 9H), 1.21-1.09 (m, 3H); [M+H] + =844.6.

[0112] Example 2: (R)-3-(tert-butyl)-N-(1-(4-(6-((4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000079.tif4382(R)-3-(tert-butyl)-N-(1-(5-fluoro-2-methyl-4-(6-((4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide 2,2,2-trifluoroacetate salt (80 mg, 0 A mixture of 1-(2-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (76 mg, 0.24 mmol), 1-(2-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (76 mg, 0.24 mmol), (cyanomethyl)trimethylphosphonium iodide (58 mg, 0.24 mmol), and DIEA (46 mg, 0.36 mmol) was stirred at 100 °C for 16 h under a N atmosphere. The mixture was cooled and concentrated under reduced pressure. The mixture was purified by SiO gel column (DCM:MeOH = 10:1) and preparative TLC (DCM:MeOH = 7:1) to give the product (30 mg, 29%). 1H NMR (500MHz, DMSO) δ 10.34 (d, J = 22.8Hz, 1H), 9.85 (d, J = 7.8Hz, 1H), 9.62-9.44 (m, 1H), 8.63 (s, 1H), 7.88 (d, J = 8.0Hz, 1H), 7.60-7.44 (m, 2H), 7.42 (d, J = 13.0Hz, 1H), 7.20-7.09 (m, 2H), 6.97-6.93 (m, 2H), 6.56-6.43 (m, 2H), 5.29 (t, J = 7.3Hz, 1H), 3.82-3.67 (m, 1H), 3.66-3.42 (m, 3H), 3.40-3.38 (m, 1H), 3.22-3.20 (m, 2H), 3.12-3.08 (m, 3H), 3.03-2.85 (m, 2H), 2.79-2.63 (m, 2H), 2.40-2.38 (m, 5H), 2.27-2.14 (m, 1H), 2.13-2.01 (m, 1H), 1.92-1.73 (m, 1H), 1.60-1.57 (m, 2H), 1.50 (d, J = 6.9Hz, 3H), 1.37 (s, 9H), 1.27-1.24 (m, 2H); [M+H] + = 862.6.

[0113] Example 3: (R)-3-(tert-butyl)-N-(1-(4-(6-((4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound TIFF2025501082000080.tif4382 was synthesized in the same manner as in Example 2. 1H NMR (500MHz, DMSO) δ 10.30 (s, 1H), 9.85 (d, J = 7.9Hz, 1H), 9.54 (d, J = 40.6Hz, 1H), 8.64 (s, 1H), 7.88 (d, J = 8.1Hz, 1H), 7.52 (d, J = 35.4Hz, 2H), 7.42 (d, J = 13.0Hz, 1H), 7.13 (d, J = 29.7Hz, 2H), 7.01 (dd, J = 20.7, 12.9Hz, 3H), 6.71 (s, 1H), 5.31-5.27 (m, 1H), 3.85-3.57 (m, 5H), 3.55-3.44 (m, 1H), 3.43-3.34 (m, 2H), 3.30-3.12 (m, 4H), 3.13-3.00 (m, 3H), 3.00-2.89 (m, 1H), 2.72-2.61 (m, 2H), 2.41 (s, [M+H] + = 862.6.

[0114] Example 4: 3-(tert-butyl)-N-((1R)-1-(4-(6-((4-(4-(2-(1-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound TIFF2025501082000081.tif4189 was synthesized in the same manner as in Example 2. 1H NMR (500MHz, DMSO) δ 10.80 (s, 1H), 9.85 (d, J = 7.8Hz, 1H), 9.50 (s, 1H), 8.63 (s, 1H), 7.88 (d, J = 8.0Hz, 1H), 7.49 (s, 2H), 7.42 (d, J = 13.1Hz, 1H), 7.13 (s, 1H), 7.06 (t, J = 8.7Hz, 1H), 6.94 (s, 2H), 6.71 (d, J = 10.5Hz, 2H), 5.33-5.24 (m, 1H), 3.87 (dd, J = 12.2, 4.8Hz, 1H), 3.76-3.65 (m, 2H), 3.18-3.00 (m, 4H), 2.77-2.60 (m, 4H), 2.59-2.53 (m, 2H), 2.44-2.31 (m, 5H), 2.17-2.09 (m, 1H), 1.98-1.91 (m, 1H), 1.75 (d, J = 11.5Hz, 2H), 1.50 (d, J = 6.9Hz, 3H), 1.48-1.41 (m, 3H), 1.37 (s, 9H), 1.30-1.18 (m, 4H); [M+H] + = 875.6.

[0115] Example 5: (R)-3-(tert-butyl)-N-(1-(4-(6-((3-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0116] Step 1: tert-butyl 4-(3-((6-chloropyrimidin-4-yl)amino)phenyl)piperazine-1-carboxylate TIFF2025501082000082.tif2343 To a stirred mixture of tert-butyl 4-(3-aminophenyl)piperazine-1-carboxylate (1.5 g, 5.41 mmol) and 4,6-dichloropyrimidine (0.926 g, 5.95 mmol) in ethanol (30 mL) was added DIEA (2.1 g, 16.23 mmol) at room temperature. The resulting mixture was stirred at 78 °C under a nitrogen atmosphere for 6 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 5% to 50% EtOAc in petroleum ether to give the product (1.4 g, 65%). [M+H] + = 390.1.

[0117] Step 2: (R)-tert-butyl 4-(3-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-2-fluoro-5-methylphenyl)pyrimidin-4-yl)amino)phenyl)piperazine-1-carboxylate TIFF2025501082000083.tif4860 To a stirred mixture of tert-butyl 4-(3-((6-chloropyrimidin-4-yl)amino)phenyl)piperazine-1-carboxylate (296 mg, 0.759 mmol) and (R)-3-(tert-butyl)-N-(1-(5-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (360 mg, 0.835 mmol) in dioxane (12 mL) and HO (3 mL) under a nitrogen atmosphere at room temperature, KCO (210 mg, 1.52 mmol) and Pd(dppf)Cl (31 mg, 0.038 mmol) were added. The resulting mixture was stirred at 89°C under a nitrogen atmosphere for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 10%-90% EtOAc in petroleum ether to give the product (290 mg, 58%). [M+H] + = 659.3.

[0118] Step 3: (R)-3-(tert-butyl)-N-(1-(5-fluoro-2-methyl-4-(6-((3-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000084.tif4652To a stirred solution of (R)-tert-butyl 4-(3-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-2-fluoro-5-methylphenyl)pyrimidin-4-yl)amino)phenyl)piperazine-1-carboxylate (290 mg, 0.44 mmol) in DCM (5 mL) at room temperature is added TFA (5 mL). The resulting solution is stirred at room temperature for 2 h and concentrated in vacuo. The residue (234 mg, crude) is used directly in the next step without further purification. [M+H] + = 559.3.

[0119] Step 4: (R)-3-(tert-butyl)-N-(1-(4-(6-((3-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide TIFF2025501082000085.tif4687A mixture of (R)-3-(tert-butyl)-N-(1-(5-fluoro-2-methyl-4-(6-((3-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (0.234 g, 0.418 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (0.189 g, 0.628 mmol) in 1,2-dichloroethane (8 mL) and HOAc (25 mg) was stirred at room temperature for 0.5 h in a round-bottom flask. The mixture was added with NaBH(OAc)3 (0.222 g, 1.04 mmol) and stirred at room temperature for 12 hours. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (0.097 g, 27%). 1 H NMR(500MHz, DMSO) δ 10.25 (s, 1H), 9.85 (d, J = 7.9Hz, 1H), 9.62 (s, 1H), 8.70 (s, 1H), 7.91 (d, J = 8.1Hz, 1H), 7.43 (d, J = 13.1Hz, 1H), 7.25 (d, J = 11.5Hz, 2H), 7.19-7.08 (m, 4H), 6.93 (d, J = 9.1Hz, 2H), 6.65 (d, J = 7.1Hz, 1H), 5.30 (t, J = 7.1Hz, 1H), 3.69 (t, J = 6.7Hz, 4H), 3.19-3.10 (m, 4H), 2.69-2.65 (m, 4H), 2.39 (s, 4H), 2.22 (d, J = 7.1Hz, 2H), 1.87-1.65 (m, 4H), 1.50 (d, J = 7.0Hz, 3H), 1.37 (s, 9H), 1.29-1.15 (m, 4H), 0.87-0.71 (m, 1H); [M+H] + = 844.6.

[0120] Example 6: 3-(tert-butyl)-N-((1R)-1-(4-(6-((3-(4-(3-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)cyclobutyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide The title compound TIFF2025501082000086.tif3393 was synthesized in the same manner as in Example 5. 1 H NMR (500MHz, DMSO) δ 10.76 (s, 1H), 9.85 (d, J = 7.9Hz, 1H), 9.62 (s, 1H), 8.70 (s, 1H), 7.91 (d, J = 8.1Hz, 1H), 7.43 (d, J = 13.1Hz, 1H), 7.24 (s, 2H), 7.16 (d, J = 4.9Hz, 2H), 6.97 (d, J = 8.5Hz, 2H), 6.67-6.59 (m, 3H), 5.67 (d, J = 7.6Hz, 1H), 5.30 (t, J = 7.3Hz, 1H), 4.31-4.24 (m, 1H), 3.15 (s, 4H), 2.98 (t, J = 7.8Hz, 1H), 2.78-2.54 (m, 3H), 2.48-2.32 (m, 9H), 2.14-2.06 (m, 1H), 1.89-1.77 (m, 2H), 1.50 (d, J = 7.0Hz, 3H), 1.37 (s, 9H); [M+H] + = 815.5.

[0121] Example 7: (R)-3-(tert-butyl)-N-(1-(4-(6-((4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound of TIFF2025501082000087.tif4585 was synthesized in the same manner as in Example 1. 1H NMR (500MHz, DMSO) δ 10.18 (s, 1H), 9.80 (d, J = 7.8Hz, 1H), 9.34 (s, 1H), 8.53 (s, 1H), 7.74 (s, 2H), 7.52 (d, J = 8.1Hz, 1H), 7.42 (d, J = 8.5Hz, 2H), 7.10-6.97 (m, 3H), 6.86 (dd, J = 8.2, 5.8Hz, 4H), 5.28-5.24 (m, 1H), 3.63-3.60 (m, 4H), 3.39-3.15 (m, 4H), 3.09-2.96 (m, 4H), 2.62-2.57 (m, 4H), 2.39 (s, 3H), 2.15 (d, J = 6.8Hz, 2H), 1.74 (d, J = 12.3Hz, 2H), 1.70-1.59 (m, 1H), 1.44 (d, J = 6.9Hz, 3H), 1.29 (s, 9H), 1.21-1.10 (m, 2H); [M+H] + = 826.6.

[0122] Example 8: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide The title compound of TIFF2025501082000088.tif4585 was synthesized in the same manner as in Example 1. 1H NMR (500MHz, DMSO) δ 10.19 (s, 1H), 10.03 (s, 1H), 9.81 (d, J = 7.8Hz, 1H), 8.66 (s, 1H), 7.94 (d, J = 2.3Hz, 2H), 7.76 (d, J = 8.0Hz, 1H), 7.64 (s, 1H), 7.37 (t, J = 11.7Hz, 2H), 7.06 (d, J = 8.8Hz, 2H), 6.86 (d, J = 8.9Hz, 2H), 5.25-5.21 (m, 1H), 3.63-3.60 (m, 4H), 3.14-3.02 (m, 4H), 2.64-2.58 (m, 4H), 2.58-2.55 (m, 1H), 2.54-2.46 (m, 3H), 2.35 (s, 3H), 2.25-2.16 (m, 2H), 1.74 (d, J = 12.4Hz, 2H), 1.69-1.61 (m, 1H), 1.44 (d, J = 6.9Hz, 3H), 1.30 (s, 9H), 1.23-1.11 (m, 2H); [M+H] + = 845.6.

[0123] Example 9: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide The title compound TIFF2025501082000089.tif3973 was synthesized in the same manner as in Example 1. 1H NMR (500MHz, DMSO) δ 10.25 (s, 1H), 10.08 (s, 1H), 9.93 (d, J = 10.0Hz, 1H), 8.72 (s, 1H), 8.01-7.97 (m, 2H), 7.83-7.71 (m, 2H), 7.46-7.43 (m, 2H), 7.13 (d, J = 10.0Hz, 2H), 6.92 (d, J = 10.0Hz, 2H), 5.35-5.32 (m, 1H), 3.70-3.67 (m, 4H), 3.13 (s, 4H), 2.69-2.64 (m, 4H), 2.53-2.52 (m, [M+H] + = 845.7.

[0124] Example 10: (R)—N-(1-(4-(6-((6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazol-5-carboxamide The title compound of TIFF2025501082000090.tif4074 was synthesized in the same manner as in Example 1. 1H NMR (500MHz, DMSO) δ 10.25 (s, 1H), 9.80 (d, J = 7.8Hz, 1H), 9.42 (s, 1H), 8.59 (s, 1H), 8.32 (s, 1H), 7.87-7.75 (m, 3H), 7.56 (d, J = 5.0Hz, 1H), 7.14-7.08 (m, 3H), 6.93 (d, J = 10.0Hz, 2H), 6.86 (d, J = 5.0Hz, 1H), 5.30 (q, J = 5.0Hz, 1H), 3.71-3.68 (m, 4H), 3.44 (s, 4H), 2.69-2.65 (m, 4H), [M+H] + = 825.6.

[0125] Example 11: (R)—N-(1-(4-(6-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazol-5-carboxamide

[0126] Step 1: (R)—N-(1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazol-5-carboxamide TIFF2025501082000091.tif2344 To a solution of 3-(1-methylcyclopropyl)-1,2,4-oxadiazol-5-carboxylate (1.0 g, 5.1 mmol) in EtOH (20 mL) was added (R)-1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-amine hydrochloride (1.52 g, 5.1 mmol). The mixture was stirred overnight at 90 °C under N2. The mixture was purified by combi flash elution with EA:PE=1:2 to give the product (1.8 g, 86%). [M+H] + = 412.2.

[0127] Step 2: (R)-tert-butyl 4-(6-((6-(3-methyl-4-(1-(3-(1-methylcyclopropyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)phenyl)pyrimidin-4-yl)amino)pyridin-3-yl)piperazine-1-carboxylate TIFF2025501082000092.tif3643 (R)-N-(1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazol-5-carboxamide (200 mg, To a solution of 0.49 mmol) of tert-butyl 4-(6-((6-chloropyrimidin-4-yl)amino)pyridin-3-yl)piperazine-1-carboxylate (compound obtained in a manner similar to that in Example 5) (192 mg, 0.49 mmol), Pd(dppf)Cl2 (54 mg, 0.0735 mmol), and K2CO3 (133 mg, 0.98 mmol) were added. The resulting mixture was stirred at 100 °C under a N2 atmosphere for 2 h. The mixture was purified by silica gel column chromatography, eluting with EtOAc to give the product (100 mg, 32%). [M+H] + = 640.3.

[0128] Step 3: (R)—N-(1-(2-methyl-4-(6-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazol-5-carboxamide hydrochloride TIFF2025501082000093.tif3437To a stirred solution of (R)-tert-butyl 4-(6-((6-(3-methyl-4-(1-(3-(1-methylcyclopropyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)phenyl)pyrimidin-4-yl)amino)pyridin-3-yl)piperazine-1-carboxylate (100 mg, 0.156 mmol) in DCM (10 mL) is added a solution of HCl in 1,4-dioxane (4N, 10 mL) at room temperature. The resulting solution is stirred at room temperature overnight. The resulting mixture is concentrated in vacuo to give the product (80 mg, 89%). [M+H] + = 540.3.

[0129] Step 4: (R)—N-(1-(4-(6-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazol-5-carboxamide To a solution of (R)-N-(1-(2-methyl-4-(6-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazol-5-carboxamide hydrochloride (100 mg, 0.174 mmol) in DCM (20 mL), MeOH (4 mL), and AcOH (0.3 mL) was added 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (63 mg, 0.2088 mmol). The mixture was stirred at rt overnight. The mixture was added with NaBH(OAc) (74 mg, 0.348 mmol) and stirred at room temperature for an additional 2 h. The reaction was quenched with NaCO (aq., saturated, 20 mL) and extracted with DCM (30 mL x 3). The organic layer was purified by combi flash elution with a gradient of DCM:MeOH (1:0 to 10:1) to give the product (30 mg, 21%). 1 H NMR (500MHz, DMSO) δ 10.25 (s, 1H), 9.98 (s, 1H), 9.81 (d, J = 10.0Hz, 1H), 8.70 (s, 1H), 8.04-8.01 (m, 2H), 7.82 (s, 2H), 7.68 (s, 1H), 7.58 (d, J = 10.0Hz, 1H), 7.46 (dd, J = 5.0Hz, 1H), 7.13 (d, J = 10.0Hz, 2H), 6.93 (d, J = 10.0Hz, 2H), 5.32-5.30 (m, 1H), 3.71-3.68 (m, 4H), 3.14 (s, 4H), 2.69-2.66 (m, 4H), 2.53-2.52 (m, 3H), 2.46 (s, 3H), 2.23-2.22 (m, 2H), 1.82-1.72 (m, 3H), 1.50-1.48 (m, 6H), 1.26-1.16 (m, 5H), 0.99-0.98 (m, 2H); [M+H] + = 825.6.

[0130] Example 12: (R)—N-(1-(4-(6-((5-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidin-3-yl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazol-5-carboxamide The title compound TIFF2025501082000095.tif3667 was synthesized in the same manner as in Example 11. 1 H NMR (500MHz, DMSO) δ 10.23 (s, 1H), 9.99 (s, 1H), 9.81 (d, J = 7.8Hz, 1H), 8.70 (s, 1H), 8.04 (t, J = 7.1Hz, 2H), 7.82 (s, 2H), 7.69 (s, 1H), 7.60-7.55 (m, 1H), 7.46 (dd, J = 9.1, 2.9Hz, 1H), 7.12 (d, J = 8.7Hz, 2H), 6.45 (d, J = 8.7Hz, 2H), 5.31 (t, J = 7.3Hz, 1H), 3.95 (t, J = 7.1Hz, 2H), 3.69-3.60 (m, 4H), 3.16 (s, 4H), 2.68 (t, J = 6.7Hz, 2H), 2.55-2.50 (m, 5H), 2.46 (s, 3H), 1.51-1.46 (m, 6H), 1.19 (d, J = 2.6Hz, 2H), 0.98 (q, J = 4.3Hz, 2H); [M+H] + = 783.0.

[0131] Example 13: (R)-3-(tert-butyl)-N-(1-(4-(6-((6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0132] Step 1: tert-butyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate TIFF2025501082000096.tif1835To a stirred solution of 2-fluoro-5-nitropyridine (4 g, 28.15 mmol) and tert-butyl piperazine-1-carboxylate (5.77 g, 31.02 mmol) in THF (100 mL) was added DIEA (10.92 g, 84.45 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 35 °C under a nitrogen atmosphere for 3 h and cooled to ambient temperature. The resulting mixture was diluted with brine (100 mL) and the aqueous layer was extracted with EtOAc (3 x 100 mL). The resulting organic layer was dried over NaSO. The resulting mixture was concentrated under reduced pressure. The product (7.84 g, crude) was used directly in the next step without further purification. [M+H] + = 309.2.

[0133] Step 2: tert-butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate TIFF2025501082000097.tif1935To a stirred solution of tert-butyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate (7.8 g, 25.30 mmol) in AcOH (200 mL) was added Fe (14.13 g, 252.97 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 16 h and concentrated under reduced pressure. The residue was dissolved in water (100 mL), and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (10:1) to give the product (3 g, 43%). [M+H] + = 279.1.

[0134] Step 3: (R)-tert-butyl 4-(5-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyridin-2-yl)piperazine-1-carboxylate TIFF2025501082000098.tif4257 To a stirred solution of (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (compound obtained in a manner similar to that in Example 5) (1 g, 2.50 mmol) and tert-butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate (0.84 g, 3.00 mmol) in dioxane (20 mL) was added Pd(OAc) (0.06 g, 0.25 mmol), BINAP (0.31 g, 0.50 mmol), and CsCO (1.63 g, 5.00 mmol) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred overnight at 100°C under nitrogen atmosphere and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 1-60% EtOAc in petroleum ether to give the product (280 mg, 18%). [M+H] + = 642.0.

[0135] Step 4: (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride TIFF2025501082000099.tif4153 A mixture of (R)-tert-butyl 4-(5-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyridin-2-yl)piperazine-1-carboxylate (280 mg, 0.436 mmol) in 4 M HCl (3 mL) in DCM (10 mL) and 1,4-dioxane was stirred at ambient temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with EtO (40 mL) to give the product (204 mg, 81%). 1 H NMR (400MHz, DMSO) δ 11.75 (s, 1H), 9.98 (d, J = 7.6Hz, 1H), 9.54 (s, 2H), 8.87 (s, 1H), 8.51 (s, 1H), 8.02 (d, J = 8.8Hz, 1H), 7.79 (s, 2H), 7.70 (d, J = 8.0Hz, 1H), 7.41 (s, 1H), 7.16 (d, J = 9.2Hz, 1H), 5.36-5.32 (m, 1H), 3.84 (t, J = 5.2Hz, 4H), 3.20 (d, J = 7.2Hz, 4H), 2.50 (s, 3H), 1.52 (d, J = 7.2Hz, 3H), 1.37 (s, 9H); [M+H] + = 542.4.

[0136] Step 5: (R)-3-(tert-butyl)-N-(1-(4-(6-((6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide TIFF2025501082000100.tif3973 A mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide hydrochloride (0.05 g, 0.086 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (0.039 g, 0.129 mmol) in 1,2-dichloroethane (5 mL) and HOAc (5.2 mg) was stirred in a round-bottom flask at room temperature for 0.5 h. The mixture was added with NaBH(OAc)3 (0.046 g, 0.215 mmol) and stirred at room temperature for 3 hours. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (47.78 mg, 67%). 1 H NMR (500MHz, DMSO) δ 10.26 (s, 1H), 9.88 (d, J = 7.7Hz, 1H), 9.62 (s, 1H), 9.55 (s, 1H), 8.61 (s, 1H), 8.42 (s, 1H), 7.95 (s, 1H), 7.83 (d, J = 8.2Hz, 2H), 7.59 (d, J = 7.8Hz, 1H), 7.18-7.08 (m, 3H), 6.98 (dd, J = 22.6, 8.6Hz, 3H), 5.33 (t, J = 7.3Hz, 1H), 4.29 (d, J = 13.1Hz, 2H), 3.76-3.57 (m, 6H), 3.30-3.05 (m, 4H), 2.77-2.62 (m, 4H), 2.54 (s, 3H), 2.46 (s, 2H), 2.10-1.81 (m, 3H), 1.51 (d, J = 6.9Hz, 3H), 1.40-1.27 (m, 11H); [M+H] + = 827.7.

[0137] Example 14: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0138] Step 1: 5-Bromo-N,N-bis(4-methoxybenzyl)pyrimidin-2-amine TIFF2025501082000101.tif1626To a stirred mixture of 5-bromopyrimidin-2-amine (9.0 g, 51.72 mmol) in THF (180 mL) is added NaH (6.2 g, 155.17 mmol, 60% in mineral oil) portionwise at 0 °C under a nitrogen atmosphere. The resulting mixture is stirred at 0 °C for 1 h under a nitrogen atmosphere. PMBCl (24.3 g, 155.17 mmol) is added dropwise to the above mixture at 0 °C. The resulting mixture is stirred at 75 °C for an additional 16 h. The mixture is cooled to room temperature and quenched at 0 °C with saturated NH4Cl (aq). The resulting mixture is extracted with EtOAc (3 x 500 mL). The combined organic layers are washed with brine (3 x 400 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 3%-10% EtOAc in petroleum ether to give the product (8.6 g, 40%). [M+H] + = 414.0.

[0139] Step 2: tert-butyl 4-(2-(bis(4-methoxybenzyl)amino)pyrimidin-5-yl)piperazine-1-carboxylate TIFF2025501082000102.tif2237 To a stirred mixture of 5-bromo-N,N-bis(4-methoxybenzyl)pyrimidin-2-amine (8.6 g, 20.76 mmol) and tert-butyl piperazine-1-carboxylate (4.6 g, 24.91 mmol) in toluene (160 mL) was added t-BuONa (3.0 g, 31.14 mmol), BINAP (1.3 g, 2.08 mmol), and Pd2(dba)3 (0.95 g, 1.04 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16 h under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 10%-30% EtOAc in petroleum ether to give the product (10.4 g, 96%). [M+H] + = 520.3.

[0140] Step 3: 5-(piperazin-1-yl)pyrimidin-2-amine bis(2,2,2-trifluoroacetate) salt TIFF2025501082000103.tif3231 A solution of tert-butyl 4-(2-(bis(4-methoxybenzyl)amino)pyrimidin-5-yl)piperazine-1-carboxylate (10.4 g, 20.014 mmol) in TFA (100 mL) is stirred at 75 °C for 1 h. The mixture is cooled to room temperature and concentrated under reduced pressure. The residue is triturated with EtO (200 mL). The resulting mixture is filtered and the filter cake is washed with EtO (3 x 50 mL). The solid is dried under vacuum. This afforded the product (8.1 g, 99%). [M+H] + = 180.1.

[0141] Step 4: tert-Butyl 4-(2-aminopyrimidin-5-yl)piperazine-1-carboxylate TIFF2025501082000104.tif1933 To a stirred mixture of 5-(piperazin-1-yl)pyrimidin-2-amine bis(2,2,2-trifluoroacetate) salt (4.0 g, 9.821 mmol) and TEA (4.1 mL) in CHCl (80 mL) was added BocO (2.6 g, 12.04 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 4%-8% MeOH in DCM to give the product (2.0 g, 73%). [M+H] + = 280.2.

[0142] Step 5: (R)-tert-butyl 4-(2-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyrimidin-5-yl)piperazine-1-carboxylate To a stirred mixture of (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (800 mg, 2.00 mmol) and tert-butyl 4-(2-aminopyrimidin-5-yl)piperazine-1-carboxylate (670 mg, 2.40 mmol) in 1,4-dioxane (16 mL) was added CsCO (1.30 g, 4.00 mmol), XPhos (287 mg, 0.60 mmol), and XPhos Pd G (254 mg, 0.30 mmol) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 30% to 60% EtOAc in CH2Cl2 to give the product (800 mg, 62%). [M+H] + = 643.4.

[0143] Step 6: (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-((5-(piperazin-1-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000106.tif4151 To a stirred solution of (R)-tert-butyl 4-(2-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyrimidin-5-yl)piperazine-1-carboxylate (800 mg, 1.25 mmol) in CHCl (8 mL) at room temperature, 4 M HCl in 1,4-dioxane (8 mL) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was triturated with EtO (80 mL). The resulting mixture was filtered and the filter cake was washed with EtO (3 × 10 mL). The solid was dried under infrared light. This gave the product (643 mg, 89%). 1 H NMR (400MHz, DMSO) δ 11.51 (s, 1H), 9.98 (d, J = 7.6Hz, 1H), 9.50 (s, 2H), 8.96 (d, J = 2.8Hz, 1H), 8.65-8.56 (m, 3H), 7.91-7.84 (m, 2H), 7.68 (d, J = 8.1Hz, 1H), 5.38-5.30 (m, 1H), 3.51 (s, 4H), 3.24 (s, 4H), 2.51-2.50 (m, 3H), 1.53 (d, J = 7.0Hz, 3H), 1.37 (s, 9H); [M+H] + = 543.4.

[0144] Step 7: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000107.tif3972 A mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-((5-(piperazin-1-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (0.08 g, 0.138 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (0.063 g, 0.207 mmol) in 1,2-dichloroethane (6 mL) and HOAc (8.3 mg) was stirred at room temperature for 0.5 h in a round-bottom flask. The mixture was added with NaBH(OAc)3 (0.073 g, 0.345 mmol) and stirred at room temperature for 3 hours. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (63.71 mg, 56%). 1 H NMR (500MHz, DMSO) δ 10.26 (d, J = 9.0Hz, 2H), 9.90 (d, J = 7.7Hz, 1H), 8.75 (d, J = 0.9Hz, 1H), 8.66 (s, 1H), 8.46 (s, 2H), 7.88 (d, J = 9.1Hz, 2H), 7.61 (d, J = 8.0Hz, 1H), 7.13 (d, J = 8.9Hz, 2H), 6.93 (d, J = 9.0Hz, 2H), 5.37-5.29 (m, 1H), 3.69 (t, J = 6.7Hz, 4H), 3.19 (s, 4H), 2.71-2.61 (m, 4H), 2.53 (s, 3H), 2.48 (s, 4H), 2.23 (d, J = 6.7Hz, 2H), 1.78 (t, J = 24.7Hz, 3H), 1.52 (d, J = 7.0Hz, 3H), 1.36 (s, 9H), 1.28-1.15 (m, 3H); [M+H] + = 828.6.

[0145] Example 15: (R)-3-(tert-butyl)-N-(1-(4-(2-((6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridazin-3-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0146] Step 1: tert-Butyl 4-(6-chloropyridazin-3-yl)piperazine-1-carboxylate TIFF2025501082000108.tif2425To a stirred solution of 3,6-dichloropyridazine (5 g, 33.56 mmol) and tert-butyl piperazine-1-carboxylate (9.4 g, 50.35 mmol) in DMF (100 mL) was added TEA (10.2 g, 100.69 mmol) dropwise at room temperature. The resulting mixture was stirred at 80 °C for 16 h and diluted with water (500 mL). The resulting mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (2 x 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (8.1 g, 81%). [M+H] + = 299.1.

[0147] Step 2: tert-butyl 4-(6-((diphenylmethylene)amino)pyridazin-3-yl)piperazine-1-carboxylate TIFF2025501082000109.tif2435 To a stirred mixture of tert-butyl 4-(6-chloropyridazin-3-yl)piperazine-1-carboxylate (2 g, 6.69 mmol) and diphenylmethanimine (1.8 g, 10.04 mmol) in toluene (40.00 mL), Pd2(dba)3 (0.31 g, 0.34 mmol), BINAP (0.42 g, 0.67 mmol), and Cs2CO3 (4.36 g, 13.39 mmol) were added portionwise at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title product (1.4 g, 47%). [M+H] + = 444.2.

[0148] Step 3: tert-Butyl 4-(6-aminopyridazin-3-yl)piperazine-1-carboxylate TIFF2025501082000110.tif3117To a stirred mixture of tert-butyl 4-(6-((diphenylmethylene)amino)pyridazin-3-yl)piperazine-1-carboxylate (1.35 g, 3.04 mmol) and citric acid (13.5 mL, 70.27 mmol) in THF (20 mL) is added HO (13.5 mL) dropwise at room temperature. The resulting mixture is stirred overnight at room temperature and concentrated in vacuo. The residue is purified by silica gel column chromatography to give the title product (710 mg, 83%). [M+H] + = 280.2.

[0149] Step 4: (R)-tert-butyl 4-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyridazin-3-yl)piperazine-1-carboxylate TIFF2025501082000111.tif4257 To a stirred mixture of tert-butyl 4-(6-aminopyridazin-3-yl)piperazine-1-carboxylate (500 mg, 1.79 mmol) and (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (858.90 mg, 2.15 mmol) in dioxane (10 mL) was added XPhos (170.66 mg, 0.36 mmol), XPhos Pd G3 (151.51 mg, 0.18 mmol), and Cs2CO3 (1.17 g, 3.58 mmol) in small portions at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 100°C for 16 h and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title product (314 mg, 27%). [M+H] + = 643.2.

[0150] Step 5: (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-((6-(piperazin-1-yl)pyridazin-3-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000112.tif4050 A solution of (R)-tert-butyl 4-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyridazin-3-yl)piperazine-1-carboxylate (314 mg, 0.49 mmol) in DCM (6 mL) and HCl in 1,4-dioxane (6 mL) is stirred at room temperature for 1 h. The resulting mixture is concentrated in vacuo. The residue is triturated with EtO to give the title product (254 mg, 89%). [M+H] + = 543.3.

[0151] Step 6: (R)-3-(tert-butyl)-N-(1-(4-(2-((6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridazin-3-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide A mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-((6-(piperazin-1-yl)pyridazin-3-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (100 mg, 0.17 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (60 mg, 0.2 mmol), NaBH(OAc) (106 mg, 0.5 mmol), and NaOAc (82 mg, 1.0 mmol) in TIFF2025501082000113.tif5284DCE was stirred at room temperature for 16 h. The mixture was concentrated and purified by silica gel column chromatography to give the title product (50 mg, 36%). 1 H NMR (500MHz, DMSO) δ 10.24 (d, J = 5.3Hz, 2H), 9.89 (d, J = 7.8Hz, 1H), 8.72 (s, 1H), 8.05-7.79 (m, 4H), 7.62 (d, J = 8.6Hz, 1H), 7.40 (d, J = 9.9Hz, 1H), 7.13 (d, J = 8.7Hz, 2H), 6.93 (d, J = 8.9Hz, 2H), 5.39-5.29 (m, 1H), 3.74-3.64 (m, 4H), 3.52 (s, 4H), 2.71-2.61 (m, 4H), 2.51-2.44 (m, 7H), 2.23 (d, J = 7.1Hz, 2H), 1.82 (d, J = 11.7Hz, 2H), 1.78-1.68 (m, 1H), 1.51 (d, J = 6.9Hz, 3H), 1.36 (s, 9H), 1.30-1.26 (m, 2H); [M+H] + = 828.6.

[0152] Example 16: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound TIFF2025501082000114.tif4585 was synthesized in the same manner as in Example 15. 1 H NMR (500MHz, DMSO) δ 10.25 (s, 1H), 9.98 (s, 1H), 9.88 (d, J = 7.8Hz, 1H), 8.70 (s, 1H), 8.04 (d, J = 2.8Hz, 2H), 7.84 (d, J = 6.0Hz, 2H), 7.69 (s, 1H), 7.61 (d, J = 8.7Hz, 1H), 7.45 (dd, J = 9.1, 2.8Hz, 1H), 7.13 (d, J = 8.9Hz, 2H), 6.92 (d, J = 8.9Hz, 2H), 5.35-5.31 (m, 1H), 3.72-3.63 (m, 4H), 3.17-3.08 (m, 4H), 2.69-2.64 (m, 4H), 2.54-2.50 (m, 4H), 2.47 (s, 3H), 2.23 (d, J = 7.1Hz, 2H), 1.81 (d, J = 12.1Hz, 2H), 1.75-1.67 (m, 1H), 1.51 (d, J = 7.0Hz, 3H), 1.36 (s, 9H), 1.26-1.18 (m, 2H); [M+H] + = 827.6.

[0153] Example 17: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide The title compound TIFF2025501082000115.tif4788 was synthesized in the same manner as in Example 15. 1 H NMR (500MHz, DMSO) δ 10.32 (s, 1H), 9.98 (s, 1H), 9.87 (d, J = 5.0Hz, 1H), 8.70 (s, 1H), 8.04-8.02 (m, 2H), 7.84-7.83 (m, 2H), 7.68 (s, 1H), 7.61 (d, J = 5.0Hz, 1H), 7.45 (d, J = 5.0Hz, 1H), 7.14 (t, J = 10.0Hz, 2H), 6.37-6.32 (m, 2H), 5.36-5.30 (m, 1H), 3.59 (t, J = 5.0Hz, 2H), 3.43 (t, J = 5.0Hz, 1H), 3.24-3.19 (m, 1H), 3.14 (s, 4H), 2.88 (t, J = 10.0Hz, 1H), 2.68 (t, J = 5.0Hz, 1H), 2.55-2.54 (m, 3H), 2.47 (s, 3H), 2.43-2.40 (m, 2H), 2.31-2.28 (m, 1H), 2.16-2.13 (m, 1H), 1.67-1.61 (m, 3H), 1.51 (d, J = 5.0Hz, 3H), 1.36 (s, 9H), 1.27-1.19 (m, 2H); [M+H] + = 845.7.

[0154] Example 18: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide The title compound of TIFF2025501082000116.tif4474 was synthesized in the same manner as in Example 15. 1 H NMR (500MHz, DMSO) δ 10.23 (s, 1H), 9.98 (s, 1H), 9.88 (d, J = 7.8Hz, 1H), 8.70 (s, 1H), 8.04 (d, J = 2.7Hz, 2H), 7.83 (d, J = 5.9Hz, 2H), 7.68 (s, 1H), 7.61 (d, J = 8.7Hz, 1H), 7.45 (dd, J = 9.1, 2.8Hz, 1H), 7.04 (d, J = 8.6Hz, 1H), 6.81 (d, J = 2.3Hz, 1H), 6.77 (dd, J = 8.8, 2.4Hz, 1H), 5.33 (t, J = 7.2Hz, 1H), 3.72-3.63 (m, 3H), 3.46 (dt, J = 12.4, 6.2Hz, 1H), 3.14 (s, 4H), 2.75-2.62 (m, 4H), 2.55-2.50 (m, 4H), 2.47 (s, [M+H] + = 841.6.

[0155] Example 19: 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-(4-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)methyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide The title compound TIFF2025501082000117.tif4172 was synthesized in the same manner as in Example 15. 1 H NMR (500MHz, DMSO) δ 10.75 (s, 1H), 9.99 (s, 1H), 9.89 (d, J = 5.0Hz, 1H), 8.70 (s, 1H), 8.04-8.01 (m, 2H), 7.84-7.83 (m, 2H), 7.68 (s, 1H), 7.61 (d, J = 5.0Hz, 1H), 7.46 (dd, J = 5.0Hz, 10.0Hz, 1H), 7.00 (d, J = 10.0Hz, 2H), 6.39 (d, J = 10.0Hz, 2H), 5.36-5.32 (m, 1H), 3.94-3.91 (m, 2H), 3.71-3.68 (m, 1H), 3.47-3.44 (m, 2H), 3.13 (s, 4H), 2.97-2.94 (m, 1H), 2.64-2.60 (m, 3H), 2.56-2.54 (m, 4H), 2.47-2.43 (m, 4H), 2.12-1.98 (m, 2H), 1.52 (d, J = 5.0Hz, 3H), 1.36 (s, 9H); [M+H] + = 798.6.

[0156] Example 20: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(3-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)methyl)azetidin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0157] Step 1: (1-(6-nitropyridin-3-yl)azetidin-3-yl)methanol TIFF2025501082000118.tif1634 To a stirred solution of 5-bromo-2-nitropyridine (6 g, 29.557 mmol) and azetidin-3-ylmethanol hydrochloride (4.38 g, 35.468 mmol) in dioxane (200 mL), Pd2(dba)3 (2.71 g, 2.956 mmol), DavePhos (2.33 g, 5.911 mmol), and Cs2CO3 (19.26 g, 59.114 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluting with 1–60% EtOAc in PE to give the product (3.6 g, 58%). [M+H] + = 210.2.

[0158] Step 2: (1-(6-aminopyridin-3-yl)azetidin-3-yl)methanol TIFF2025501082000119.tif1534 To a solution of (1-(6-nitropyridin-3-yl)azetidin-3-yl)methanol (3.6 g, 17.208 mmol) in MeOH (40 mL) was added Pd / C (10%, 2 g). The mixture was hydrogenated using a hydrogen gas balloon at room temperature for 10 h, filtered through a pad of diatomaceous earth, and concentrated under reduced pressure to give the product (3 g, 97%). [M+H] + = 180.1.

[0159] Step 3: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(3-(hydroxymethyl)azetidin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide To a solution of (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (1.75 g, 9.753 mmol) and (1-(6-aminopyridin-3-yl)azetidin-3-yl)methanol in dioxane (100 mL) was added XPhos Pd G3 (0.64 g, 0.750 mmol), Cs2CO3 (4.89 g, 15.004 mmol), and XPhos (0.72 g, 1.500 mmol). After stirring overnight at 100 °C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 1-70% EtOAc in CH2Cl2 to give the product (1.001 g, 25%). 1 H NMR (400MHz, DMSO) δ 9.90-9.88 (m, 2H), 8.68 (s, 1H), 7.95 (s, 1H), 7.85-7.81 (m, 2H), 7.70-7.55 (m, 3H), 6.94 (dd, J = 8.9, 3.0Hz, 1H), 5.36-5.32 (m, 1H), 4.77 (t, J = 5.3Hz, 1H), 3.86 (t, J = 7.5Hz, 2H), 3.59 (q, J = 6.4Hz, 4H), 2.83-2.76 (m, 1H), 2.47 (s, 3H), 1.52 (d, J = 6.9Hz, 3H), 1.37 (s, 9H); [M+H] + = 543.2.

[0160] Step 4: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(3-formylazetidin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000121.tif4153 To a stirred solution of DMSO (60 mg, 0.774 mmol) in dichloromethane (10 mL) is added oxalyl chloride (2 N, 0.22 mL) in dichloromethane under a nitrogen atmosphere at −78° C. The resulting mixture is stirred for 0.5 h. (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(3-(hydroxymethyl)azetidin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (200 mg, 0.369 mmol) in dichloromethane (2 mL) is added at −78° C., and the mixture is stirred for 1 h. TEA (186 mg, 1.84 mmol) is added at -78 °C, and the mixture is stirred at 0 °C. The reaction is quenched with saturated NH4Cl (aq) at 0 °C. The resulting mixture is extracted with dichloromethane (3 x 15 mL). The combined organic layers are washed with brine (3 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate is concentrated under reduced pressure to give the product (180 mg, crude), which is used directly in the next step without further purification. [M+H] + = 541.2.

[0161] Step 5: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(3-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)methyl)azetidin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide TIFF2025501082000122.tif5072 A mixture of (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(3-formylazetidin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (0.10 g, 0.185 mmol) and 1-(4-(piperazin-1-yl)phenyl)-dihydropyrimidine-2,4(1H,3H)-dione (0.051 g, 0.185 mmol) in dichloromethane (10 mL) and HOAc (20 mg) was stirred at room temperature for 0.5 h in a round-bottom flask. The mixture was added with NaBH(OAc)3 (0.059 g, 0.277 mmol) and stirred at room temperature for 1 hour. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (66.82 mg, 45%). 1 H NMR (500MHz, DMSO) δ 10.26 (s, 1H), 9.91-9.85 (m, 2H), 8.67 (s, 1H), 7.94 (s, 1H), 7.82 (d, J = 5.5Hz, 2H), 7.68-7.57 (m, 3H), 7.15 (d, J = 8.9Hz, 2H), 6.95 (dd, J = 14.5, 5.9Hz, 3H), 5.33 (t, J = 7.3Hz, 1H), 3.97 (t, J = 7.4Hz, 2H), 3.70 (t, J = 6.7Hz, 2H), 3.52 (t, J = 6.4Hz, 2H), 3.13 (s, 4H), 3.04-2.96 (m, 1H), 2.71-2.62 (m, 4H), 2.54 (s, 4H), 2.47 (s, 3H), 1.50 (d, J = 7.9Hz, 3H), 1.36 (s, 9H); [M+H] + = 799.6.

[0162] Example 21: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide Step 1: 4-(1,3-dioxolan-2-yl)piperidine-1-carboxylate TIFF2025501082000123.tif2410 To a stirred solution of benzyl 4-formylpiperidine-1-carboxylate (15.0 g, 60.657 mmol) and ethylene glycol (15.1 g, 242.628 mmol) in toluene (300 mL) was added TsOH (1.0 g, 6.06 mmol) at room temperature. The resulting mixture was stirred at 110 °C for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. Water (300 mL) was added to the resulting mixture and extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (10% to 30%) to give the product (15.9 g, 90%). [M+H] + = 292.1.

[0163] Step 2: 4-(1,3-Dioxolan-2-yl)piperidine TIFF2025501082000124.tif2311To a solution of 4-(1,3-dioxolan-2-yl)piperidine-1-carboxylate (10.8 g, 37.069 mmol) in 200 mL MeOH in a 500 mL round-bottom flask under a nitrogen atmosphere, Pd / C (10%, 10 g) was added. The mixture was hydrogenated under a hydrogen atmosphere using a hydrogen gas balloon at room temperature for 16 h, filtered through a pad of diatomaceous earth, and concentrated under reduced pressure to give the product (5.5 g, 94%). [M+H] + = 158.1.

[0164] Step 3: 5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-2-nitropyridine To a stirred mixture of 5-bromo-2-nitropyridine (4.5 g, 22.168 mmol) and 4-(1,3-dioxolan-2-yl)piperidine (4.2 g, 26.602 mmol) in dioxane (90 mL), XPhos Pd G3 (1.9 g, 2.217 mmol), XPhos (2.1 g, 4.434 mmol), and Cs2CO3 (14.4 g, 44.336 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc (20% to 60%) in PE to give the product (3.1 g, 50%). [M+H] + = 280.1.

[0165] Step 4: 5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)pyridin-2-amine TIFF2025501082000126.tif2337To a solution of 5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)-2-nitropyridine (3.1 g, 11.099 mmol) in 60 mL MeOH in a 100 mL round-bottom flask under a nitrogen atmosphere, Pd / C (10%, 3 g) was added. The mixture was hydrogenated under a hydrogen atmosphere using a hydrogen gas balloon at room temperature for 16 h, filtered through a pad of diatomaceous earth, and concentrated under reduced pressure to give the product (2.5 g, 90%). [M+H] + = 250.1.

[0166] Step 5: (R)—N-(1-(4-(6-((5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000127.tif4158 To a stirred mixture of (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (2.0 g, 5.002 mmol) and 5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)pyridin-2-amine (1.5 g, 6.002 mmol) in dioxane (40 mL) was added XPhos Pd G3 (635 mg, 0.750 mmol), XPhos (715 mg, 1.501 mmol), and Cs2CO3 (3.3 g, 10.004 mmol) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc (30% to 70%) in DCM to give the product (1.5 g, 48%). 1 H NMR (400MHz, CDCl3) δ 8.82 (s, 1H), 8.05 (d, J = 3.0Hz, 1H), 7.93-7.87 (m, 2H), 7.82 (s, 1H), 7.56-7.50 (m, 2H), 7.37 (dd, J = 9.0, 3.0Hz, 1H), 7.26 (d, J = 8.0Hz, 1H), 5.56-5.52 (m, 1H), 4.73 (d, J = 4.9Hz, 1H), 4.05-3.85 (m, 4H), 3.72-3.64 (m, 2H), 2.75 (td, J = 12.0, 2.6Hz, 2H), 2.53 (s, 3H), 1.92 (d, J = 12.3Hz, 2H), 1.76-1.55 (m, 7H), 1.41 (s, 9H); [M+H] + = 613.4.

[0167] Step 6: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-formylpiperidin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000128.tif4153 To a stirred solution of (R)-N-(1-(4-(6-((5-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamide (450 mg, 0.734 mmol) in dioxane (5 mL) is added concentrated HCl (3 mL) at room temperature. The resulting mixture is stirred for 3 hours. The reaction is quenched with NaHCO3 (aq) at 0°C to pH = 7. The mixture is lyophilized to give the product (400 mg, crude), which is used directly in the next step without further purification. [M+H] + = 569.2.

[0168] Step 7: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide TIFF2025501082000129.tif4373 A mixture of (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-formylpiperidin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (0.10 g, 0.176 mmol) and 1-(4-(piperazin-1-yl)phenyl)-dihydropyrimidine-2,4(1H,3H)-dione (0.06 g, 0.211 mmol) in 1,2-dichloroethane (5 mL) and HOAc (25 mg) was stirred at room temperature for 0.5 h in a round-bottom flask. The mixture was added with NaBH(OAc)3 (0.056 g, 0.264 mmol) and stirred at room temperature for 12 hours. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (62.9 mg, 43%). 1H NMR (500MHz, DMSO) δ 10.26 (s, 1H), 9.97 (s, 1H), 9.88 (d, J = 7.8Hz, 1H), 8.70 (d, J = 0.8Hz, 1H), 8.03 (t, J = 5.6Hz, 2H), 7.83 (d, J = 5.8Hz, 2H), 7.67 (s, 1H), 7.60 (d, J = 8.7Hz, 1H), 7.44 (dd, J = 9.2, 2.9Hz, 1H), 7.15 (d, J = 8.9Hz, 2H), 6.93 (d, J = 9.1Hz, 2H), 5.37-5.28 (m, 1H), 3.73-3.60 (m, 4H), 3.14 (s, 4H), 2.67 (dd, J = 16.0, 9.2Hz, 4H), 2.55-2.45 (m, 7H), 2.23 (d, J = 7.2Hz, 2H), 1.83 (d, J = 12.0Hz, 2H), 1.75-1.65 (m, 1H), 1.51 (d, J = 7.0Hz, 3H), 1.36 (s, 9H), 1.27 (t, J = 10.6Hz, 2H); [M+H] + = 827.6.

[0169] Example 22: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidin-3-yl)methyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0170] Step 1: 4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyl trifluoromethanesulfonate To a solution of 1-(4-hydroxyphenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (compound obtained in the same manner as in WO2021219070A) (500 mg, 1.49 mmol) in DCM, pyridine (235 mg, 2.98 mmol) was added. TfO (630 mg, 2.24 mmol) was then added dropwise at 0°C to 5°C. The mixture was stirred at 0°C to RT and then at RT for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (100%:0% to 50%:50%) to give the product (644 mg, 92%). [M+H] + = 469.5.

[0171] Step 2: 1-(4-(3-(hydroxymethyl)azetidin-1-yl)phenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione A mixture of 4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyl trifluoromethanesulfonic acid (100 mg, 0.213 mmol), azetidin-3-ylmethanol hydrochloride (39 mg, 0.320 mmol), Pd(dba) (19.5 mg, 0.0213 mmol), RuPhos (20 mg, 0.0426 mmol), and CsCO (138 mg, 0.426 mmol) in dioxane (10 mL) is stirred overnight at 100 °C under nitrogen. After completion of the reaction by LCMS, the mixture is cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (100%:0% to 50%:50%) to give the product (67 mg, 78%). [M+H] + = 407.4.

[0172] Step 3: 1-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbaldehyde TIFF2025501082000132.tif3915To a solution of 1-(4-(3-(hydroxymethyl)azetidin-1-yl)phenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (132 mg, 0.325 mmol) in DMSO (10 mL) was added IBX (114 mg, 0.406 mmol). The mixture was stirred at room temperature overnight. The resulting mixture was extracted with EA (50 mL*3), washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to give the product (140 mg, crude). [M+H] + =405.5.

[0173] Step 4: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyl)azetidin-3-yl)methyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000133.tif4473 A mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (the compound obtained in a manner similar to that in Example 21) (201 mg, 0.373 mmol), 1-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbaldehyde (150 mg, 0.37 mmol) in dichloromethane (20 mL) and MeOH (5 mL) was stirred at room temperature for 5 minutes. Then, HOAc (0.06 mL) was added. The mixture was stirred overnight at room temperature. Then, NaBH(OAc)3 (157 mg, 0.74 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (DCM:MeOH = 100%:0% to 90%:10% gradient elution) to give the product (140 mg, crude). [M+H] + = 929.4.

[0174] Step 5: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidin-3-yl)methyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide TIFF2025501082000134.tif4171 To a solution of (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyl)azetidin-3-yl)methyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (140 mg, crude) in dichloromethane (5 mL) is added TFA (5 mL). The mixture is stirred at room temperature overnight. The reaction mixture is concentrated in vacuo, and the residue is diluted with MeOH (5 mL). NH3·H2O (0.5 mL) was added dropwise, and the mixture was stirred at room temperature for 0.5 h. The mixture was then concentrated in vacuo, and the residue was purified by preparative TLC (DCM:MeOH = 10:1) to give the desired product (118 mg, 98%). 1 H NMR (500MHz, DMSO) δ 10.23 (s, 1H), 9.99 (s, 1H), 9.89 (d, J = 5.0Hz, 1H), 8.70 (s, 1H), 8.04-8.01 (m, 2H), 7.84-7.83 (m, 2H), 7.68 (s, 1H), 7.61 (d, J = 5.0Hz, 1H), 7.46 (d, J = 5.0Hz, 1H), 7.10 (d, J = 10.0Hz, 2H), 6.42 (d, J = 10.0Hz, 2H), 5.36-5.32 (m, 1H), 3.96-3.93 (m, 2H), 3.68-3.65 (m, 2H), 3.49-3.46 (m, 2H), 3.13 (s, 4H), 2.98-2.95 (m, 1H), 2.67-2.63 (m, 4H), 2.56-2.54 (m, 4H), 2.47 (s, 3H), 1.52 (d, J = 5.0Hz, 3H), 1.36 (s, 9H); [M+H] + = 799.6.

[0175] Example 23: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)azetidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0176] Step 1: tert-butyl 3-(6-((6-chloropyrimidin-4-yl)amino)pyridin-3-yl)azetidine-1-carboxylate To a stirred mixture of 4,6-dichloropyrimidine (0.594 g, 4.01 mmol) and tert-butyl 3-(6-aminopyridin-3-yl)azetidine-1-carboxylate (1 g, 4.01 mmol) in dioxane (20 mL), Pd(dba) (201 mg, 0.22 mmol), XantPhos (255 mg, 0.44 mmol), and NaCO (0.723 g, 6.82 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc (30% to 70%) in DCM to give the product (0.29 g, 20%). [M+H] + = 362.1.

[0177] Step 2: (R)-tert-butyl 3-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)azetidine-1-carboxylate TIFF2025501082000136.tif3840 tert-Butyl 3-(6-((6-chloropyrimidin-4-yl)amino)pyridin-3-yl)azetidine-1-carboxylate (0.29 g, 0.8 mmol) and (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(4,4,5,5-tetramethyl)-2-methyl-4-methyl ...2-methyl-4-methyl-2-methyl-2-methyl-4-methyl-2-methyl-2-methyl-4-methyl-2-methyl-2-methyl-4-methyl-2-methyl-2-methyl-4-methyl-2-methyl-2-methyl-4-methyl-2-methyl-2 To a stirred mixture of (1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (compound obtained by the same method as in WO2021219070A) (0.365 g, 0.88 mmol), Pd(dppf)Cl2 (33 mg, 0.04 mmol) and K2CO3 (0.221 g, 1.6 mmol) were added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 15 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc (30% to 70%) in DCM to give the product (0.3 g, 61%). [M+H] + = 613.3.

[0178] Step 3: (R)—N-(1-(4-(6-((5-(azetidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide To a stirred solution of (R)-tert-butyl 3-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)azetidine-1-carboxylate (150 mg, 0.245 mmol) in DCM (5 mL) is added TFA (4 mL) at room temperature. The resulting solution is stirred at room temperature for 1 h and concentrated in vacuo. The residue (150 mg, crude) is used directly in the next step without further purification. [M+H] + = 513.2.

[0179] Step 4: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)azetidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000138.tif4773 A mixture of (R)-N-(1-(4-(6-((5-(azetidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamide (0.05 g, 0.098 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (0.038 g, 0.12 mmol) in 1,2-dichloroethane (3 mL) and HOAc (25 mg) was stirred at room temperature for 0.5 h in a round-bottom flask. The mixture was added with NaBH(OAc)3 (0.032 g, 0.15 mmol) and stirred at room temperature for 1 hour. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (43.57 mg, 56%). 1H NMR (500MHz, DMSO) δ 10.24 (d, J = 13.6Hz, 2H), 9.89 (d, J = 7.7Hz, 1H), 8.76 (s, 1H), 8.31 (s, 1H), 8.17 (d, J = 6.2Hz, 2H), 7.82 (dt, J = 31.6, 7.5Hz, 4H), 7.62 (d, J = 8.5Hz, 1H), 7.13 (d, J = 8.7Hz, 2H), 6.92 (d, J = 8.8Hz, 2H), 5.34 (t, J = 7.2Hz, 1H), 3.73-3.57 (m, 7H), 3.19 (s, 2H), 2.71-2.59 (m, 4H), 2.48 (s, 3H), 2.44 (d, J = 6.5Hz, 2H), 1.79 (d, J = 12.1Hz, 2H), 1.55-1.45 (m, 4H), 1.36 (s, 9H), 1.30-1.17 (m, 2H); [M+H] + = 798.7.

[0180] Example 24: 3-(tert-butyl)-N-((R)-1-(4-(6-((5-(4-(((S)-1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidin-3-yl)methyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide The title compound of TIFF2025501082000139.tif3877 was synthesized in the same manner as in Example 22. 1H NMR (500MHz, DMSO) δ 10.20 (s, 1H), 9.99 (s, 1H), 9.88 (d, J = 5.0Hz, 1H), 8.70 (s, 1H), 8.05-8.03 (m, 2H), 7.84-7.83 (m, 2H), 7.69 (s, 1H), 7.61 (d, J = 10.0Hz, 1H), 7.46 (dd, J = 10.0Hz, 5.0Hz, 1H), 7.09 (d, J = 10.0Hz, 2H), 6.51 (d, J = 10.0Hz, 2H), 5.35-5.32 (m, 1H), 3.66 (t, J = 5.0Hz, 2H), 3.40-3.36 (m, 2H), 3.30-3.29 (m, 1H), 3.15 (s, 4H), 3.02-2.98 (m, 1H), 2.69-2.66 (m, 2H), 2.64-2.54 (m, 4H), 2.47 (s, 3H), 2.43-2.39 (m, 2H), 2.15-2.11 (m, 1H), 1.76-1.72 (m, 1H), 1.52 (d, J = 5.0Hz, 3H), 1.36 (s, 9H); [M+H] + = 813.1.

[0181] Example 25: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbonyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide

[0182] Step 1: tert-butyl 1-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carboxylate A mixture of 4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyl trifluoromethanesulfonic acid (468 mg, 1.0 mmol), tert-butyl azetidine-3-carboxylate hydrochloride (188 mg, 1.2 mmol), Pd(dba) (92 mg, 0.1 mmol), RuPhos (93.4 mg, 0.2 mmol), and CsCO (652 mg, 2.0 mmol) in dioxane (50 mL) is stirred under nitrogen at 90 °C overnight. After completion of the reaction by LCMS, the mixture is cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (100%:0% to 50%:50%) to give the product (460 mg, 97%). [M+H] + = 476.2.

[0183] Step 2: 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carboxylic acid TIFF2025501082000141.tif4215 To a solution of tert-butyl 1-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carboxylate (460 mg, 0.97 mmol) in dichloromethane (10 mL) is added TFA (10 mL). The mixture is stirred at room temperature overnight. The reaction mixture is concentrated in vacuo, and the residue is diluted with MeOH (20 mL). NH3·H2O (0.5 mL) is added dropwise, and the mixture is stirred at room temperature for 0.5 h. The mixture is then concentrated in vacuo to give the desired product (260 mg, 93%). [M+H] + = 290.1.

[0184] Step 3: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbonyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide To a solution of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (35 mg, 0.065 mmol) in DMF (6 mL) was added 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carboxylic acid (23 mg, 0.078 mmol), HATU (37 mg, 0.0975 mmol), and DIEA (0.5 mL). The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was added with HO (30 mL) and extracted with DCM (30 mL × 3). The organic layer was purified by combi flash and eluted with a gradient of DCM:MeOH (1:0 to 10:1) to give the product (21 mg, 40%). 1H NMR (500MHz, DMSO) δ 10.23 (s, 1H), 10.03 (s, 1H), 9.89 (s, 1H), 8.71 (s, 1H), 8.08-8.04 (m, 2H), 7.84-7.83 (m, 2H), 7.72 (s, 1H), 7.61 (d, J = 10.0Hz, 1H), 7.51 (dd, J = 5.0Hz, 10.0Hz, 1H), 7.12 (d, J = 10.0Hz, 2H), 6.46 (d, J = 10.0Hz, 2H), 5.35-5.31 (m, 1H), 4.06- 4.04 (m, 2H), 3.93-3.89 (m, 3H), 3.68-3.66 (m, 4H), 3.51 (s, 2H), 3.16-3.12 (m, 4H), 2.69-2.66 (m, 2H), 2.47 (s, 3H), 1.52 (d, J = 5.0Hz, 3H), 1.36 (s, 9H); [M+H] + = 813.7.

[0185] Example 26: 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidine-3-carbonyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound TIFF2025501082000143.tif4274 was synthesized in the same manner as in Example 25. 1H NMR (500MHz, DMSO) δ 10.75 (s, 1H), 10.03 (s, 1H), 9.89 (d, J = 5.0Hz, 1H), 8.71 (s, 1H), 8.08 (d, J = 5.0Hz, 1H), 8.04 (s, 1H), 7.84-7.83 (m, 2H), 7.72 (s, 1H), 7.61 (d, J = 10.0Hz, 1H), 7.50 (dd, J = 10.0Hz, 5.0Hz, 1H), 7.02 (d, J = 10.0Hz, 2H), 6.43 (d, J = 10.0Hz, 2H), 5.35-5.31 (m, 1H), 4.03 (s, 2H), 3.89 (s, 2H), 3.72-3.64 (m, 3H), 3.52-3.51 (m, 2H), 3.16-3.11 (m, 4H), 2.66-2.60 (m, 1H), 2.47 (s, 3H), 2.45-2.43 (m, 2H), 2.15-1.97 (m, 2H), 1.52 (d, J = 5.0Hz, 3H), 1.36 (s, 9H); [M+H] + = 812.7.

[0186] Example 27: 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound TIFF2025501082000144.tif4171 was synthesized in the same manner as in Example 25. 1H NMR (500MHz, DMSO) δ 10.85 (s, 1H), 10.03 (s, 1H), 9.89 (s, 1H), 8.71 (s, 1H), 8.08 (d, J = 5.0Hz, 1H), 8.04 (s, 1H), 7.84-7.83 (m, 2H), 7.72 (s, 1H), 7.61 (d, J = 10.0Hz, 1H), 7.50 (dd, J = 10.0Hz, 5.0Hz, 1H), 6.17 (d, J = 10.0Hz, 2H), 5.36-5.31 (m, 1H), 4.08-3.89 (m, 6H), 3.66 (s, 2H), 3.49 (s, 2H), 3.15-3.12 (m, 4H), 2.78-2.74 (m, 1H), 2.49-2.47 (m, 4H), 2.09-2.04 (m, 1H), 1.96-1.93 (m, 1H), 1.52 (d, J = 5.0Hz, 3H), 1.36 (s, 9H); [M+H] + = 848.5.

[0187] Example 28: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbonyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide The title compound TIFF2025501082000145.tif4375 was synthesized in the same manner as in Example 25. 1H NMR (500MHz, DMSO) δ 10.26 (s, 1H), 10.03 (s, 1H), 9.89 (d, J = 5.0Hz, 1H), 8.71 (s, 1H), 8.08 (d, J = 5.0Hz, 1H), 8.04 (s, 1H), 7.84-7.83 (m, 2H), 7.72 (s, 1H), 7.61 (d, J = 10.0Hz, 1H), 7.50 (dd, J = 10.0Hz, 5.0Hz, 1H), 7.14 (d, J = 10.0Hz, 2H), 6.94 (d, J = 10.0Hz, 2H), 5.35-5.32 (m, 1H), 3.71-3.64 (m, 8H), 3.61-3.10 (m, 4H), 2.87 (s, 1H), 2.80-2.67 (m, 4H), 2.47 (s, 3H), 1.72-1.70 (m, 4H), 1.52 (d, J = 5.0Hz, 3H), 1.36 (s, 9H); [M+H] + = 841.0.

[0188] Example 29: 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide The title compound TIFF2025501082000146.tif3678 was synthesized in the same manner as in Example 25. 1H NMR (500MHz, DMSO) δ 10.21 (s, 1H), 10.03 (s, 1H), 9.89 (d, J = 5.0Hz, 1H), 8.71 (s, 1H), 8.09 (d, J = 5.0Hz, 1H), 8.04 (s, 1H), 7.84-7.83 (m, 2H), 7.72 (s, 1H), 7.61 (d, J = 10.0Hz, 1H), 7.51 (dd, J = 10.0Hz, 5.0Hz, 1H), 7.10 (d, J = 10.0Hz, 2H), 6.55 (d, J = 10.0Hz, 2H), 5.35-5.31 (m, 1H), 3.75 (s, 2H), 3.67-3.59 (m, 5H), 3.51-3.47 (m, 1H), 3.39-3.33 (m, 2H), 3.29-3.26 (m, 1H), 3.21-3.18 (m, 2H), 3.13-3.11 (m, 2H), 2.69-2.66 (m, 2H), 2.47 (s, 3H), 2.21-2.12 (m, 2H), 1.52 (d, J = 5.0Hz, 3H), 1.36 (s, 9H); [M+H] + = 827.7.

[0189] Example 30: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(6-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound TIFF2025501082000147.tif4977 was synthesized in the same manner as in Example 25. 1H NMR (400MHz, DMSO) δ 10.27 (s, 1H), 9.94-9.88 (m, 2H), 8.67 (s, 1H), 7.95 (s, 1H), 7.82 (s, 2H), 7.60 (d, J = 8.4Hz, 3H), 7.12 (d, J = 8.9Hz, 2H), 6.97-6.88 (m, 3H), 5.33 (t, J = 7.3Hz, 1H), 3.89 (s, 4H), 3.72-3.61 (m, 4H), 3.29 (s, 4H), 2.70-2.55 (m, 4H), 2.47 (s, 3H), 2.28 (d, J = 6.5Hz, [M+H] + = 839.6.

[0190] Example 31: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(2-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2,8-diazaspiro[4.5]decan-8-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0191] Step 1: tert-Butyl 8-(6-nitropyridin-3-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate To a stirred mixture of 5-bromo-2-nitropyridine (2.1 g, 10.345 mmol) and tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (2.98 g, 12.414 mmol) in dioxane (40 mL), XPhos Pd G3 (876 mg, 1.035 mmol), XPhos (986 mg, 2.069 mmol), and Cs2CO3 (6.74 g, 20.690 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 16 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc (0-50%) in PE to give the product (2.93 g, 63%). [M+H] + = 363.0.

[0192] Step 2: tert-Butyl 8-(6-aminopyridin-3-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate TIFF2025501082000149.tif2435To a solution of tert-butyl 8-(6-nitropyridin-3-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (2.9 g, 8.002 mmol) in 60 mL of MeOH, Pd / C (10 wt%, 2.9 g) was added at room temperature under a nitrogen atmosphere. The reaction was degassed under vacuum and purged with H2 multiple times. The reaction was then hydrogenated under a H2 gas balloon (2 atm) at 25 °C for 16 h. The reaction progress was monitored by TLC and LCMS. Upon completion of the reaction, the Pd / C was filtered through diatomaceous earth and the filter cake was washed with MeOH (3 x 20 mL). The filtrate was concentrated under reduced pressure to give the product (2.44 g, 92%). [M+H] + = 333.1.

[0193] Step 3: (R)-tert-butyl 8-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate TIFF2025501082000150.tif4263 To a stirred mixture of (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (1.5 g, 3.751 mmol) and tert-butyl 8-(6-aminopyridin-3-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (1.5 g, 4.501 mmol) in dioxane (30 mL) was added XPhos (537 mg, 1.125 mmol), CsCO (2.44 g, 7.502 mmol), and XPhos Pd G (476 mg, 0.563 mmol) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 100 °C for 16 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc (20% to 70%) in DCM to give the product (1.1 g, 43%). [M+H] + = 696.0.

[0194] Step 4: (R)—N-(1-(4-(6-((5-(2,8-diazaspiro[4.5]decan-8-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride TIFF2025501082000151.tif4158To a stirred solution of (R)-tert-butyl 8-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (1.1 g, 1.581 mmol) in DCM (10 mL) is added dropwise at room temperature HCl in 1,4-dioxane (10 mL). The resulting mixture is stirred at room temperature for 1 h and concentrated under reduced pressure. EtO (80 mL) is added to the residue and stirred at room temperature for 1 h. The resulting mixture is filtered and the filter cake is washed with EtO (3 x 10 mL). The solid is dried under infrared light. This gave the product (926.2 mg, 93%).1 H NMR (400MHz, DMSO) δ 11.71 (s, 1H), 9.96 (d, J = 7.6Hz, 1H), 9.42 (brs, 2H), 8.94 (s, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7.91-7.81 (m, 3H), 7.69-7.65 (m, 2H), 5.34 (t, J = 7.2Hz, 1H), 3.33-3.20 (m, 6H), 3.05 (t, J = 6.0Hz, 2H), 2.52 (s, 3H), 1.86 (t, J = 8.4Hz, 2H), 1.80-1.70 (m, 4H), 1.53 (d, J = 7.2Hz, 3H), 1.37 (s, 9H); [M+H] + = 596.5.

[0195] Step 5: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(2-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2,8-diazaspiro[4.5]decan-8-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000152.tif3481 A mixture of (R)-N-(1-(4-(6-((5-(2,8-diazaspiro[4.5]decan-8-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride (0.10 g, 0.158 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (0.058 g, 0.19 mmol) in 1,2-dichloroethane (5 mL) and HOAc (25 mg) was stirred at room temperature for 0.5 h in a round-bottom flask. The mixture was added with NaBH(OAc)3 (0.051 g, 0.237 mmol) and stirred at room temperature for 12 hours. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (61.34 mg, 44%). 1 H NMR (400MHz, DMSO) δ 10.27 (s, 1H), 9.99 (s, 1H), 9.91 (d, J = 7.7Hz, 1H), 8.70 (s, 1H), 8.03 (t, J = 6.2Hz, 2H), 7.83 (d, J = 6.1Hz, 2H), 7.67 (s, 1H), 7.60 (d, J = 8.7Hz, 1H), 7.45 (dd, J = 9.0, 2.8Hz, 1H), 7.12 (d, J = 8.8Hz, 2H), 6.92 (d, J = 8.9Hz, 2H), 5.33 (t, J = 7.2Hz, 1H), 3.68 (dd, J = 13.8, 7.2Hz, 4H), 3.19-3.03 (m, 4H), 2.70-2.59 (m, 4H), 2.55-2.45 (m, 5H), 2.37 (s, 2H), 2.27 (d, J = 7.2Hz, 2H), 1.80 (d, J = 11.3Hz, 2H), 1.71-1.56 (m, 7H), 1.51 (d, J=7.0Hz, 3H), 1.36 (s, 9H), 1.28-1.13 (m, 2H); + = 881.7.

[0196] Example 32: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(2-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound TIFF2025501082000153.tif4077 was synthesized in the same manner as in Example 31. 1 H NMR (500MHz, DMSO) δ 10.25 (s, 1H), 9.97 (s, 1H), 9.88 (d, J = 7.8Hz, 1H), 8.69 (d, J = 0.8Hz, 1H), 8.03 (t, J = 6.1Hz, 2H), 7.83 (d, J = 6.5Hz, 2H), 7.67 (s, 1H), 7.60 (d, J = 8.7Hz, 1H), 7.44 (dd, J = 9.1, 3.0Hz, 1H), 7.12 (d, J = 8.9Hz, 2H), 6.91 (d, J = 9.1Hz, 2H), 5.33 (s, 1H), 3.72-3.60 (m, 4H), 3.07 (s, 4H), 2.98 (s, 4H), 2.67 (t, J = 6.7Hz, 2H), 2.62 (d, J = 12.9Hz, 2H), 2.47 (s, 3H), 2.34 (d, J = 6.5Hz, 2H), 1.85-1.75 (m, 6H), 1.51 (d, J = 7.0Hz, 3H), 1.36 (s, 10H), 1.26-1.15 (m, 2H); [M+H] + = 867.6.

[0197] Example 33: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(7-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0198] Step 1: tert-Butyl 2-(6-nitropyridin-3-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate To a stirred solution of 5-bromo-2-nitropyridine (2.1 g, 10.345 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (2.8 g, 12.414 mmol) in dioxane (40 mL), CsCO (6.7 g, 20.690 mmol), XPhos Pd G (0.9 g, 1.035 mmol), and XPhos (1.0 g, 2.069 mmol) were added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc (20% to 50%) in PE to give the product (2.5 g, 69%). [M+H] + = 349.2.

[0199] Step 2: tert-Butyl 2-(6-aminopyridin-3-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate TIFF2025501082000155.tif20372To a solution of tert-butyl 2-(6-nitropyridin-3-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (2.5 g, 7.176 mmol) in 50 mL MeOH in a 50 mL round-bottom flask, under a nitrogen atmosphere, was added Pd / C (10%, 3 g). The mixture was hydrogenated under a hydrogen atmosphere using a hydrogen gas balloon at room temperature overnight, filtered through a pad of diatomaceous earth, and concentrated under reduced pressure to give the product (1.9 g, 83%). [M+H] + = 319.2.

[0200] Step 3: (R)-tert-butyl 2-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate TIFF2025501082000156.tif4161 To a stirred solution of 2-(6-aminopyridin-3-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (1.4 g, 4.501 mmol) and (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (1.5 g, 3.751 mmol) in dioxane (30 mL) was added CsCO (2.4 g, 7.502 mmol), XPhos Pd G (0.3 g, 0.375 mmol), and XPhos (0.3 g, 0.750 mmol) in small portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred under nitrogen atmosphere at 100°C overnight and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc to give the product (1.6g, 62%). [M+H] + = 682.3.

[0201] Step 4: (R)—N-(1-(4-(6-((5-(2,7-diazaspiro[3.5]nonan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide To a stirred solution of (R)-tert-butyl 2-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (1.5 g, 2.200 mmol) in DCM (32 mL) was added TFA (8 mL) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: Column: Spherical C18, 20-40 μm, 330 g; Mobile phase A: water (with 10 mM NH4HCO3); Mobile phase B: ACN; Flow rate: 100 mL / min; Gradient: 5% to 5% B in 10 min, 33% B to 45% B in 20 min; Detector: 220 nm. Fractions containing the desired product were collected in 35% B and concentrated under reduced pressure to give the product (0.95 g, 74%). 1 H NMR (400MHz, DMSO) δ 9.87-9.85 (m, 2H), 8.67 (s, 1H), 7.94 (s, 1H), 7.87-7.75 (m, 2H), 7.71-7.50 (m, 3H), 6.95 (dd, J = 8.9, 3.0Hz, 1H), 5.36-5.32 (m, 1H), 3.58 (s, 4H), 2.71-2.68 (m, 4H), 2.47 (s, 3H), 2.31 (s, 1H), 1.71-1.67 (m, 4H), 1.52 (d, J = 7.0Hz, 3H), 1.37 (s, 9H); [M+H] + = 582.5.

[0202] Step 5: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(7-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000158.tif4279 In a round-bottom flask, a mixture of (R)-N-(1-(4-(6-((5-(2,7-diazaspiro[3.5]nonan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide (0.10 g, 0.172 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (0.062 g, 0.206 mmol) in 1,2-dichloroethane (5 mL) and HOAc (25 mg) was stirred at room temperature for 0.5 h. The mixture was added with NaBH(OAc)3 (0.055 g, 0.258 mmol) and stirred at room temperature for 12 hours. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (88.07 mg, 59%). 1H NMR (400MHz, DMSO) δ 10.27 (s, 1H), 9.90 (d, J = 4.3Hz, 2H), 8.67 (s, 1H), 8.17 (s, 1H), 7.94 (s, 1H), 7.81 (s, 2H), 7.60 (d, J = 8.9Hz, 3H), 7.13 (d, J = 8.7Hz, 2H), 6.93 (t, J = 10.3Hz, 3H), 5.33 (t, J = 7.3Hz, 1H), 3.68 (dd, J = 13.1, 6.7Hz, 5H), 3.57 (s, 4H), 2.71-2.59 (m, 4H), 2.47 (s, 3H), 2.33 (s, 3H), 2.15 (d, J = 6.6Hz, 2H), 1.80-1.62 (m, 7H), 1.51 (d, J = 6.9Hz, 3H), 1.36 (s, 9H), 1.26-1.12 (m, 2H); [M+H] + = 867.6.

[0203] Example 34: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(9-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0204] Step 1: tert-Butyl 9-(6-nitropyridin-3-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate To a stirred mixture of 5-bromo-2-nitropyridine (2.5 g, 12.316 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (3.7 g, 14.779 mmol) in dioxane (50 mL), XPhos (1.2 g, 2.463 mmol), XPhos Pd G3 (1.1 g, 1.232 mmol), and Cs2CO3 (8.0 g, 24.632 mmol) were added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (20% to 50%) to give the product (2.8 g, 60%). [M+H] + = 377.2.

[0205] Step 2: tert-Butyl 9-(6-aminopyridin-3-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate TIFF2025501082000160.tif31322To a solution of tert-butyl 9-(6-nitropyridin-3-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (2.8 g, 7.438 mmol) in 60 mL of MeOH in a 50 mL round-bottom flask, under a nitrogen atmosphere, was added Pd / C (10%, 2.8 g). The mixture was hydrogenated under a hydrogen atmosphere using a hydrogen gas balloon at room temperature for 16 h, filtered through a pad of diatomaceous earth, and concentrated under reduced pressure to give the product (2.3 g, 89%). [M+H] + = 347.1.

[0206] Step 3: (R)-tert-butyl 9-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate TIFF2025501082000161.tif4162 To a stirred mixture of (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (1.7 g, 4.251 mmol) and tert-butyl 9-(6-aminopyridin-3-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.8 g, 5.101 mmol) in dioxane (34 mL) was added XPhos (608 mg, 1.275 mmol), XPhos Pd G3 (539 mg, 0.638 mmol), and Cs2CO3 (2770 mg, 8.502 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (30% to 70%) to give the product (1.3 g, 43%). [M+H] + = 710.4.

[0207] Step 4: (R)—N-(1-(4-(6-((5-(3,9-diazaspiro[5.5]undecan-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride TIFF2025501082000162.tif4259To a stirred solution of (R)-tert-butyl 9-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.3 g, 1.831 mmol) in DCM (10 mL) is added HCl in 1,4-dioxane (10 mL) at room temperature. The resulting mixture is stirred at room temperature for 1 h and concentrated under reduced pressure. EtO (50 mL) is added to the resulting mixture and filtered. The filter cake is washed with EtO (3 x 10 mL). The solid is dried under infrared light. This gave the product (1.1 g, 92%). 1H NMR (400MHz, DMSO) δ 11.51 (s, 1H), 9.93 (d, J = 7.6Hz, 1H), 8.91 (s, 1H), 8.75 (brs, 2H), 8.21 (s, 1H), 8.07-7.84 (m, 4H), 7.69-7.66 (m, 2H), 5.39-5.31 (m, 1H), 3.30-3.26 (m, 4H), 3.09-3.04 (m, 4H), 2.53 (s, 3H), 1.74-1.66 (m, 8H), 1.53 (d, J = 7.0Hz, 3H), 1.37 (s, 9H); [M+H] + = 610.4.

[0208] Step 5: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(9-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000163.tif4080 In a round-bottom flask, a mixture of (R)-N-(1-(4-(6-((5-(3,9-diazaspiro[5.5]undecan-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride (0.10 g, 0.155 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (0.056 g, 0.186 mmol) in 1,2-dichloroethane (5 mL) and HOAc (25 mg) was stirred at room temperature for 0.5 h. The mixture was added with NaBH(OAc)3 (0.050 g, 0.233 mmol) and stirred at room temperature for 12 hours. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (52.69 mg, 38%). 1H NMR (400MHz, DMSO) δ 10.27 (s, 1H), 9.98 (s, 1H), 9.91 (d, J = 7.7Hz, 1H), 8.69 (s, 1H), 8.03 (t, J = 5.9Hz, 2H), 7.83 (d, J = 6.5Hz, 2H), 7.67 (s, 1H), 7.60 (d, J = 8.7Hz, 1H), 7.45 (d, J = 9.4Hz, 1H), 7.13 (d, J = 8.8Hz, 2H), 6.92 (d, J = 8.9Hz, 2H), 5.33 (t, J = 7.3Hz, 1H), 3.68 (dd, J = 14.7, 8.1Hz, 4H), 3.11 (s, 4H), 2.72-2.60 (m, 4H), 2.47 (s, 3H), 2.35 (s, 4H), 2.17 (d, J = 6.9Hz, 2H), 1.77 (d, J = 12.3Hz, 2H), 1.71-1.46 (m, 12H), 1.36 (s, 9H), 1.25-1.10 (m, 2H); [M+H] + = 895.8.

[0209] Example 35: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(6-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0210] Step 1: tert-Butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate TIFF2025501082000164.tif2037 To a stirred mixture of 5-bromo-2-nitropyridine (2.9 g, 14.286 mmol) and 2,6-diazaspiro[3.3]heptane-2-carboxylate (3.40 g, 17.143 mmol) in dioxane (58.00 mL), XPhos Pd G3 (1.21 g, 1.429 mmol) and Cs2CO3 (9.31 g, 28.572 mmol) were added portionwise at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The desired product was detected by LCMS. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1 to 1:1) to give the product (2.4 g, 52%). [M + H] + = 321.0.

[0211] Step 2: tert-Butyl 6-(6-aminopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate TIFF2025501082000165.tif2037 A mixture of tert-butyl 6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (2.4 g, 7.492 mmol) and Pd / C (10 wt%, 2 g) in MeOH (45 mL) was degassed in vacuo under an argon atmosphere and purged multiple times with H. The mixture was then hydrogenated under a H gas balloon (2 atm) at 25 °C for 16 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the Pd / C was filtered through diatomaceous earth and the filter cake was washed with MeOH (2 x 200 mL). The filtrate was concentrated under reduced pressure to give the product (1.9 g, 87%). [M+H] + = 291.1.

[0212] Step 3: (R)-tert-butyl 6-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate TIFF2025501082000166.tif4360To a stirred solution of tert-butyl 6-(6-aminopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1.57 g, 5.401 mmol) and (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (1.8 g, 4.501 mmol) in 1,4-dioxane (40 mL), XPhos (0.43 g, 0.900 mmol), XPhos Pd G3 (0.38 g, 0.450 mmol) and Cs2CO3 (2.93 g, 9.002 mmol) were added portionwise under a nitrogen atmosphere at 100 °C. The desired product was detected by LCMS. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with PE / EA (7:1 to 2:1) to give the product (1.4 g, 48%). [M + H] + = 654.3.

[0213] Step 4: (R)—N-(1-(4-(6-((5-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide A solution of (R)-tert-butyl 6-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1.3 g, 1.988 mmol) and TFA (4.64 mL) in DCM (23.21 mL) was stirred at room temperature for 2 h. The desired product was detected by LCMS. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography under the following conditions: Column: Spherical C18, 20-40 μm, 330 g; Mobile phase A: water (with 10 mM NH4HCO3); Mobile phase B: ACN; Flow rate: 100 mL / min; Gradient: 5% to 5% B in 10 min, 15% to 40% B in 30 min; Detector: 220 nm. Fractions containing the desired product were collected in 37% B and concentrated under reduced pressure to give the product (1.0084 g, 91%). 1 H NMR (400MHz, DMSO) δ 9.89-9.84 (m, 2H), 8.68 (s, 1H), 7.95 (s, 1H), 7.83-7.81 (m, 2H), 7.68-7.57 (m, 3H), 6.95 (dd, J = 8.8, 3.0Hz, [M+H] + = 554.5.

[0214] Step 5: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(6-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide To a solution of (R)-N-(1-(4-(6-((5-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide (100 mg, 0.18 mmol) in DMF (6 mL) was added 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carboxylic acid (62 mg, 0.22 mmol), HATU (103 mg, 0.27 mmol), and DIEA (0.5 mL). The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was added with HO (30 mL) and extracted with DCM (30 mL x 3). The organic layer was purified by combi flash and eluted with a gradient of DCM:MeOH (1:0 to 10:1) to give the product (23 mg, 15%). 1 H NMR (500MHz, DMSO) δ 10.24 (s, 1H), 9.93 (s, 1H), 9.88 (d, J = 10.0Hz, 1H), 8.68 (s, 1H), 7.95 (s, 1H), 7.82 (s, 2H), 7.64-7.59 (m, 3H), 7.12 (d, J = 10.0Hz, 2H), 6.99 (dd, J = 10.0Hz, 5.0Hz, 1H), 6.44 (d, J = 10.0Hz, 2H), 5.35-5.32 (m, 1H), 4.31 (s, 2H), 4.09 (s, 2H), 3.99-3.96 (m, 6H), 3.82-3.79 (m, 2H), 3.69-3.66 (m, 1H), 3.59-3.53 (m, 1H), 2.69-2.66 (m, 2H), 2.47 (s, 3H), 1.84 (s, 4H), 1.52 (d, J = 5.0Hz, 3H), 1.36 (s, 9H); [M+H] + = 825.8.

[0215] Example 36: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbonyl)-2,7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0216] Step 1: tert-Butyl 7-(6-nitropyridin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate To a stirred solution of 5-bromo-2-nitropyridine (2.1 g, 10.345 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (2.8 g, 12.414 mmol) in dioxane (40 mL), CsCO (6.7 g, 20.690 mmol), XPhos Pd G (0.8 g, 1.035 mmol), and XPhos (0.9 g, 2.069 mmol) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (5:1 to 1:1) to give the product (3.1 g, 86%). [M+H] + = 349.3.

[0217] Step 2: tert-Butyl 7-(6-aminopyridin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate TIFF2025501082000170.tif21382To a solution of tert-butyl 7-(6-nitropyridin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (3.1 g, 8.898 mmol) in 60 mL of MeOH in a 50 mL round-bottom flask, under a nitrogen atmosphere, was added Pd / C (10%, 3 g). The mixture was hydrogenated under a hydrogen atmosphere using a hydrogen gas balloon at room temperature overnight, filtered through a pad of diatomaceous earth, and concentrated under reduced pressure to give the product (2.4 g, 84%). [M+H] + = 319.2.

[0218] Step 3: (R)-tert-butyl 7-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate TIFF2025501082000171.tif4261 To a stirred solution of (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (1.2 g, 3.001 mmol) and tert-butyl 7-(6-aminopyridin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (1.1 g, 3.601 mmol) in dioxane (24 mL) was added XPhos Pd G3 (0.3 g, 0.300 mmol), XPhos (0.3 g, 0.600 mmol), and Cs2CO3 (1.9 g, 6.002 mmol) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred overnight at 100°C under a nitrogen atmosphere and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (5:1 to 1:1) to give the product (1.5 g, 73%). [M+H] + = 682.4.

[0219] Step 4: (R)—N-(1-(4-(6-((5-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide To a stirred solution of (R)-tert-butyl 7-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (1.5 g, 2.127 mmol) in DCM (32 mL) was added TFA (8 mL) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: Column: Spherical C18, 20-40 μm, 330 g; Mobile phase A: water (with 10 mM NH4HCO3); Mobile phase B: ACN; Flow rate: 100 mL / min; Gradient: 5% to 5% B in 10 min, 33% B to 45% B in 20 min; Detector: 220 nm. Fractions containing the desired product were collected in 40% B and concentrated under reduced pressure to give the product (1.1 g, 89%). 1 H NMR (400MHz, DMSO) δ 9.97 (s, 1H), 9.88 (s, 1H), 8.70 (s, 1H), 8.17-7.91 (m, 2H), 7.90-7.75 (m, 2H), 7.70-7.67 (m, 1H), 7.64-7.60 (m, 1H), 7.45 (dd, J = 9.1, 3.0Hz, 1H), 5.34 (q, J = 6.9Hz, 1H), 3.58-3.56 (m, 1H), 3.28-3.24 (m, 4H), 3.08-3.04 (m, 4H), 2.48 (s, 3H), 1.81 (t, J = 5.6Hz, 4H), 1.52 (d, J = 6.9Hz, 3H), 1.37 (s, 9H); [M+H] + = 582.3.

[0220] Step 5: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbonyl)-2,7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide To a solution of (R)-N-(1-(4-(6-((5-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide (120 mg, 0.206 mmol) in DMF (6 mL) was added 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carboxylic acid (71 mg, 0.247 mmol), HATU (117 mg, 0.309 mmol), and DIEA (0.5 mL). The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was added with HO (30 mL) and extracted with DCM (30 mL × 3). The organic layer was purified by combi flash and eluted with a gradient of DCM:MeOH (1:0 to 10:1) to give the product (36 mg, 21%). 1H NMR (500MHz, DMSO) δ 10.24 (s, 1H), 9.98 (s, 1H), 9.89 (d, J = 5.0Hz, 1H), 8.70 (s, 1H), 8.06-8.02 (m, 2H), 7.84-7.83 (m, 2H), 7.68 (s, 1H), 7.61 (d, J = 5.0Hz, 1H), 7.47 (dd, J = 10.0Hz, 5.0Hz, 1H), 7.12 (d, J = 10.0Hz, 2H), 6.44 (d, J = 10.0Hz, 2H), 5.35-5.32 (m, 1H), 4.00-3.97 (m, 2H), 3.86-3.81 (m, 4H), 3.69-3.57 (m, 5H), 3.15-3.07 (m, 4H), 2.69-2.66 (m, 2H), 2.47 (s, 3H), 1.84 (s, 4H), 1.52 (d, J = 5.0Hz, 3H), 1.36 (s, 9H); [M+H] + = 853.7.

[0221] Example 37: 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-(6-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000174.tif3679 The title compound was synthesized in the same manner as in Example 35. 1H NMR (500MHz, DMSO) δ 10.21 (s, 1H), 9.93 (s, 1H), 9.88 (d, J = 10.0Hz, 1H), 8.68 (s, 1H), 7.96 (s, 1H), 7.82 (s, 2H), 7.66-7.59 (m, 3H), 7.10 (d, J = 10.0Hz, 2H), 6.99 (dd, J = 10.0Hz, 5.0Hz, 1H), 6.53 (d, J = 10.0Hz, 2H), 5.35-5.32 (m, 1H), 4.46-4.41 (m, 2H), 4.08 (s, 2H), 4.00 (s, 4H), 3.68-3.65 (m, 2H), 3.46-3.43 (m, 1H), 3.35-3.34 (m, 1H), 3.28-3.25 (m, 2H), 3.17-3.14 (m, 1H), 2.69-2.66 (m, 2H), 2.47 (s, 3H), 2.17-2.05 (m, 2H), 1.52 (d, J = 5.0Hz, 3H), 1.36 (s, 9H); [M+H] + = 839.7.

[0222] Example 38: 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-(2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carbonyl)-2,7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound TIFF2025501082000175.tif3582 was synthesized in the same manner as in Example 36. 1H NMR (500MHz, DMSO) δ 10.21 (s, 1H), 9.98 (s, 1H), 9.89 (d, J = 5.0Hz, 1H), 8.70 (s, 1H), 8.07 (d, J = 5.0Hz, 1H), 8.02 (s, 1H), 7.84-7.83 (m, 2H), 7.69 (s, 1H), 7.61 (d, J = 5.0Hz, 1H), 7.48 (dd, J = 10.0Hz, 5.0Hz, 1H), 7.10 (d, J = 10.0Hz, 2H), 6.54 (d, J = 10.0Hz, 2H), 5.35-5.31 (m, 1H), 4.01-3.96 (m, 2H), 3.68-3.64 (m, 4H), 3.47-3.44 (m, 1H), 3.35-3.34 (m, 1H), 3.28-3.09 (m, 7H), 2.69-2.66 (m, 2H), 2.47 (s, 3H), 2.18-2.07 (m, 2H), 1.85 (s, 4H), 1.52 (d, J = 5.0Hz, 3H), 1.36 (s, 9H); + = 867.6.

[0223] Example 39: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-(1'-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-[1,3'-biazetidin]-3-yl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0224] Step 1: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-(1'-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyl)-[1,3'-biazetidin]-3-yl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000176.tif4278 In a round-bottom flask, (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxylate in 1,2-dichloroethane (10 mL) and HOAc (9 mg) A mixture of thiaminamide (0.08 g, 0.148 mmol) and 1-(4-(3-oxo-[1,3'-biazetidin]-1'-yl)phenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (compound obtained in the same manner as in WO2021219070A) (0.098 g, 0.221 mmol) was stirred at room temperature for 0.5 hours. NaBH(OAc)3 (0.785 g, 0.37 mmol) was added to the mixture and stirred at room temperature for 3 hours. The mixture was then evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography eluting with 1% to 10% MeOH in DCM to give the product (0.115 g, 80%). [M+H] + = 970.5.

[0225] Step 2: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-(1'-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-[1,3'-biazetidin]-3-yl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide TIFF2025501082000177.tif4174 In a round-bottom flask, a mixture of (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-(1'-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyl)-[1,3'-biazetidin]-3-yl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (0.115 g, 0.118 mmol) and trifluoroacetic acid (5 mL) in dichloromethane (5 mL) is stirred at room temperature overnight. The mixture is evaporated in vacuo to give a brown oil. Then, MeOH (5 mL) and NH3 / H2O (2 mL) were added to the residue, and the mixture was stirred at 0 °C for 30 min. LCMS showed the reaction was complete. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (37.27 mg, 38%). 1 H NMR (500MHz, DMSO) δ 10.23 (s, 1H), 9.99 (s, 1H), 9.88 (d, J = 7.7Hz, 1H), 8.70 (s, 1H), 8.04 (s, 2H), 7.83 (d, J = 6.3Hz, 2H), 7.68 (s, 1H), 7.60 (d, J = 8.7Hz, 1H), 7.48-7.43 (m, 1H), 7.11 (d, J = 8.6Hz, 2H), 6.43 (d, J = 8.6Hz, 2H), 5.33 (s, 1H), 3.85 (s, 2H), 3.70-3.55 (m, 5H), 3.14 (s, 4H), 2.67 (t, J = 6.7Hz, 2H), 2.51-2.35 (m, 12H), 1.51 (d, J = 6.9Hz, 3H), 1.36 (s, 9H); [M+H] + = 840.6.

[0226] Example 40: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidin-3-yl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000178.tif3668 The title compound was synthesized in the same manner as in Example 15. 1 H NMR (500MHz, DMSO) δ 10.23 (s, 1H), 9.99 (s, 1H), 9.88 (d, J = 5.0Hz, 1H), 8.70 (s, 1H), 8.05-8.03 (m, 2H), 7.84-7.83 (m, 2H), 7.68 (s, 1H), 7.61 (d, J = 5.0Hz, 1H), 7.47 (d, J = 5.0Hz, 1H), 7.12 (d, J = 5.0Hz, 2H), 6.45 (d, J = 5.0Hz, 2H), 5.35-5.32 (m, 1H), 3.96-3.94 (m, 2H), 3.68-3.63 (m, 4H), 3.36-3.32 (m, 1H), 3.16 (s, 4H), 2.69-2.66 (m, 2H), 2.56-2.54 (m, 4H), 2.47 (s, 3H), 1.52 (d, J = 5.0Hz, 3H), 1.36 (s, 9H); [M+H] + = 785.5.

[0227] Example 41: 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide

[0228] Step 1: 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-(4-(1-(4-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)phenyl)azetidin-3-yl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000179.tif3772 In a round-bottom flask, a mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (0.08 g, 0.148 mmol) and 3-(4-(3-oxoazetidin-1-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (0.086 g, 0.221 mmol) in 1,2-dichloroethane (10 mL) and HOAc (25 mg) was stirred at room temperature for 0.5 h. The mixture was added with NaBH(OAc)3 (0.785 g, 0.37 mmol) and stirred at room temperature for 3 h. The mixture was then evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography eluting with 1% to 15% MeOH in DCM to give the product (0.108 g, 80%). [M+H] + = 914.4.

[0229] Step 2: 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidin-3-yl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide TIFF2025501082000180.tif3869 In a round-bottom flask, a mixture of 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-(4-(1-(4-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)phenyl)azetidin-3-yl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (0.108 g, 0.118 mmol) and trifluoroacetic acid (5 mL) in dichloromethane (5 mL) is stirred at room temperature overnight. The mixture is evaporated in vacuo to give a brown oil. Then, MeOH (5 mL) and NH3 / H2O (2 mL) were added to the residue, and the mixture was stirred at 0 °C for 30 min. LCMS showed the reaction was complete. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (15.51 mg, 17%). 1 H NMR (500MHz, DMSO) δ 10.75 (s, 1H), 9.99 (s, 1H), 9.88 (d, J = 7.8Hz, 1H), 8.70 (s, 1H), 8.09 (d, J = 43.9Hz, 2H), 7.83 (d, J = 5.7Hz, 2H), 7.69 (s, 1H), 7.60 (d, J = 8.6Hz, 1H), 7.47 (d, J = 8.7Hz, 1H), 7.02 (d, J = 8.2Hz, 2H), 6.42 (d, J = 8.0Hz, 2H), 5.33 (t, J = 7.2Hz, 1H), 5.08 (d, J = 7.2Hz, 1H), 4.01-3.82 (m, 2H), 3.75-3.55 (m, 2H), 3.16 (s, 4H), 2.75-2.45 (m, 9H), 2.16-1.96 (m, 1H), 1.51 (d, J = 6.9Hz, 3H), 1.36 (s, 9H); [M+H] + = 784.6.

[0230] Example 42: 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-(4-(1'-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[1,3'-biazetidin]-3-yl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound of TIFF2025501082000181.tif4276 was synthesized in the same manner as in Example 41. 1 H NMR (400MHz, DMSO) δ 10.78 (s, 1H), 10.03 (s, 1H), 9.91 (d, J = 7.7Hz, 1H), 8.71 (s, 1H), 8.05 (d, J = 16.0Hz, 2H), 7.83 (d, J = 7.6Hz, 2H), 7.70 (s, 1H), 7.60 (d, J = 8.0Hz, 1H), 7.49 (d, J = 8.0Hz, 1H), 7.05 (d, J = 8.0Hz, 2H), 6.47 (d, J = 7.6Hz, 2H), 5.38-5.28 (m, 1H), 4.72-3.66 (m, 10H), 3.25-2.85 (m, 6H), 2.70-2.41 (m, 11H), 2.20-1.95 (m, 2H), 1.51 (d, J = 6.8Hz, 3H), 1.36 (s, 9H); [M+H] + = 839.7.

[0231] Example 43: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-(7-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide The title compound TIFF2025501082000182.tif4783 was synthesized in the same manner as in Example 15. 1H NMR (500MHz, DMSO) δ 10.25 (s, 1H), 9.98 (s, 1H), 9.88 (d, J = 7.8Hz, 1H), 8.70 (s, 1H), 8.03 (d, J = 2.7Hz, 2H), 7.83 (d, J = 5.9Hz, 2H), 7.68 (s, 1H), 7.60 (d, J = 8.7Hz, 1H), 7.45 (dd, J = 9.1, 2.9Hz, 1H), 7.13 (d, J = 8.9Hz, 2H), 6.93 (d, J = 9.1Hz, 2H), 5.38-5.28 (m, 1H), 3.69 (t, J = 6.7Hz, 2H), 3.13 (s, 6H), 3.05 (s, 2H), 2.79-2.71 (m, 1H), 2.68 (t, J = 6.7Hz, 2H), 2.47 (s, 3H), 2.41 (s, 4H), 2.01 (t, J = 8.5Hz, 2H), 1.68 (s, 2H), 1.64-1.56 (m, 4H), 1.51 (d, J = 7.0Hz, 3H), 1.36 (s, 9H); [M+H] + = 853.6.

[0232] Example 44: 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-(4-(1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoindol-5-yl)-[1,3'-biazetidin]-3-yl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide

[0233] Step 1: 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-(4-(1'-(2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1,3-dioxoindol-5-yl)-[1,3'-biazetidin]-3-yl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide TIFF2025501082000183.tif4085 (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazine in 1,2-dichloroethane (10 mL) and HOAc (25 mg) in a round-bottom flask. A mixture of azole-5-carboxamide (0.12 g, 0.222 mmol) and 2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-5-(3-oxo-[1,3'-biazetidin]-1'-yl)isoindoline-1,3-dione (0.171 g, 0.333 mmol) was stirred at room temperature for 0.5 h. NaBH(OAc)3 (0.117 g, 0.55 mmol) was added to the mixture and stirred at room temperature for 12 h. The mixture was then evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography eluting with 1% to 15% MeOH in DCM to give the product (0.185 g, 81%). [M+H] + =1038.5.

[0234] Step 2: 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-(4-(1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoindol-5-yl)-[1,3'-biazetidin]-3-yl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide TIFF2025501082000184.tif4187 In a round-bottom flask, a mixture of 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-(4-(1'-(2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1,3-dioxoindol-5-yl)-[1,3'-biazetidin]-3-yl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (0.185 g, 0.178 mmol) and trifluoroacetic acid (5 mL) in dichloromethane (5 mL) is stirred at room temperature overnight. The mixture is evaporated in vacuo to give a brown oil. Then, MeOH (5 mL) and NH3 / H2O (2 mL) are added to the residue, and the mixture is stirred at 0 °C for 30 min. LCMS shows the reaction is complete. The mixture is then evaporated in vacuo to give the crude product, which is purified by preparative HPLC to give the product (40.13 mg, 25%). 1 H NMR (500MHz, DMSO) δ 11.07 (s, 1H), 9.99 (s, 1H), 9.88 (d, J = 7.8Hz, 1H), 8.70 (s, 1H), 8.04 (d, J = 2.4Hz, 2H), 7.83 (d, J = 5.6Hz, 2H), 7.73-7.55 (m, 3H), 7.48-7.41 (m, 1H), 6.80 (s, 1H), 6.66 (d, J = 8.4Hz, 1H), 5.38-5.30 (m, 1H), 5.05 (dd, J = 12.8, 5.2Hz, 1H), 4.05 (t, J = 7.8Hz, 2H), 3.81 (dd, J = 8.7, 4.2Hz, 2H), 3.64 (s, 1H), 3.42 (s, 2H), 3.13 (s, 4H), 2.99 (s, 3H), 2.88 (t, J = 12.8Hz, 1H), 2.65-2.35 (m, 9H), 2.05-1.97 (m, 1H), 1.51 (d, J = 6.9Hz, 3H), 1.36 (s, 9H); [M+H] + = 908.6.

[0235] Example 45: 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-(4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide The title compound TIFF2025501082000185.tif3668 was synthesized in the same manner as in Example 15. 1 H NMR (500MHz, DMSO) δ 10.95 (s, 1H), 9.99 (s, 1H), 9.89 (d, J = 5.0Hz, 1H), 8.70 (s, 1H), 8.05-8.03 (m, 2H), 7.84-7.83 (m, 2H), 7.68-7.60 (m, 2H), 7.46 (d, J = 10.0Hz, 1H), 7.06 (d, J = 10.0Hz, 2H), 5.35-5.31 (m, 1H), 4.22-4.18 (m, 1H), 3.14 (s, 4H), 2.82-2.77 (m, 3H), 2.62-2.60 (m, 5H), 2.47 (s, 3H), 2.15-2.09 (m, 1H), 2.01-1.98 (m, 1H), 1.51 (d, J = 5.0Hz, 3H), 1.38-1.34 (m, 9H), 1.23-1.18 (m, 2H); [M+H] + = 793.5.

[0236] Example 46: 3-(tert-butyl)-N-((R)-1-(4-(6-((5-(4-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound TIFF2025501082000186.tif3667 was synthesized in the same manner as in Example 15. 1H NMR (500MHz, DMSO) δ 10.95 (s, 1H), 9.99 (s, 1H), 9.89 (d, J = 5.0Hz, 1H), 8.70 (s, 1H), 8.05-8.03 (m, 2H), 7.84-7.83 (m, 2H), 7.69-7.60 (m, 2H), 7.46 (dd, J = 10.0Hz, 5.0Hz, 1H), 7.06 (d, J = 10.0Hz, 2H), 5.35-5.31 (m, 1H), 4.22-4.18 (m, 1H), 3.14 (s, 4H), 2.83-2.77 (m, 3H), 2.62-2.60 (m, 5H), 2.47 (s, 3H), 2.15-2.11 (m, 1H), 2.01-1.99 (m, 1H), 1.51 (d, J = 5.0Hz, 3H), 1.38-1.34 (m, 9H), 1.23-1.18 (m, 2H); [M+H] + = 793.7.

[0237] Example 47: 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-(4-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenethyl)piperazin)-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide The title compound of TIFF2025501082000187.tif3565 was synthesized in the same manner as in Example 15. 1H NMR (500MHz, DMSO) δ 10.86 (s, 1H), 9.99 (s, 1H), 9.88 (d, J = 10.0Hz, 1H), 8.70 (s, 1H), 8.05-8.04 (m, 2H), 7.84-7.83 (m, 2H), 7.68-7.60 (m, 2H), 7.46 (d, J = 10.0Hz, 1H), 7.23-7.20 (m, 1H), 7.11 (d, J = 10.0Hz, 1H), 7.07 (d, J = 10.0Hz, 1H), 5.35-5.31 (m, 1H), 4.02-3.98 (m, 1H), 3.14 (s, 4H), 2.81-2.71 (m, 3H), 2.61-2.60 (m, 5H), 2.47 (s, 3H), 2.20-2.17 (m, 1H), 2.00-1.97 (m, 1H), 1.51 (d, J = 5.0Hz, 3H), 1.38-1.34 (m, 9H), 1.23-1.17 (m, 2H); [M+H] + = 775.5.

[0238] Example 48: 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-(4-(4-(2,6-dioxopiperidin-3-yl)-3-methylphenethyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide The title compound of TIFF2025501082000188.tif3565 was synthesized in the same manner as in Example 15. 1H NMR (500MHz, DMSO) δ 10.81 (s, 1H), 9.99 (s, 1H), 9.88 (d, J = 10.0Hz, 1H), 8.70 (s, 1H), 8.05-8.04 (m, 2H), 7.84-7.83 (m, 2H), 7.68 (s, 1H), 7.61 (d, J = 5.0Hz, 1H), 7.46 (d, J = 10.0Hz, 1H), 7.07-7.00 (m, 3H), 5.35-5.31 (m, 1H), 4.01-3.97 (m, 1H), 3.15 (s, 4H), 2.76-2.69 (m, 3H), 2.61-2.55 (m, 5H), 2.47 (s, 3H), 2.24 (s, 3H), 2.17-2.14 (m, 1H), 1.98-1.95 (m, 1H), 1.51 (d, J = 5.0Hz, 3H), 1.38-1.34 (m, 9H), 1.27-1.18 (m, 2H); [M+H] + = 771.6.

[0239] Example 49: 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-(4-(2-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)ethyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide The title compound of TIFF2025501082000189.tif4545 was synthesized in the same manner as in Example 15. 1H NMR (500MHz, DMSO) δ 11.20 (s, 1H), 9.99 (s, 1H), 9.89 (d, J = 5.0Hz, 1H), 8.70 (s, 1H), 8.05 (d, J = 5.0Hz, 1H), 8.03 (s, 1H), 7.84-7.83 (m, 2H), 7.68 (s, 1H), 7.61 (d, J = 5.0Hz, 1H), 7.46 (dd, J = 10.0Hz, 5.0Hz, 1H), 7.33 (s, 1H), 7.17 (d, J = 10.0Hz, 1H), 7.11 (d, J = 10.0Hz, 1H), 5.37-5.31 (m, 2H), 3.14 (s, 4H), 2.89-2.81 (m, 3H), 2.71-2.57 (m, 8H), 2.47 (s, 3H), 2.17-2.14 (m, 1H), 1.52 (d, J = 5.0Hz, 3H), 1.36 (s, 9H); [M+H] + = 814.7.

[0240] Example 50: 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide The title compound TIFF2025501082000190.tif5263 was synthesized in the same manner as in Example 15. 1H NMR (500MHz, DMSO) δ 11.09 (s, 1H), 9.99 (s, 1H), 9.89 (d, J = 5.0Hz, 1H), 8.70 (s, 1H), 8.05 (d, J = 5.0Hz, 1H), 8.03 (s, 1H), 7.84-7.83 (m, 2H), 7.69 (s, 1H), 7.61 (d, J = 10.0Hz, 1H), 7.47 (dd, J = 10.0Hz, 5.0Hz, 1H), 6.99-6.93 (m, 3H), 5.39-5.31 (m, 2H), 3.61 (s, 3H), 3.16-3.10 (m, 6H), 2.89-2.86 (m, 1H), 2.69-2.61 (m, 8H), 2.47 (s, 3H), 2.01-1.99 (m, 1H), 1.52 (d, J = 5.0Hz, 3H), 1.36 (s, 9H); [M+H] + = 827.7.

[0241] Example 51: 3-(tert-butyl)-N-((1R)-1-(4-(6-((5-(4-(2-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)ethyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide formate The title compound TIFF2025501082000191.tif4160 was synthesized in the same manner as in Example 15. 1H NMR (500MHz, DMSO) δ 11.21 (s, 1H), 9.99 (s, 1H), 9.88 (d, J = 10.0Hz, 1H), 8.70 (s, 1H), 8.13 (s, 1H), 8.05 (d, J = 5.0Hz, 1H), 8.03 (s, 1H), 7.84-7.83 (m, 2H), 7.69 (s, 1H), 7.61 (d, J = 5.0Hz, 1H), 7.46 (dd, J = 10.0Hz, 5.0Hz, 1H), 7.17-7.09 (m, 3H), 5.38-5.32 (m, 2H), 3.15 (s, 4H), 2.93-2.86 (m, 3H), 2.72-2.64 (m, 8H), 2.47 (s, 3H), 2.18-2.15 (m, 1H), 1.52 (d, J = 5.0Hz, 3H), 1.36 (s, 9H); [M+H] + = 814.1.

[0242] Example 52: 3-(tert-butyl)-N-((R)-1-(4-(6-((5-(4-((1S,3s)-3-(4-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)cyclobutyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide The title compound TIFF2025501082000192.tif3670 was synthesized in the same manner as in Example 15. 1H NMR (500MHz, DMSO) δ 10.76 (s, 1H), 9.99 (s, 1H), 9.89 (d, J = 5.0Hz, 1H), 8.70 (s, 1H), 8.04 (s, 2H), 7.84-7.83 (m, 2H), 7.68 (s, 1H), 7.61 (d, J = 10.0Hz, 1H), 7.46 (dd, J = 10.0Hz, 5.0Hz, 1H), 6.97 (d, J = 10.0Hz, 2H), 6.62 (d, J = 10.0Hz, 2H), 5.68 (d, J = 5.0Hz, 1H), 5.36-5.31 (m, 1H), 4.30-4.26 (m, 1H), 3.14 (s, 4H), 3.00-2.95 (m, 1H), 2.77-2.66 (m, 3H), 2.47-2.40 (m, 9H), 2.12-2.08 (m, 1H), 1.88-1.76 (m, 3H), 1.52 (d, J = 5.0Hz, 3H), 1.36 (s, 9H); [M+H] + = 798.2.

[0243] Example 53: 3-(tert-butyl)-N-((R)-1-(4-(6-((5-(4-((1S,3r)-3-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)cyclobutyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide formate The title compound TIFF2025501082000193.tif3682 was synthesized in the same manner as in Example 15. 1H NMR (500MHz, DMSO) δ 10.78 (s, 1H), 10.07 (s, 1H), 9.89-9.74 (m, 2H), 8.72 (s, 1H), 8.13-8.05 (m, 2H), 7.84-7.83 (m, 2H), 7.74 (s, 1H), 7.61 (d, J = 5.0Hz, 1H), 7.55-7.47 (m, 1H), 7.06 (d, J = 10.0Hz, 2H), 6.66 (d, J = 10.0Hz, 2H), 5.78-5.69 (m, 1H), 5.36-5.30 (m, 1H), 4.30 (s, 1H), 4.00-3.86 (m, 2H), 3.54-3.43 (m, 2H), 3.15-2.89 (m, 5H), 2.78-2.71 (m, 2H), 2.64-2.54 (m, 2H), 2.47 (s, 3H), 2.36-2.35 (m, 2H), 2.12-2.09 (m, 2H), 1.91-1.84 (m, 1H), 1.52 (d, J = 5.0Hz, 3H), 1.36 (s, 9H); + = 798.2.

[0244] Example 54: 3-(tert-butyl)-N-((R)-1-(4-(6-((5-(4-((1R,3s)-3-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)cyclobutyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide The title compound TIFF2025501082000194.tif3670 was synthesized in the same manner as in Example 15. 1H NMR (500MHz, DMSO) δ 10.76 (s, 1H), 9.99 (s, 1H), 9.89 (d, J = 5.0Hz, 1H), 8.70 (s, 1H), 8.04 (s, 2H), 7.84-7.83 (m, 2H), 7.68 (s, 1H), 7.61 (d, J = 5.0Hz, 1H), 7.46 (dd, J = 10.0Hz, 5.0Hz, 1H), 6.97 (d, J = 10.0Hz, 2H), 6.62 (d, J = 10.0Hz, 2H), 5.67 (d, J = 10.0Hz, 1H), 5.36-5.31 (m, 1H), 4.30-4.26 (m, 1H), 3.14 (s, 4H), 3.00-2.97 (m, 1H), 2.73-2.64 (m, 2H), 2.59-2.54 (m, 1H), 2.45-2.40 (m, 9H), 2.12-2.08 (m, 1H), 1.88-1.76 (m, 3H), 1.52 (d, J = 5.0Hz, 3H), 1.36 (s, 9H); [M+H] + = 798.2.

[0245] Example 55: 3-(tert-butyl)-N-((R)-1-(4-(6-((5-(4-((1R,3r)-3-(4-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)cyclobutyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide The title compound of TIFF2025501082000195.tif3670 was synthesized in the same manner as in Example 15. 1H NMR (500MHz, DMSO) δ 10.78 (s, 1H), 10.07 (s, 1H), 9.90-9.74 (m, 2H), 8.72 (s, 1H), 8.13-8.05 (m, 2H), 7.84-7.83 (m, 2H), 7.74 (s, 1H), 7.61 (d, J = 5.0Hz, 1H), 7.55-7.47 (m, 1H), 7.06 (d, J = 5.0Hz, 2H), 6.66 (d, J = 5.0Hz, 2H), 5.78-5.69 (m, 1H), 5.36-5.30 (m, 1H), 4.30 (s, 1H), 4.01-3.86 (m, 2H), 3.54-3.43 (m, 2H), 3.15-2.99 (m, 4H), 2.78-2.71 (m, 2H), 2.64 -2.54 (m, 3H), 2.47 (s, 3H), 2.36-2.35 (m, 2H), 2.12-2.09 (m, 2H), 1.91-1.84 (m, 1H), 1.52 (d, J = 5.0Hz, 3H), 1.36 (s, 9H); + = 798.2.

[0246] Example 56: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-(2-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)acetyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound TIFF2025501082000196.tif3566 was synthesized in the same manner as in Example 15. 1H NMR (500MHz, DMSO) δ 10.36 (s, 1H), 10.01 (s, 1H), 9.89 (d, J = 5.0Hz, 1H), 8.71 (s, 1H), 8.04 (d, J = 5.0Hz, 1H), 8.03 (s, 1H), 7.84-7.83 (m, 2H), 7.70 (s, 1H), 7.61 (d, J = 5.0Hz, 1H), 7.46 (dd, J = 10.0Hz, 5.0Hz, 1H), 7.35-7.32 (m, 1H), 7.22-7.19 (m, 2H), 7.12 (d, J = 10.0Hz, 1H), 5.35-5.32 (m, 1H), 3.80-3.76 (m, 4H), 3.66-3.64 (m, 4H), 3.10-3.06 (m, 4H), 2.71-2.69 (m, 2H), 2.47 (s, 3H), 1.52 (d, J = 5.0Hz, 3H), 1.36 (s, 9H); [M+H] + = 772.0.

[0247] Example 57: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(3-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide

[0248] Step 1: 3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione TIFF2025501082000197.tif1520To a stirred mixture of 5,6-dihydrouracil (14 g, 122.695 mmol) and Cs2CO3 (79.95 g, 245.390 mmol) in DMF (280 mL) under a nitrogen atmosphere at 0 °C, SEMCl (26.11 mL, 147.234 mmol) was added dropwise. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 h and filtered. The filter cake was washed with EtOAc (2 x 200 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (2 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH (0-5%) in DCM to give the product (14 g, 47%). [M+H] + = 245.0.

[0249] Step 2: 1-(3-Bromobenzyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione TIFF2025501082000198.tif1637To a stirred mixture of 3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (4 g, 16.369 mmol) in DMF (60 mL) was added NaH (720 mg, 18.006 mmol) portionwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 0.5 h under a nitrogen atmosphere. To the above mixture was added dropwise 1-bromo-3-(bromomethyl)benzene (4.5 g, 18.006 mmol) in DMF (30 mL) at 0 °C. The resulting mixture was stirred at room temperature for 16 h and quenched with saturated NH4Cl (aq) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (2x100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (0%-30%) to give the product (3.3 g, 49%). [M+H] + = 413.1.

[0250] Step 3: 1-(3-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)benzyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione To a stirred mixture of 1-(3-bromobenzyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (3 g, 7.257 mmol) and 4-(1,3-dioxolan-2-yl)piperidine (1.37 g, 8.708 mmol) in dioxane (60 mL) was added XPhos Pd G3 (921 mg, 1.089 mmol), XPhos (1.04 g, 2.177 mmol), and Cs2CO3 (4.73 g, 14.514 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (0% to 30%) to give the product (2.77 g, 78%). [M+H] + = 490.3.

[0251] Step 4: 1-(3-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)benzyl)dihydropyrimidine-2,4(1H,3H)-dione TIFF2025501082000200.tif2146A solution of 1-(3-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)benzyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (2.7 g, 5.514 mmol) in TFA (15 mL) and DCM (60 mL) is stirred at room temperature for 2 h. The resulting mixture is concentrated under reduced pressure. To the residue is added DCM (30 mL) and basified with NH3·H2O to pH 8. The resulting mixture is stirred at room temperature for 24 h and concentrated under reduced pressure. Water (20 mL) is added to the resulting mixture and filtered. The filter cake is washed with water (3×10 mL). The solid is dried under infrared light. This afforded the product (1.64 g, 83%). [M+H] + = 360.2.

[0252] Step 5: 1-(3-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)phenyl)piperidine-4-carbaldehyde A solution of 1-(3-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)benzyl)dihydropyrimidine-2,4(1H,3H)-dione (1.6 g, 4.452 mmol) in HCl (15 mL) and THF (15 mL) was stirred at 40° C. for 16 h. The mixture was basified to pH 6 with NaOH and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: Column: Spherical C18, 20-40 μm, 120 g; Mobile phase A: water (with 5 mM NH4HCO3); Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient (%B): 5% to 10% in 4 min, 10% to 50% in 20 min, 50% to 95% in 2 min, 95% in 5 min; Detector: 254 nm. Fractions containing the desired product were collected in 30% B and concentrated under reduced pressure to give the product (1.1552 g, 82%). 1H NMR (400MHz, DMSO) δ 10.16 (s, 1H), 9.64 (s, 1H), 7.22-7.13 (m, 1H), 6.89-6.81 (m, 2H), 6.70-6.63 (m, 1H), 4.58-4.36 (m, 2H), [M+H] + = 316.1.

[0253] Step 6: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(3-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide TIFF2025501082000202.tif4365 In a round-bottom flask, a mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (0.06 g, 0.222 mmol) and 1-(3-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)phenyl)piperidine-4-carbaldehyde (0.028 g, 0.133 mmol) in 1,2-dichloroethane (4 mL) and HOAc (25 mg) is stirred at room temperature for 0.5 h. The mixture was added with NaBH(OAc)3 (0.036 g, 0.166 mmol) and stirred at room temperature for 12 hours. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (45.73 mg, 49%). 1H NMR (500MHz, DMSO) δ 10.17 (s, 1H), 9.98 (s, 1H), 9.88 (d, J = 7.8Hz, 1H), 8.70 (s, 1H), 8.04 (d, J = 2.9Hz, 2H), 7.83 (d, J = 6.0Hz, 2H), 7.68 (s, 1H), 7.60 (d, J = 8.7Hz, 1H), 7.45 (dd, J = 9.2, 2.9Hz, 1H), 7.16 (t, J = 8.1Hz, 1H), 6.84 (d, J = 6.8Hz, 2H), 6.65 (d, J = 7.4Hz, 1H), 5.33 (t, J = 7.3Hz, 1H), 4.44 (s, 2H), 3.67 (d, J = 12.2Hz, 2H), 3.26 (d, J = 6.8Hz, 3H), 3.14 (s, 4H), 2.66 (t, J = 11.0Hz, 2H), 2.55-2.52 (m, 6H), 2.47 (s, 3H), 2.23 (d, J = 7.1Hz, 2H), 1.81 (d, J = 12.0Hz, 2H), 1.71 (s, 1H), 1.51 (d, J = 8.1Hz, 3H), 1.36 (s, 9H), 1.27-1.16 (m, 2H); [M+H] + = 841.1.

[0254] Example 58: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-(2-(3-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)-2-oxopyridin-1(2H)-yl)ethyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0255] Step 1: 1-Allyl-2-oxo-1,2-dihydropyridine-3-carbaldehyde TIFF2025501082000203.tif1526To a stirred solution of 2-oxo-1H-pyridine-3-carbaldehyde (14 g, 113.719 mmol) and allyl bromide (16.5 g, 136.463 mmol) in DMF (300 mL) was added K2CO3 (31.4 g, 227.438 mmol) portionwise at room temperature. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with water (600 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (3 x 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (8:1 to 2:1) to give the product (9.5 g, 51%). [M+H] + = 164.1.

[0256] Step 2: 1-Allyl-3-(hydroxymethyl)pyridin-2(1H)-one A solution of 1-allyl-2-oxo-1,2-dihydropyridine-3-carbaldehyde (9.5 g, 58.219 mmol) in MeOH (220 mL) was stirred at 0 °C under a nitrogen atmosphere for 5 min, followed by the addition of NaBH (3.3 g, 87.329 mmol) portionwise at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with CHCl / MeOH (20:1 to 10:1) to give the product (9.0 g, 93%). [M+H] + = 166.1.

[0257] Step 3: 1-Allyl-3-(chloromethyl)pyridin-2(1H)-one TIFF2025501082000205.tif1527To a stirred solution of 1-allyl-3-(hydroxymethyl)pyridin-2(1H)-one (9.0 g, 54.482 mmol) in DCM (180 mL) was added dropwise at -20 °C under a nitrogen atmosphere with SOCl2 (32.4 g, 272.410 mmol). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 h and concentrated under reduced pressure. The residue was basified to pH 8 with saturated NaHCO3 (aq). The resulting mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1 to 1:1) to give the product (8.3 g, 83%).

[0258] Step 4: 1-((1-allyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione TIFF2025501082000206.tif1541 To a stirred mixture of 3-[2-(trimethylsilyl)ethoxy]methyl-1,3-diazine-2,4-dione (13.2 g, 54.236 mmol) in DMF (170 mL) was added NaH (2.2 g, 54.236 mmol, 60%) portionwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. To the above mixture was added 1-allyl-3-(chloromethyl)pyridin-2(1H)-one (8.3 g, 45.197 mmol) at 0 °C. The resulting mixture was further stirred at room temperature for 2 h. The reaction was quenched with saturated NH4Cl (aq) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1 to 1:1) to give the product (9.3 g, 52%). [M+H] + = 392.2.

[0259] Step 5: 2-(3-((2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)methyl)-2-oxopyridin-1(2H)-yl)acetaldehyde To a stirred mixture of 1-((1-allyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (9.3 g, 23.752 mmol) and NaIO (20.3 g, 95.008 mmol) in THF (180 mL) and HO (45 mL) under a nitrogen atmosphere at 0 °C, was added KOsO.2HO (87.51 mg, 0.238 mmol). The resulting mixture was stirred at room temperature for 2 h and quenched with saturated NaSO (aq) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 400 mL). The combined organic layer was washed with brine (300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (30:1 to 15:1) to give the product (4.6 g, 49%). [M+H] + = 394.2.

[0260] Step 6: 2-(3-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)-2-oxopyridin-1(2H)-yl)acetaldehyde TIFF2025501082000208.tif1538To a stirred solution of 2-(3-((2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)methyl)-2-oxopyridin-1(2H)-yl)acetaldehyde (2.3 g, 5.845 mmol) in DCM (30 mL) at room temperature, TFA (6 mL) was added. The resulting mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was basified to pH 9 with NH3·H2O. The resulting mixture was stirred at room temperature for 16 h and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: Column: Spherical C18, 20-40 μm, 330 g; Mobile phase A: water (with 5 mM NH4HCO3); Mobile phase B: ACN; Flow rate: 100 mL / min; Gradient: 5% to 5% B in 10 min, 5% B to 30% B in 20 min; Detector: 220 nm. Fractions containing the desired product were collected in 12% B and concentrated under reduced pressure to give the product (768 g, 50%). 1 H NMR (400MHz, DMSO) δ 10.12 (s, 1H), 7.58-7.49 (m, 1H), 7.29-7.21 (m, 1H), 6.32-6.08 (m, 1H), 4.28-4.24 (m, 2H), 3.89-3.83 (m, 2H), 3.75-3.71 (m, 1H), 3.44-3.37 (m, 2H), 2.60-2.55 (m, 2H); [M+H] + = 264.1.

[0261] Step 7: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-(2-(3-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)-2-oxopyridin-1(2H)-yl)ethyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000209.tif3962 In a round-bottom flask, a mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (0.03 g, 0.055 mmol) and 2-(3-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)-2-oxopyridin-1(2H)-yl)acetaldehyde (0.022 g, 0.083 mmol) in 1,2-dichloroethane (5 mL) and HOAc (25 mg) is stirred at room temperature for 0.5 h. The mixture was added with NaBH(OAc)3 (0.018 g, 0.083 mmol) and stirred at room temperature for 12 hours. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (17.57 mg, 40%). 1 H NMR (500MHz, DMSO) δ 10.15 (s, 1H), 9.98 (s, 1H), 9.88 (d, J = 7.8Hz, 1H), 8.70 (s, 1H), 8.03 (d, J = 2.9Hz, 2H), 7.83 (d, J = 6.4Hz, 2H), 7.72-7.58 (m, 3H), 7.45 (dd, J = 9.1, 2.9Hz, 1H), 7.28 (d, J = 6.1Hz, 1H), 6.22 (t, J = 6.8Hz, 1H), 5.37-5.30 (m, 1H), 4.28 (s, 2H), 4.07 (t, J = 6.4Hz, 2H), 3.42 (t, J = 6.8Hz, 2H), 3.11 (s, 4H), 2.65-2.54 (m, 8H), 2.47 (s, 3H), 1.51 (d, J = 7.0Hz, 3H), 1.36 (s, 9H); [M+H] + = 789.2.

[0262] Example 59: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(4-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide

[0263] Step 1: 1-(4-Bromobenzyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione TIFF2025501082000210.tif163 Sodium hydride (60% in oil, 0.8 g) was added to a solution of 3-[2-(trimethylsilyl)ethoxy]methyl-1,3-diazine-2,4-dione (5 g, 20.461 mmol) in DMF (100 mL) at 50 °C. The mixture was stirred for 15 min. 1-Bromo-4-(bromomethyl)benzene (5.1 g, 20.461 mmol) was added, and the mixture was heated to RT and stirred for 4 h. The reaction mixture was quenched with water (500 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with DCM (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (4:1 to 1:1) to give the product (3.5 g, 41%). [M+H] + = 413.1.

[0264] Step 2: 1-(4-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)benzyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione To a stirred solution of 1-(4-bromobenzyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (3.5 g, 8.467 mmol) and 4-(1,3-dioxolan-2-yl)piperidine (1.6 g, 10.160 mmol) in dioxane (60 mL) was added XPhos Pd G3 (0.7 g, 0.847 mmol), Cs2CO3 (4.1 g, 12.701 mmol), and XPhos (0.8 g, 1.693 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 110 °C under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (2:1 to 1:1) to give the product (2.8 g, 67%). [M+H] + = 490.3.

[0265] Step 3: 1-(4-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)benzyl)dihydropyrimidine-2,4(1H,3H)-dione TIFF2025501082000212.tif2546To a stirred solution of 1-(4-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)benzyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (2.8 g, 5.718 mmol) in DCM (40 mL) was added dropwise at room temperature under a nitrogen atmosphere to TFA (10 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h and concentrated under reduced pressure. The resulting mixture was diluted with DCM (20 mL) and basified to pH 8 with NH3·H2O. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (2:1 to 1:1) to give the product (1.6 g, 77%). [M+H] + = 360.1.

[0266] Step 4: 1-(4-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)phenyl)piperidine-4-carbaldehyde TIFF2025501082000213.tif2144To a stirred solution of 1-(4-(4-(1,3-dioxolan-2-yl)piperidin-1-yl)benzyl)dihydropyrimidine-2,4(1H,3H)-dione (1.5 g, 4.173 mmol) in THF (15 mL) is added dropwise at room temperature under a nitrogen atmosphere with HCl (6 M, 15 mL). The resulting mixture is stirred overnight at 40° C. under a nitrogen atmosphere. The mixture is cooled to room temperature and concentrated under reduced pressure. The residue is purified by reverse-phase flash chromatography under the following conditions: Column: Spherical C18, 20-40 μm, 330 g; Mobile phase A: water (with 5 mM NH4HCO3); Mobile phase B: ACN; Flow rate: 80 mL / min; Gradient: 5% to 5% B in 10 min, 33% B to 45% B in 20 min; Detector: 220 nm. Fractions containing the desired product were collected in 40% B and concentrated under reduced pressure to give the product (1.0 g, 76%). 1 H NMR (400MHz, DMSO) δ 10.12 (s, 1H), 9.64 (s, 1H), 7.14-7.10 (m, 2H), 6.93-6.88 (m, 2H), 5.51 (d, J = 6.2Hz, 1H), 4.54-4.50 (m, 1H), 3.69-3.66 (m, 1H), 3.61-3.58 (m, 1H), 3.23 (dd, J = 6.9, 1.7Hz, 2H), 2.84-2.78 (m, 1H), 2.59-2.47 (m, 3H), 2.00-1.72 (m, 2H), 1.63-1.54 (m, 1H), 1.48-1.20 (m, 2H); [M+H] + = 316.1.

[0267] Step 5: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(4-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide TIFF2025501082000214.tif4476 In a round-bottom flask, a mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (0.06 g, 0.111 mmol) and 1-(4-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)phenyl)piperidine-4-carbaldehyde (0.028 g, 0.133 mmol) in 1,2-dichloroethane (5 mL) and HOAc (25 mg) was stirred at room temperature for 0.5 h. The mixture was added with NaBH(OAc)3 (0.036 g, 0.166 mmol) and stirred at room temperature for 3 hours. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (45.96 mg, 49%). 1H NMR (500MHz, DMSO) δ 10.14 (s, 1H), 9.98 (s, 1H), 9.88 (d, J = 7.8Hz, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.04 (d, J = 2.9Hz, 2H), 7.83 (d, J = 5.9Hz, 2H), 7.69 (s, 1H), 7.60 (d, J = 8.7Hz, 1H), 7.45 (dd, J = 9.1, 2.9Hz, 1H), 7.12 (d, J = 8.6Hz, 2H), 6.90 (d, J = 8.7Hz, 2H), 5.33 (t, J = 7.2Hz, 1H), 4.39 (s, 2H), 3.67 (d, J = 12.2Hz, 2H), 3.23 (t, J = 6.8Hz, 2H), 3.13 (s, 4H), 2.64 (t, J = 11.2Hz, 2H), 2.55-2.50 (m, 6H), 2.47 (s, 3H), 2.22 (d, J = 7.1Hz, 2H), 1.81 (d, J = 11.8Hz, 2H), 1.70 (s, 1H), 1.51 (d, J = 7.0Hz, 3H), 1.36 (s, 9H), 1.26-1.17 (m, 2H); [M+H] + = 841.1.

[0268] Example 60: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-6-ethylpyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide

[0269] Step 1: 5-Bromo-6-ethylpyridin-2-amine To a stirred solution of 6-ethylpyridin-2-amine (5 g, 40.926 mmol) in CHCl3 (200 mL) was added NBS (8.0 g, 45.019 mmol) portionwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 1 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (10:1 to 5:1) to give the product (6.7 g, 81%). [M+H] + = 200.9.

[0270] Step 2: 3-Bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-ethylpyridine TIFF2025501082000216.tif1724 To a stirred solution of 5-bromo-6-ethylpyridin-2-amine (3 g, 14.920 mmol) and 2,5-hexanedione (2.5 g, 22.380 mmol) in toluene (80 mL) was added p-toluenesulfonic acid (0.3 g, 1.492 mmol) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 140 °C under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (5:1 to 1:1) to give the product (3.5 g, 84%) [M+H]. + = 279.0.

[0271] Step 3: tert-butyl 4-(6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-ethylpyridin-3-yl)piperazine-1-carboxylate TIFF2025501082000217.tif2335 To a stirred solution of 3-bromo-6-(2,5-dimethylpyrrol-1-yl)-2-ethylpyridine (4 g, 14.328 mmol) and tert-butyl piperazine-1-carboxylate (4 g, 21.492 mmol) in dioxane (80 mL) was added CPhos Pd G3 (0.6 g, 0.716 mmol) and t-BuONa (4.1 g, 42.984 mmol) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (5:1 to 1:1) to give the product (4.6 g, 83%). [M+H] + = 385.6.

[0272] Step 4: tert-butyl 4-(6-amino-2-ethylpyridin-3-yl)piperazine-1-carboxylate To a stirred solution of tert-butyl 4-(6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-ethylpyridin-3-yl)piperazine-1-carboxylate (4.5 g, 11.703 mmol) and NHOH.HCl (4.1 g, 58.515 mmol) in EtOH (30 mL) and HO (15 mL) was added TEA (1.2 g, 11.703 mmol) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (10:1 to 5:1) to give the product (3.3 g, 92%). [M+H] + = 307.2.

[0273] Step 5: (R)-tert-butyl 4-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)-2-ethylpyridin-3-yl)piperazine-1-carboxylate TIFF2025501082000219.tif4053 To a stirred solution of tert-butyl 4-(6-amino-2-ethylpyridin-3-yl)piperazine-1-carboxylate (551.70 mg, 1.800 mmol), Cs2CO3 (977.7 mg, 3.000 mmol), and (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (600 mg, 1.500 mmol) in dioxane (12 mL) was added XPhos Pd G3 (190.5 mg, 0.225 mmol) and XPhos (214.5 mg, 0.450 mmol) in small portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 100°C under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with petroleum ether / EtOAc (5:1 to 1:1) to give the product (410 mg, 40%). [M+H] + = 670.3.

[0274] Step 6: (R)-3-(tert-butyl)-N-(1-(4-(6-((6-ethyl-5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide hydrochloride To a stirred solution of (R)-4-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)-2-ethylpyridin-3-yl)piperazine-1-carboxylate (410 mg, 0.612 mmol) in DCM (7 mL) was added dropwise HCl in 1,4-dioxane (7 mL) at room temperature under a nitrogen atmosphere. The final reaction mixture was irradiated with microwave radiation at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with ethyl ether (20 mL) to give the product (220 mg, 59%). 1H NMR (400MHz, DMSO) δ 11.12 (s, 1H), 9.92 (d, J = 7.7Hz, 1H), 9.06 (brs, 2H), 8.86 (s, 1H), 8.49 (s, 1H), 7.99-7.74 (m, 2H), 7.69-7.64 (m, 2H), 7.47 (s, 1H), 5.36 (q, J = 7.1Hz, 1H), 3.28-3.24 (m, 4H), 3.07-3.03 (m, 4H), 2.89 (q, J = 7.4Hz, 2H), 2.49 (s, 3H), 1.52 (d, J = 7.4Hz, 3H), 1.37 (s, 9H); [M+H] + = 570.5.

[0275] Step 7: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-6-ethylpyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide TIFF2025501082000221.tif4872 In a round-bottom flask, a mixture of (R)-3-(tert-butyl)-N-(1-(4-(6-((6-ethyl-5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide hydrochloride (0.05 g, 0.083 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (0.037 g, 0.124 mmol) in 1,2-dichloroethane (5 mL) and HOAc (25 mg) was stirred at room temperature for 0.5 h. The mixture was added with NaBH(OAc)3 (0.044 g, 0.206 mmol) and stirred at room temperature for 3 hours. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (42.99 mg, 61%). 1H NMR (500MHz, DMSO) δ 10.25 (s, 1H), 10.08 (s, 1H), 9.87 (d, J = 7.8 Hz, 1H), 8.72 (s, 1H), 8.46 (s, 1H), 7.91-7.84 (m, 2H), 7.62 (d, J = 8.1Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.42 (s, 1H), 7.13 (d, J = 8.9 Hz, 2H), 6.93 (d, J = 9.1Hz, 2H), 5.38-5.31 (m, 1H), 3.69 (t, J = 6.7Hz, 4H), 2.87-2.76 (m, 6H), 2.67 (dd, J = 16.4, 9.6Hz, 4H), 2.55-2.42 (m, 7H), 2.24 (s, 2H), 1.85-1.65 (m, 3H), 1.51 (d, J = 7.0 Hz, 3H), 1.39-1.31 (m, 12H), 1.27-1.17 (m, 2H). [M+H] + = 855.6.

[0276] Example 61: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-6-methylpyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0277] Step 1: 3-Bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylpyridine TIFF2025501082000222.tif1723 To a stirred solution of 5-bromo-6-methylpyridin-2-amine (5.0 g, 26.732 mmol) and 2,5-hexanedione (4.6 g, 40.098 mmol) in toluene (130 mL) was added p-TsOH (460 mg, 2.673 mmol) at room temperature. The resulting mixture was stirred at 140 °C for 16 h via a Dean-Stark trap to remove water. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was added with water (300 mL) and extracted with EtOAc (2 × 300 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 5% to 10% EtOAc in petroleum ether to give the product (5.5 g, 77%). [M+H] + = 265.0.

[0278] Step 2: tert-butyl 4-(6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylpyridin-3-yl)piperazine-1-carboxylate TIFF2025501082000223.tif2335 To a stirred mixture of 3-bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylpyridine (3.0 g, 11.314 mmol) and tert-butyl piperazine-1-carboxylate (3.2 g, 16.971 mmol) in dioxane (60 mL) was added t-BuONa (3.3 g, 33.94 mmol) and CPhos Pd G3 (465 mg, 0.566 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 10% to 20% EtOAc in petroleum ether to give the product (3.6 g, 85%). [M+H] + = 371.2.

[0279] Step 3: tert-butyl 4-(6-amino-2-methylpyridin-3-yl)piperazine-1-carboxylate To a stirred mixture of tert-butyl 4-(6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylpyridin-3-yl)piperazine-1-carboxylate (3.6 g, 9.717 mmol) and NHOH·HCl (3.4 g, 48.585 mmol) in EtOH (36 mL) and HO (18 mL) was added TEA (980 mg, 9.717 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. The mixture was cooled to room temperature and concentrated. The residue was purified by reverse-phase flash chromatography using the following conditions: Column: C18, Mobile phase A: water (with 10 mM NH4HCO3), Phase B: ACN, 40% to 70% gradient in 30 min, Detector: UV 254 / 220 nm. This gave the product (2.1 g, 74%). [M+H] + = 293.1.

[0280] Step 4: (R)-tert-butyl 4-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)-2-methylpyridin-3-yl)piperazine-1-carboxylate To a stirred mixture of (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (600 mg, 1.50 mmol) and tert-butyl 4-(6-amino-2-methylpyridin-3-yl)piperazine-1-carboxylate (526 mg, 1.80 mmol) in dioxane (12 mL) was added XPhos Pd G3 (190 mg, 0.23 mmol), XPhos (214 mg, 0.45 mmol), and Cs2CO3 (977 mg, 3.00 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 30% to 60% EtOAc in CH2Cl2 to give the product (560 mg, 57%). [M+H] + = 656.4.

[0281] Step 5: (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-((6-methyl-5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride TIFF2025501082000226.tif4151To a stirred solution of (R)-tert-butyl 4-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)-2-methylpyridin-3-yl)piperazine-1-carboxylate (600 mg, 0.915 mmol) in CHCl (10 mL) is added dropwise at room temperature 4 M HCl in 1,4-dioxane (10 mL). The resulting mixture is stirred at room temperature for 1 h and concentrated under reduced pressure. The resulting mixture is triturated with EtO (50 mL) and filtered. The filter cake is washed with EtO (3 x 10 mL). The solid is dried under infrared light. This gave the product (455 mg, 84%). 1H NMR (400MHz, DMSO) δ 10.90 (s, 1H), 9.93 (d, J = 7.8Hz, 1H), 9.13 (s, 2H), 8.87 (s, 1H), 8.18 (s, 1H), 7.84 (d, J = 8.5Hz, 2H), 7.70-7.58 (m, 3H), 5.38-5.31 (m, 1H), 3.26 (s, 4H), 3.08 (t, J = 5.1Hz, 4H), 2.52-2.50 (m, 6H), 1.53 (d, J = 7.0Hz, 3H), 1.37 (s, 9H); [M+H] + = 556.5.

[0282] Step 6: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-6-methylpyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide TIFF2025501082000227.tif4073 In a round-bottom flask, a mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-((6-methyl-5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide hydrochloride (0.06 g, 0.101 mmol) and 1-(4-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)methyl)phenyl)piperidine-4-carbaldehyde (0.046 g, 0.152 mmol) in 1,2-dichloroethane (5 mL) and HOAc (25 mg) was stirred at room temperature for 0.5 h. The mixture was added with NaBH(OAc)3 (0.044 g, 0.206 mmol) and stirred at room temperature for 3 hours. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (46.14 mg, 54%). 1H NMR (500MHz, DMSO) δ 10.25 (s, 1H), 10.07 (s, 1H), 9.87 (d, J = 7.8Hz, 1H), 8.72 (s, 1H), 8.16 (d, J = 15.7Hz, 1H), 7.84 (d, J = 5.6Hz, 2H), 7.62 (d, J = 8.7Hz, 2H), 7.51 (d, J = 8.7Hz, 1H), 7.13 (d, J = 8.9Hz, 2H), 6.93 (d, J = 9.0Hz, 2H), 5.38-5.29 (m, 1H), 3.69 (t, J = 6.7Hz, 4H), 2.85 (s, 4H), 2.67 (dd, J = 16.1, 9.3Hz, 4H), 2.58-2.45 (m, 10H), 2.25 (d, J = 7.1Hz, 2H), 1.85-1.65 (m, 3H), 1.51 (t, J = 8.6Hz, 3H), 1.36 (s, 9H), 1.27-1.19 (m, 2H); [M+H] + = 841.6.

[0283] Example 62: (R)-3-(tert-butyl)-N-(1-(4-(2-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-4-methylpyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide

[0284] Step 1: 5-Bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridine TIFF2025501082000228.tif1923 To a stirred solution of 5-bromo-4-methylpyridin-2-amine (10 g, 53.46 mmol) and hexane-2,5-dione (7.93 g, 69.50 mmol) in toluene (200 mL) was added p-TsOH (0.92 g, 5.35 mmol) at room temperature. The resulting mixture was stirred at 140 °C for 16 h via a Dean-Stark trap to remove water. The mixture was cooled to room temperature and concentrated under reduced pressure. Water (300 mL) was added to the residue and extracted with EtOAc (2 × 300 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (12 g, 85%). [M+H] + = 265.0.

[0285] Step 2: tert-butyl 4-(6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridin-3-yl)piperazine-1-carboxylate TIFF2025501082000229.tif3224 To a stirred solution of 5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridine (5 g, 18.86 mmol) and tert-butyl piperazine-1-carboxylate (5.27 g, 28.29 mmol) in dioxane (100 mL) was added CPhos Pd G3 (0.78 g, 0.94 mmol) and t-BuONa (5.44 g, 56.57 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (5 g, 72%). [M+H] + = 371.2.

[0286] Step 3: tert-butyl 4-(6-amino-4-methylpyridin-3-yl)piperazine-1-carboxylate To a stirred solution of tert-butyl 4-(6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridin-3-yl)piperazine-1-carboxylate (5 g, 13.50 mmol) in EtOH (80 mL) and water (40 mL) was added TEA (1.37 g, 13.50 mmol) and NH2OH·HCl (4.69 g, 67.48 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: Column: C18, Mobile phase: ACN (0.5 M NH4HCO3) in water, 10% to 70% gradient in 10 min, Detector: UV 254 nm. This gave the title product (3.6 g, 92%). [M+H] + = 293.2.

[0287] Step 4: (R)-tert-butyl 4-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)-4-methylpyridin-3-yl)piperazine-1-carboxylate To a stirred solution of tert-butyl 4-(6-amino-4-methylpyridin-3-yl)piperazine-1-carboxylate (0.86 g, 2.93 mmol) and (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (900 mg, 2.25 mmol) in dioxane (30 mL) was added XPhos Pd G3 (190.51 mg, 0.23 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 100° C. under a nitrogen atmosphere and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title product (600 mg, 41%). [M+H] + = 656.4.

[0288] Step 5: (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-((4-methyl-5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000232.tif4151To a stirred solution of (R)-tert-butyl 4-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)-4-methylpyridin-3-yl)piperazine-1-carboxylate (600 mg, 0.92 mmol) in DCM (10 mL) is added dropwise at room temperature under a nitrogen atmosphere to 4.0 M HCl in 1,4-dioxane (10 mL). The resulting mixture is stirred at room temperature under a nitrogen atmosphere for 2 h and concentrated in vacuo. The residue is purified by trituration with EtO (30 mL). The resulting mixture is filtered to give the title product (359 mg, 67%). [M+H] + = 556.5.

[0289] Step 6: (R)-3-(tert-butyl)-N-(1-(4-(2-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-4-methylpyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide A mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-((4-methyl-5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (100 mg, 0.17 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (60 mg, 0.2 mmol), NaBH(OAc) (106 mg, 0.5 mmol), and NaOAc (82 mg, 1.0 mmol) in DCE was stirred at room temperature for 16 h. The mixture was concentrated and purified by silica gel column chromatography to give the title product (45 mg, 31%). 1 H NMR (500MHz, DMSO) δ 10.25 (s, 1H), 10.02 (s, 1H), 9.89 (d, J = 7.8Hz, 1H), 8.73 (d, J = 0.9Hz, 1H), 8.16 (s, 1H), 8.03 (s, 1H), 7.84 (d, J = 5.7Hz, 2H), 7.64-7.52 (m, 2H), 7.13 (d, J = 8.9Hz, 2H), 6.93 (d, J = 9.1Hz, 2H), 5.39-5.29 (m, 1H), 3.73-3.64 (m, 4H), 2.92 (s, 4H), 2.72-2.62 (m, 4H), 2.53-2.48 (m, 7H), 2.30-2.21 (m, 5H), 1.82 (d, J = 11.6Hz, 2H), 1.75-1.67 (m, 1H), 1.51 (d, J = 7.1Hz, 3H), 1.36 (s, 9H), 1.28-1.21 (m, 2H); [M+H] + = 841.6.

[0290] Example 63: (R)-3-(tert-butyl)-N-(1-(4-(2-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-6-methoxypyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide

[0291] Step 1: 5-Bromo-6-methoxypyridin-2-amine TIFF2025501082000234.tif1719To a stirred solution of 6-methoxypyridin-2-amine (5 g, 40.28 mmol) in ACN (20 mL) was added NBS (7.89 g, 44.30 mmol) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (4.3 g, 52%). [M+H] + = 203.0.

[0292] Step 2: 3-Bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methoxypyridine TIFF2025501082000235.tif2221 To a stirred solution of 5-bromo-6-methoxypyridin-2-amine (4.3 g, 21.18 mmol) and hexane-2,5-dione (3.14 g, 27.53 mmol) in toluene (200 mL) was added p-TsOH·H2O (0.40 g, 2.12 mmol) at room temperature. The resulting mixture was stirred at 140 °C for 16 h via a Dean-Stark trap to remove water. The mixture was cooled to room temperature and concentrated under reduced pressure. Water (300 mL) was added to the residue and extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with brine (3 x 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (5 g, 84%). [M+H] + = 281.0.

[0293] Step 3: tert-butyl 4-(6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methoxypyridin-3-yl)piperazine-1-carboxylate TIFF2025501082000236.tif3225 To a stirred solution of tert-butyl piperazine-1-carboxylate (900 mg, 4.84 mmol) and 3-bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methoxypyridine (1.04 g, 3.70 mmol) in dioxane (30 mL) at room temperature, XPhos Pd G3 (191 mg, 0.23 mmol) was added. The resulting mixture was stirred at 100 °C for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (600 mg, 42%). [M+H] + = 387.2.

[0294] Step 4: tert-Butyl 4-(6-amino-2-methoxypyridin-3-yl)piperazine-1-carboxylate To a stirred solution of tert-butyl 4-(6-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methoxypyridin-3-yl)piperazine-1-carboxylate (6.1 g, 15.78 mmol) in EtOH (100 mL) and water (50 mL) was added TEA (1.60 g, 15.78 mmol) and NH2OH·HCl (5.48 g, 78.92 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: Column: C18, Mobile phase: ACN (0.5 M NH4HCO3) in water, 10% to 70% gradient in 10 min, Detector: UV 254 nm. This gave the title product (2.4 g, 50%). [M+H] + = 309.2.

[0295] Step 5: (R)-tert-butyl 4-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)-2-methoxypyridin-3-yl)piperazine-1-carboxylate TIFF2025501082000238.tif4256 To a stirred solution of (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (900 mg, 2.25 mmol) and tert-butyl 4-(6-amino-2-methoxypyridin-3-yl)piperazine-1-carboxylate (1.04 g, 3.38 mmol) in dioxane (30 mL) was added XPhos Pd G3 (190.51 mg, 0.23 mmol) at room temperature. The resulting mixture was stirred at 100° C. for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (600 mg, 40%). [M+H] + = 672.4.

[0296] Step 6: (R)-3-(tert-butyl)-N-(1-(4-(6-((6-methoxy-5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide TIFF2025501082000239.tif4252To a stirred solution of (R)-tert-butyl 4-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)-2-methoxypyridin-3-yl)piperazine-1-carboxylate (600 mg, 0.89 mmol) in DCM (10 mL) is added dropwise at room temperature under a nitrogen atmosphere 4 M HCl in 1,4-dioxane (10 mL). The resulting mixture is stirred at room temperature under a nitrogen atmosphere for 2 h and concentrated in vacuo. The residue is purified by trituration with EtO (30 mL). The resulting mixture is filtered to give the title product (353 mg, 65%). [M+H] + = 572.3.

[0297] Step 7: (R)-3-(tert-butyl)-N-(1-(4-(2-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-6-methoxypyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide A mixture of (R)-3-(tert-butyl)-N-(1-(4-(6-((6-methoxy-5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (100 mg, 0.16 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (60 mg, 0.2 mmol), NaBH(OAc) (106 mg, 0.5 mmol), and NaOAc (82 mg, 1.0 mmol) in 3DCE was stirred at room temperature for 16 h. The mixture was concentrated and purified by silica gel column chromatography to give the title product (50 mg, 36%). 1H NMR (500MHz, DMSO) δ 10.25 (s, 1H), 9.96 (s, 1H), 9.88 (d, J = 7.9Hz, 1H), 8.71 (s, 1H), 8.27 (s, 1H), 7.92-7.82 (m, 2H), 7.61 (d, J = 8.1Hz, 1H), 7.29 (d, J = 8.3Hz, 1H), 7.13 (d, J = 8.8Hz, 3H), 6.93 (d, J = 8.9Hz, 2H), 5.39-5.28 (m, 1H), 4.01 (s, 3H), 3.73-3.64 (m, 4H), 2.96 (s, 3H), 2.72-2.61 (m, 4H), 2.58-2.39 (m, 8H), 2.22 (d, J = 7.0Hz, 2H), 1.81 (d, J = 11.4Hz, 2H), 1.70 (s, 1H), 1.50 (d, J = 7.4Hz, 3H), 1.36 (s, 9H), 1.29-1.23 (m, 2H); [M+H] + =857.6.

[0298] Example 64: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-4-methoxypyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide

[0299] Step 1: 5-Bromo-4-methoxypyridin-2-amine TIFF2025501082000241.tif1720To a stirred solution of 4-methoxypyridin-2-amine (6.2 g, 49.94 mmol) in AcOH (175 mL) was added dropwise at room temperature Br2 (7.98 g, 49.94 mmol) in AcOH (50 mL). The resulting mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The precipitated solid was collected by filtration and washed with EtOAc (3 x 50 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-20% MeOH in DCM to give the product (4 g, 30%). [M+H] + = 204.9.

[0300] Step 2: 5-Bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methoxypyridine A mixture of 5-bromo-4-methoxypyridin-2-amine (3.8 g, 18.72 mmol), p-toluenesulfonic acid (323 mg, 1.87 mmol), and 2,5-hexanedione (2.78 g, 24.33 mmol) in toluene (76 mL) was stirred at 140 °C for 16 h via a Dean-Stark trap to remove water. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0% to 20% EtOAc in petroleum ether to give the product (1.19 g, 23%). [M+H] + = 280.9.

[0301] Step 3: tert-butyl 4-(6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methoxypyridin-3-yl)piperazine-1-carboxylate TIFF2025501082000243.tif2234 To a stirred mixture of 5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methoxypyridine (2 g, 7.11 mmol) and tert-butyl piperazine-1-carboxylate (1.99 g, 10.671 mmol) in dioxane (40 mL) was added CPhos PD G3 (293 mg, 0.36 mmol) and t-BuONa (2.05 g, 21.34 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 4 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0% to 30% EtOAc in petroleum ether to give the product (2.3 g, 84%). [M+H] + = 387.3.

[0302] Step 4: tert-butyl 4-(6-amino-4-methoxypyridin-3-yl)piperazine-1-carboxylate A solution of tert-butyl 4-(6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methoxypyridin-3-yl)piperazine-1-carboxylate (2 g, 5.175 mmol), TEA (524 mg, 5.175 mmol), and NH2OH.HCl (1.8 g, 25.875 mmol) in EtOH (14 mL) and HO (7 mL) was stirred at 80 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-20% MeOH in DCM to give the product (1.5 g, 94%). [M+H] + = 309.3.

[0303] Step 5: (R)-tert-butyl 4-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)piperazine-1-carboxylate TIFF2025501082000245.tif4155 To a stirred mixture of (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (600 mg, 1.50 mmol) and tert-butyl 4-(6-amino-4-methoxypyridin-3-yl)piperazine-1-carboxylate (694 mg, 2.25 mmol) in dioxane (12 mL) under a nitrogen atmosphere at room temperature, XPhos (215 mg, 0.45 mmol), CsCO (978 mg, 3.00 mmol), and XPhos Pd G (191 mg, 0.23 mmol) were added. The resulting mixture was stirred under nitrogen atmosphere at 100°C for 16 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 20% to 70% EtOAc in DCM to give the product (510 mg, 51%). [M+H] + = 672.4.

[0304] Step 6: (R)-3-(tert-butyl)-N-(1-(4-(6-((4-methoxy-5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide hydrochloride TIFF2025501082000246.tif4253To a stirred solution of (R)-tert-butyl 4-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)piperazine-1-carboxylate (500 mg, 0.74 mmol) in DCM (10 mL) was added dropwise at room temperature HCl in 1,4-dioxane (10 mL). The resulting mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was triturated with EtO (80 mL). The solid was dried under infrared light. This gave the product (409.7 mg, 91%). 1H NMR (400MHz, DMSO) δ 12.30 (s, 1H), 9.95 (d, J = 7.6Hz, 1H), 9.30 (s, 2H), 8.97 (s, 1H), 7.93-7.84 (m, 4H), 7.67 (d, J = 8.4Hz, 1H), 7.30 (s, 1H), 5.40-5.29 (m, 1H), 4.02 (s, 3H), 3.25 (s, 8H), 2.52-2.50 (m, 3H), 1.53 (d, J = 6.8Hz, 3H), 1.37 (s, 9H); [M+H] + = 572.4.

[0305] Step 7: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-4-methoxypyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000247.tif4073 In a round-bottom flask, a mixture of (R)-3-(tert-butyl)-N-(1-(4-(6-((4-methoxy-5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide hydrochloride (0.06 g, 0.099 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (0.045 g, 0.148 mmol) in 1,2-dichloroethane (5 mL) and HOAc (25 mg) was stirred at room temperature for 0.5 h. The mixture was added with NaBH(OAc)3 (0.053 g, 0.247 mmol) and stirred at room temperature for 10 hours. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (37.74 mg, 45%). 1H NMR (500MHz, DMSO) δ 10.25 (s, 1H), 9.98 (s, 1H), 9.89 (d, J = 7.7Hz, 1H), 8.73 (d, J = 0.9Hz, 1H), 8.25 (s, 1H), 7.86-7.78 (m, 3H), 7.64-7.59 (m, 1H), 7.38 (s, 1H), 7.13 (d, J = 9.0Hz, 2H), 6.93 (d, J = 9.1Hz, 2H), 5.38-5.30 (m, 1H), 3.86 (s, 3H), 3.69 (dd, J = 12.6, 5.9Hz, 4H), 3.32 (s, 2H), 2.99 (s, 4H), 2.67 (dd, J = 16.3, 9.5Hz, 4H), 2.48 (s, 2H), 2.22 (d, J = 7.0Hz, 2H), 1.77 (t, J = 29.9Hz, 3H), 1.51 (t, J = 8.1Hz, 3H), 1.36 (s, 9H), 1.22 (dd, J = 21.7, 11.2Hz, 2H); [M+H] + = 857.4.

[0306] Example 65: (R)-3-(tert-butyl)-N-(1-(4-(2-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-4-fluoropyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide

[0307] Step 1: 5-Bromo-4-fluoro-N,N-bis(4-methoxybenzyl)pyridin-2-amine TIFF2025501082000248.tif2119To a stirred mixture of 5-bromo-4-fluoropyridin-2-amine (2.5 g, 13.09 mmol) in THF (50 mL) is added NaH (1.57 g, 39.27 mmol) portionwise at 0 °C under a nitrogen atmosphere. The resulting mixture is stirred at 0 °C for 1 h under a nitrogen atmosphere. PMBCl (6.1 g, 39.27 mmol) is added dropwise to the above mixture at 0 °C. The resulting mixture is stirred at 75 °C for an additional 16 h. The mixture is cooled to room temperature and quenched with saturated NH4Cl (aq) at 0 °C. The resulting mixture is extracted with EtOAc (3 x 200 mL). The combined organic layers are washed with brine (2 x 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (3.5 g, 62%). [M+H] + = 433.1.

[0308] Step 2: tert-butyl 4-(6-(bis(4-methoxybenzyl)amino)-4-fluoropyridin-3-yl)piperazine-1-carboxylate TIFF2025501082000249.tif3128 To a stirred mixture of 5-bromo-4-fluoro-N,N-bis(4-methoxybenzyl)pyridin-2-amine (3.3 g, 7.65 mmol) and tert-butyl piperazine-1-carboxylate (1.7 g, 9.18 mmol) in toluene (66 mL) was added Pd2(dba)3 (700 mg, 0.77 mmol), t-BuONa (1.1 g, 11.47 mmol), and BINAP (952 mg, 1.53 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16 h under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (3.6 g, 87%). [M+H] + = 537.3.

[0309] Step 3: 4-Fluoro-5-(piperazin-1-yl)pyridin-2-amine TIFF2025501082000250.tif2420 A solution of tert-butyl 4-(6-(bis(4-methoxybenzyl)amino)-4-fluoropyridin-3-yl)piperazine-1-carboxylate (3.6 g, 6.71 mmol) in TFA (40 mL) was stirred at 75 °C under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. EtO (50 mL) was added to the resulting mixture and filtered. The filter cake was washed with EtO (3 x 10 mL). The solid was dried under infrared light to give the title product (2.3 g, 80%). [M+H] + = 197.1.

[0310] Step 4: tert-butyl 4-(6-amino-4-fluoropyridin-3-yl)piperazine-1-carboxylate To a stirred mixture of 4-fluoro-5-(piperazin-1-yl)pyridin-2-amine (2.3 g, 5.421 mmol) and TEA (2.2 g, 21.68 mmol) in CHCl (40 mL) was added BocO (1.4 g, 6.51 mmol) at 0° C. The resulting mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (1.3 g, 81%). [M+H] + = 297.2.

[0311] Step 5: (R)-tert-butyl 4-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)-4-fluoropyridin-3-yl)piperazine-1-carboxylate To a stirred mixture of (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (500 mg, 1.25 mmol) and tert-butyl 4-(6-amino-4-fluoropyridin-3-yl)piperazine-1-carboxylate (444 mg, 1.50 mmol) in dioxane (10 mL) was added XPhos Pd G (158 mg, 0.19 mmol), XPhos (178 mg, 0.38 mmol), and CsCO (815 mg, 2.50 mmol) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (600 mg, 73%). [M+H] + = 660.3.

[0312] Step 6: (R)-3-(tert-butyl)-N-(1-(4-(6-((4-fluoro-5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000253.tif4050To a stirred mixture of (R)-tert-butyl 4-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)-4-fluoropyridin-3-yl)piperazine-1-carboxylate (650 mg, 0.99 mmol) in DCM (10 mL) at room temperature, HCl in 1,4-dioxane (10 mL) was added dropwise. The resulting mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. EtO (50 mL) was added to the resulting mixture and filtered. The filter cake was washed with EtO (3 x 10 mL). The solid was dried under infrared light to give the title product (563 mg, 96%). [M+H] + = 560.3.

[0313] Step 7: (R)-3-(tert-butyl)-N-(1-(4-(2-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-4-fluoropyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide A mixture of (R)-3-(tert-butyl)-N-(1-(4-(6-((4-fluoro-5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (100 mg, 0.167 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (50 mg, 0.166 mmol), NaBH(OAc) (150 mg, 0.65 mmol), and NaOAc (150 mg, 1.9 mmol) in DCM / MeOH (20 mL / 5 mL) was stirred at room temperature for 16 h. The mixture was concentrated and purified by silica gel column chromatography to give the title product (90 mg, 64%). 1H NMR (500MHz, DMSO) δ 10.26 (d, J = 5.6Hz, 2H), 9.89 (d, J = 7.8Hz, 1H), 8.77 (s, 1H), 8.08 (d, J = 11.6Hz, 1H), 8.00 (s, 1H), 7.87-7.73 (m, 3H), 7.61 (d, J = 8.6Hz, 1H), 7.13 (d, J = 8.8Hz, 2H), 6.93 (d, J = 8.9Hz, 2H), 5.37-5.30 (m, 1H), 3.73-3.64 (m, 4H), 3.05 (s, 4H), 2.71-2.62 (m, 4H), 2.57-2.44 (m, 7H), 2.23 (d, J = 7.0Hz, 2H), 1.81 (d, J = 11.9Hz, 2H), 1.71 (s, 1H), 1.51 (d, J = 6.9Hz, 3H), 1.36 (s, 9H), 1.29-1.23 (m, 2H); [M+H] + = 845.6.

[0314] Example 66: (R)-3-(tert-butyl)-N-(1-(4-(2-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-6-fluoropyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0315] Step 1: 5-Bromo-6-fluoro-N,N-bis(4-methoxybenzyl)pyridin-2-amine To a stirred mixture of 5-bromo-6-fluoropyridin-2-amine (2.5 g, 13.09 mmol) in THF (50 mL) was added NaH (1.57 g, 39.27 mmol) portionwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. PMBCl (6.15 g, 39.27 mmol) was added dropwise to the above mixture at 0 °C. The resulting mixture was further stirred at 25 °C for 16 h and quenched at 0 °C by the addition of saturated NH Cl (aq) (50 mL). The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na SO . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (3.56 g, 63%). [M+H] + = 433.1.

[0316] Step 2: tert-butyl 4-(6-(bis(4-methoxybenzyl)amino)-2-fluoropyridin-3-yl)piperazine-1-carboxylate TIFF2025501082000256.tif3027 To a stirred mixture of 5-bromo-6-fluoro-N,N-bis(4-methoxybenzyl)pyridin-2-amine (3.5 g, 8.12 mmol) and tert-butyl piperazine-1-carboxylate (1.96 g, 10.55 mmol) in toluene (50 mL) was added BINAP (1.01 g, 1.62 mmol), Pd2(dba)3 (743 mg, 0.81 mmol), and t-BuONa (1.17 g, 12.17 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 16 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (3.1 g, 71%). [M+H] + = 537.3.

[0317] Step 3: 6-Fluoro-5-(piperazin-1-yl)pyridin-2-amine A solution of tert-butyl 4-(6-(bis(4-methoxybenzyl)amino)-2-fluoropyridin-3-yl)piperazine-1-carboxylate (3 g, 5.59 mmol) in TFA (60 mL) is stirred at 72° C. under a nitrogen atmosphere for 2 h. The resulting mixture is concentrated under reduced pressure. The crude product is used directly in the next step without further purification. [M+H] + = 197.1.

[0318] Step 4: tert-butyl 4-(6-amino-2-fluoropyridin-3-yl)piperazine-1-carboxylate To a stirred mixture of 6-fluoro-5-(piperazin-1-yl)pyridin-2-amine (3 g, 3.54 mmol) and EtN (1.97 mL, 14.14 mmol) in 3DCM (60 mL) was added BocO (0.93 g, 4.24 mmol) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (710 mg, 68%). [M+H] + = 297.2.

[0319] Step 5: (R)-tert-butyl 4-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)-2-fluoropyridin-3-yl)piperazine-1-carboxylate TIFF2025501082000259.tif4155 To a stirred mixture of (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (500 mg, 1.25 mmol) and tert-butyl 4-(6-amino-2-fluoropyridin-3-yl)piperazine-1-carboxylate (445 mg, 1.50 mmol) in dioxane (10 mL) was added XPhos (179 mg, 0.38 mmol), CsCO (815 mg, 2.50 mmol), and XPhos Pd G (159 mg, 0.19 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred under nitrogen atmosphere at 100°C for 16 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (370 mg, 45%). [M+H] + = 660.3.

[0320] Step 6: (R)-3-(tert-butyl)-N-(1-(4-(6-((6-fluoro-5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000260.tif4251To a stirred solution of (R)-tert-butyl 4-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)-2-fluoropyridin-3-yl)piperazine-1-carboxylate (370 mg, 0.56 mmol) in DCM (5 mL) at room temperature, 4 M HCl in 1,4-dioxane (5 mL) was added dropwise. The resulting mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by trituration with EtO (50 mL) to give the title product (277.6 mg, 83%). [M+H] + = 560.3.

[0321] Step 7: (R)-3-(tert-butyl)-N-(1-(4-(2-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-6-fluoropyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide TIFF2025501082000261.tif5181 A mixture of (R)-3-(tert-butyl)-N-(1-(4-(6-((6-fluoro-5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (80 mg, 0.13 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (40 mg, 0.13 mmol), NaBH(OAc) (100 mg, 0.43 mmol), and NaOAc (100 mg, 1.3 mmol) in DCM / MeOH (10 mL / 2 mL) was stirred at room temperature for 16 h. The mixture was concentrated and purified by silica gel column chromatography to give the title product (50 mg, 35%). 1 H NMR (500MHz, DMSO) δ 10.24 (d, J = 15.2Hz, 2H), 9.88 (d, J = 7.8Hz, 1H), 8.76 (s, 1H), 7.86-7.77 (m, 4H), 7.65-7.56 (m, 2H), 7.13 (d, J = 8.9Hz, 2H), 6.93 (d, J = 9.0Hz, 2H), 5.38-5.29 (m, 1H), 3.69 (t, J = 6.7Hz, 4H), 3.01 (s, 4H), 2.72-2.62 (m, 4H), 2.55-2.44 (m, 7H), 2.23 (d, J = 7.0Hz, 2H), 1.81 (d, J = 11.5Hz, 2H), 1.70 (s, 1H), 1.51 (d, J = 6.9Hz, 3H), 1.36 (s, 9H), 1.29-1.22 (m, 2H); [M+H] + = 844.9.

[0322] Example 67: (R)-3-(tert-butyl)-N-(1-(4-(2-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide

[0323] Step 1: tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate TIFF2025501082000262.tif1833 To a stirred mixture of 5-bromo-2-nitropyridine (5 g, 24.63 mmol) and tert-butyl piperazine-1-carboxylate (6.88 g, 36.94 mmol) in dioxane (100 mL) was added X-Phos (3.52 g, 7.38 mmol), Cs2CO3 (16.05 g, 49.26 mmol), and XPhos Pd G3 (3.13 g, 3.69 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title product (3.5 g, 46%). [M+H] + = 309.3.

[0324] Step 2: tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate TIFF2025501082000263.tif1834 A mixture of tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (3.5 g, 11.35 mmol) and Fe (6.34 g, 113.51 mmol) in AcOH (80 mL) is stirred at 30 °C for 4 h. The resulting mixture is filtered. The filter cake is washed with EtOAc (2 x 300 mL). The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give the title product (3.1 g, 98%). [M+H] + = 279.2.

[0325] Step 3: (R)-tert-butyl 4-(6-((4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate TIFF2025501082000264.tif4156 To a stirred mixture of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (300 mg, 1.08 mmol) and (R)-3-(tert-butyl)-N-(1-(4-(2-chloropyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (the compound was obtained in a manner similar to that in Example 1) (430.97 mg, 1.08 mmol) in dioxane (6.00 mL) was added X-Phos (102.76 mg, 0.216 mmol), XPhos Pd G3 (91.23 mg, 0.11 mmol), and Cs2CO3 (702.31 mg, 2.16 mmol) in small portions at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 100°C for 16 h and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title product (710 mg, 98%). [M+H] + = 642.2.

[0326] Step 4: (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide TIFF2025501082000265.tif4151 A solution of (R)-tert-butyl 4-(6-((4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate (741 mg, 1.16 mmol) in DCM (10 mL) and HCl in 1,4-dioxane (10 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. The residue was triturated with EtO to give the title product (640 mg, 95%). 1 H NMR (400MHz, DMSO) δ 11.65 (s, 1H), 9.96 (d, J = 7.7Hz, 1H), 9.50 (brs, 2H), 8.74 (d, J = 5.5Hz, 1H), 8.15-8.11 (m, 1H), 8.09-8.00 (m, 3H), 7.81-7.74 (m, 2H), 7.67 (d, J = 8.1Hz, 1H), 5.37-5.33 (m, 1H), 3.48-3.43 (m, 4H), 3.28-3.24 (m, 4H), 2.48 (s, 3H),1.53 (d, J = 7.0Hz, 3H), 1.37 (s, 9H); [M+H] + = 542.4.

[0327] Step 5: (R)-3-(tert-butyl)-N-(1-(4-(2-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide A mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (100 mg, 0.17 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (60 mg, 0.2 mmol), NaBH(OAc) (106 mg, 0.5 mmol), and NaOAc (82 mg, 1.0 mmol) in 1DCE was stirred at room temperature for 16 h. The mixture was concentrated and purified by silica gel column chromatography to give the title product (45 mg, 32%). 1 H NMR (500MHz, DMSO) δ 10.25 (s, 1H), 9.89 (d, J = 7.8Hz, 1H), 9.45 (s, 1H), 8.53 (d, J = 5.2Hz, 1H), 8.18 (d, J = 9.1Hz, 1H), 8.04-7.94 (m, 3H), 7.62 (d, J = 8.1Hz, 1H), 7.48 (dd, J = 9.2, 2.9Hz, 1H), 7.40 (d, J = 5.2Hz, 1H), 7.13 (d, J = 8.9Hz, 2H), 6.93 (d, J = 9.0Hz, 2H), 5.39-5.29 (m, 1H), 3.73-3.64 (m, 4H), 3.14 (s, 4H), 2.71-2.62 (m, 4H), 2.57-2.52 (m, 4H), 2.48 (s, 3H), 2.23 (d, J = 7.2Hz, 2H), 1.81 (d, J = [M+H] + = 827.5.

[0328] Example 68: (R)-3-(tert-butyl)-N-(1-(4-(2-((5-(4-(7-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0329] Step 1: 7-Azaspiro[3.5]nonan-2-ol To a solution of 7-azaspiro[3.5]nonan-2-one (200 mg, 1.1 mmol) in MeOH (10 mL) was slowly added NaBH (45 mg, 1.2 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (140 mg, 90%). 1 H NMR (500MHz, DMSO) δ 4.10-4.00 (m, 1H), 2.62-2.51 (m, 4H), 2.11-2.03 (m, 2H), 1.52-1.46 (m, 2H), 1.39-1.33 (m, 4H).

[0330] Step 2: 1-(4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)phenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione TIFF2025501082000268.tif2646 A mixture of 7-azaspiro[3.5]nonan-2-ol (130 mg, 0.92 mmol), 4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyl trifluoromethanesulfonic acid (450 mg, 0.96 mmol), Pd2dba3 (40 mg, 0.044 mmol), RuPhos (40 mg, 0.086 mmol), and Cs2CO3 (600 mg, 1.84 mmol) in dioxane was heated to reflux for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (60 mg, 14%). [M+H] + = 458.3.

[0331] Step 3: (R)-3-(tert-butyl)-N-(1-(4-(2-((5-(4-(7-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide TIFF2025501082000269.tif4883 (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (37 mg, 0.068 mmol), 1- A mixture of (4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)phenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (40 mg, 0.087 mmol), NaBH(OAc)3 (50 mg, 0.23 mmol), and NaOAc (71 mg, 0.86 mmol) was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (30 mg, 45%). [M+H]+ = 982.7.

[0332] Step 4: (R)-3-(tert-butyl)-N-(1-(4-(2-((5-(4-(7-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide A solution of (R)-3-(tert-butyl)-N-(1-(4-(2-((5-(4-(7-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (30 mg, 0.031 mmol) in HCl / dioxane (4 N, 10 mL) was stirred at room temperature for 16 h. The mixture was concentrated and stirred with NH3 / MeOH (7 N, 5 mL) at room temperature for 10 min. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title product (12 mg, 45%). 1H NMR (500MHz, DMSO) δ 10.25 (s, 1H), 9.89 (d, J = 7.8Hz, 1H), 9.44 (s, 1H), 8.53 (d, J = 5.2Hz, 1H), 8.17 (d, J = 9.1Hz, 1H), 8.03-7.94 (m, 3H), 7.61 (d, J = 8.1Hz, 1H), 7.47 (dd, J = 9.2, 2.8Hz, 1H), 7.40 (d, J = 5.3Hz, 1H), 7.13 (d, J = 8.9Hz, 2H), 6.93 (d, J = 9.0Hz, 2H), 5.37-5.30 (m, 1H), 3.69 (t, J = 6.7Hz, 2H), 3.13 (s, 6H), 3.05 (s, 2H), 2.78-2.72 (m, 1H), 2.68 (t, J = 6.7Hz, 2H), 2.48 (s, 3H), 2.41 (s, 4H), 2.01 (t, J = 9.0Hz, 2H), 1.71-1.56 (m, 6H), 1.52 (d, J = 7.0Hz, 3H), 1.36 (s, 9H); + = 853.8.

[0333] Example 69: (R)-3-(tert-butyl)-N-(1-(4-(2-((4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0334] Step 1: Benzyl 4-(4-nitrophenyl)piperazine-1-carboxylate TIFF2025501082000271.tif1832To a stirred solution of 4-fluoronitrobenzene (5 g, 35.436 mmol) and piperazine-1-carboxylate (9.3 g, 42.523 mmol) in DMSO (100 mL) was added dropwise at room temperature under a nitrogen atmosphere with TEA (10.7 g, 106.308 mmol). The resulting mixture was stirred overnight at 100°C under a nitrogen atmosphere and diluted with water (500 mL). The resulting mixture was filtered. The filter cake was washed with water (3 x 50 mL). The filter cake was collected and dried in vacuo to give the product (10 g, 82%). [M+H] + = 342.0.

[0335] Step 2: Benzyl 4-(4-aminophenyl)piperazine-1-carboxylate TIFF2025501082000272.tif1834To a stirred solution of benzyl 4-(4-nitrophenyl)piperazine-1-carboxylate (9.5 g, 27.829 mmol) in AcOH (260 mL) was added Fe powder (15.5 g, 278.290 mmol) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere and filtered. The filter cake was washed with EtOAc (3 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 40% to 60% petroleum ether in EtOAc to give the product (9 g, 93%). [M+H] + = 312.1.

[0336] Step 3: (R)-Benzyl 4-(4-((4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate To a stirred solution of (R)-3-(tert-butyl)-N-(1-(4-(2-chloropyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (900 mg, 2.251 mmol) and benzyl 4-(4-aminophenyl)piperazine-1-carboxylate (840 mg, 2.701 mmol) in dioxane (18 mL) was added XPhos Pd G3 (285 mg, 0.338 mmol), Cs2CO3 (1.4 g, 4.502 mmol), and XPhos (321 mg, 0.675 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography eluting with 20% to 50% petroleum ether in EtOAc to give the product (890 mg, 58%). [M+H] + = 675.3.

[0337] Step 4: (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(2-((4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000274.tif3746 To a 50 mL round-bottom flask was added (R)-benzyl 4-(4-((4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (890 mg, 1.319 mmol) and TFA (15 mL) at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at 70° C. overnight and concentrated under reduced pressure. The residue was purified by trituration with ethyl ether (20 mL) to give the product (636 mg, 73%). 1H NMR (400MHz, DMSO) δ 9.89 (d, J = 7.8Hz, 1H), 9.41 (s, 1H), 8.47 (d, J = 5.2Hz, 1H), 8.25 (s, 1H), 8.01-7.95 (m, 2H), 7.96 (s, 1H), 7.72-7.64 (m, 2H), 7.62 (d, J = 8.7Hz, 1H), 7.30 (d, J = 5.2Hz, 1H), 6.94 (d, J = 9.0Hz, 2H), 5.36-5.32 (m, 1H), 3.13-3.09 (m, 4H), 3.03-2.99 (m, 4H), 2.48 (s, 3H), 1.52 (d, J = 6.9Hz, 3H), 1.37 (s, 9H); [M+H] + = 541.3.

[0338] Step 5: (R)-3-(tert-butyl)-N-(1-(4-(2-((4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000275.tif3971 A mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(2-((4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (0.06 g, 0.092 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (0.042 g, 0.137 mmol) in 1,2-dichloroethane (5 mL) and HOAc (25 mg) was stirred in a round-bottom flask at room temperature for 0.5 h. The mixture was added with NaBH(OAc)3 (0.044 g, 0.206 mmol) and stirred at room temperature for 3 hours. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (41.51 mg, 55%). 1H NMR (500MHz, DMSO) δ 10.25 (s, 1H), 9.88 (d, J = 7.8Hz, 1H), 9.37 (s, 1H), 8.46 (d, J = 5.2Hz, 1H), 7.96 (d, J = 8.0Hz, 2H), 7.65 (d, J = 8.9Hz, 2H), 7.61 (d, J = 8.0Hz, 1H), 7.29 (d, J = 5.2Hz, 1H), 7.13 (d, J = 8.9Hz, 2H), 6.92 (dd, J = 8.9, 4.8Hz, 4H), 5.37-5.29 (m, 1H), 3.69 (t, J = 6.7Hz, 4H), 3.08 (s, 4H), 2.70-2.63 (m, 4H), 2.55-2.50 (m, 4H), 2.47 (s, 3H), 2.23 (d, J = 6.9Hz, 2H), 1.81 (d, J = 11.7Hz, 2H), 1.71 (s, 1H), 1.51 (d, J = 7.0Hz, 3H), 1.36 (s, 9H), 1.28-1.17 (m, 2H); [M+H] + = 826.6.

[0339] Example 70: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound TIFF2025501082000276.tif4174 was synthesized in the same manner as in Example 68. 1H NMR (500MHz, DMSO) δ 10.25 (s, 1H), 9.90 (d, J = 10.0Hz, 1H), 9.72 (s, 1H), 8.48 (s, 1H), 8.09-8.05 (m, 1H), 7.95 (d, J = 10.0Hz, 2H), 7.82-7.79 (m, 2H), 7.63 (d, J = 5.0Hz, 1H), 7.45 (d, J = 5.0Hz, 1H), 7.13 (d, J = 10.0Hz, 2H), 6.93 (d, J = 10.0Hz, 2H), 5.36-5.33 (m, 1H), 3.71-3.68 (m, 4H), 3.17 (s, 4H), 2.69-2.65 (m, 4H), 2.55-2.53 (m, 4H), 2.47 (s, 3H), 2.24-2.23 (m, 2H), 1.83-1.72 (m, 3H), 1.52 (d, J = 10.0Hz, 3H), 1.36 (s, 9H), 1.26-1.20 (m, 2H); [M+H] + = 845.6.

[0340] Example 71: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)thiazol-2-yl)amino)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide

[0341] Step 1: tert-butyl 4-(2-aminothiazol-5-yl)piperazine-1-carboxylate TIFF2025501082000277.tif1733 To a stirred mixture of 5-bromothiazole-2-amine hydrobromide (1.5 g, 5.77 mmol) and tert-butyl piperazine-1-carboxylate (1.29 g, 6.93 mmol) in DMF (20 mL) was added K2CO3 (2.4 g, 17.39 mmol) at room temperature. The resulting mixture was stirred at 50 °C under a nitrogen atmosphere for 3 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 5% to 90% EtOAc in petroleum ether to give the product (1.4 g, 85%). [M+H] + = 285.1.

[0342] Step 2: tert-butyl 4-(2-((6-chloropyrimidin-4-yl)amino)thiazol-5-yl)piperazine-1-carboxylate TIFF2025501082000278.tif2637 To a stirred mixture of tert-butyl 4-(2-aminothiazol-5-yl)piperazine-1-carboxylate (1.4 g, 4.92 mmol) and 4,6-dichloropyrimidine (1.4 g, 9.39 mmol) in ethanol (40 mL) was added DIEA (1.27 g, 9.84 mmol) at room temperature. The resulting mixture was stirred at 75 °C under a nitrogen atmosphere for 12 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 5% to 90% EtOAc in petroleum ether to give the product (1.2 g, 77%). [M+H] + = 397.1.

[0343] Step 3: (R)-tert-butyl 4-(2-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-2-fluoro-5-methylphenyl)pyrimidin-4-yl)amino)thiazol-5-yl)piperazine-1-carboxylate TIFF2025501082000279.tif4257 tert-Butyl 4-(2-((6-chloropyrimidin-4-yl)amino)thiazol-5-yl)piperazine-1-carboxylate (400 mg, 1.007 mmol) and (R)-3-(tert-butyl)-N-(1-(5-fluoro-2-methyl)-2-pyridin-4-yl)amino)thiazol-5-yl)piperazine-1-carboxylate (400 mg, 1.007 mmol) in dioxane (8 mL) and H2O (2 mL) To a stirred mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl-1,2,4-oxadiazol-5-carboxamide (480 mg, 1.114 mmol) was added K2CO3 (280 mg, 2.029 mmol) and Pd(dppf)Cl2 (80 mg, 0.098 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 89 °C for 16 h under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 10% to 95% EtOAc in petroleum ether to give the product (280 mg, 42%). [M+H] + = 666.3.

[0344] Step 4: (R)-3-(tert-butyl)-N-(1-(5-fluoro-2-methyl-4-(6-((5-(piperazin-1-yl)thiazol-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000280.tif4353To a stirred solution of (R)-tert-butyl 4-(2-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-2-fluoro-5-methylphenyl)pyrimidin-4-yl)amino)thiazol-5-yl)piperazine-1-carboxylate (75 mg, 0.132 mmol) in DCM (5 mL) at room temperature, TFA (1 mL) is added. The resulting solution is stirred at room temperature for 0.5 h and concentrated in vacuo. The residue (100 mg, crude) is used directly in the next step without further purification. [M+H] + = 566.2.

[0345] Step 5: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)thiazol-2-yl)amino)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide TIFF2025501082000281.tif4368A mixture of (R)-3-(tert-butyl)-N-(1-(5-fluoro-2-methyl-4-(6-((5-(piperazin-1-yl)thiazol-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (0.1 g, crude) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (0.05 g, 0.166 mmol) in 1,2-dichloroethane (5 mL) and HOAc (25 mg) was stirred at room temperature for 0.5 h in a round-bottom flask. The mixture was added with NaBH(OAc)3 (0.04 g, 0.189 mmol) and stirred at room temperature for 12 hours. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (19.58 mg, 21%). 1H NMR (500MHz, DMSO) δ 11.45 (s, 1H), 10.25 (s, 1H), 9.87 (d, J = 7.9Hz, 1H), 8.83 (d, J = 0.9Hz, 1H), 7.90 (d, J = 8.0Hz, 1H), 7.44 (d, J = 12.9Hz, 2H), 7.13 (d, J = 8.9Hz, 2H), 6.93 (d, J = 8.9Hz, 2H), 6.66 (s, 1H), 5.29 (t, J = 7.1Hz, 1H), 3.69 (t, J = 6.7Hz, 4H), 3.05 (s, 4H), 2.67 (dd, J = 16.1, [M+H] + = 851.6.

[0346] Example 72: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0347] Step 1: tert-butyl 4-(5-amino-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate TIFF2025501082000282.tif1134 A mixture of 5-bromo-1,3,4-thiadiazol-2-amine (5 g, 27 mmol), tert-butyl piperazine-1-carboxylate (7.5 g, 40 mmol), and K2CO3 (7.0 g, 51 mmol) in DMA (50 mL) was stirred at 100 °C for 16 h. The mixture was cooled, and water (250 mL) was added. The resulting mixture was extracted with EA (2100 mL). The combined organic layers were washed with saturated NaCl (aq) (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the product (5.2 g, 67%). [M+H] + = 285.9.

[0348] Step 2: tert-butyl 4-(5-((6-chloropyrimidin-4-yl)amino)-1,3,4 thiadiazol-2-yl)piperazine-1-carboxylate TIFF2025501082000283.tif1741 A mixture of tert-butyl 4-(5-amino-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (590 mg, 2.1 mmol), 4,6-dichloropyrimidine (300 mg, 2.0 mmol), Pd2dba3 (60 mg, 0.066 mmol), XantPhos (100 mg, 0.172 mmol), and Na2CO3 (580 mg, 5.47 mmol) in dioxane (20 mL) was stirred at 110 °C for 16 h. The resulting mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the product (410 mg, 52%). [M+H] + = 398.2.

[0349] Step 3: (R)-tert-butyl 4-(5-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)-1,3,4 thiadiazol-2-yl)piperazine-1-carboxylate TIFF2025501082000284.tif4853 (R)-tert-butyl 4-(5-((6-chloropyrimidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (260 mg, 0.65 mmol), (R)-3-(tert-butyl)-N-(1-( A mixture of 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (230 mg, 0.56 mmol), Pd(dppf)Cl2 (50 mg, 0.068 mmol), and K2CO3 (300 mg, 2.17 mmol) was stirred at 110 °C for 16 hours. The resulting mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the product (200 mg, 55%). [M+H] + = 649.4.

[0350] Step 4: (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-((5-(piperazin-1-yl)-1,3,4 thiadiazol-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025501082000285.tif4849 To a stirred solution of (R)-tert-butyl 4-(5-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazol-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (77 mg, 0.12 mmol) in dioxane (4 mL) at room temperature, add 4N HCl / dioxane (4 mL). The resulting solution is stirred at room temperature for 16 h. The resulting mixture is concentrated in vacuo to give the product (85 mg, crude). [M+H] + = 549.5.

[0351] Step 5: (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1,3,4 thiadiazol-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide A mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-((5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)amino)pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazol-5-carboxamide (85 mg, crude), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (40 mg, 0.13 mmol), NaOAc (100 mg, 1.2 mmol), and NaBH(OAc) (100 mg, 0.47 mmol) in DCE (10 mL) was stirred at room temperature for 2 h. The mixture was concentrated and purified by silica gel column chromatography to give the title product (15 mg, 15%). 1 H NMR (500MHz, DMSO) δ 11.68 (s, 1H), 10.25 (s, 1H), 9.89 (d, J = 7.8Hz, 1H), 8.80 (s, 1H), 7.84 (s, 2H), 7.62 (d, J = 8.7Hz, 1H), 7.37 (s, 1H), 7.13 (d, J = 8.9Hz, 2H), 6.93 (d, J = 9.1Hz, 2H), 5.37-5.28 (m, 1H), 3.72-3.64 (m, 4H), 3.46-3.36 (m, 4H), 2.71-2.61 (m, 4H), 2.52-2.44 (m, 7H), 2.23 (d, J = 7.0Hz, 2H), 1.81 (d, J = 12.1Hz, 2H), 1.71 (s, 1H), 1.51 (d, J = 6.9Hz, 3H), 1.36 (s, 9H), 1.27-1.18 (m, 2H); [M+H] += 834.6.

[0352] cell degradation Cell treatment TMD-8 cells were seeded in a Corning 96-well plate (Cat. No. 3799) at 20,000 cells / well in a volume of 15 μl / well in cell culture medium [RPMI 1640 (Gibco, phenol red-free, Cat. No. 11835-030), 10% heat-inactivated FBS, 1% PS (Gibco, Cat. No. 10378)]. TMD-8 cells were treated with compounds diluted in 0.2% DMSO according to the following protocol: (1) A 500x stock solution was prepared by six-fold dilution from 1 mM in DMSO, containing a total of 8 doses. (2) A 2x solution was prepared in cell culture medium by transferring 0.5 μl of the 500x stock solution to 125 μl of medium. (3) 15 μl of the 2x solution was added to the cells and incubated for 6 h.

[0353] HTFR measurement After 6 h of treatment, 10 μl of 4x lysis buffer was added to each well, the plate was sealed and incubated on a plate shaker at room temperature for 30 min. Once the cells were lysed, 16 μL of cell lysate was transferred to a PE 384-well HTRF detection plate, 4 μL of premixed HTRF antibody was added to each well, the plate was covered with a plate sealer, then spun at 1000 rpm for 1 min, and then incubated at room temperature overnight. The results were read on a BMG PheraStar using the HTRF protocol (337 nm-665 nm-620 nm). The inhibition (decomposition) rate (%) of the compound was calculated as follows: Inhibition rate (%) of compound = 100 - 100 x (signal - low control) / (high control - low control), where signal = each test compound group. Low control = lysis buffer only, no cells, showing complete degradation of BTK. High control = cells with DMSO and no compound added, showing microplate readings with no BTK degradation. Dmax is the maximum percentage of inhibition (degradation). Compound IC 50 (DC 50 ) values ​​can be obtained by fitting the following equation: Y = Bottom + (Top-Bottom) / (1 + ((IC 50 / X) ^Hillslope)) where X and Y are known values ​​and IC 50 , Hillslope, top, and bottom are parameters obtained by fitting via software. Y is the inhibition rate (calculated from the formula), X is the compound concentration, and IC 50 is the concentration of compound at which 50% inhibition is achieved. IC 50 The smaller the IC value, the greater the inhibitory potential of the compound. 50 The higher the value, the lower the inhibitory potency of the compound. The Hill slope represents the gradient of the fitted curve and is usually about 1*. The bottom represents the minimum value of the curve obtained by data fitting and is usually 0%±20%. The top represents the maximum value of the curve obtained by data fitting and is usually 100%±20%. The experimental data were fitted by calculation and analysis using Dotmatics data analysis software.

[0354] HEK-293 cell treatment HEK-293 cells were seeded in a Corning 96-well plate (Cat. No. 3903) at 2000 cells / well in a volume of 50 μl / well in cell culture medium [DMEM (Gibco, Cat. No. 11965-092), 10% heat-inactivated FBS (Gibco, Cat. No. 10099), 1% PS (Gibco, Cat. No. 10378)] and incubated overnight. HEK-293 cells were treated with compounds diluted in 0.2% DMSO according to the following protocol: (1) A 500x stock solution was prepared by 4-fold dilution from 5 mM in DMSO, containing a total of 8 doses. (2) A 2x solution was prepared in cell culture medium by transferring 0.5 μl of the 500x stock solution to 125 μl of medium. (3) 50 μl of the 2x solution was added to the cells and incubated for 72 h.

[0355] Cytotoxicity detection 25 μl of CellTiter-Glo® Reagent (Promega - Catalog No. G7572) was added to each well of a 96-well plate. The contents were mixed on an orbital shaker for 2 minutes to induce cell lysis. The plate was then incubated at room temperature for 10 minutes to allow the luminescence signal to stabilize. Luminescence was recorded on a BMG PheraStar using the luminescence protocol.

[0356] IC50 calculation The inhibition rate (%) of the compound was calculated as follows: Inhibition rate (%) of the compound = 100 - 100 x (signal - low control) / (high control - low control), where signal = each test compound group. Low control = medium only (no cells), showing complete inhibition of cell proliferation. High control = cells with DMSO and no compound added, showing no inhibition of cell proliferation. Imax is the maximum percentage of inhibition. Compound IC 50 The value can be obtained by fitting the following equation: Y = Bottom + (Top-Bottom) / (1 + ((IC50 / X) ^Hillslope)) In the formula, X and Y are known values, and IC50, Hillslope, top, and bottom are parameters obtained by fitting via software. Y is the inhibition rate (calculated from the formula), X is the compound concentration, and IC50 is the compound concentration at which 50% inhibition is achieved. The smaller the IC50 value, the greater the inhibitory potency of the compound. Conversely, the higher the IC50 value, the less inhibitory potency of the compound. Hillslope represents the gradient of the fitted curve, usually approximately 1*. Bottom represents the minimum value of the curve obtained by data fitting, usually 0% ± 20%. Top represents the maximum value of the curve obtained by data fitting, usually 100% ± 20%. Experimental data were fitted by calculation and analysis using Dotmatics data analysis software.

[0357] TIFF2025501082000287.tif231161TIFF2025501082000288.tif232161

[0358] The foregoing examples and descriptions of specific embodiments are to be considered illustrative and not limiting of the invention as defined by the claims. As will be readily appreciated, many variations and combinations of the features described above can be utilized without departing from the invention as set forth in the claims. All such variations are intended to be within the scope of the present invention. All cited references are incorporated herein by reference in their entirety. Where any prior art publication is referred to in this specification, such reference does not constitute an admission that the publication forms part of the common general knowledge in the art in any country.

Claims

1. Compounds of formula (I) or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, During the ceremony, The part is and an E3 ubiquitin ligase portion selected from Cy1a, Cy1b and Cy1c each independently represent a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered saturated or unsaturated ring containing 0 to 3 heteroatoms selected from nitrogen, oxygen and sulfur as ring members; Cy2 is a 5- or 6-membered saturated or unsaturated ring (preferably an aromatic ring) containing 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur as ring members; Cy3 is a 5- or 6-membered saturated or unsaturated ring containing no additional heteroatoms; L ａ , L ｂ , L ｃ and L ｄ each independently represents a single bond, —O—, —S—, —C(O)—, or —(CR ａ R ｂ ) ｎ -or-NR ｃ - and L １ and L ２ each independently represents a single bond, —O—, —S—, —C(O)—, or —(CR ａ R ｂ ) ｎ -or-NR ｃ - and Z １ and Z ２ are each independently CH, CR １４ or N, X ｅ are each independently １４ or N, R １ , R ２ , R ３ , R ４ , R ８ , R ９ , R １０ , R １１ , R １３ and R １４ Each occurrence independently represents hydrogen, halogen, -C １－８ Alkyl, -C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -NO ２ , -OR ｃ , -SO ２ R ｃ , -COR ｃ , -CO ２ R ｃ , -CONR ｃ R ｄ , -C(=NR ｃ ) N.R. ｄ R ｅ , -NR ｃ R ｄ , -NR ｃ C.O.R. ｄ , -NR ｃ C.O.N.R. ｄ R ｅ , -NR ｃ CO ２ R ｄ , -NR ｃ SONR ｄ R ｅ , -NR ｃ SO ２ N.R. ｄ R ｅ , or -NR ｃ SO ２ R ｄ and said -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Each of alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally halogen, hydroxy, -haloC １－８ Alkyl, -C １－８ substituted with alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; R ６ , R ７ and R １２ are each independently hydrogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Each of alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally halogen, hydroxy, -haloC １－８ Alkyl, -C １－８ substituted with alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; R ５ is a 5- or 6-membered aromatic ring containing 0 to 3 heteroatoms selected from nitrogen, oxygen and sulfur as ring members, and the aromatic ring is optionally selected from halogen, —C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, -C １－８ Alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO ２ , -OR ｃ , -SO ２ R ｃ , -COR ｃ , -CO ２ R ｃ , -CONR ｃ R ｄ , -C(=NR ｃ ) N.R. ｄ R ｅ , -NR ｃ R ｄ , -NR ｃ C.O.R. ｄ , -NR ｃ C.O.N.R. ｄ R ｅ , -NR ｃ CO ２ R ｄ , -NR ｃ SONR ｄ R ｅ , -NR ｃ SO ２ N.R. ｄ R ｅ , or -NR ｃ SO ２ R ｄ and the -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Each of alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally -C １－８ Alkyl, halogen, hydroxy, -haloC １－８ Alkyl, -C １－８ substituted with alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; p1, p2, p3, p4, p5 and p6 are each independently 0, 1, 2, 3 or 4; s1, s2 and s3 each independently represent 0 or 1; n is 0, 1, 2, 3, 4, 5 or 6; R ａ and R ｂ are each independently hydrogen, halogen, or -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, -C １－８ Alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -NO ２ , -OR ｃ , -SO ２ R ｃ , -COR ｃ , -CO ２ R ｃ , -CONR ｃ R ｄ , -C(=NR ｃ ) N.R. ｄ R ｅ , -NR ｃ R ｄ , -NR ｃ C.O.R. ｄ , -NR ｃ C.O.N.R. ｄ R ｅ , -NR ｃ CO ２ R ｄ , -NR ｃ SONR ｄ R ｅ , -NR ｃ SO ２ N.R. ｄ R ｅ , or -NR ｃ SO ２ R ｄ and said -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Each of alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally halogen, hydroxy, -haloC １－８ Alkyl, -C １－８ substituted with alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; R ａ and R ｂ are taken together with the atoms to which they are attached to form a 3- to 12-membered ring, said ring containing 0, 1 or 2 additional heteroatoms as ring members independently selected from nitrogen, oxygen or optionally oxidized sulfur, said ring optionally being selected from halogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN or -NO ２ and is substituted with at least one substituent independently selected from R ｃ , R ｄ and R ｅ are each independently hydrogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; or (R ｃ and R ｄ ) or (R ｄ and R ｅ ) together with the atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0, 1 or 2 additional heteroatoms as ring members independently selected from nitrogen, oxygen or optionally oxidized sulfur, said ring optionally being selected from halogen, —C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN or -NO ２ A compound substituted with at least one substituent independently selected from:

2. The portion comprises: is selected from Cy3 is a 6-membered saturated or unsaturated ring containing no additional heteroatoms; L １ , X ｅ , R １２ , R １３ and p6 are as defined in claim 1.

3. The portion is selected from L １ , X ｅ , R １２ , R １３ and p6 is as defined in claim 1.

4. The portion is selected from L １ , L ２ , Z １ , Z ２ , X ｅ , R １２ , R １３ and p6 are as defined in claim 1.

5. The portion comprises: is selected from L １ , L ２ , X ｅ , R １２ , R １３ and p6 is as defined in claim 1.

6. L １ and L ２ each independently represents a single bond, —O—, —S—, —C(O)—, or —(CR ａ R ｂ ) ｎ -or-NR ｃ - and n is 1, 2, 3, 4, 5 or 6; R ａ and R ｂ are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl, or R ａ and R ｂ are taken together with the atoms to which they are attached to form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms as ring members, independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally being selected from halogen, —C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN or -NO ２ and is substituted with at least one substituent independently selected from R ｃ are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ The compound according to any one of claims 1 to 5, which is alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl.

7. p6 is independently 0, 1, 2, 3 or 4; X ｅ are each independently １４ or N, R １３ and R １４ are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, heterocyclyl, phenyl, heteroaryl, oxo (=O), -CN, -NO ２ , -OR ｃ , -SO ２ R ｃ , -COR ｃ , -CO ２ R ｃ , -CONR ｃ R ｄ , -C(=NR ｃ ) N.R. ｄ R ｅ , -NR ｃ R ｄ , -NR ｃ C.O.R. ｄ , -NR ｃ C.O.N.R. ｄ R ｅ , -NR ｃ CO ２ R ｄ , -NR ｃ SONR ｄ R ｅ , -NR ｃ SO ２ N.R. ｄ R ｅ , or -NR ｃ SO ２ R ｄ and The methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ２－８ Alkenyl, -C ２－８ Each of alkynyl, heterocyclyl, phenyl, or heteroaryl is optionally F, Cl, Br, I, hydroxy, -haloC １－８ Alkyl, -C １－８ substituted with alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; R ｃ , R ｄ and R ｅ are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl, or (R ｃ and R ｄ ) or (R ｄ and R ｅ ) together with the atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, said ring optionally being selected from halogen, —C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN or -NO ２ and is substituted with at least one substituent independently selected from R １２ are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, -C ２－８ Alkenyl, -C ２－８ Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl is optionally F, Cl, Br, I, hydroxy, -haloC １－８ Alkyl, -C １－８ The compound of any one of claims 1 to 6, which is substituted with alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl.

8. L ａ , L ｂ , L ｃ and L ｄ each independently represents a single bond, —O—, —CO—, or —(CR ａ R ｂ ) ｎ -or-NR ｃ - selected from n is 1, 2, 3, 4 or 5; R ａ and R ｂ are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -NO ２ , -OR ｃ , -SO ２ R ｃ , -COR ｃ , -CO ２ R ｃ , -CONR ｃ R ｄ , -C(=NR ｃ ) N.R. ｄ R ｅ , -NR ｃ R ｄ , -NR ｃ C.O.R. ｄ , -NR ｃ C.O.N.R. ｄ R ｅ , -NR ｃ CO ２ R ｄ , -NR ｃ SONR ｄ R ｅ , -NR ｃ SO ２ N.R. ｄ R ｅ Or -NR ｃ SO ２ R ｄ and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Each of alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl is optionally F, Cl, Br, I, hydroxy, -haloC １－８ substituted with alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl; R ａ and R ｂ are taken together with the atoms to which they are attached to form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms as ring members independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring optionally being selected from F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, oxo, -CN or -NO ２ The compound according to any one of claims 1 to 7, substituted with at least one substituent independently selected from:

9. L ａ , L ｂ , L ｃ and L ｄ each independently represents a single bond, —O—, —CO—, or —(CR ａ R ｂ ) ｎ -or-NR ｃ - selected from n is 1, 2, 3, 4 or 5; R ａ and R ｂ are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -NO ２ , -OR ｃ , -SO ２ R ｃ , -COR ｃ , -CO ２ R ｃ , -CONR ｃ R ｄ , -C(=NR ｃ ) N.R. ｄ R ｅ , -NR ｃ R ｄ , -NR ｃ C.O.R. ｄ , -NR ｃ C.O.N.R. ｄ R ｅ , -NR ｃ CO ２ R ｄ , -NR ｃ SONR ｄ R ｅ , -NR ｃ SO ２ N.R. ｄ R ｅ Or -NR ｃ SO ２ R ｄ The compound according to any one of claims 1 to 8,

10. L ａ , L ｂ , L ｃ and L ｄ each independently represents a single bond, —O—, —CO—, or —N(CH ３ )-, -NH-, -(CH ２ ) ｎ -, -[CH(CH ３ ) ] ｎ -, -[C(CH ３ ) ２ ] ｎ -, n is 1, 2, 3, 4 or 5, preferably L ａ , L ｂ , L ｃ and L ｄ each independently represents a single bond, —O—, —CO—, or —N(CH ３ )-, -NH-, -CH ２ --, --CH ２ CH ２ --, --CH ２ CH ２ CH ２ --, --CH ２ CH ２ CH ２ CH ２ The compound according to any one of claims 1 to 9, selected from:

11. Each Cy1a is independently and Each of the groups may optionally be R ９ is replaced by n1, n2, n3, n4, and n5 each independently represent 0, 1, 2, 3, or 4; X ３ and X ４ Each independently represents -CR ａ or N; X ５ , X ６ and X ７ Each independently represents -NR ｃ -, -O-, -S- and -CR ａ R ｂ - selected from R ａ , R ｂ and R ｃ is as defined in claim 1, *1a is **1a indicates the position at which the molecule is bonded to the The compound of any one of claims 1 to 10, wherein the moiety is linked to

12. Each Cy1a is independently and Each of the groups may optionally be R ９ is replaced by X ３ and X ４ Each independently represents -CR ａ or N; X ５ , X ６ and X ７ Each independently represents -NR ｃ -, -O-, -S- and -CR ａ R ｂ - selected from R ａ and R ｂ are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -NO ２ , -OR ｃ , -SO ２ R ｃ , -COR ｃ , -CO ２ R ｃ , -CONR ｃ R ｄ , -C(=NR ｃ ) N.R. ｄ R ｅ , -NR ｃ R ｄ , -NR ｃ C.O.R. ｄ , -NR ｃ C.O.N.R. ｄ R ｅ , -NR ｃ CO ２ R ｄ , -NR ｃ SONR ｄ R ｅ , -NR ｃ SO ２ N.R. ｄ R ｅ Or -NR ｃ SO ２ R ｄ and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Each of alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl is optionally F, Cl, Br, I, hydroxy, -haloC １－８ substituted with alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; R ｃ are independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ The compound according to any one of claims 1 to 11, selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl.

13. Each Cy1a is independently The compound according to any one of claims 1 to 11,

14. Cy1b each independently represents and Each of the groups may optionally be R １０ is replaced by n1, n2, n3, n4, and n5 each independently represent 0, 1, 2, 3, or 4; X ３ and X ４ Each independently represents -CR ａ or N; X ５ , X ６ and X ７ Each independently represents -NR ｃ -, -O-, -S- and -CR ａ R ｂ - selected from R ａ , R ｂ and R ｃ is as defined in claim 1, *1b is **1b indicates the position where the molecule is bonded to the The compound of any one of claims 1 to 13, wherein the moiety is linked to

15. Each Cy1b is independently and Each of the groups may optionally be R １０ is replaced by X ３ and X ４ Each independently represents -CR ａ or N; X ５ , X ６ and X ７ Each independently represents -NR ｃ -, -O-, -S- and -CR ａ R ｂ - selected from R ａ and R ｂ are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -NO ２ , -OR ｃ , -SO ２ R ｃ , -COR ｃ , -CO ２ R ｃ , -CONR ｃ R ｄ , -C(=NR ｃ ) N.R. ｄ R ｅ , -NR ｃ R ｄ , -NR ｃ C.O.R. ｄ , -NR ｃ C.O.N.R. ｄ R ｅ , -NR ｃ CO ２ R ｄ , -NR ｃ SONR ｄ R ｅ , -NR ｃ SO ２ N.R. ｄ R ｅ Or -NR ｃ SO ２ R ｄ and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Each of alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl is optionally F, Cl, Br, I, hydroxy, -haloC １－８ substituted with alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; R ｃ are independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ The compound according to any one of claims 1 to 14, selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl.

16. Each Cy1b is independently The compound according to any one of claims 1 to 15,

17. Cy1c is independently and Each of the groups may optionally be R １１ is replaced by n1, n2, n3, n4, and n5 each independently represent 0, 1, 2, 3, or 4; X ３ and X ４ Each independently represents -CR ａ or N; X ５ , X ６ and X ７ Each independently represents -NR ｃ -, -O-, -S- and -CR ａ R ｂ - selected from R ａ , R ｂ and R ｃ is as defined in claim 1, *1c is **1c indicates the position where the molecule is bonded to the The compound of any one of claims 1 to 16, wherein the moiety is linked to

18. Each Cy1c is independently and Each of the groups may optionally be R １１ is replaced by X ３ and X ４ Each independently represents -CR ａ or N; X ５ , X ６ and X ７ Each independently represents -NR ｃ -, -O-, -S- and -CR ａ R ｂ - selected from R ａ and R ｂ are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, oxo (=O), -CN, -NO ２ , -OR ｃ , -SO ２ R ｃ , -COR ｃ , -CO ２ R ｃ , -CONR ｃ R ｄ , -C(=NR ｃ ) N.R. ｄ R ｅ , -NR ｃ R ｄ , -NR ｃ C.O.R. ｄ , -NR ｃ C.O.N.R. ｄ R ｅ , -NR ｃ CO ２ R ｄ , -NR ｃ SONR ｄ R ｅ , -NR ｃ SO ２ N.R. ｄ R ｅ Or -NR ｃ SO ２ R ｄ and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Each of alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl is optionally F, Cl, Br, I, hydroxy, -haloC １－８ substituted with alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl; R ｃ are independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ The compound according to any one of claims 1 to 17, selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl.

19. Cy1c is independently The compound according to any one of claims 1 to 18,

20. The part and *La is *Lb indicates the position where the molecule is bonded to the The compound of any one of claims 1 to 19, wherein the moiety is linked to

21. R １ is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO ２ , -OR ｃ , -SO ２ R ｃ , -COR ｃ , -CO ２ R ｃ , -CONR ｃ R ｄ , -C(=NR ｃ ) N.R. ｄ R ｅ , -NR ｃ R ｄ , -NR ｃ C.O.R. ｄ , -NR ｃ C.O.N.R. ｄ R ｅ , -NR ｃ CO ２ R ｄ , -NR ｃ SONR ｄ R ｅ , -NR ｃ SO ２ N.R. ｄ R ｅ , or -NR ｃ SO ２ R ｄ and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl is optionally F, Cl, Br, I, hydroxy, -haloC １－８ substituted with alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl; R ｃ , R ｄ and R ｅ are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl, or (R ｃ and R ｄ ) or (R ｄ and R ｅ ) together with the atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, said ring optionally being selected from halogen, —C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN or -NO ２ The compound of any one of claims 1 to 20, substituted with at least one substituent independently selected from:

22. R １ is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN or -NO ２ and preferably, R １ is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl.

23. R ２ is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO ２ , -OR ｃ , -SO ２ R ｃ , -COR ｃ , -CO ２ R ｃ , -CONR ｃ R ｄ , -C(=NR ｃ ) N.R. ｄ R ｅ , -NR ｃ R ｄ , -NR ｃ C.O.R. ｄ , -NR ｃ C.O.N.R. ｄ R ｅ , -NR ｃ CO ２ R ｄ , -NR ｃ SONR ｄ R ｅ , -NR ｃ SO ２ N.R. ｄ R ｅ , or -NR ｃ SO ２ R ｄ and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl is optionally F, Cl, Br, I, hydroxy, -haloC １－８ substituted with alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl; R ｃ , R ｄ and R ｅ are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl, or (R ｃ and R ｄ ) or (R ｄ and R ｅ ) together with the atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, said ring optionally being selected from halogen, —C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN or -NO ２ The compound of any one of claims 1 to 22, substituted with at least one substituent independently selected from:

24. R ２ is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN or -NO ２ and preferably, R ２ is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, -CN or -NO ２ The compound according to any one of claims 1 to 23,

25. R ３ and R ４ are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO ２ , -OR ｃ , -SO ２ R ｃ , -COR ｃ , -CO ２ R ｃ , -CONR ｃ R ｄ , -C(=NR ｃ ) N.R. ｄ R ｅ , -NR ｃ R ｄ , -NR ｃ C.O.R. ｄ , -NR ｃ C.O.N.R. ｄ R ｅ , -NR ｃ CO ２ R ｄ , -NR ｃ SONR ｄ R ｅ , -NR ｃ SO ２ N.R. ｄ R ｅ , or -NR ｃ SO ２ R ｄ and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl is optionally F, Cl, Br, I, hydroxy, -haloC １－８ substituted with alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl; R ｃ , R ｄ and R ｅ are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl, or (R ｃ and R ｄ ) or (R ｄ and R ｅ ) together with the atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, said ring optionally being selected from halogen, —C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN or -NO ２ The compound of any one of claims 1 to 24, substituted with at least one substituent independently selected from:

26. R ３ and R ４ are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, or -CN, and preferably R ３ and R ４ The compound of any one of claims 1 to 25, wherein each is independently hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, or cyclopentyl.

27. ​​The part And *3 is **3 indicates the position where the molecule is bonded to the The compound of any one of claims 1 to 26, wherein the moiety is linked to the compound.

28. R ６ and R ７ are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl is optionally F, Cl, Br, I, hydroxy, -haloC １－８ and is substituted with alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, or heteroaryl, preferably R ６ and R ７ is independently H, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

29. R ５ teeth, And Y １ , Y ２ , Y ３ and Y ４ are each independently selected from CH, O, S, or N; R １５ are independently hydrogen, halogen, -C １－８ Alkyl, -C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO ２ , -OR ｃ , -SO ２ R ｃ , -COR ｃ , -CO ２ R ｃ , -CONR ｃ R ｄ , -C(=NR ｃ ) N.R. ｄ R ｅ , -NR ｃ R ｄ , -NR ｃ C.O.R. ｄ , -NR ｃ C.O.N.R. ｄ R ｅ , -NR ｃ CO ２ R ｄ , -NR ｃ SONR ｄ R ｅ , -NR ｃ SO ２ N.R. ｄ R ｅ , or -NR ｃ SO ２ R ｄ and said -C １－８ Alkyl, -C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Each of alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally halogen, hydroxy, -haloC １－８ Alkyl, -C １－８ substituted with alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; R ｃ , R ｄ , and R ｅ are each independently as defined in claim 1; p ７ The compound according to any one of claims 1 to 28, wherein is 0, 1, 2, 3 or 4.

30. Y １ is CH, S, N or O; Y ２ is CH, S, O or N; Y ３ is CH, O, S or N, and Y ４ is CH, O, S or N.

31. 29. The compound of claim 28, selected from:

32. R １５ is -H, -F, -Cl, -Br, -I, -CH ３ , -C ２ H ５ , -C ３ H ７ , -C ４ H ９ , -C ５ H １１ , -C ６ H １３ , methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, -CH ２ OH, -CH ２ CH ２ OH, -CH(OH)CH ３ , -CH ２ CH ２ CH ２ OH, -CH(OH)CH ２ CH ３ , -CH ２ CH(OH)CH ３ , -CH ２ OCH ３ , -CFH ２ , -CF ２ H, -CF ３ , -CH ２ CF ３ , -CH ２ CH ２ CF ３ and said -CH ３ , -C ２ H ５ , -C ３ H ７ , -C ４ H ９ , -C ５ H １１ , -C ６ H １３ , methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C ２－８ Alkenyl, -C ２－８ Each alkynyl may optionally be selected from at least one of F, Cl, Br, I, hydroxy, -haloC １－８ Alkyl, -C １－８ 30. The compound of claim 29, which is substituted with alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

33. R １５ teeth, 30. The compound of claim 29, selected from:

34. The portion comprises: The compound according to any one of claims 1 to 33,

35. The compound according to any one of claims 1 to 34, wherein Cy2 is a 5- or 6-membered aromatic ring containing 0 to 3 heteroatoms selected from nitrogen, oxygen and sulfur as ring members.

36. and Y １ , Y ２ , Y ３ and Y ４ are each independently as defined in claim 29; *Cy2 is **3 indicates the position at which the molecule is bonded to the The compound of any one of claims 1 to 35, wherein the moiety is linked to

37. The compound according to any one of claims 1 to 36,

38. R ８ is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO ２ , -OR ｃ , -SO ２ R ｃ , -COR ｃ , -CO ２ R ｃ , -CONR ｃ R ｄ , -C(=NR ｃ ) N.R. ｄ R ｅ , -NR ｃ R ｄ , -NR ｃ C.O.R. ｄ , -NR ｃ C.O.N.R. ｄ R ｅ , -NR ｃ CO ２ R ｄ , -NR ｃ SONR ｄ R ｅ , -NR ｃ SO ２ N.R. ｄ R ｅ , or -NR ｃ SO ２ R ｄ and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl is optionally F, Cl, Br, I, hydroxy, -haloC １－８ substituted with alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl; R ｃ , R ｄ and R ｅ are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl, or (R ｃ and R ｄ ) or (R ｄ and R ｅ ) together with the atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, said ring optionally being selected from halogen, —C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN or -NO ２ The compound of any one of claims 1 to 37, substituted with at least one substituent independently selected from:

39. R ８ is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN or -NO ２ and preferably, R ２ is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, -CN or -NO ２ The compound according to any one of claims 1 to 38,

40. The compound according to any one of claims 1 to 39,

41. The portion comprises: The compound according to any one of claims 1 to 39, selected from:

42. The compound according to any one of claims 1 to 41, selected from the following compounds:

43. 43. A pharmaceutical composition comprising a compound according to any one of claims 1 to 42, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier or excipient.

44. 43. A method of inhibiting BTK activity comprising administering to a subject a compound according to any one of claims 1 to 42, including a compound of formula (I) or the specific compounds exemplified herein, or a pharma- ceutically acceptable salt thereof.

45. A method of treating a disease or disorder in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 42, or a pharma- ceutically acceptable salt thereof, as a BTK kinase inhibitor, wherein the disease or disorder is associated with inhibition of BTK, preferably, the disease or disorder is cancer.

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