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 new strategy for selective knockdown of target proteins by 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 involved in the removal of degenerated, mutated or harmful proteins in cells. The normal physiological function of the ubiquitin-protease system is involved in the removal of degenerated, mutated or harmful proteins in cells. The ubiquitin-proteasome system (UPS), also called 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 modified molecule that is highly conserved in eukaryotic cells, is covalently attached to and labels target substrates through a series of enzymatic reactions involving E1, E2, and E3 enzymes. The modified substrates are then recognized by the 26S proteasome complex to carry out ubiquitination-mediated degradation. To date, two E1 enzymes, called UBA1 and UBA6, have been discovered. Meanwhile, there are about 40 E2 enzymes and more than 600 E3 enzymes, which provide functional diversity to control 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 capable of inducing 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 antitumor 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., EBioMedicine, 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(5):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 No. 7011590, WO2017030814, WO2017079267, WO2017182418, WO2017197036, WO2017197046, WO2017197051, WO2017197056, WO2017201449, WO2017211924, WO2018033556, WO2018071606, US 20200297725, US20200239430, WO 2020142228, WO2020163823, WO2020198711, WO2020201080, and other published patents.

[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 mainly 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 the development and differentiation of B cells (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 need to be precisely regulated. Mutations in the gene encoding Btk result in a human inherited B cell-specific immunodeficiency called X-linked agammaglobulinemia (XLA) (Conley et al., Annu. Rev. Immunol. 27: 199-227, 2009). Aberrant BCR-mediated signaling can lead to dysregulation of B cell activation, resulting in a variety of 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 to deplete 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 in 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 improve autoimmune diseases (e.g., rheumatoid arthritis and lupus). It has also been reported that alternative strategies can inhibit BTK, for example by degrading it (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 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, such as 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): TIFF2025503463000001.tif54161 or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, During the ceremony, Cy1 is a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered saturated ring containing 0-3 heteroatoms selected from nitrogen, oxygen, and sulfur; Cy2 has the structure of formula (I) TIFF2025503463000002.tif1619, said ring being an aromatic ring or a non-aromatic ring (preferably an aromatic ring); Cy3 is a saturated or unsaturated ring (preferably an aromatic ring);

[0009] L a , L b and L c are each independently a single bond, -O-, -S-, -C(O)-, -(CR c R d ) n -OR-NR c - and The TIFF2025503463000003.tif818 part is an E3 ubiquitin ligase portion selected from TIFF2025503463000004.tif35161; L 1 and L 2 are each independently a single bond, -O-, -S-, -C(O)-, -(CR c R d ) n -OR-NR c - and Z 1 When is part of a double bond in a ring, Z 1 is N or CR za (=N- or =CR za -), or Z 1 is not part of a double bond in a ring, Z 1 is NR za or C(R za ) 2 (-NR za -or-C(R za ) 2- (also called

[0010] Z 2 When is part of a double bond in a ring, Z 2 is N or CR za (=N- or =CR za -), or Z 2 is not part of a double bond in a ring, Z 2 is NR za or C(R za ) 2 (-NR za -or-C(R za ) 2 - (also called Z 3 When is part of a triple bond in a ring, Z 3 is N or CR za (=N- or =C(R za )-), or Z 3 is not part of a double bond in a ring, Z 3 is NR za or C(R za ) 2 (-NR za -or-C(R za ) 2 - (also called Z 4 When is part of a double bond in a ring, Z 4 is N or CR za (=N- or =CR za -), or Z 4 is not part of a double bond in a ring, Z 4 is NR za or C(R za ) 2 (-NR za -or-C(R za ) 2 -), where Z 1 , Z 2 , Z 3 and Z 4 Not all of are =N-, Z 5 When is part of a double bond in a ring, Z 5 is C, or Z 5is not part of a double bond in a ring, Z 5 is N or CR za and Z 6 and Z 7 are each independently za or N, X a , X b , X c , X d and X e are each independently 13 or N, R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , R 11 , R 13 and R za 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, -CN, -NO 2 , -OR a , -SO 2 R a , -COR a , -CO 2 R a , -CONR a R b , -C(=NR a )NR b R c , -NR a R b , -NR a COR b , -NR a CONR b R c , -NR a CO 2 R b , -NR a SONR b R c , -NR a SO 2 NRb R c or -NR a SO 2 R b and said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally selected from halogen, hydroxy, -haloC 1-8 Alkyl, -C 1-8 optionally substituted with alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; Or, R 1 and R 3 is R 1 and R 3 forms a 3- to 12-membered ring together with the atom to which it is attached, said ring containing 0, 1 or 2 additional heteroatoms as ring members independently selected from nitrogen, oxygen or optionally oxidized sulfur, said ring optionally containing halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 , -OR a , -SO 2 R a , -COR a , -CO 2 R a , -CONR a R b , -C(=NR a )NR b R c , -NR a R b , -NR a COR b , -NR a CONR b R c , -NR a CO 2 R b , -NR a SONR b R c , -NR a SO 2 NR b Rc or -NR a SO 2 R b and wherein the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally selected from halogen, hydroxy, -haloC 1-8 Alkyl, -C 1-8 substituted with alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0011] R 5 , R 6 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 selected from halogen, hydroxy, -haloC 1-8 Alkyl, -C 1-8 substituted with alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; R 10 is a 5- or 6-membered aromatic ring containing 0 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, 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 a , -SO 2 R a , -COR a , -CO 2 R a , -CONR a Rb , -C(=NR a )NR b R c , -NR a R b , -NR a COR b , -NR a CONR b R c , -NR a CO 2 R b , -NR a SONR b R c , -NR a SO 2 NR b R c or -NR a SO 2 R b and -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; Or, R 5 and R 10 is R 5 and R 10 forms a 3- to 12-membered ring together with the atom to which it is attached, said ring containing 0, 1 or 2 additional heteroatoms as ring members independently selected from nitrogen, oxygen or optionally oxidized sulfur, said ring optionally containing halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 , -OR a , -SO 2 R a , -COR a , -CO 2 R a , -CONR aR b , -C(=NR a )NR b R c , -NR a R b , -NR a COR b , -NR a CONR b R c , -NR a CO 2 R b , -NR a SONR b R c , -NR a SO 2 NR b R c or -NR a SO 2 R b and wherein the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally selected from halogen, hydroxy, -haloC 1-8 Alkyl, -C 1-8 substituted with alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0012] m1, m2, m3, m4, p1, p2, p3, p4, and p5 are each independently 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, 4, 5 or 6; r is 0 or 1; s is 0 or 1; R a and R b are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; or R a and R b is R a and R bforms a 3-12 membered ring together with the atom to which it is attached, said ring containing 0, 1 or 2 additional heteroatoms as ring members independently selected from nitrogen, oxygen or optionally oxidized sulfur, said ring optionally containing 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 and R d 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 is R c and R d forms a 3-12 membered ring together with the atom to which it is attached, said ring containing 0, 1 or 2 additional heteroatoms as ring members independently selected from nitrogen, oxygen or optionally oxidized sulfur, said ring optionally containing halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN or -NO 2 is substituted with at least one substituent independently selected from

[0013] In some embodiments, Z 2 and Z 3 When at least one of the following is part of a double bond in a ring, it is =CH-; when it is not part of a double bond in a ring, it is -CH 2 -, =CH- or -CH 2 - Any of the parts Provides the position of binding to the TIFF2025503463000005.tif2693 portion.

[0014] Aspect 2. According to the compound according to aspect 1, the compound is selected from formula (II) and formula (III), TIFF2025503463000006.tif116161 However, Cy1, Cy2, Cy3, L a , L b , L c , TIFF2025503463000007.tif818,Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , X a , X b , X c , X d , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , m1, m2, m3, m4, p1, p2, p3, p4, r and s are as defined in embodiment 1.

[0015] Aspect 3. According to the compound according to aspect 1, the compound is selected from formula (IV) and formula (V), TIFF2025503463000008.tif127161

[0016] However, Cy1, Cy2, Cy3, L a , L b , L c , TIFF2025503463000009.tif818,Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , X a , X b , X c , X d , R 1 , R 2 , R 3 , R 4 , R 5 , R6 , R 7 , R 8 , R 9 , R 10 , m1, m2, m3, m4, p1, p2, p3, p4, r and s are as defined in embodiment 1.

[0017] According to the compound of embodiment 1, Cy1 is TIFF2025503463000010.tif45161, but X f and X g are each independently CR 11 or N, * 1 is TIFF2025503463000011.tif5757 indicates the position where the sequence is bound to the region. ** 1 is Indicates the position binding to the TIFF2025503463000012.tif3180 part.

[0018] According to the compound of embodiment 1, Cy1 is The file is TIFF2025503463000013.tif77161.

[0019] According to the compound of embodiment 1, Cy1 is Selected from TIFF2025503463000014.tif111161.

[0020] Embodiment 7. According to the compound of embodiment 1, p2 is 0, 1, or 2, and each R 7 are independently hydrogen, -F, -Br, -Cl, -I, -CH 3 , -C 2 H 5 , -C 3 H 7 , -C 4 H 9 , -C 5 H 11 , -C 6 H 13 , -C 7 H 15 , -C 8 H 17, -OCH 3 , -OC 2 H 5 , -OC 3 H 7 , -OC 4 H 9 , -OC 5 H 11 , -OC 6 H 13 , -OC 7 H 15 , -OC 8 H 17 , -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO 2 , -OR a , -SO 2 R a , -COR a , -CO 2 R a , -CONR a R b , -C(=NR a )NR b R c , -NR a R b , -NR a COR b , -NR a CONR b R c , -NR a CO 2 R b , -NR a SONR b R c , -NR a SO 2 NR b R c or -NR a SO 2 R b wherein the -CH 3 , -C 2 H 5 , -C 3 H 7 , -C 4 H 9 , -C 5 H11 , -C 6 H 13 , -C 7 H 15 , -C 8 H 17 , -OCH 3 , -OC 2 H 5 , -OC 3 H 7 , -OC 4 H 9 , -OC 5 H 11 , -OC 6 H 13 , -OC 7 H 15 , -OC 8 H 17 , -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, and heteroaryl each optionally represent -F, -Br, -Cl, -I, hydroxy, -haloC 1-8 Alkyl, -C 1-8 substituted with alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; R a , R b and R c is as defined in embodiment 1.

[0021] Embodiment 8. According to the compound of embodiment 1, p2 is 0, 1, or 2, and each R 7 are independently hydrogen, -F, -Br, -Cl, -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 or cyclohexyl.

[0022] Aspect 9. According to the compound according to aspect 1, The TIFF2025503463000015.tif818 part is Selected from TIFF2025503463000016.tif207161, R 11 is hydrogen, -F, -Br, -Cl, -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 or cyclohexyl; R c and R d are each independently hydrogen, -CH 3 , -C 2 H 5 , -C 3 H 7 , -C 4 H 9 , -C 5 H 11 , -C 6 H 13 , -C 2-8 Alkenyl, -C 2-8 selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclyl, aryl or heteroaryl; or R c and R d is R c and R d forms a 3-12 membered ring together with the atom to which it is attached, said ring containing 0, 1 or 2 additional heteroatoms as ring members independently selected from nitrogen, oxygen or optionally oxidized sulfur, said ring optionally containing halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN or -NO 2 and is substituted with at least one substituent independently selected from and p5 is 0 or 1.

[0023] Aspect 10. According to the compound according to aspect 6, The TIFF2025503463000017.tif818 part is Selected from TIFF2025503463000018.tif201161.

[0024] Aspect 11. According to the compound according to aspect 6, The TIFF2025503463000019.tif818 part is Selected from TIFF2025503463000020.tif166161.

[0025] Aspect 12. According to the compound of aspect 1, L a , L b and L c are each independently a single bond, -O-, -S-, -C(O)-, -(CR c R d ) n -OR-NR c - selected from n is 1, 2, 3, 4, 5 or 6; R c and R d are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl, or R c and R d is R c and R dtogether with the atom to which it is attached form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-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 -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 is substituted with at least one substituent independently selected from

[0026] Aspect 13. According to the compound of aspect 1, L a , L b and L c are each independently a single bond, -O-, -CO-, -(CH 2 ) n -, -[CH(CH 3 )] n -, -[C(CH 3 ) 2 ] n - or -NH-, where n is 1, 2, 3, 4 or 5.

[0027] Aspect 14. According to the compound of aspect 1, R 13 is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0028] Embodiment 15. According to the compound according to embodiment 1, m1, m2, m3 and m4 are each independently selected from 0 or 1.

[0029] Aspect 16. According to the compound of aspect 1, p3 and p4 are each independently 0 or 1; R 8 and R9 are each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0030] Aspect 17. According to the compound according to aspect 1, The TIFF2025503463000021.tif2735 part is Selected from TIFF2025503463000022.tif79161, however, * a is TIFF2025503463000023.tif5171 indicates the position where the molecule binds to the 1 part. ** b is Indicates the position binding to the TIFF2025503463000024.tif2953 part.

[0031] Aspect 18. According to the compound according to aspect 1, The TIFF2025503463000025.tif2735 part is Selected from TIFF2025503463000026.tif57161, however, * a is TIFF2025503463000027.tif5171 indicates the position where the molecule binds to the part, ** b is Indicates the position binding to the TIFF2025503463000028.tif2953 part.

[0032] Aspect 19. According to the compound according to aspect 1, The TIFF2025503463000029.tif2434 part is Selected from TIFF2025503463000030.tif78161, however, * a is TIFF2025503463000031.tif5193 indicates the position where the sequence binds to the region.** b is Indicates the position binding to the TIFF2025503463000032.tif926 portion.

[0033] Aspect 20. According to the compound according to aspect 1, The TIFF2025503463000033.tif2434 part is Selected from TIFF2025503463000034.tif57161, however, * a is TIFF2025503463000035.tif5295 indicates the position where the sequence is bound to the region. ** b is Indicates the position binding to the TIFF2025503463000036.tif926 portion.

[0034] Aspect 21. According to the compound according to aspect 1, The TIFF2025503463000037.tif3066 part is -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, Selected from TIFF2025503463000038.tif167161, * L is TIFF2025503463000039.tif6177 indicates the position where the molecule binds to the target molecule. ** L is Indicates the position binding to the TIFF2025503463000040.tif1026 portion.

[0035] Aspect 22. According to the compound of aspect 1, Z 1 and Z 4 are each independently za or N and R zais hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, heterocyclyl, aryl, heteroaryl, -CN. Aspect 23. According to the compound of aspect 1, Z 2 and Z 3 is C and is linked to Cy1, and Z 2 and Z 3 The other is CR za or N and R za is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, heterocyclyl, aryl, heteroaryl, -CN. Aspect 24. According to the compound of aspect 1, Z 1 , Z 2 , Z 3 and Z 4 At most two of them are N. Embodiment 25. According to the compound of embodiment 1, Z 1 , Z 2 , Z 3 and Z 4 At most one of them is N.

[0036] Aspect 26. According to the compound of aspect 1, R 1 is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -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 or -CH 2 CH 2 CF 3 It is.

[0037] Aspect 27. According to the compound of aspect 1, R 1 and R 3 is R 1 and R 3 together with the atom to which it is attached forms a 3-, 4-, 5-, 6-, 7- or 8-membered ring, said ring containing 0, 1 or 2 additional N atoms as ring members, said ring being optionally -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or -CH 2 OH.

[0038] Aspect 28. According to the compound of aspect 1, R 2 is H, -F, -Cl, -Br, -I, methyl, ethyl or propyl, and p1 is 0, 1 or 2. Aspect 29. According to the compound of aspect 1, R 3 and R 4 are each independently -H, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0039] Aspect 30. According to the compound of aspect 1, The TIFF2025503463000041.tif2719 part is TIFF2025503463000042.tif41161, where * 3 is TIFF2025503463000043.tif2220 indicates the position where the sequence is bound, and ** 3 is Indicates the position binding to the TIFF2025503463000044.tif40131 part.

[0040] Aspect 31. According to the compound of aspect 1, R 5 sum R 6 are each independently -H, methyl, ethyl, or propyl. Aspect 32. According to the compound of aspect 1, R 10 teeth TIFF2025503463000045.tif2022, Y 1 , Y 2 , Y 3 and Y 4 is selected from CH, O, S or N; R 14 is 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 a , -SO 2 R a , -COR a , -CO 2 R a , -CONR a R b , -C(=NR a )NR b R c , -NR a R b , -NR a COR b , -NR a CONR b R c , -NR a CO 2 Rb , -NR a SONR b R c , -NR a SO 2 NR b R c or -NR a SO 2 R b -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 selected from halogen, hydroxy, -haloC 1-8 Alkyl, -C 1-8 substituted with alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R a , R b and R c are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; and p6 is 0, 1, 2, 3 or 4.

[0041] Aspect 33. According to the compound of aspect 25, 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. Aspect 34. According to the compound according to aspect 25, TIFF2025503463000046.tif2326 is Selected from TIFF2025503463000047.tif31161.

[0042] Aspect 35. According to the compound of aspect 25, R 14 -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 wherein the -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 the group consisting of at least one halogen, hydroxy, -haloC 1-8 Alkyl, -C 1-8 It may be substituted with alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl. Aspect 36. According to the compound of aspect 25, R 14 teeth, Selected from TIFF2025503463000048.tif20161.

[0043] According to the compound according to embodiment 1, the compound is TIFF2025503463000049.tif220161TIFF2025503463000050.tif231161TIFF2025503463000051.tif 216161TIFF2025503463000052.tif230161TIFF2025503463000053.tif237161TIFF202550346300005 4.tif216161TIFF2025503463000055.tif242161TIFF2025503463000056.tif231161TIFF2025503463000057.tif226161TIFF2025503463000058.tif230161TIFF2025503463000059.tif141161 is selected.

[0044] Aspect 38. A pharmaceutical composition comprising a compound according to any one of aspects 1 to 37, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier or excipient. Aspect 39. A method of inhibiting BTK activity, comprising administering to a subject a compound according to any one of Aspects 1 to 37, including a compound of formula (I) or any of the specific compounds exemplified herein, or a pharma- ceutically acceptable salt thereof. Aspect 40. A method of treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to any one of Aspects 1-37, or a pharma- ceutically 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 PREFERRED EMBODIMENTS

[0045] 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.

[0046] The term "alkyl" refers to a hydrocarbon group selected from linear 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. 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").

[0047] 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.

[0048] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). The term "haloalkyl group" refers to an alkyl group in which one or more hydrogens are replaced with one or more halogen atoms, such as fluorine, chlorine, bromine, and iodine. Examples of haloalkyl groups include haloC 1-8 Alkyl, haloC 1-6 Alkyl or haloC 1-4 Alkyl, e.g. -CF 3 , -CH 2 Cl, -CH 2 CF 3 , -CHCl 2 , -CF 3 These include, but are not limited to, the following. The term "alkenyl" refers to a hydrocarbon group selected from linear 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. Alkenyl (e.g., C 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. 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.

[0049] 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, the 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, the cycloalkyl group 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.

[0050] The term "spirocycloalkyl" refers to a cyclic structure containing carbon atoms and formed by at least two rings that share one atom. The term "7-12 membered spirocycloalkyl" refers to a cyclic 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 carbon atoms and sharing two atoms that are not adjacent to each other. The term "7-10 membered bridged cycloalkyl" refers to a cyclic structure formed by two rings containing 7-12 carbon atoms and sharing two atoms that are not adjacent to each other. 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.

[0051] 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 sharing two adjacent atoms. The term "cycloalkynyl" refers to a non-aromatic cycloalkyl group of from 5 to 10 carbon atoms, which is monocyclic or polycyclic and has at least one triple bond. The term "fused cycloalkynyl" refers to a bicyclic cycloalkyl, as defined herein, which contains at least one triple bond and is formed by two or more rings sharing two adjacent atoms.

[0052] 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 TIFF2025503463000060.tif78 or TIFF2025503463000061.tif78, where the wavy lines indicate the joins. 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. 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 3-8 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.

[0053] 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, such as fluorenyl, and aromatic. The terms "aromatic hydrocarbon ring" and "aryl" 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.

[0054] The term "heteroaryl" means 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.

[0055] 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 may be the same or different. Nitrogen atoms in one or more rings of a heteroaryl group may be oxidized to form an N-oxide. In particular, the term "bicyclic fused heteroaryl" refers to a 7-12 membered, preferably 7-10 membered, more preferably 9 or 10 membered, fused bicyclic heteroaryl ring as defined herein. Typically, a bicyclic fused heteroaryl is a 5 / 5 membered, 5 / 6 membered, 6 / 6 membered or 6 / 7 membered bicyclic ring. Such groups may be attached to the remainder of the molecule via either ring.

[0056] 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, quinolyl (or quinolyl), quinoxalinyl, thiazolopyridinyl, thienopyrazinyl, thienopyrazolyl, thienopyridinyl, thienopyrrolyl, thienothienyl or triazolopyridinyl.

[0057] 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. The terms "aromatic heterocycle" and "aryl" are used interchangeably throughout the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic heterocycle 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, the monocyclic or bicyclic aromatic heterocycle 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, the monocyclic or bicyclic aromatic heterocycle 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.

[0058] Examples of heteroaryls or monocyclic or bicyclic aromatic heterocycles 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), tetracyclic, ... azolyl, 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, Examples of the aryl radical include, but are not limited to, 1-thia-2,4-oxadiazolyl, 1-thia-2,5-oxadiazolyl, 1-thia-3,4-oxadiazolyl, furazanyl (e.g., furazan-2-yl, furazan-3-yl), benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (e.g., benzo[d]thiazol-6-yl), and indazolyl (e.g., 1H-indazol-5-yl).

[0059] "Aromatic ring" refers to aromatic carbocycles (eg, aryl as defined above) and aromatic heterocycles (eg, heteroaryl as defined above). "Heterocyclyl", "heterocycle" or "heterocyclic" are interchangeable and include non-aromatic heterocyclic groups that contain one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, and include monocyclic, fused, bridged and spiro rings, i.e., monocyclic heterocyclyl, bridged heterocyclyl, spiro heterocyclyl and fused heterocyclyl. As used herein, the term "optionally oxidized sulfur" means S, SO or SO 2 Refers to...

[0060] 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 aryl, homopiperidinyl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxepanyl, thiepanyl, 1,4-oxathiepanyi, 1,4-dioxepanyl, 1,4-oxathiepanyi, 1-4-oxazepanyl, 1,4-dithianyl, 1,4-thiazepanyl and 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathiepanyi, oxazepinyl, diazepinyl, thiazepinyl, dihydrothiophenyl, dihydropyranyl, dihydrothiophenyl ... Examples of pyrrolinyl include, but are not limited to, pyrofuranyl, 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.

[0061] The term "spiroheterocyclyl" refers to a 5-20 membered polycyclic heterocyclyl having rings connected by one common carbon atom (called a spiro atom) and 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, a dispiroheterocyclyl or a polyspiroheterocyclyl, preferably a monospiroheterocyclyl or a 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]heptane). ]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.

[0062] The term "fused heterocyclyl" refers to a 5-20 membered polycyclic heterocyclyl in which each ring in the system contains one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, and shares adjacent atom pairs (carbon and carbon atoms or carbon and nitrogen atoms) with another ring, with the remaining ring members being carbon. One or more rings of the fused heterocyclyl may contain one or more double bonds, but the fused heterocyclyl does not have a completely conjugated pi-electron system. Preferably, the fused heterocyclyl has 6 to 14 members, more preferably 7 to 12 members, or 7 to 10 members. The fused heterocyclyl may be a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl, depending on the number of constituent rings. Such groups may be attached to the remainder of the molecule via any ring.

[0063] In particular, the term "bicyclic fused heterocyclyl" refers to a 7-12 membered, preferably 7-10 membered, more preferably 9 or 10 membered fused heterocyclyl as defined herein, containing two fused rings and containing 1-4 heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members. Generally, the 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]dioxine, indolinyl, isoindolinyl, benzopyranyl, dihydrothiazolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl (or (tetrahydroisoquinolinyl)), dihydrobenzofuranyl, dihydrobenzoxazinyl, dihydrobenzimidazolyl, tetrahydroisoquinolyl, benzothiophenyl, 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).

[0064] 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. The term "bridged heterocyclyl" refers to a 5-14 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 the 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 6-14 members, more preferably 7-10 members. Depending on the number of constituent rings, the bridged heterocyclyl may be a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, 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. The term "at least one substituent" 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 6d " is R 6d The group includes 1 to 4 (eg 1 to 3, or even 1 or 2) substituents selected from the list below.

[0065] 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 further 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 their pharma- ceutically acceptable salts are intended to be included. Reference to one isomer applies to any possible isomer, unless otherwise specified. All possible isomers are included unless the isomeric composition is specified.

[0066] 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, 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. When the compounds disclosed herein contain olefinic double bonds, such double bonds, unless otherwise specified, are intended to include both E and Z geometric isomers.

[0067] When the compounds disclosed herein contain a disubstituted cyclic ring system, the substituents found on such ring system can adopt cis and trans form.Cis form means that both of the 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, disubstituted cyclic ring system can be a cyclohexyl ring or a cyclobutyl ring.

[0068] It may be advantageous to separate reaction products from each other and / or from starting materials. The desired products of each step or sequence of steps are separated and / or purified (hereinafter separated) to the desired degree of homogeneity by techniques commonly used in the art. Typically, such separation involves multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation or chromatography. Chromatography may include any number of methods, including, for example, reverse and normal phase chromatography, size exclusion chromatography, ion exchange chromatography, high-, medium- and low-pressure liquid chromatography methods and equipment, 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. The skilled artisan will use the technique most likely to achieve the desired separation.

[0069] "Diastereomers" refers to stereoisomers of a compound 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 a suitable 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 into the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers and diastereomers can also be separated by using chiral HPLC columns.

[0070] Single stereoisomers (e.g., substantially pure enantiomers) can be obtained by resolution of the racemic mixture 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, CH 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, and (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.

[0071] "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 free base functional groups with a suitable organic acid, or by reacting acidic groups with a suitable base. Furthermore, when the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, an addition salt such as a pharma-ceutically 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, without undue experimentation, a variety of synthetic methods that can be used to prepare non-toxic pharma-ceutically acceptable addition salts. As defined herein, "a pharma- ceutically acceptable salt thereof" includes at least one salt of a compound of formula (I) and stereoisomeric salts, such as enantiomeric and / or diastereomeric salts, of a compound of formula (I).

[0072] 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 an 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.

[0073] The term "effective amount" or "therapeutically effective amount" refers to an amount of an active ingredient (such as a compound) sufficient to affect the treatment of a disease, or at least one clinical symptom of a disease or disorder, when administered to a subject. 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 of the subject being treated, and / or the 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 pharma- ceutically acceptable salt thereof effective to "treat" a disease or disorder as defined herein in a subject. In the case of a combination therapy, the term "therapeutically effective amount" refers to the total amount of the combined objects for effective treatment of a disease, disorder, or condition.

[0074] The pharmaceutical composition comprising the compound 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 tablet, powder, granule, capsule, liquid formulation such as aqueous or oily suspension, or other liquid formulation such as syrup, solution, suspension, etc., and for parenteral administration, the pharmaceutical composition may be a solution, aqueous solution, oily suspension concentrate, lyophilized powder, etc. Preferably, the dosage form of the pharmaceutical composition is selected from tablet, coated tablet, capsule, suppository, nasal spray or injection, more preferably tablet or capsule. The pharmaceutical composition may be a single unit administration with a precise dosage. In addition, the pharmaceutical composition may include additional active ingredients.

[0075] All formulations of the pharmaceutical compositions disclosed herein can be prepared by conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients, and then the desired formulation can be prepared. The term "pharmaceutical acceptable excipient" refers to conventional pharmaceutical carriers suitable 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, polyvinylpyrrolidone (PVP), wetting agents such as glycerin, disintegrants such as agar, calcium carbonate, sodium bicarbonate, absorption enhancers such as quaternary ammonium compounds, surfactants such as cetyl alcohol, absorption carriers such as kaolin and bentonite clay, lubricants such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical composition further includes other pharmaceutical acceptable excipients such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, flavors, sweeteners, dyes, etc. The term "disease" refers to any disease, ailment, illness, symptom, or indication, and is interchangeable with the terms "disorder" or "condition."

[0076] 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 "comprise" may be substituted with "containing," "including," or sometimes "having." Throughout the specification and in the accompanying claims, n-m " denotes a range inclusive of the endpoints, where n and m are integers and denote 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. EXAMPLES

[0077] The following examples are intended to be illustrative only and should not be considered 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 in anhydrous solvents under a positive pressure of nitrogen or argon or with 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.

[0078] 1 1 H NMR spectra were recorded on an Agilent instrument operating at a frequency of 400 MHz. 1 H NMR spectra were obtained using CDCl as the solvent. 3 , CD 2 Cl 2 , CD 3 O.D., D. 2 O, d 6 -DMSO, d 6 -Acetone or (CD 3 ) 2 CO was used as the reference standard, and tetramethylsilane (0.00 ppm) or residual solvent (CDCl 3 : 7.25ppm; C.D. 3 OD: 3.31ppm; D 2 O: 4.79ppm; d 6 -DMSO: 2.50ppm; 6 -Acetone: 2.05; (CD 3 ) 3CO: 2.05). When reporting peak multiplicities, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sexlet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz).

[0079] 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, 4.6x50mm, 2.7pm, gradient method: flow rate: 1.8mL / min, time (min) A (%) B (%)

[0080] TIFF2025503463000062.tif31161LCMS, LCMS-3: LC-MS spectrometer (Agilent 1260 Infinity II), detector: MWD (190-400nm), 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, 4.6x50mm, 2.7pm, gradient method: flow rate: 1.8mL / min, time (min) A (%) B (%)

[0081] TIFF2025503463000063.tif31161LCMS-2: LC-MS spectrometer (Agilent 1290 Infinity II), detector: MWD (190-400nm), 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, 4.6x50mm, 2.7pm, gradient method: flow rate: 1.2mL / min, time (min) A (%) B (%)

[0082] TIFF2025503463000064.tif31161 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, injection volume of 2 mL, 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% NH 3 .H 2 Gradient table: Mobile phase A (20%-90%, 30%-90%, 40%-90% or 50%-90%), time (min): 0-15 min, 0-17 min or 0-20 min.

[0083] In the examples below, the following abbreviations are used: TIFF2025503463000065.tif248161TIFF2025503463000066.tif234161

[0084] Example 1: 3-(tert-butyl)-N-(4-(6-(4-((1-(4-(2,4-dioxo2,4-dioxo)tetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-(yl)(methyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide

[0085] Step 1: tert-Butyl 4-(3-chloro-4-nitrophenyl)piperazine-1-carboxylate TIFF2025503463000067.tif23332-Chloro-4-fluoro-1-nitrobenzene (25 g, 142.4 mmol), tert-butyl piperazine-1-carboxylate (29 g, 156.7 mmol) and K in DMF (250 mL). 2 CO 3(59 g, 427.2 mmol) is stirred at 100° C. for 16 h. The mixture is cooled and water (250 mL) is added. The precipitated solid is collected by filtration and washed with water (2×100 mL). The resulting solid is dried to give the product (46 g, 95%).

[0086] Step 2: tert-Butyl 4-(3-(1-cyano-2-ethoxy-2-oxoethyl)-4-nitrophenyl)piperazine-1-carboxylate TIFF2025503463000068.tif1634To a stirred solution of NaH (60% in mineral oil) (6.4 g, 160.9 mmol, 60%) in DMF (250 mL), ethyl cyanoacetate (12.4 g, 109.7 mmol) was added with N 2 The mixture is stirred at room temperature for 1 h. To the above solution is added tert-butyl 4-(3-chloro-4-nitrophenyl)piperazine-1-carboxylate (25 g, 73.144 mmol). The resulting mixture is diluted with N 2 Stir at 70° C. under ambient temperature for 16 h. Cool the mixture and add water (200 mL). Acidify the resulting mixture with 1M HCl(aq) to pH=6 and extract with DCM (3×250 mL). Wash the combined organic layers with saturated NaCl(aq) (200 mL) and dilute with anhydrous Na 2 SO 4 Dry at 50° C. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography eluting with hexane / EtOAc (1:1) to give the product (22 g, 72%). [M+H] + =419.2.

[0087] Step 3: 2-amino-5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1H-indole-3-carboxylate ethyl TIFF2025503463000069.tif1939To a solution of tert-butyl 4-(3-(1-cyano-2-ethoxy-2-oxoethyl)-4-nitrophenyl)piperazine-1-carboxylate (10 g, 23.9 mmol) in AcOH (100 mL), Zn (7.8 g, 119.5 mmol) is added. The resulting mixture is stirred at room temperature for 3 h. The mixture is filtered and the filter cake is washed with AcOH (2×20 mL). The filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (1:1) to give the product (7.8 g, 84%). [M+H] + =389.1.

[0088] Step 4: tert-Butyl 4-(4-oxo-4,9-dihydro-3H-pyrimido[4,5-b]indol-6-yl)piperazine-1-carboxylate TIFF2025503463000070.tif2335A solution of ethyl 2-amino-5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1H-indole-3-carboxylate (6 g, 15.4 mmol) and formamidine (3.2 g, 30.9 mmol) in methylene glycol (60 mL) is stirred at 120 °C for 24 h. The resulting mixture is cooled and concentrated under reduced pressure. The residue is dissolved in saturated NaHCO 3 The mixture is basified with (aq) to pH=8. The resulting mixture is extracted with DCM (3×100 mL). The combined organic layers are washed with saturated NaCl (aq) (50 mL) and anhydrous Na 2 SO 4 Dry at 40° C. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography eluted with a gradient of DCM:MeOH 1:0 to 10:1 to give the product (5 g, 88%). [M+H] + =370.2.

[0089] Step 5: 4-Chloro-6-(piperazin-1-yl)-9H-pyrimido[4,5-b]indole TIFF2025503463000071.tif2128 tert-Butyl 4-(4-oxo-4,9-dihydro-3H-pyrimido[4,5-b]indol-6-yl)piperazine-1-carboxylate (5 g, 13.5 mmol) in dioxane (10 mL) and POCl 3 (10 mL) is stirred at 90 °C for 4 h. The mixture is cooled. Water (15 mL) and EA (20 mL) are added and saturated NaHCO 3 The residue is basified to pH 8 with (aqueous). The resulting mixture is filtered and the filter cake is washed with water (2×10 mL). The filtrate is concentrated under reduced pressure to give the product (2.4 g, 62%). [M+H] + =288.2.

[0090] Step 6: tert-Butyl 4-(4-chloro-9H-pyrimido[4,5-b]indol-6-yl)piperazine-1-carboxylate TIFF2025503463000072.tif2330THF (10 mL) and H 2 4-Chloro-6-(piperazin-1-yl)-9H-pyrimido[4,5-b]indole (500 mg, 1.3 mmol) in 2H2O (5 mL) and NaHCO 3 To a stirred solution of (218 mg, 2.6 mmol) at 0° C., 2 Add 2H2O (305 mg, 1.4 mmol) in portions. Stir the resulting mixture at room temperature for 16 h. Concentrate the resulting mixture under reduced pressure. Add water (20 mL) to the resulting mixture and extract with EtOAc (3 x 50 mL). Wash the combined organic layers with saturated NaCl(aq) (20 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with EA to give the product (150 mg, 29.8%). [M+H] + =388.2.

[0091] Step 7: tert-butyl 4-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-methylphenyl)-9H-pyrimido[4,5-b]indol-6-yl)piperazine-1-carboxylate TIFF2025503463000073.tif3741 tert-Butyl 4-(4-chloro-9H-pyrimido[4,5-b]indol-6-yl)piperazine-1-carboxylate (120 mg, 0.3 mmol), 3-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (a compound obtained in a similar manner to US20160096834A1) (161 mg, 0.4 mmol), Pd(dppf)Cl 2 (23 mg, 0.031 mmol) and K 3 PO 4 (131 mg, 0.6 mmol) in dioxane (3 mL) and water (0.5 mL), 2 Stir at 80° C. under ambient atmosphere for 4 h. Cool the mixture. Add water (15 mL) to the resulting mixture and extract with DCM (3×20 mL). Wash the combined organic layers with saturated NaCl (15 mL) and anhydrous Na 2 SO 4 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 (130 mg, 67%). [M+H] + =625.0.

[0092] Step 8: 3-(tert-butyl)-N-(2-methyl-4-(6-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000074.tif3737To a stirred solution of tert-butyl 4-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-methylphenyl)-9H-pyrimido[4,5-b]indol-6-yl)piperazine-1-carboxylate (130 mg, 0.2 mmol) in DCM (1 mL) was added TFA (1 mL) at room temperature. The resulting solution was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase A, 0.1% FA in water, mobile phase B, ACN, gradient from 10% to 50% (B%) in 25 min; detector, UV 254 nm. This gave the product (53 mg, 45%). 1 H NMR (300 MHz, DMSO) δ 12.26 (s, 1H), 9.96-9.92 (m, 1H), 8.91 (s, 1H), 8.23 ​​(s, 1H), 7.79-7.74 (m, 2H), 7.56-7.47 (m, 2H), 7.34-7.28 (m, 2H), 4.60 (d, J = 5.7 Hz 2H), 2.98-3.02 (m, 8H), 2.51-2.49 (m, 3H), 1.43-1.34 (m, 9H), [M+H] + = 525.2.

[0093] Step 9: 3-(tert-butyl)-N-(4-(6-(4-((1-(4-(2,4-dioxo2,4-dioxo)tetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-(yl)(methyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000075.tif35593-(tert-Butyl)-N-(2-methyl-4-(6-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (50 mg, 0.1 mmol) was dissolved in MeOH / DCM (10:1, 2 mL). 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (30 mg, 0.1 mmol) was added portionwise to the solution and the resulting mixture was stirred at room temperature for 16 h until LC-MS showed all starting material was consumed. The mixture was concentrated and purified by SiO 2 -Purification by gel column (DCM:MeOH=10:1) afforded the title product (29 mg, 35.8%). 1 H NMR (400 MHz, DMSO) δ 12.21 (s, 1H), 10.26 (s, 1H), 9.95 (s, 1H), 8.90 (s, 1H), 7.77-7.73 (m, 2H), 7.56-7.53 (m, 1H), 7.51-7.43 (m, 1H), 7.34 (s, 1H), 7.30-7.24 (m, 1H), 7.14-7.12 (m, 2H), 7.03-6.90 (m, 2H), 4.59 (s, 2H), 3.69-3.67 (m, 4H), 3.34-3.32 (m, 4H), 3.03-2.97 (m, 4H), 2.48-2.46 (m, 4H), 2.25-2.22 (m, 4H), 2.20-2.19 (m, 2H), 1.85-1.74 (m, 3H), 1.36 (s, 9H), 1.24-1.23 (m, 1H); [M+H] + =810.4.

[0094] Example 2: 3-(tert-butyl)-N-(4-(6-(1-((1-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide

[0095] Step 1: 2-(5-bromo-2-nitrophenyl)-2-cyanoethyl acetate TIFF2025503463000076.tif1923To a stirred solution of NaH (60% in mineral oil, 10.2 g, 253.8 mmol) in DMF (300 mL), ethyl cyanoacetate (21.5 g, 190.3 mmol) was added with N 2 The mixture was added dropwise at 0° C. under atmospheric pressure. The mixture was stirred at room temperature for 1 h. 4-Bromo-2-chloro-1-nitrobenzene (44.7 g, 190.3 mmol) was added to the above solution. The resulting mixture was subjected to N 2 Stir at 70° C. under ambient temperature for 5 h. Cool the mixture and add water (100 mL). Acidify the resulting mixture with 1M HCl(aq) to pH=6 and extract with DCM (3×250 mL). Wash the combined organic layers with saturated NaCl(aq) (200 mL) and dilute with anhydrous Na 2 SO 4 Dry at 40° C. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a gradient of hexane / EA=10:1 to give the product (34 g, 85.6%). [MH] - =311.0.

[0096] Step 2: Ethyl 2-amino-5-bromo-1H-indole-3-carboxylate TIFF2025503463000077.tif1725To a solution of ethyl 2-(5-bromo-2-nitrophenyl)-2-cyanoacetate (2.00 g, 76.7 mmol) in AcOH (100 mL), Zn (3.9 g, 59.7 mmol) was added to the 2 Add in portions under atmospheric pressure at rt over 1 h. Stir the resulting mixture at 70 °C for 24 h. Filter the mixture and wash the filter cake with AcOH (2 x 10 mL). Concentrate the filtrate under reduced pressure. Add water (200 mL) to the residue. Wash the mixture with saturated NaHCO 3 Basify to pH=8 with (aq) and extract with EA (3x200 mL). The residue was purified by silica gel column chromatography eluting with a gradient of hexane / EtOAc 1:1 to give the product (7.5 g, 34.6%). [M+H]+ =285.0.

[0097] Step 3: 6-Bromo-3,9-dihydro-4H-pyrimido[4,5-b]indol-4-one TIFF2025503463000078.tif1623 A solution of ethyl 2-amino-5-bromo-1H-indole-3-carboxylate (7.5 g, 26.5 mmol) and formamidine (13.8 g, 132.5 mmol) in methyl glycol (75 mL) is stirred at 120 °C for 24 h. The resulting mixture is cooled, concentrated and water (100 mL) is added. The precipitated solid is collected by filtration and washed with water (2 x 20 mL). The resulting solid is dried to give the product (6.5 g, 92.9%). [M+H] + =266.0.

[0098] Step 4: tert-Butyl 4-(4-oxo-4,9-dihydro-3H-pyrimido[4,5-b]indol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate TIFF2025503463000079.tif28286-Bromo-3,9-dihydro-4H-pyrimido[4,5-b]indol-4-one (500 mg, 1.893 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (761 mg, 2.461 mmol), Pd(dppf)Cl 2 (138 mg, 0.189 mmol) and K 3 PO 4 (804 mg, 3.787 mmol) in dioxane (5 mL) and H 2 In a mixture of N2O (1 mL), 2 The mixture was stirred at 90° C. under atmospheric pressure for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM:MeOH (100:1 to 10:1) to give the product (366 mg, 52.85%). [M+H] + =367.1.

[0099] Step 5: tert-Butyl 4-(4-oxo-4,9-dihydro-3H-pyrimido[4,5-b]indol-6-yl)piperidine-1-carboxylate TIFF2025503463000080.tif2828To a stirred mixture of tert-butyl 4-(4-oxo-4,9-dihydro-3H-pyrimido[4,5-b]indol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.5 g, 4.1 mmol) in MeOH (15 mL), add Pd / C (1.7 g, 16.4 mmol). The resulting mixture is heated to 37° C. for 1 hour. 2 Stir at rt under ambient for 16 h. Filter the resulting mixture and wash the filter cake with MeOH (2x15 mL). Concentrate the filtrate under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: Column, C18; Mobile phase A, 10 mM NH in water 4 HCO 3 , Mobile phase B: ACN; gradient from 20% to 60% (B%) in 25 min; detector, UV 254 nm. This gave the product (410 mg, 27.18%). [M+H] + =369.2.

[0100] Step 6: 4-Chloro-6-(piperidin-4-yl)-9H-pyrimido[4,5-b]indole TIFF2025503463000081.tif2125A stirred solution of tert-butyl 4-(4-oxo-4,9-dihydro-3H-pyrimido[4,5-b]indol-6-yl)piperidine-1-carboxylate (200 mg, 2.3 mmol) in dioxane (10 mL) was added to POCl at ambient temperature. 3 (10 mL, 107.3 mmol) is added dropwise. The resulting mixture is stirred at 100° C. for 3 h and concentrated. The residue is diluted with toluene (100 mL) and concentrated under reduced pressure. This procedure is repeated three times to give the product (410 mg, crude). [M+H] + =287.1.

[0101] Step 7: tert-Butyl 6-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-chloro-9H-pyrimido[4,5-b]indole-9-carboxylate TIFF2025503463000082.tif2328A stirred solution of 4-chloro-6-(piperidin-4-yl)-9H-pyrimido[4,5-b]indole (410 mg, 1.4 mmol) in NMP (10 mL) was treated with TEA (723 mg, 7.2 mmol) and Boc (1.0 mmol) at room temperature under a nitrogen atmosphere. 2 O (1.2 g, 5.7 mmol) was added portionwise. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (2x30 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (20:1 to 4:1) to give the product (200 mg, 28.7%). [M+H] + =487.1.

[0102] Step 8: tert-Butyl 6-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-methylphenyl)-9H-pyrimido[4,5-b]indole-9-carboxylate TIFF2025503463000083.tif37291,4-Dioxane (5.0 mL) and H 2To a stirred mixture of tert-butyl 6-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-chloro-9H-pyrimido[4,5-b]indole-9-carboxylate (180 mg, 0.4 mmol), 3-tert-butyl-N-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-1,2,4-oxadiazole-5-carboxamide (a compound obtained by a method similar to that in US20160096834A1) (177 mg, 0.4 mmol) in 20O (1 mL) was added Pd(dppf)Cl at room temperature. 2 (27 mg, 0.037 mmol) and K 3 PO 4 (157 mg, 0.74 mmol) is added in portions. The resulting mixture is stirred at 80 °C under nitrogen atmosphere for 2 h. The resulting mixture is extracted with EtOAc (3x10 mL). The combined organic layers are washed with brine (2x5 mL) and anhydrous Na 2 SO 4 The mixture was dried at 50° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase flash chromatography with the following conditions: column, C18; mobile phase A, 0.1% FA in water, mobile phase B, ACN, gradient from 40% to 95% in 25 min; detector, UV 254 nm. This gave the product (120 mg, 31.4%). [M+H] + =724.5.

[0103] Step 9: 3-(tert-butyl)-N-(2-methyl-4-(6-(piperidin-4-yl)-9H-pyrimido[4,5-b]indol-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000084.tif3530To a stirred solution of tert-butyl 6-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-methylphenyl)-9H-pyrimido[4,5-b]indole-9-carboxylate (120 mg, 0.166 mmol) in DCM (2 mL) is added TFA (0.4 mL) at 0° C. The resulting solution is stirred at room temperature for 1 h and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase A, 0.1% FA in water, mobile phase B, ACN, gradient from 10% to 50% in 25 min; detector, UV 254 nm. This gave the product (61.3 mg, 64.65%). 1 H NMR (400 MHz, DMSO) δ 12.46 (s, 1H), 10.09 (s, 1H), 8.95 (s, 1H), 8.40 (s, 1H), 7.84-7.72 (m, 3H), 7.55 (dd, J = 8.0, 2.4 Hz, 2H), 7.42 (dd, J = 8.4, 1.6 Hz, 1H), 4.63 (d, J = 4.4 Hz, 2H), 3.22 (d, J = 12.0 Hz, 2H), 2.88-2.73 (m, 3H), 2.51 (s, 3H),1.85 (d, J = 13.2 Hz, 2H), 1.64 (q, J = 13 Hz, 2H), 1.38 (s, 9H); [M+H] + = 524.2.

[0104] Step 10: 3-(tert-butyl)-N-(4-(6-(1-((1-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000085.tif35623-(tert-Butyl)-N-(2-methyl-4-(6-(piperidin-4-yl)-9H-pyrimido[4,5-b]indol-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (50 mg, 0.1 mmol) was dissolved in MeOH / DCM (10:1, 2 mL). 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (30.1 mg, 0.1 mmol) was added portionwise to the solution and the resulting mixture was stirred at room temperature for 16 h until LC-MS showed all starting material was consumed. The mixture was concentrated and purified by SiO 2 -Purification by gel column (DCM:MeOH=10:1) afforded the title product (29 mg, 35.8%). 1 H NMR (400 MHz, DMSO) δ 12.39 (s, 1H), 11.97 (s, 1H), 10.27 (s, 1H), 9.93 (s, 1H), 8.94 (s, 1H), 7.84 (s, 1H), 7.80-7.78 (m, 2H), 7.58-7.54 (m, 1H), 7.47-7.44 (m, 1H), 7.14-7.12 (m, 2H), 6.96-6.92 (m, 2H), 4.60 (s, 2H), 3.72-3.68 (m, 4H), 3.18-3.05 (m, 1H), 3.05-2.72 (m, 2H), 2.70-2.66 (m, 4H), 2.47 (s, 3H), 2.19-2.17 (m, 2H), 2.15-1.95 (m, 2H), 1.92-1.90 (m, 2H), 1.84-1.78 (m, 3H), 1.75-1.70 (m, 2H), 1.38 (s, 9H), 1.25-1.22 (m, 2H); [M+H] + = 809.7.

[0105] Example 3: 3-(tert-butyl)-N-(4-(7-(1-(3-(4-((2,6-dioxopiperidin-3-yl)amino)phenoxy)propyl)piperidin-4-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide

[0106] Step 1: 2-(4-bromo-2-nitrophenyl)-2-cyanoethyl acetate TIFF2025503463000086.tif1623To a stirred mixture of NaH (10.2 g, 253.8 mmol, 60%) in DMF (200 mL) is added dropwise ethyl cyanoacetate (15 mL) in DMF (150 mL) at 0 °C under nitrogen atmosphere. The resulting mixture is stirred at 0 °C for 0.5 h under nitrogen atmosphere. To the above mixture is added 4-bromo-1-chloro-2-nitrobenzene (15 g, 63.4 mmol) at 0 °C. The resulting mixture is further stirred at 70 °C for 4 h. The mixture is cooled to room temperature and acidified to pH 6 with HCl (aq) (1 M). The resulting mixture is extracted with EtOAc (3x300 mL). The combined organic layers are washed with brine (3x100 mL) and anhydrous Na 2 SO 4 Dry at 40° C. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography eluting with hexane / EtOAc (1:1) to give the product (14.5 g, 73%). [MH] - =311.0.

[0107] Step 2: Ethyl 2-amino-6-bromo-1H-indole-3-carboxylate TIFF2025503463000087.tif1828Ethyl 2-(4-bromo-2-nitrophenyl)-2-cyanoacetate (14 g, 44.7 mmol), Fe (25.0 g, 447.1 mmol) and NH in EtOH (140 mL). 4A mixture of 1.2g of ethyl acetate (1.2g, 100mmol) and 1.2g of ethyl acetate (1.2g, 100mmol) is stirred at 80°C for 2h. The mixture is cooled to room temperature. The resulting mixture is filtered and the filter cake is washed with MeOH (2x100mL). The filtrate is concentrated under reduced pressure. The resulting mixture is extracted with EtOAc (3x200mL). The combined organic layers are washed with brine (2x100mL) and anhydrous Na 2 SO 4 Dry at 50° C. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography eluting with hexane / EtOAc (1:1) to give the product (6.7 g, 52.0%). [M+H] + =283.0.

[0108] Step 3: 7-Bromo-3,9-dihydro-4H-pyrimido[4,5-b]indol-4-one TIFF2025503463000088.tif1928A mixture of ethyl 2-amino-6-bromo-1H-indole-3-carboxylate (3 g, 10.6 mmol) and formamidine acetate (4.4 g, 42.4 mmol) in 2-methoxyethanol (30 mL) is stirred at 125 °C for 24 h. The mixture is cooled to room temperature. Water is added to the resulting mixture and filtered. The filter cake is washed with water (3x20 mL). The solid is dried under infrared light to give the product (2.5 g, 85%). [M+H] + =264.0.

[0109] Step 4: 7-Bromo-4-chloro-9H-pyrimido[4,5-b]indole TIFF2025503463000089.tif1723POCl 3 A solution of 7-bromo-3,9-dihydro-4H-pyrimido[4,5-b]indol-4-one (2.5 g, 9.467 mmol) in 1,2-dichloro-4H-pyrimido[4,5-b]indol-4-one (2.5 g, 9.467 mmol) in 1,2-dichloro-4H-pyrimido[4,5-b]indol-4-one (25 mL) and dioxane (25 mL) was stirred at 100° C. for 1 h. The resulting mixture was concentrated in vacuo. The mixture was diluted with saturated NaHCO 3 Basify to pH=8 with EtOAc (3x50 mL) and extract with EtOAc (3x50 mL). The combined organic layers are washed with brine (50 mL) and anhydrous Na 2 SO 4Dry at 40° C. After filtration, concentrate the filtrate under reduced pressure. Collect the solid by filtration and wash with diethyl ether (2×30 mL) to give the product (2.6 g, 97%). [M+H] + =282.0.

[0110] Step 5: tert-Butyl 4-(4-chloro-9H-pyrimido[4,5-b]indol-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate TIFF2025503463000090.tif1834Dioxane (50 mL) and H 2 A stirred mixture of 7-bromo-4-chloro-9H-pyrimido[4,5-b]indole (2.4 g, 8.5 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2.4 g, 7.6 mmol) in 2H2O (10 mL) was treated with Pd(dppf)Cl at room temperature under a nitrogen atmosphere. 2 (621 mg, 0.8 mmol) and K 3 PO 4 (3.6 g, 17.0 mmol) is added. The resulting mixture is stirred at 80 °C under nitrogen atmosphere for 16 h. The mixture is cooled to room temperature. The resulting mixture is added with water (10 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers are washed with brine (10 mL) and anhydrous Na 2 SO 4 Dry at 40° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (30%-80%) to give the product (1.8 g, 55%). [M+H] + = 385.2.

[0111] Step 6: Benzyl (4-bromo-2-methylbenzyl)carbamate TIFF2025503463000091.tif1817THF (100 mL) and H 2To a stirred solution of 1-(4-bromo-2-methylphenyl)methanamine (10 g, 49.980 mmol) in 2H2O (100 mL) was added NaOH (2.1 g, 52.479 mmol) at 0 °C. To the above solution was added benzyl chloroformate (8.95 g, 52.479 mmol) dropwise at 0 °C. The resulting solution was further stirred at room temperature for 16 h. The resulting mixture was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (100 mL) and washed with anhydrous Na 2 SO 4 Dry at 50° C. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography eluting with hexane / EtOAc (3:1) to give the product (6.7 g, 40%). [M+H] + =335.0.

[0112] Step 7: Benzyl (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate TIFF2025503463000092.tif28191,4-A stirred solution of benzyl (4-bromo-2-methylbenzyl)carbamate (6.5 g, 19.4 mmol) and bis(pinacolato)diboron (5.9 g, 23.3 mmol) in dioxane (65 mL) was treated with Cs at room temperature under a nitrogen atmosphere. 2 CO 3 (12.7 g, 38.9 mmol) and Pd(dppf)Cl 2 (1.4 g, 1.9 mmol) was added. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 16 h. The mixture was cooled to room temperature. The resulting mixture was added with water (30 mL) and extracted with EtOAc (3x80 mL). The combined organic layers were washed with brine (10 mL) and extracted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with hexane / EtOAc (30%-80% EtOAc) to give the product (5.7 g, 76.0%). [M+H] + =382.2.

[0113] Step 8: tert-Butyl 4-(4-(((benzyloxy)carbonyl)amino)methyl)-3-methylphenyl)-9H-pyrimido[4,5-b]indol-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate TIFF2025503463000093.tif2839Dioxane (40 mL) and H 2 A stirred mixture of tert-butyl 4-(4-chloro-9H-pyrimido[4,5-b]indol-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.8 g, 4.7 mmol) and benzyl (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (2.1 g, 5.6 mmol) in 20O (8 mL) was incubated at room temperature under a nitrogen atmosphere with K 3 PO 4 (1.0 g, 9.4 mmol) and Pd(dppf)Cl 2 (342 mg, 0.5 mmol) was added. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 16 h. The mixture was cooled to room temperature. Water (30 mL) was added to the resulting mixture and extracted with EtOAc (3x80 mL). The combined organic layers were washed with brine (10 mL) and extracted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (0%-10% MeOH) to give the product (1.6 g, 56%). [M+H] + =604.3.

[0114] Step 9: tert-Butyl 4-[4-(aminomethyl)-3-methylphenyl]-9H-pyrimido[4,5-b]indol-7-yl]piperidine-1-carboxylate TIFF2025503463000094.tif2834To a stirred mixture of tert-butyl 4-(4-(((benzyloxy)carbonyl)amino)methyl)-3-methylphenyl)-9H-pyrimido[4,5-b]indol-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.6 g, 2.7 mmol) in EtOH (16 mL), EtOAc (7 mL) and DCM (16 mL) is added Pd / C (2.8 g, 26.5 mmol) at room temperature under nitrogen atmosphere. The final reaction mixture is heated to 30° C. for 2 h. 2 The mixture was stirred at room temperature under (2 MPa) for 48 h. The resulting mixture was filtered and the filter cake was washed with MeOH (3x80 mL). The filtrate was concentrated under reduced pressure to give the product (1.2 g, 96%). [M+H] + =472.4.

[0115] Step 10: tert-Butyl 4-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-methylphenyl)-9H-pyrimido[4,5-b]indol-7-yl)piperidine-1-carboxylate TIFF2025503463000095.tif3351To a stirred solution of 3-tert-butyl-1,2,4-oxadiazole-5-carboxylic acid (840 mg, 4.9 mmol) and tert-butyl 4-[4-(aminomethyl)-3-methylphenyl]-9H-pyrimido[4,5-b]indol-7-yl]piperidine-1-carboxylate (540 mg, 1.1 mmol) in DCM (8 mL) was added DCC (2.0 g, 9.9 mmol) and DMAP (603 mg, 4.9 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h and diluted with water (70 mL). The resulting mixture was extracted with EtOAc (3x120 mL). The combined organic layers were washed with brine (2 x 100 mL) and diluted with anhydrous Na 2 SO 4 Dry at 40° C. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with 0-10% (MeOH in DCM) to give the product (410 mg, 13%). [M+H] + =624.3.

[0116] Step 11: 3-(tert-butyl)-N-(2-methyl-4-(7-(piperidin-4-yl)-9H-pyrimido[4,5-b]indol-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000096.tif3348A mixture of tert-butyl 4-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-methylphenyl)-9H-pyrimido[4,5-b]indol-7-yl)piperidine-1-carboxylate (410 mg, 0.7 mmol) in TFA (1 mL) and DCM (4 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 10% to 50% in 15 min; detector, UV 254 nm. This gave the product (171.6 mg, 45%). 1 H NMR (400 MHz, DMSO) δ 12.47 (s, 1H), 9.93 (t, J = 6.0 Hz, 1H), 8.95 (s, 1H), 8.29 (s, 1H), 7.86-7.69 (m, 3H), 7.53 (d, J = 8.4 Hz, 1H), 7.41 (s, 1H), 7.10 (d, J = 8.0 Hz, 1H), 4.61 (d, J = 6.0 Hz, 2H), 2.98-2.88 (m, 3H), 2.55 (s, 2H), 2.47 (s, 3H), 1.98-1.89 (m, 2H), 1.84-1.75 (m, 2H), 1.39 (s, 9H); [M+H] + = 524.3.

[0117] Step 12: 3-(4-((2,6-dioxopiperidin-3-yl)amino)phenoxy)propyl 4-methylbenzenesulfonate TIFF2025503463000097.tif14413-((4-(3-hydroxypropoxy)phenyl)amino)piperidine-2,6-dione (100 mg, 0.36 mmol) and DIEA (93 mg, 0.72 mmol) are dissolved in DCM (2 mL). TsCl (138 mg, 0.72 mmol) is added portionwise to the solution at 0° C., and the resulting mixture is stirred at room temperature for 16 h until LC-MS shows that all starting material has been consumed. The resulting mixture is slowly added to ice water and extracted three times with EtOAc. The combined organic layers are washed with anhydrous NaCl. 2 SO 4 Dry and concentrate with SiO 2 -Purification by gel column (eluted with DCM / MeOH=95:5) gave the desired product (52 mg, 33%). [M+H] + =433.2.

[0118] Step 13: 3-(tert-butyl)-N-(4-(1-(3-(4-((2,6-dioxopiperidin-3-yl)amino)phenoxy)propyl)piperidin-4-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000098.tif3362 3-(tert-Butyl)-N-(2-methyl-4-(7-(piperidin-4-yl)-9H-pyrimido[4,5-b]indol-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (52 mg, 0.1 mmol), 3-(4-((2,6-dioxopiperidin-3-yl)amino)phenoxy)propyl 4-methylbenzenesulfonate (50 mg, 0.12 mmol) and DIEA (31 mg, 0.24 mmol) are dissolved in MeCN (5 mL). The resulting mixture is stirred at 80° C. for 16 h until LC-MS indicates all starting material has been consumed. The mixture is concentrated and purified by preparative HPLC to give the product (6 mg, 7.7%). 1H NMR (400 MHz, DMSO) δ 12.40 (s, 1H), 10.77 (s, 1H), 9.92 (s, 1H), 8.92 (s, 1H), 8.37-8.35 (m, 2H), 7.78-7.75 (m, 2H), 7.54-7.52 (m, 1H), 7.41 (s, 1H), 7.15-7.12 (m, 1H), 6.73 (d, J = 8.0 Hz, 2H), 6.64 (d, J = 8.0 Hz, 2H), 5.46-5.44 (m, 1H), 4.61 (s, 2H), 4.25-4.20 (m, 1H), 3.92-3.88 (m, 2H), 3.21-3.15 (m, 2H), 3.15-3.05 (m, 2H), 3.05-2.95 (m, 2H), 2.50 (s, 3H), 2.18-2.08 (m, 2H), 1.93-1.82 (m, 1H), 1.77-1.72 (m, 2H), 1.72-1.66 (m, 3H), 1.38 (s, 9H); [M+H] + = 784.4.

[0119] Example 4: 3-(tert-butyl)-N-(4-(1-((1-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000099.tif33553-(tert-Butyl)-N-(2-methyl-4-(7-(piperidin-4-yl)-9H-pyrimido[4,5-b]indol-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (100 mg, 0.19 mmol) was dissolved in MeOH / DCM (10:1, 2 mL). 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (57.2 mg, 0.19 mmol) was added portionwise to the solution and the resulting mixture was stirred at room temperature for 16 h until LC-MS showed all starting material was consumed. The mixture was concentrated and purified by SiO2 -Purification by gel column (DCM:MeOH=10:1) afforded the title product (73 mg, 47.6%). 1 H NMR (400 MHz, DMSO) δ 12.41 (s, 1H), 11.97 (s, 1H), 10.27 (s, 1H), 9.93 (s, 1H), 8.94 (s, 1H), 7.78-7.74 (m, 2H), 7.53-7.51 (m, 1H), 7.42 (s, 1H), 7.14-7.12 (m, 3H), 6.96-6.92 (m, 2H), 4.60 (s, 2H), 3.72-3.68 (m, 4H), 3.18-3.05 (m, 1H), 3.05-2.72 (m, 2H), 2.70-2.66 (m, 4H), 2.47 (s, 3H), 2.21-2.18 (m, 2H), 2.15-1.95 (m, 2H), 1.92-1.90 (m, 2H), 1.84-1.78 (m, 3H), 1.75-1.70 (m, 2H), 1.38 (s, 9H), 1.25-1.22 (m, 2H); [M+H] + = 810.4.

[0120] Example 5: (R)-3-(tert-butyl)-N-(1-(4-(1-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0121] Step 1: tert-Butyl 4-[4-oxo-3H,9H-pyrimido[4,5-b]indol-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate 3 TIFF2025503463000100.tif2135Dioxane (300 mL) and H 2A stirred mixture of 7-bromo-3,9-dihydro-4H-pyrimido[4,5-b]indol-4-one (16.5 g, 62.5 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (29.0 g, 93.7 mmol) in HO (60 mL) was treated with Pd(dppf)Cl at room temperature under a nitrogen atmosphere. 2 (4.6 g, 6.2 mmol) and K 3 PO 4 (26.5 g, 125.0 mmol) is added. The resulting mixture is stirred at 80 °C under nitrogen atmosphere for 16 h. The mixture is cooled to room temperature. The resulting mixture is added with water (100 mL) and extracted with EtOAc (3x300 mL). The combined organic layers are washed with brine (100 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH (0-10%) in DCM to give the product (16 g, 69.9%). [M+H] + =367.3.

[0122] Step 2: tert-Butyl 4-(4-oxo-4,9-dihydro-3H-pyrimido[4,5-b]indol-7-yl)piperidine-1-carboxylate TIFF2025503463000101.tif1637To a stirred solution of tert-butyl 4-[4-oxo-3H,9H-pyrimido[4,5-b]indol-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (16 g, 43.7 mmol) in DCM (500 mL), EtOAc (250 mL) and EtOH (500 mL) is added Pd / C (30 g) at room temperature under a nitrogen atmosphere. The final reaction mixture is heated to 100° C. for 2 h. 2 The mixture was stirred at room temperature under (2 MPa) for 48 h. The resulting mixture was filtered and the filter cake was washed with MeOH (3x80 mL). The filtrate was concentrated under reduced pressure to give the product (14 g, 60.9%). [M+H] + =369.1.

[0123] Step 3: 4-Chloro-7-(piperidin-4-yl)-9H-pyrimido[4,5-b]indole TIFF2025503463000102.tif1632POCl 3 (75.9 mL, 814.3 mmol) and a solution of tert-butyl 4-(4-oxo-4,9-dihydro-3H-pyrimido[4,5-b]indol-7-yl)piperidine-1-carboxylate (10 g, 27.1 mmol) in dioxane (200 mL) is stirred at 110° C. for 16 h. The resulting mixture is concentrated in vacuo. The mixture is diluted with saturated NaHCO 3 (aqueous) to pH=8. Collect the product by filtration and wash with water (2×50 mL). Dry the solid under infrared to give the product (10.5 g, crude). [M+H] + =287.2.

[0124] Step 4: tert-Butyl 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-chloro-9H-pyrimido[4,5-b]indole-9-carboxylate TIFF2025503463000103.tif1633A stirred solution of 4-chloro-7-(piperidin-4-yl)-9H-pyrimido[4,5-b]indole (10 g, 34.9 mmol) in NMP (40 mL) and DCM (200 mL) was treated with TEA (24 mL, 239.5 mmol), DMAP (426 mg, 3.5 mmol) and Boc (1.0 mmol) at room temperature under a nitrogen atmosphere. 2 Add 22 mL of HO (102.6 mmol). The resulting mixture is stirred at room temperature for 16 h and extracted with DCM (3x200 mL). The combined organic layers are washed with brine (2 x 50 mL) and anhydrous Na 2 SO 4 Dry at 40° C. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography eluting with EtOAc in petroleum ether (1% to 10%) to give the product (1.3 g, 7.6%). [M+H] + =487.2.

[0125] Step 5: tert-Butyl (R)-7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-9H-pyrimido[4,5-b]indole-9-carboxylate TIFF2025503463000104.tif3435Dioxane (20 mL) and H 2 To a stirred mixture of 3-tert-butyl-N-[(1R)-1-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide (a compound obtained in a manner similar to that in WO2021219070A) (2.0 g, 4.9 mmol) and tert-butyl 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-chloro-9H-pyrimido[4,5-b]indole-9-carboxylate (2 g, 4.1 mmol) in 2H2O (4 mL) was added Pd(dppf)Cl at room temperature under a nitrogen atmosphere. 2 (300 mg, 0.4 mmol) and K 3 PO 4 (1.7 g, 8.2 mmol) is added. The resulting mixture is stirred at 80 °C under nitrogen atmosphere for 16 h. The mixture is cooled to room temperature. The resulting mixture is added with water (20 mL) and extracted with EtOAc (3x50 mL). The combined organic layers are washed with brine (20 mL) and anhydrous Na 2 SO 4 Dry at 50° C. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography eluting with EtOAc / petroleum ether (0-40%) to give the product (2.7 g, 89.1%). [M+H] + =738.3.

[0126] Step 6: (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(7-(piperidin-4-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000105.tif3533A mixture of tert-butyl (R)-7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-9H-pyrimido[4,5-b]indole-9-carboxylate (2.8 g, 3.8 mmol) in TFA (7 mL) and DCM (28 mL) is stirred at room temperature for 2 h. The resulting mixture is concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 10% to 50% in 15 min; detector, UV 254 nm. This gave the product (1.7 g, 83.1%). 1 H NMR (300 MHz, DMSO) δ 12.47 (s, 1H), 9.93 (d, J = 7.8 Hz, 1H), 8.94 (s, 1H), 7.85-7.66 (m, 4H), 7.40 (s, 1H), 7.11 (d, J = 8.4 Hz, 1H), 5.42 (t, J = 7.5 Hz, 1H), 3.40 (d, J = 12.0 Hz, 2H), 3.10-2.96 (m, 3H), 2.50-2.48 (m, 3H), 2.00 (d, J = 13.2 Hz, 2H), 1.92-1.76 (m, 2H), 1.58 (d, J = 6.9 Hz, 3H), 1.37 (s, 9H). [M+H] + =538.35.

[0127] Step 7: (R)-3-(tert-butyl)-N-(1-(4-(1-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000106.tif3353(R)-3-(tert-butyl)-N-(1-(2-methyl-4-(7-(piperidin-4-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (100 mg, 0.19 mmol) was dissolved in MeOH / DCM (10:1, 2 mL). 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (57.2 mg, 0.19 mmol) was added portionwise to the solution and the resulting mixture was stirred at room temperature for 16 h until LC-MS showed all starting material was consumed. The mixture was concentrated and purified by HCl / HCl chromatography. 2 -Purification by gel column (DCM:MeOH=10:1) afforded the title product (98 mg, 42.7%). 1 H NMR (400 MHz, DMSO) δ 12.07 (s, 1H), 10.34 (s, 1H), 10.04 (s, 1H), 9.01 (s, 1H), 7.78-7.56 (m, 4H), 7.37 (s, 1H), 7.14-7.12 (m, 3H), 6.96-6.92 (m, 2H), 5.68 (s, 1H), 3.72-3.68 (m, 4H), 3.18-2.92 (m, 4H), 2.61-2.54 (m, 4H), 2.47 (s, 3H), 2.21-2.18 (m, 2H), 2.15-1.95 (m, 2H), 1.92-1.90 (m, 3H), 1.84-1.78 (m, 2H), 1.78-1.76 (m, 4H), 1.38 (s, 9H), 1.25-1.22 (m, 2H); [M+H] + = 823.5.

[0128] Example 6: (R)-3-(tert-butyl)-N-(1-(4-(4-((1-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000107.tif4258 (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (a compound obtained in a manner similar to that of Example 5) (100 mg, 0.19 mmol) is dissolved in MeOH / DCM (10:1, 2 mL). 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (57.2 mg, 0.19 mmol) is added portionwise to the solution and the resulting mixture is stirred at room temperature for 16 h until LC-MS indicates that all starting material has been consumed. The mixture is concentrated and SiO 2 -Purification by gel column (DCM:MeOH=10:1) afforded the title product (58 mg, 37.1%). 1 H NMR (400 MHz, DMSO) δ 12.21 (s, 1H), 10.27 (s, 1H), 9.96 (s, 1H), 8.83 (s, 1H), 7.81-7.71 (m, 4H), 7.14 (d, J = 8.0 Hz, 2H), 6.96-6.92 (m, 4H), 5.42(s, 1H), 3.72-3.68 (m, 4H), 3.18-2.92 (m, 4H), 2.75-2.65 (m, 5H), 2.61-2.55 (m, 2H), 2.47 (s, 3H), 2.21-2.18 (m, 1H), 2.15-1.95 (m, 1H), 1.87-1.68(m, 3H), 1.60-1.58(m, 3H), 1.37(s, 9H), 1.25-1.20(m, 3H); + = 824.5.

[0129] Example 7: (R)-3-(tert-butyl)-N-(1-(4-(7-(1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000108.tif4450A mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide hydrobromide (200 mg, 0.33 mmol) and 1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperidine-4-carbaldehyde (110 mg, 0.364 mmol) in MeOH (10 mL) was stirred at room temperature for 30 min in a round-bottom flask. NaBH(OAc) 3 (140 mg, 0.66 mmol) and stir at room temperature for 2 h. The reaction was quenched with water and the mixture was washed with saturated aqueous NaHCO 3 The organic layer was washed once with DCM and extracted with anhydrous Na 2 SO 4 Drying at rt and evaporation in vacuo gave the crude product which was further purified by preparative HPLC to give the product (5 mg, 1.8%). 1H NMR (400 MHz, DMSO) δ 12.17 (s, 1H), 10.31 (s, 1H), 9.94 (d, J = 7.6 Hz, 1H), 8.80 (s, 1H), 7.97 (d, J = 2.8 Hz, 1H), 7.79-7.75 (m, 1H), 7.72 (s, 1H), 7.70-7.64 (m, 2H), 7.42 (dd, J = 8.8, 2.8 Hz, 1H), 6.93-6.88 (m, 2H), 6.41 (d, J = 9.2 Hz, 1H), 5.44-5.34 (m, 1H), 3.70-3.57 (m, 4H), 3.52-3.49 (m, 1H), 3.27-3.20 (m, 5H), 3.02-2.91 (m, 1H), 2.67 (t, J = 6.8 Hz, 2H), 2.54 (s, 5H), 2.60-2.50 (m, 5H), 2.45-2.35 (m, 3H), 2.35-2.20 (m, 2H), 2.18-2.05 (m, 2H), 1.68-1.58 (m, 4H), 1.56 (d, J = 7.2 Hz, 4H), 1.35 (s, 9H); [M+H] + = 825.5.

[0130] Example 8: (R)-3-(tert-butyl)-N-(1-(4-(7-(1-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000109.tif3957A mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide hydrobromide (200 mg, 0.33 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidine-4-carbaldehyde (115 mg, 0.364 mmol) in MeOH (10 mL) is stirred at room temperature for 30 min in a round-bottom flask. Then, NaBH(OAc) 3 (140 mg, 0.66 mmol) and stir at room temperature for 2 h. The reaction was quenched with water and the mixture was washed with saturated aqueous NaHCO 3 The organic layer was washed once with DCM and extracted with anhydrous Na 2 SO 4 Drying at rt and evaporation in vacuo gave the crude product which was further purified by preparative HPLC to give the product (105 mg, 38%). 1 H NMR (400 MHz, DMSO) δ 12.18 (s, 1H), 10.24 (s, 2H), 9.94 (d, J = 7.6 Hz, 2H), 8.80 (s, 1H), 7.80-7.61 (m, 4H), 7.09-6.86 (m, 3H), 6.85-6.73 (m, 2H), 5.44-5.36 (m, 1H), 3.80-3.55 (m, 4H), 3.47-3.40 (m, 1H), 3.30-3.20 (m, 4H), 2.75-2.60 (m, 5H), 2.55-2.50 (m, 3H), 2.25-2.18 (m, 1H), 2.10 (s, 3H), 1.84-1.75 (m, 1H), 1.75-1.65 (m, 1H), 1.56 (d, J = 7.2 Hz, 2H), 1.35 (s, 9H); [M+H] + = 838.6.

[0131] Example 9: (R)-3-(tert-butyl)-N-(1-(4-(7-(1-((1-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0132] Step 1: 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)piperidine-4-carbaldehyde TIFF2025503463000110.tif21371-(2-Fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg, 0.62 mmol) is placed in DMSO (5 mL) and IBX (349 mg, 1.2 mmol) is added portionwise to the solution at room temperature. The resulting mixture is stirred at room temperature for 16 hours until TLC shows all starting material is consumed. The resulting mixture is diluted with water (25 mL) and extracted with EtOAc (25 mL*3). The combined organic layer is washed with brine (50 mL*2) and diluted with Na 2 SO 4 and concentrated to give the desired product (160 mg, crude), which is used directly without further purification. [M+H] + =320.2.

[0133] Step 2: (R)-3-(tert-butyl)-N-(1-(4-(1-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000111.tif3355(R)-3-(tert-butyl)-N-(1-(2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl))phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (100 mg, 0.19 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)piperidine-4-carbaldehyde (160 mg, 0.50 mmol) and AcOH (0.02 mL) are dissolved in MeOH / DCM (1:10, 5 mL). The mixture is stirred at room temperature for 1 h and then cooled to 5° C. with NaBH(OAc). 3 (201.0 mg, 0.95 mmol) was added portionwise to the solution. The resulting mixture was stirred at room temperature for an additional 1 h until LC-MS showed all starting material was consumed. The mixture was concentrated and diluted with SiO 2 -Purification by gel column (DCM:MeOH=10:1) afforded the title product (27.7 mg, 17.3%). 1 H NMR (400 MHz, DMSO) δ 12.25 (s, 1H), 10.45 (s, 1H), 10.01 (d, J = 7.7 Hz, 1H), 8.90 (s, 1H), 7.92-7.69 (m, 4H), 7.26 (t, J = 8.9 Hz, 1H), 7.00 (d, J = 7.3 Hz, 2H), 6.86 (dd, J = 19.1, 11.6 Hz, 2H), 5.61-5.36 (m, 1H), 3.83 (d, J = 11.8 Hz, 2H), 3.70 (t, J = 6.4 Hz, 2H), 3.42 (s, 2H), 3.33 (s, 4H), 2.87-2.72 (m, 5H), 2.62 (s, 3H), 2.31 (s, 2H), 1.86 (t, J = 11.4 Hz, 3H), 1.64 (t, J = 12.0 Hz, 3H), 1.45 (s, 9H), 1.34-1.20 (m, 3H); [M+H] + = 842.6.

[0134] Examples 10 and 11: (R)-3-(tert-butyl)-N-(1-(4-(7-(1-(((1-(4-(2,4-dioxotetrahydropyrimidine-1(2H)- (R)-3-(tert-butyl)-N-(1-(4-(7-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-1H-pyrrol-3-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0135] Step 1: 2-(4-bromo-2-nitrophenyl)-2-cyanoethyl acetate TIFF2025503463000112.tif1721To a stirred mixture of NaH (10.15 g, 253.753 mmol, 60%) in DMF (200 mL) is added dropwise ethyl cyanoacetate (15 mL) in DMF (150 mL) under nitrogen atmosphere at 0 °C. The resulting mixture is stirred at 0 °C for 0.5 h under nitrogen atmosphere. To the above mixture is added 4-bromo-1-chloro-2-nitrobenzene (15 g, 63.438 mmol) at 0 °C. The resulting mixture is further stirred at 70 °C for 4 h. The mixture is cooled to room temperature and acidified to pH = 6 with HCl (aq) (1 M). The resulting mixture is extracted with EtOAc (3x300 mL). The combined organic layers are washed with brine (3x100 mL) and anhydrous Na 2 SO 4 Dry at 40° C. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography eluting with petroleum ether / EtOAc (1:1) to give the product (14.5 g, 73%). [MH] - =310.9.

[0136] Step 2: Ethyl 2-amino-6-bromo-1H-indole-3-carboxylate TIFF2025503463000113.tif1623Ethyl 2-(4-bromo-2-nitrophenyl)-2-cyanoacetate (14 g, 44.713 mmol), Fe (24.97 g, 447.131 mmol) and NH in EtOH (140 mL). 4 A mixture of 1.2M NaCl (2.39 g, 44.713 mmol) and 1.2M NaCl is stirred at 80 °C for 2 h. The mixture is cooled to room temperature. The resulting mixture is filtered and the filter cake is washed with MeOH (2x100 mL). The filtrate is concentrated under reduced pressure. The resulting mixture is extracted with EtOAc (3x200 mL). The combined organic layers are washed with brine (2x100 mL) and anhydrous Na 2 SO 4 Dry at 50° C. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography eluting with petroleum ether / EtOAc (1:1) to give the product (6.7 g, 52%). [M+H] + =283.0.

[0137] Step 3: 7-Bromo-3,9-dihydro-4H-pyrimido[4,5-b]indol-4-one TIFF2025503463000114.tif1623A mixture of ethyl 2-amino-6-bromo-1H-indole-3-carboxylate (3 g, 10.596 mmol) and formamidine acetate (4.41 g, 42.384 mmol) in 2-methoxyethanol (30 mL) is stirred at 125 °C for 24 h. The mixture is cooled to room temperature. Water is added to the resulting mixture and filtered. The filter cake is washed with water (3x20 mL). The solid is dried under infrared light to give the product (2.5 g, 85%). [M+H] + =264.0.

[0138] Step 4: tert-Butyl 3-(4-oxo-4,9-dihydro-3H-pyrimido[4,5-b]indol-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate TIFF2025503463000115.tif1633Dioxane (45 mL) and H 2A stirred mixture of 7-bromo-3,9-dihydro-4H-pyrimido[4,5-b]indol-4-one (6.1 g, 23.099 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-pyrrole-1-carboxylate (8.9 g, 30.015 mmol) in 200 (9 mL) was treated with Pd(dppf)Cl at room temperature under a nitrogen atmosphere. 2 (1.7 g, 2.310 mmol) and K 3 PO 4 (9.8 g, 46.198 mmol) is added. The resulting mixture is stirred at 80° C. for 16 h under nitrogen atmosphere. The desired product is detected by LCMS. The mixture is cooled to room temperature and concentrated in vacuo. The residue is purified by silica gel column chromatography and purified in CH 2 Cl 2 Elution with 50:1 to 5:1 MeOH gave the product (4.8 g, 59%). [M+H] + =353.1.

[0139] Step 5: 4-Chloro-7-(2,5-dihydro-1H-pyrrol-3-yl)-9H-pyrimido[4,5-b]indole TIFF2025503463000116.tif1930POCl 3 A mixture of tert-butyl 3-(4-oxo-4,9-dihydro-3H-pyrimido[4,5-b]indol-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (4.8 g, 13.621 mmol) in (75 mL) is stirred at 110° C. for 16 hours. The desired product is detected by LCMS. The resulting mixture is concentrated in vacuo to give the product (3.7 g, crude). [M+H] + =271.1.

[0140] Step 6: tert-Butyl 3-(4-chloro-9H-pyrimido[4,5-b]indol-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate TIFF2025503463000117.tif1932Crude 4-chloro-7-(2,5-dihydro-1H-pyrrol-3-yl)-9H-pyrimido[4,5-b]indole (3.6 g, crude) was dissolved in saturated NaHCO 3 (aqueous) to pH 7. The mixture was added DMF (80 mL), Boc 2 O (29 g, 132.979 mmol) and DMAP (0.16 g, 1.330 mmol) are added at room temperature. The resulting mixture is stirred at room temperature for 16 h. The desired product is detected by LCMS. The resulting mixture is concentrated in vacuo to give the product (2.9 g, 59%). [M+H] + =371.1.

[0141] Step 7: tert-butyl 7-(1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)-4-chloro-9H-pyrimido[4,5-b]indole-9-carboxylate TIFF2025503463000118.tif1933A stirred mixture of tert-butyl 3-(4-chloro-9H-pyrimido[4,5-b]indol-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (2.9 g, 7.820 mmol) and DIEA (4 g, 31.280 mmol) in DMF (60 mL) was treated with DMAP (0.10 g, 0.782 mmol) and Boc (0.10 g, 0.782 mmol) at room temperature. 2 2H2O (8.5 g, 39.084 mmol) is added in portions. The resulting mixture is stirred at room temperature for 16 h. The desired product is detected by LCMS. The resulting mixture is extracted with EtOAc. The combined organic layers are washed with brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified with CH 2 Cl 2 Elution with 25:1 to 5:1 / MeOH gave the product (2.2 g, 61%). 1 H NMR (400 MHz, CDCl 3) δ 8.97 (s, 1H), 8.38 (d, J = 8.3 Hz, 2H),7.62 (s, 1H), 6.35 (s, 1H), 4.62 (s, 2H), 4.41 (d, J = 15.9 Hz, 2H), 1.82 (s, 9H), 1.55 (s, 9H); [M+H] + = 471.1.

[0142] Step 8: tert-Butyl (R)-7-(1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)-4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-9H-pyrimido[4,5-b]indole-9-carboxylate TIFF2025503463000119.tif39461,4-Dioxane (10 mL) and H 2 tert-Butyl 7-(1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)-4-chloro-9H-pyrimido[4,5-b]indole-9-carboxylate (200 mg, 0.425 mmol), (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (174 mg, 0.425 mmol), Pd(dppf)Cl in O (2 mL). 2 (15.5 mg, 0.021 mmol) and K 2 CO 3 (95 mg, 0.68 mmol) was stirred in a round-bottom flask at 90 °C overnight. The mixture was concentrated in vacuo to give the crude product, which was further purified by silica gel column chromatography (PE:EA = 100%:0% to 0%:100%) to give the product (174 mg, 56%). [M+H] + =722.0.

[0143] Step 9: (R)-3-(tert-butyl)-N-(1-(4-(7-(2,5-dihydro-1H-pyrrol-3-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride TIFF2025503463000120.tif3544 A solution of tert-butyl (R)-7-(1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)-4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-9H-pyrimido[4,5-b]indole-9-carboxylate (174 mg, 0.241 mmol) in 4 M hydrochloric acid (10 mL) in dioxane is stirred at room temperature for 2 h in a round-bottom flask. The mixture is subsequently stirred overnight at room temperature. The mixture is evaporated in vacuum to give the product (220 mg, crude), which is used in the next step without further purification.

[0144] Step 10: (R)-3-(tert-butyl)-N-(1-(4-(7-(1-(((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2,5-dihydro-1H-pyrrol-3-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5- Carboxamide and (R)-3-(tert-butyl)-N-(1-(4-(7-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-1H-pyrrol-3-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000121.tif58161 To a solution of (R)-3-(tert-butyl)-N-(1-(4-(7-(2,5-dihydro-1H-pyrrol-3-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride (220 mg, crude) in dichloromethane (6 mL) and MeOH (6 mL) is added NaOAc (104 mg, 1.269 mmol). The mixture is stirred at room temperature for 5 min. Then, 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (191 mg, 0.635 mmol) and HOAc (0.06 mL) are added. The mixture is stirred at room temperature overnight. Then NaBH(OAc) 3 (447 mg, 2.11 mmol) was added and stirred at room temperature for 2 hours. The mixture was then concentrated in vacuo, and the residue was purified by silica gel column chromatography (elution with a gradient of DCM:MeOH=100%:0% to 90%:10%) to give a crude product, which was further purified by preparative HPLC to give Example 10 (9.45 mg, 2.7%) and Example 11 (3.4 mg, 1%). Example 10: 1 H NMR (500 MHz, DMSO) δ 12.49 (s, 1H), 10.27 (s, 1H), 9.97 (d, J = 5 Hz, 1H), 8.95 (s, 1H), 7.83-7.68 (m, 4H), 7.48 (s, 1H), 7.40 (d, J = 10 Hz, 1H), 7.14 (d, J = 10 Hz, 2H), 6.94 (d, J = 10 Hz, 2H), 6.44 (s, 1H), 5.49-5.39 (m, 1H), 3.87 (s, 2H), 3.75-3.66 (m, 4H), 3.64 (s, 2H), 2.72-2.63 (m, 4H), 2.58 (d, J = 5.0 Hz, 2H), 2.53-2.51 (m, 3H), 1.87 (d, J = 10 Hz, 2H), 1.59 (d, J = 5.0 Hz, 3H), 1.37 (s, 9H), 1.30-1.21 (m, 2H); [M+H] += 807.7. Example 11: 1 H NMR (500 MHz, DMSO) δ 12.37 (s, 1H), 10.27 (s, 1H), 9.97 (d, J = 5.0 Hz, 1H), 8.90 (s, 1H), 7.85-7.70 (m, 4H), 7.61 (s, 1H), 7.41 (dd, J = 10.0, 1.5 Hz, 1H), 7.37-7.32 (m, 1H), 7.12 (d, J = 10.0 Hz, 2H), 6.92 (d, J = 10.0 Hz, 2H), 6.85 (t, J = 2.5 Hz, 1H), 6.49 (d, J = 2.0Hz, 1H), 5.48-5.40 (m, 1H), 3.85 (d, J = 10.0 Hz, 2H), 3.77-3.63 (m, 4H), 2.70-2.60 (m, 4H), 2.55-2.50 (m, 4H), 1.91 (s, 1H), 1.59 (d, J = 10.0 Hz, 5H), 1.38 (s, 9H), 1.34-1.28 (m, 2H); [M+H] + = 805.6.

[0145] Example 12: 3-(tert-butyl)-N-((1R)-1-(4-(1-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-3-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0146] Step 1: tert-Butyl 3-(4-oxo-4,9-dihydro-3H-pyrimido[4,5-b]indol-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate TIFF2025503463000122.tif1634Dioxane (45 mL) and H 2A stirred mixture of 7-bromo-3,9-dihydro-4H-pyrimido[4,5-b]indol-4-one (6.1 g, 23.1 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-pyrrole-1-carboxylate (8.9 g, 30.0 mmol) in 20O (9 mL) was treated with Pd(dppf)Cl at room temperature under a nitrogen atmosphere. 2 (1.7 g, 2.31 mmol) and K 3 PO 4 (9.8 g, 46.20 mmol) is added. The resulting mixture is stirred at 80° C. under nitrogen atmosphere for 16 h. The desired product is detected by LCMS. The mixture is cooled to room temperature. The resulting mixture is concentrated in vacuo. The residue is purified by silica gel column chromatography and purified in CH 2 Cl 2 Elution with 50:1 to 5:1 MeOH gave the product (4.8 g, 59%). [M+H] + =353.1.

[0147] Step 2: tert-Butyl 3-(4-oxo-4,9-dihydro-3H-pyrimido[4,5-b]indol-7-yl)pyrrolidine-1-carboxylate TIFF2025503463000123.tif1934To a stirred solution of tert-butyl 3-(4-oxo-4,9-dihydro-3H-pyrimido[4,5-b]indol-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (7 g, 19.8 mmol) in MeOH (140 mL), EtOAc (80 mL) and DCM (80 mL), Pd / C (2.1 g, 19.8 mmol) and Pd(OH) 2 Add / C (2.79 g, 19.9 mmol). The resulting mixture is stirred at 50° C. under 20 atm hydrogen atmosphere for 7 days. The mixture is cooled to rt. The resulting mixture is filtered and the filter cake is washed with MeOH (3×50 mL). The filtrate is concentrated under reduced pressure to give the product (5.3 g, 75%). [M+H] + =355.2.

[0148] Step 3: 4-Chloro-7-(pyrrolidin-3-yl)-9H-pyrimido[4,5-b]indole TIFF2025503463000124.tif1830POCl 3 A mixture of tert-butyl 3-(4-oxo-4,9-dihydro-3H-pyrimido[4,5-b]indol-7-yl)pyrrolidine-1-carboxylate (5.1 g, 14.39 mmol) in (100 mL) is stirred at 110° C. for 2 hours. The resulting mixture is concentrated under vacuum and diluted with toluene. The resulting mixture is concentrated under vacuum to give the crude product (7.4 g, 98%), which is used directly in the next step without further purification. [M+H] + =273.0.

[0149] Step 4: tert-Butyl 3-(4-chloro-9H-pyrimido[4,5-b]indol-7-yl)pyrrolidine-1-carboxylate TIFF2025503463000125.tif1833Crude 4-chloro-7-(pyrrolidin-3-yl)-9H-pyrimido[4,5-b]indole (7.4 g, 27.132 mmol) was dissolved in saturated NaHCO 3 (aqueous) to pH = 8. Then, DMF (75 mL), Boc 2 2H2O (59.2 g, 271.3 mmol) and DMAP (0.33 g, 2.70 mmol) are added at room temperature. The resulting mixture is further stirred at room temperature for 16 h. The resulting mixture is diluted with water (500 mL) and extracted with EtOAc (3x200 mL). The combined organic layers are washed with brine (2x100 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate is concentrated under reduced pressure to give the product (3 g, 29.66%), which is used directly in the next step without further purification. [M+H] + =373.0.

[0150] Step 5: tert-Butyl 7-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-chloro-9H-pyrimido[4,5-b]indole-9-carboxylate TIFF2025503463000126.tif3221 A solution of tert-butyl 3-(4-chloro-9H-pyrimido[4,5-b]indol-7-yl)pyrrolidine-1-carboxylate (3 g, 11.0 mmol) in DCM (100 mL) is stirred at room temperature for 5 minutes. The mixture is added with Boc 2 O (14.4 g, 65.98 mmol) and DMAP (4.5 mg, 0.037 mmol) are added at room temperature. The resulting mixture is stirred for another 16 h. The resulting mixture is concentrated under reduced pressure. The residue is purified by silica gel column chromatography and eluted with PE / EtOAc (2:1) to give the product (2 g, 38%). [M+H] + =473.2.

[0151] Step 6: tert-butyl 7-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-(4-((R)-1-(3-(tert-butyl))-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-9H-pyrimido[4,5-b]indole-9-carboxylate TIFF2025503463000127.tif4644Dioxane (20 mL) and H 2 To a stirred solution of tert-butyl 7-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-chloro-9H-pyrimido[4,5-b]indole-9-carboxylate (2 g, 4.23 mmol) and 3-tert-butyl-N-[(1R)-1-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide (2.1 g, 5.08 mmol) in 20O (4 mL) was added K 3 PO 4 (1.8 g, 8.48 mmol) and Pd(dppf)Cl 2 (0.3 g, 0.42 mmol) was added portionwise at room temperature. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 h and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE / EtOAc (15:1-3:1) to give the product (1.2 g, 40%). [M+H]+ =724.3.

[0152] Step 7: 3-(tert-butyl)-N-((1R)-1-(2-methyl-4-(7-(pyrrolidin-3-yl)-9H-pyrimido[4,5-b)]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide formate TIFF2025503463000128.tif4235A solution of tert-butyl 7-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-(4-((R)-1-(3-(tert-butyl))-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-9H-pyrimido[4,5-b]indole-9-carboxylate (1.1 g, 1.50 mmol) and TFA (3 mL, 40.39 mmol) in DCM (9 mL) is stirred at room temperature for 1 h. The resulting mixture is 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 (0.5% FA); mobile phase B: ACN; flow rate: 80 mL / min; gradient: 5%-5% B, 10 min, 50% B-95% B gradient within 30 min; detector: 220 nm. The fraction containing the desired product was collected at 85% B and concentrated under reduced pressure to give the product (390.3 mg, 46%). [M+H] + =524.3.

[0153] Step 8: 3-(tert-butyl)-N-((1R)-1-(4-(1-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-3-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000129.tif3969A mixture of 3-(tert-butyl)-N-((1R)-1-(2-methyl-4-(7-(pyrrolidin-3-yl)-9H-pyrimido[4,5-b)]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide formate (50 mg, 0.096 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (34.5 mg, 0.115 mmol) in MeOH (5 mL) and DCM (5 mL) was stirred at rt overnight. STAB (40.5 mg, 0.19 mmol) was then added to the above mixture and stirred at rt for 5 h. The resulting mixture is diluted with water (50 mL) and extracted with DCM (3x100 mL). The combined organic layers are washed with anhydrous Na 2 SO 4 The residue was purified by silica gel column chromatography eluting with MeOH / DCM (1:7) to give the product (51.0 mg, 66.0%). 1 H NMR (400 MHz, DMSO) δ 12.42 (s, 1H), 10.26 (s, 1H), 9.55 (d, J = 4.0 Hz, 1H), 8.93 (s, 1H), 7.83-7.75 (m, 3H), 7.73-7.70 (m, 1H), 7.52 (s, 1H), 7.18 (d, J = 4.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 5.46-5.39 (m, 1H), 3.72-3.65 (m, 4H), 3.54-3.43 (m, 1H), 2.96-2.59 (m, 8H), 2.51 (s, 3H), 2.39-2.27 (m, 2H), 1.89-1.81 (m, 3H), 1.70-1.62 (m, 1H), 1.58 (d, J = 4.0 Hz, 3H), 1.37 (s, 9H), 1.32-1.20 (m, 3H); [M+H] + = 809.4.

[0154] Examples 13 and 14: 3-(tert-butyl)-N-((R)-1-(4-(7-((S)-1-((1-(4-(2,4-) dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-3-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide and 3-(tert-butyl)-N-((R)-1-(4-(7-((R)-1-((1-(4-( 2,4-Dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-3-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000130.tif37135The racemic compound of 3-(tert-butyl)-N-((1R)-1-(4-(1-((2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-3-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (48 mg) is separated by PREP_CHIRAL_HPLC with the following conditions: Column: CHIRAL ART Amylose-SA, 2*25 cm, 5um, Mobile phase A: Hexane:DCM= 3:1 (0.5% 2 M NH 3 -MeOH), mobile phase B: IPA, flow rate: 20 mL / min, gradient: 25B to 25B within 15 min; detector: 220 / 254 nm; RT1: 11.095 min, RT2: 13.144 min, injection volume: 0.6 ml, run count: 4. This gave Example 13 (15.9 mg) and Example 14 (15.5 mg). 1H NMR (400 MHz, DMSO) δ 12.39 (s, 1H), 10.24 (s, 1H), 9.92 (d, J = 8.0 Hz, 1H), 8.93 (s, 1H), 7.88-7.68 (m, 4H), 7.53 (s, 1H), 7.21-7.19 (m, 3H), 6.93 (d, J = 8.0 Hz, 2H), 5.51-5.40 (m, 1H), 3.70 (t, J = 6.7 Hz, 4H), 3.59-3.42 (m, 1H), 3.01-2.90 (m, 1H), 2.80-2.61 (m, 7H), 2.50-2.34 (m, 1.93-1.76 (m, 3H), 1.70-1.55 (m, 4H), 1.38 (s, 9H), 1.30-1.18 (m, 3H); + = 809.4. Example 14 1 H NMR (400 MHz, DMSO) δ 12.39 (s, 1H), 10.24 (s, 1H), 9.92 (d, J = 8.0 Hz, 1H), 8.93 (s, 1H), 7.87-7.68 (m, 3H), 7.53 (s, 1H), 7.21-7.10 (m, 3H), 6.93 (d, J = 8.6 Hz, 2H), 5.51-5.40 (m, 1H), 3.70 (t, J = 6.7 Hz, 3H), 3.51-3.40 (m, 1H), 2.99-2.90 (m, 1H), 2.80-2.60 (m, 10H), 2.35 (s, 3H), 1.93-1.76 (m, 3H), 1.77-1.60 (m, 4H), 1.38 (s, 9H), 1.32-1.17 (m, 3H); [M+H] + = 809.4.

[0155] Example 15: 3-(tert-butyl)-N-((1R)-1-(4-(7-(4-(3-(4-(2,6-dioxopiperidin-3-yl)phenyl))cyclobutyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000131.tif3059To a solution of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol)-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide hydrobromide (0.4 g, 0.6 mmol) and 3-(4-(3-oxocyclobutyl)phenyl)piperidine-2,6-dione (154 mg, 0.6 mmol) in DCM / EtOH (30 mL) is added NaOAc (148 mg, 1.8 mmol). After stirring for 1 h, NaBH(OAc) 3 (381 mg, 1.8 mmol) is added. The reaction mixture is stirred for an additional 18 h. The solvent is evaporated and purified by preparative TLC using DCM / MeOH (10:1) to give the product (33.0 mg, 7.1%). 1 H NMR (400 MHz, DMSO) δ 12.18 (s, 1H), 10.82 (s, 1H), 9.94 (d, J = 8.0 Hz, 1H), 8.82 (s, 1H), 7.85-7.65 (m, 4H), 7.21-7.14 (m, 4H), 6.94 (s, 2H), 5.41 (t, J = 7.6 Hz, 1H), 3.82 (dd, J = 4.8 Hz, 11.2Hz, 1H), 3.26-3.15 (m, 5H), 2.76-2.63 (m, 3H), 2.50 (brs, 10H), 2.25-2.16 (m, 1H), 2.03 (brs, 1H), 1.91 (brs, 1H), 1.58 (d, J = 6.8 Hz, 3H), 1.37 (s, 9H); [M+H] + = 780.7.

[0156] Example 16: 3-(tert-butyl)-N-((1R)-1-(4-(7-(4-(2-(5-(2,6-dioxopiperidin-3-yl)-))6-methylpyridin-2-yl)ethyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0157] Step 1: Diethyl 2-(5-bromo-6-methylpyridin-2-yl)malonate TIFF2025503463000132.tif14251,4-Dibromo-2-methylpyridine (10 g, 40 mmol), diethyl malonate (12.8 g, 80 mmol), CuI (1.53 g, 8 mmol), 2-picolinic acid (1.97 g, 16 mmol), and Cs in dioxane (100 mL). 2 CO 3 A mixture of (52.17 g, 160 mmol) was stirred in a round bottom flask at 100° C. for 16 h. The reaction was quenched by adding brine and extracted with DCM. The DCM layer was evaporated in vacuum and purified by silica gel column chromatography to give the product (18.69 g, crude).

[0158] Step 2: 2-(5-bromo-6-methylpyridin-2-yl)acetic acid TIFF2025503463000133.tif1123MeOH / H 2 To a solution of diethyl 2-(5-bromo-6-methylpyridin-2-yl)malonate (18.69 g, 57 mmol) in 2H2O (80 mL / 40 mL) is added NaOH (6.37 g, 160 mmol) at 25° C. The mixture is stirred at 25° C. for 3 h and concentrated under vacuum. The residue is dissolved in water and washed with 2 N HCl / H2O. 2 The pH was adjusted to 3-4 with O. The solution was purified by reverse phase chromatography to give the product (12 g, 92%).

[0159] Step 3: 2-(5-bromo-6-methylpyridin-2-yl)ethan-1-ol TIFF2025503463000134.tif1026A solution of 2-(5-bromo-6-methylpyridin-2-yl)acetic acid (11 g, 57 mmol) in THF (200 mL) was diluted with BH 3 Add THF (1.0 M, 70 mL) at 0 °C. Stir the mixture at 25 °C for 16 h. Quench the reaction with MeOH (70 mL) and concentrate in vacuo. The residue is diluted with saturated NaHCO 3The mixture was dissolved in 100 ml of water and extracted with DCM. The DCM layer was evaporated in vacuum to give the crude product, which was further purified by silica gel column chromatography to give the product (4.9 g, 47%). [M+H] + =216.1.

[0160] Step 4: 2-(2',6'-bis(benzyloxy)-2-methyl-[3,3'-bipyridin]-6-yl)ethan-1-ol TIFF2025503463000135.tif14321,4-Dioxane (80 mL) and H 2 2-(5-bromo-6-methylpyridin-2-yl)ethan-1-ol (4.9 g, 22.7 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)pyridine (9 g, 21.5 mmol), Pd(PPh) in 2O (20 mL). 3 )Cl 2 (0.5 g, 0.71 mmol) and Na 2 CO 3 A mixture of (5 g, 47.2 mmol) was stirred in a round bottom flask at 100° C. overnight. The mixture was evaporated in vacuum to give the crude product, which was further purified by silica gel column chromatography to give the product (11 g, crude). [M+H] + =427.4.

[0161] Step 5: 3-(6-(2-hydroxyethyl)-2-methylpyridin-3-yl)piperidine-2,6-dione TIFF2025503463000136.tif1430A mixture of 2-(2',6'-bis(benzyloxy)-2-methyl-[3,3'-bipyridin]-6-yl)ethan-1-ol (8 g, 18.8 mmol) and 10% Pd / C (2.6 g) in MeOH (70.0 mL) was heated with H 2 Stir at (4 atm) at 40° C. for 16 h. Filter the mixture through a pad of diatomaceous earth and wash with MeOH (40.0 mL). Concentrate the filtrate in vacuo to give the product (3.4 g, 73%). [M+H] + =249.1.

[0162] Step 6: Ethyl 2-(5-(2,6-dioxopiperidin-3-yl)-6-methylpyridin-2-yl)methanesulfonate TIFF2025503463000137.tif143333-(6-(2-hydroxyethyl)-2-methylpyridin-3-yl)piperidine-2,6-dione (240 mg, 0.97 mmol) in DCM (20 mL) with Et 3 To a solution of N (1 mL, 7.22 mmol) was added MsCl (420 mg, 3.66 mmol). The mixture was stirred at 25° C. for 2 h. The mixture was evaporated in vacuum to give the crude product, which was further purified by silica gel column chromatography to give the product (170 mg, 54%). [M+H] + =327.3.

[0163] Step 7: 3-(tert-butyl)-N-((1R)-1-(4-(7-(4-(2-(5-(2,6-dioxopiperidin-3-yl)-))6-methylpyridin-2-yl)ethyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000138.tif3755 Place the compound (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (50 mg, 0.093 mmol), 2-(5-(2,6-dioxopiperidin-3-yl)-6-methylpyridin-2-yl)ethyl methanesulfonate (80 mg, 0.245 mmol), KI (300 mg, 1.8 mmol) and DIPEA (100 mg, 0.78 mmol) in MeCN (20 mL) in a round-bottom flask and stir at reflux for 16 h. The mixture was evaporated in vacuum to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH=100:0 to 100:10) to give the product (10 mg, 14%). 1H NMR (400 MHz, DMSO ) δ 12.18 (s, 1H), 10.87 (s, 1H), 9.90-9.97 (m, 1H), 8.80 (s, 1H), 7.63-7.80 (m, 4H), 7.43 (s, 1H), 7.11 (s, 1H), 6.91 (s, 2H), 5.40 (s, 1H), 3.99-4.09 (m, 1H), 3.18-3.28 (m, 6H), 2.87 (s, 2H), 2.57-2.76 (m, 6H), 2.41 (s, 3H), 2.13-2.34 (m, 3H), 1.88-2.00 (m, 2H), 1.52-1.59 (m, 3H), 1.35 (s, 9H); [M+H] + = 769.6.

[0164] Example 17: (R)-3-(tert-butyl)-N-(1-(4-(7-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenethyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0165] Step 1: 2-(4-(2,6-dioxopiperidin-3-yl)phenyl)acetaldehyde TIFF2025503463000139.tif1133A mixture of 3-(4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (200 mg, 0.8 mmol) and IBX (451 mg, 1.6 mmol) in DMSO (5 mL) is stirred at room temperature in a round-bottom flask overnight. The reaction is quenched with water, and the mixture is extracted with EtOAc, washed with saturated aqueous NaCl, and saturated NaHCO 3 The organic layer was washed twice with an aqueous solution of anhydrous Na 2 SO 4 Drying in vacuo gave the product (150 mg, 75%). [M+H] + =232.3.

[0166] Step 2: (R)-3-(tert-butyl)-N-(1-(4-(7-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenethyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000140.tif3455A mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol)-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide hydrobromide (200 mg, 0.33 mmol) and 2-(4-(2,6-dioxopiperidin-3-yl)phenyl)acetaldehyde (90 mg, 0.364 mmol) in MeOH (10 mL) is stirred at room temperature for 30 min in a round-bottom flask. Then, NaBH(OAc) 3 (140 mg, 0.66 mmol) and stir at room temperature for 2 h. The reaction was quenched with water and the mixture was washed with saturated aqueous NaHCO 3 The organic layer was washed once with DCM and extracted with anhydrous Na 2 SO 4 Drying at rt and evaporation in vacuo gave the crude product which was further purified by preparative HPLC to give the product (50 mg, 19.7%). 1 H NMR (400 MHz, DMSO) δ 12.20 (s, 1H), 10.33 (s, 1H), 9.95 (s, 1H), 8.83 (s, 1H), 7.78-7.65 (m, 4H), 7.30-7.10 (m, 3H), 7.05-6.90 (m, 2H), 5.42 (s, 1H), 3.78-3.70 (m, 1H), 3.56-3.40 (m, 2H), 3.30-3.20 (m, 5H), 2.80-2.60 (m, 9H), 2.16 (s, 3H), 1.60-1.50 (m, 3H), 1.37 (s, 9H); [M+H] + = 769.5.

[0167] Example 18: 3-(tert-butyl)-N-((1R)-1-(4-(7-(4-(4-(2,6-dioxopiperidin-3-yl))-3-methylphenyl)piperazine)-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0168] Step 1: 2-(4-(2,6-dioxopiperidin-3-yl)-3-methylphenyl)acetaldehyde TIFF2025503463000141.tif12333-(4-(2-hydroxyethyl)-2-methylphenyl)piperidine-2,6-dione (300 mg, 1.2 mmol) is placed in DMSO (5 mL) and IBX (672 mg, 2.4 mmol) is added to the solution portionwise at room temperature. The resulting mixture is stirred at room temperature for 16 hours until TLC shows that all starting material has been consumed. The resulting mixture is diluted with water (25 mL) and extracted with EtOAc (25 mL*3). The combined organic layer is washed with brine (50 mL*2) and diluted with Na 2 SO 4 and concentrated to give the desired product (460 mg, crude), which is used directly without further purification. [M+H] + =246.2.

[0169] Step 2: 3-(tert-butyl)-N-((1R)-1-(4-(7-(4-(4-(2,6-dioxopiperidin-3-yl))-3-methylphenyl)piperazine)-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000142.tif4162 (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl))phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (100 mg, 0.19 mmol), 2-(4-(2,6-dioxopiperidin-3-yl)-3-methylphenyl)acetaldehyde (460 mg, crude) and AcOH (0.02 mL) are dissolved in MeOH / DCM (1:10, 5 mL). The mixture is stirred at room temperature for 1 h and then cooled to 5° C. with NaBH(OAc) 3 (201.0 mg, 0.95 mmol) was added portionwise to the solution. The resulting mixture was stirred at room temperature for an additional 1 h until LC-MS showed all starting material was consumed. The mixture was concentrated and diluted with SiO 2 -Purification by gel column (DCM:MeOH=10:1) afforded the title product (63.3 mg, 43.4%). 1 H NMR (400 MHz, DMSO) δ 12.18 (s, 1H), 10.83 (s, 1H), 9.95 (d, J = 7.3 Hz, 1H), 8.83 (s, 1H), 7.78 (s, 1H), 7.70 (d, J = 7.7 Hz, 3H), 7.15-7.08 (m, 2H), 6.94 (s, 3H), 5.42 (s, 1H), 4.00 (d, J = 7.8 Hz, 2H), 3.26 (s, 4H), 3.00 (s, 2H), 2.73 (s, 4H), 2.62 (s, 4H), 2.49-2.48 (m, 3H), 2.25 (s, 3H), 2.15 (s, 1H), 1.98-1.94 (m, 2H), 1.58 (d, J = 5.9 Hz, 3H), 1.37 (s, 9H); + =768.6.

[0170] Example 19: (R)-3-(tert-butyl)-N-(1-(4-(7-(4-(2-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)ethyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0171] Step 1: 2-(5-bromopyridin-2-yl)ethan-1-ol TIFF2025503463000143.tif723A solution of 2-(5-bromopyridin-2-yl)acetic acid (4.3 g, 20 mmol) in THF (20 mL) was treated with BH 3 Add 1N / THF (60 mL) at 0-10 °C. Stir the reaction mixture at 20-30 °C for 18 h. After quenching with MeOH, add HCl (2 mL) and HOAc (5 mL) to the mixture and stir for 30 min. Evaporate the solvent. Add EA to the residue and add NaHCO 3 (50 mL) solution and brine (50 mL). The organic phase was separated, concentrated and used directly in the next step.

[0172] Step 2: 5-Bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyridine TIFF2025503463000144.tif1030To a solution of 2-(5-bromopyridin-2-yl)ethan-1-ol (6.0 g, 30 mmol) in DMF (50 mL), add imidazole (6.1 g, 90 mmol) and TBSCl (5.4 g, 36 mmol). Stir the reaction mixture at 20-30 °C for 18 h. H 2 After quenching with O, the reaction mixture was extracted with EA. The organic phase was washed with brine (100 mL*2), concentrated, and purified by chromatography using PE / EA (100:1 to 5:1) to give the product (8 g, 84.4%). 1 H NMR (400 MHz, CDCl 3) δ 8.63 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 4.00 (t, J = 6.0 Hz, 2H), 2.99 (t, J = 6.0 Hz, 2H), 0.90 (s, 9H), 0.02 (s, 6H).

[0173] Step 3: (6-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-3-yl)boronic acid TIFF2025503463000145.tif1030To a solution of 5-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyridine (1.0 g, 3.2 mmol) and triisopropyl borate (0.77 g, 4.1 mmol) in THF (20 mL) is added dropwise at -60 to -70 °C. After stirring for 10 min at 20 to 30 °C, add BuLi (3 mL, 4.8 mmol) dropwise. 4 The reaction was quenched with Cl solution (30 mL). The organic phase was evaporated and extracted with EA (30 mL). The organic phase was separated and washed with brine (30 mL). The mixture was concentrated and used as such in the next step.

[0174] Step 4: 1-(6-(2-hydroxyethyl)pyridin-3-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(1H,3H)-dione TIFF2025503463000146.tif1234(6-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-3-yl)boronic acid (6.0 g, 21.3 mmol), Cu(OAc) in DMA (50 mL) 2 A solution of (7.7 g, 42.3 mmol), molecular sieves (6.0 g), pyridine (8.5 g, 107.6 mmol), and 3-((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(1H,3H)-dione (0.77 g, 21.5 mmol) was dissolved in O 2 The reaction was stirred at 80°C for 2 hours under 1 atm. 2Quench with O (100 mL) and extract with EA (100 mL). Filter the solid. Separate the organic phase and wash with brine (200 mL*3). Evaporate the solvent and purify by chromatography with PE / EA (100:1-1:1), DCM / MeOH (100:1-10:1). The crude product is used in the next step. [M+H] + =364.2.

[0175] Step 5: 1-(6-(2-hydroxyethyl)pyridin-3-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione TIFF2025503463000147.tif1134A solution of 1-(6-(2-hydroxyethyl)pyridin-3-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(1H,3H)-dione (1.0 g, 2.7 mmol) and Pd / C (0.1 g) in MeOH was heated with H 2 The mixture was stirred at room temperature for 18 hours under 1 atm. After filtering off the solid, the filtrate was concentrated and used directly in the next step.

[0176] Step 6: Ethyl 2-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)methanesulfonate TIFF2025503463000148.tif1134A solution of 1-(6-(2-hydroxyethyl)pyridin-3-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (0.2 g, 0.5 mmol), MsCl (0.17 g, 1.5 mmol), and DIEA (0.32 g, 2.5 mmol) in DCM is stirred at room temperature for 3 h. The solvent is evaporated and used as is in the next step.

[0177] Step 7: (R)-3-(tert-butyl)-N-(1-(4-(7-(4-(2-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)ethyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000149.tif3966A solution of ethyl 2-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)methanesulfonate (80 mg, 0.18 mmol), (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (100 mg, 0.18 mmol), DIEA (93 mg, 0.7 mmol), and KI (179 mg, 1.1 mmol) in ACN (30 mL) is stirred at 80-85 °C for 18 h. The solvent is evaporated. The residue is eluted with H 2 Dilute with 2H2O (30 mL) and extract with EA (30 mL*2). Combine the organic phases and purify by preparative TLC with PE / EA. The product was dissolved in DCM (5 mL). Hydrochloric acid was added to a solution of dioxane (4N, 20 mL). The mixture was stirred for 1 h. After evaporation of the solvent, the residue was dissolved in MeOH (10 mL). NH 4 OH solution (4 drops) was added and the mixture was stirred for 30 min. The solvent was evaporated and purified by preparative TLC with DCM / MeOH 10:1 to give the product (21.7 mg, 16%). 1H NMR (400 MHz, DMSO) δ 12.19 (s, 1H), 10.47 (s, 1H), 9.93 (d, J = 8.0 Hz, 1H), 8.82 (s, 1H), 8.48 (s, 1H), 7.91-7.67 (m, 5H), 7.37 (d, J = 8.0 Hz, 1H), 6.94 (s, 2H), 5.42 (t, J = 7.2 Hz, 1H), 3.81 (t, J = 6.8 Hz, 2H), 3.26 (s, 4H), 2.96 (s, 2H), 2.73 (t, J = 6.4 Hz, 4H), 2.64 (s, 4H), 2.50 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H), 1.37 (s, 9H); [M+H] + = 756.7.

[0178] Example 20: 3-(tert-butyl)-N-((1R)-1-(4-(4-((R)-2,6-dioxopiperidin-3-yl)phenyl)cyclobutyl)pyrrolidin-3-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide A mixture of 3-(tert-butyl)-N-((1R)-1-(2-methyl-4-(7-(pyrrolidin-3-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamidine (60 mg, 0.115 mmol) and (R)-3-(4-(3-oxocyclobutyl)phenyl)piperidine-2,6-dione (35.4 mg, 0.137 mmol) in TIFF2025503463000150.tif3962DCE (10 mL) is stirred at 80° C. under nitrogen for 16 h. Then, NaBH 3 CN (14.5 mg, 0.23 mmol) is added to the above mixture at rt. The mixture is stirred at rt for 5 h. The resulting mixture is then diluted with water (50 mL) and extracted with DCM (3x100 mL). The combined organic layers are washed with anhydrous Na 2 SO 4Dry with 50 ml, filter and concentrate in vacuo. The residue was purified by preparative TLC (DCM / MeOH=9:1) to give the product (13.07 mg, 14.9%). 1 H NMR (500 MHz, DMSO) δ 12.41 (s, 1H), 10.83 (s, 1H), 9.94 (d, J = 5.0 Hz, 1H), 8.93 (s, 1H), 7.86-7.69 (m, 4H), 7.56-7.50 (m, 1H), 7.30-7.12 (m, 5H), 5.47-5.37 (m, 1H), 3.87-3.79 (m, 1H), 3.67-3.47 (m, 2H), 3.23-3.05 (m, 3H), 2.95-2.74 (m, 3H), 2.72-2.60 (m, 3H), 2.52 (s, 3H), 2.40-2.33 (m, 1H), 2.28-2.13 (m, 2H), 2.08-1.99 (m, 2H), 1.95-1.82 (m, 1H), 1.58 (d, J = 5.0 Hz, 3H), 1.37 (s, 9H); [M+H] + = 765.4.

[0179] Example 21: 3-(tert-butyl)-N-((1R)-1-(4-(7-(3-(4-((S)-2,6-dioxopiperidin-3-yl)phenyl)cyclobutyl)pyrrolidin-3-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound TIFF2025503463000151.tif3455 was synthesized in a similar manner to that described in Example 20. 1H NMR (500 MHz, DMSO) δ 12.51 (s, 1H), 10.84 (s, 1H), 9.96 (d, J = 10.0 Hz, 1H), 8.95 (s, 1H), 7.86-7.70 (m, 4H), 7.54 (s, 1H), 7.31-7.16 (m, 5H), 5.47-5.38 (m, 1H), 3.90-3.78 (m, 2H), 3.68-3.56 (m, 2H), 3.32-3.18 (m, 4H), 2.74-2.56 (m, 6H), 2.52 (s, 3H), 2.24-2.14 (m, 2H), 2.07-1.98 (m, 2H), 1.58 (d, J = 5.0 Hz, 3H), 1.37 (s, 9H); [M+H] + = 765.4.

[0180] Example 22: (R)-5-(tert-butyl)-N-(1-(4-(7-(4-(1-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide TIFF2025503463000152.tif4258A mixture of (R)-5-(tert-butyl)-N-(1-(2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide hydrobromide (a compound obtained in a manner similar to that of Example 5) (100 mg, 0.161 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidine-4-carbaldehyde (43.7 mg, 0.178 mmol) in MeOH (10 mL) is placed in a round-bottom flask and stirred at room temperature for 30 min. Then, NaBH(OAc) 3 (68.3 mg, 0.322 mmol) and stir at room temperature for 2 h. The reaction was quenched with water and the mixture was washed with saturated aqueous NaHCO 3 The organic layer was washed once with DCM and extracted with anhydrous Na2 SO 4 Drying at rt and evaporation in vacuo gave the crude product which was further purified by preparative HPLC to give the product (20 mg, 14.8%). 1 H NMR (400 MHz, DMSO) δ 12.17 (s, 1H), 10.24 (s, 1H), 9.58-9.48 (m, 1H), 7.91-7.59 (m, 4H), 7.09-6.73 (m, 5H), 5.48-5.40 (m, 1H), 3.80-3.60 (m, 3H), 3.50-3.40 (m, 1H), 3.28-3.20 (m, 4H), 2.80-2.60 (m, 4H), 2.28-2.20 (m, 2H), 2.12 (s, 3H), 1.95-1.65 (m, 3H), 1.56 (d, J = 6.8 Hz, 3H), 1.43 (s, 9H), 1.30-1.15 (m, 3H); [M+H] + = 838.8.

[0181] Example 23: (R)-3-(tert-butyl)-N-(1-(4-(7-(4-(((1-(4-(2,4-dioxotetrahydropyrimidin-1)(2H)-yl))phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0182] Step 1: Benzyl 4-(4-chloro-3-nitrophenyl)piperazine-1-carboxylate TIFF2025503463000153.tif21281-Chloro-4-fluoro-2-nitrobenzene (30 g, 170.901 mmol), benzylpiperazine-1-carboxylate (45 g, 205.081 mmol) and K in DMSO (600 mL). 2 CO 3A mixture of (35 g, 256.352 mmol) is stirred at 100 °C for 16 h. The mixture is cooled to room temperature. The resulting mixture is diluted with EtOAc (1000 mL) and washed with water (3x500 mL). The organic layer is washed with brine (300 mL) and anhydrous Na 2 SO 4 Dry at 40° C. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography eluting with EtOAc in petroleum ether (10%-30%) to give the product (10 g, 16%). [M+H] + =376.1.

[0183] Step 2: Benzyl 4-(4-(1-cyano-2-ethoxy-2-oxoethyl)-3-nitrophenyl)piperazine-1-carboxylate TIFF2025503463000154.tif2133Cs in DMF (100 mL) 2 CO 3 To a stirred mixture of (33 g, 101.115 mmol) is added dropwise ethyl cyanoacetate (8 mL, 71.342 mmol) in DMF (50 mL) under nitrogen atmosphere at 0 °C. The resulting mixture is stirred at room temperature under nitrogen atmosphere for 0.5 h. To the above mixture is added benzyl 4-(4-chloro-3-nitrophenyl)piperazine-1-carboxylate (9.5 g, 25.279 mmol) at 0 °C. The resulting mixture is stirred at 70 °C for an additional 16 h. The mixture is cooled to room temperature. The mixture is acidified to pH 6 with hydrochloric acid (1 M). The resulting mixture is extracted with EtOAc (3x300 mL). The combined organic layers are washed with brine (100 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EtOAc (1:1) to give the product (8.4 g, 73%). [M+H] + =453.2.

[0184] Step 3: 2-amino-6-(4-((benzyloxy)carbonyl)piperazin-1-yl)-1H-indole-3-carboxylate ethyl TIFF2025503463000155.tif2337To a stirred mixture of benzyl 4-(4-(1-cyano-2-ethoxy-2-oxoethyl)-3-nitrophenyl)piperazine-1-carboxylate (8.5 g, 18.786 mmol) in EtOH (85 mL) was added Fe (8.4 g, 150.287 mmol) and NH at room temperature. 4 Cl (2 g, 37.572 mmol) is added. The resulting mixture is stirred at 80° C. for 16 h. The resulting mixture is filtered and the filter cake is diluted with DCM / CH 3 OH (10:1, 200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:5) to give the product (4.2 g, 53%). [M+H] + =423.2.

[0185] Step 4: Benzyl 4-(4-oxo-4,9-dihydro-3H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate TIFF2025503463000156.tif2137To a stirred solution of ethyl 2-amino-6-(4-((benzyloxy)carbonyl)piperazin-1-yl)-1H-indole-3-carboxylate (4 g, 9.468 mmol) in 2-methoxyethan-1-ol (40 mL) is added formamidine acetate (3.9 g, 0.038 mmol) at room temperature. The resulting mixture is stirred at 125° C. for 16 h. The mixture is cooled to room temperature. The reaction is quenched with water (50 mL) at room temperature. The precipitated solid is collected by filtration and washed with water (3×20 mL). The solid is dried under infrared light to give the product (3.8 g, 99%). [M+H] + =404.2.

[0186] Step 5: 4-(4-chloro-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate benzyl TIFF2025503463000157.tif1737To a stirred mixture of benzyl 4-(4-oxo-4,9-dihydro-3H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate (2 g, 4.957 mmol) in dioxane (20 mL), POCl was added at room temperature. 3 (4.6 mL, 30.136 mmol) is added. The resulting mixture is stirred at 90 °C for 3 h and concentrated under reduced pressure. The resulting mixture is diluted with ethyl acetate (50 mL) and saturated NaHCO 3 (aqueous, 25 mL) to pH 8. The resulting mixture is extracted with EtOAc (3x60 mL). The combined organic layers are washed with brine (10 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EtOAc (1:1) to give the product (1.2 g, 57%). [M+H] + =422.0.

[0187] Step 6: (R)-4-(4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-2-fluoro-5-methylphenyl)-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate benzyl TIFF2025503463000158.tif32341,4-Dioxane (15 mL) and H 2 Benzyl 4-(4-chloro-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate (405 mg, 0.965 mmol), (R)-3-(tert-butyl)-N-(1-(5-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (compound obtained in a similar manner to WO2021219070A) (415 mg, 0.965 mmol), Pd(dppf)Cl in O (3 mL). 2 (80 mg, 0.097 mmol) and K 2 CO 3(555 mg, 1.74 mmol) mixture was stirred at 95 °C overnight. The mixture was evaporated in vacuum to give the crude product, which was further purified by silica gel column chromatography (elution with a gradient of PE:EA = 100%:0% to 0%:100%) to give the product (290 mg, 43%). [M+H] + =691.4.

[0188] Step 7: (R)-3-(tert-butyl)-N-(1-(5-fluoro-2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000159.tif3230 A solution of (R)-4-(4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-2-fluoro-5-methylphenyl)-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate benzyl (290 mg, 0.420 mmol) in trifluoroacetic acid (10 mL) is stirred at 85° C. for 2 h. The mixture is evaporated in vacuo to give the product (520 mg, crude), which is used in the next step without further purification. [M+H] + =557.0.

[0189] Step 8: (R)-3-(tert-butyl)-N-(1-(4-(7-(4-(((1-(4-(2,4-dioxotetrahydropyrimidin-1)(2H)-yl))phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2, 4-oxadiazole-5-carboxamide TIFF2025503463000160.tif3462 To a solution of (R)-3-(tert-butyl)-N-(1-(5-fluoro-2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (120 mg, crude) in dichloromethane (4 mL) and MeOH (4 mL) is added NaOAc (53 mg, 0.636 mmol). The mixture is stirred at room temperature for 5 min. Next, 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (a compound obtained in a similar manner to WO2021219070A) (76.5 mg, 0.254 mmol) and HOAc (0.06 mL) are added. The mixture is stirred at room temperature overnight. Then, NaBH(OAc) 3 (224 mg, 0.9 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (elution with a gradient of DCM:MeOH=100%:0% to 90%:10%) to give the crude product, which was further purified by preparative TLC (DCM:MeOH=10:1) to give the desired product (15.03 mg, 8%). 1 H NMR (500 MHz, DMSO) δ 12.21 (s, 1H), 10.25 (s, 1H), 9.53 (d, J = 10.0 Hz, 1H), 8.85 (s, 1H), 7.57-7.50 (m, 2H), 7.26 (d, J = 10.0 Hz, 1H), 7.13 (d, J = 10.0 Hz, 2H), 7.01-6.87 (m, 4H), 5.46-5.34 (m, 1H), 3.73-3.65 (m, 4H), 3.29 (s, 1H), 3.25 (s, 4H), 2.71-2.66 (m, 4H), 2.65 (s, 1H), 2.58-2.52 (m, 5H), 2.45 (s, 3H), 2.24 (d, J = 10.0 Hz, 1H), 1.82 (d, J = 10.0 Hz, 2H), 1.72 (s, 1H), 1.56 (d, J = 5.0 Hz, 3H), 1.44 (s, 9H); [M+H]+ = 842.6.

[0190] Example 24: (R)-5-(tert-butyl)-N-(1-(4-(7-(4-((1-(4-(2,4-dioxotetrahydropyrimidine)-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-5-fluoromethyl-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide

[0191] Step 1: (R)-4-(4-(4-(1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)ethyl)-2-fluoro-5-methylphenyl)-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate benzyl TIFF2025503463000161.tif34341,4-Dioxane (20 mL) and water (4 mL) were mixed with 4-(4-chloro-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate benzyl (400 mg, 0.95 mmol), (R)-5-(tert-butyl)-N-(1-(5-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide (compound obtained in a similar manner to WO2021219070A) (500 mg, 1.16 mmol), Pd(dppf)Cl 2 (100 mg, 0.13 mmol) and Cs 2 CO 3 (772 mg, 2.37 mmol) in a round-bottom flask and stir at 105 °C overnight. The mixture was evaporated in vacuum to give the crude product, which was further purified by silica gel column chromatography (elution with a gradient of PE:EA = 100:0 to 0:100) to give the title product (110 mg, 17%). [M+H] + =691.3.

[0192] Step 2: (R)-5-(tert-butyl)-N-(1-(5-fluoro-2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide TIFF2025503463000162.tif3430A solution of (R)-4-(4-(4-(1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)ethyl)-2-fluoro-5-methylphenyl)-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate (110 mg, 0.17 mmol) in MeOH (2 mL) was added to CH at 0 °C. 3 Add 33% HBr in COOH (4 mL). Stir the mixture at 25° C. for 18 h. Evaporate the mixture in vacuum to give the crude product, which was further purified by C18 column chromatography (gradient elution with 0.1% FA:ACN=85:15 to 45:55 in water) to give the title product (35 mg, 37%). [M+H] + =557.3.

[0193] Step 3: (R)-5-(tert-butyl)-N-(1-(4-(7-(4-((1-(4-(2,4-dioxotetrahydropyrimidine)-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-5-fluoromethyl-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide TIFF2025503463000163.tif3455A mixture of (R)-5-(tert-butyl)-N-(1-(5-fluoro-2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide (35 mg, 0.05 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidine-4-carboxaldehyde (24 mg, 0.075 mmol) in dichloromethane (10 mL) and MeOH (2 mL) is placed in a round-bottom flask and stirred at room temperature for 1 h. The mixture is added with NaBH(OAc) 3 (106 mg, 0.50 mmol) was added and stirred at room temperature overnight in a round bottom flask. The mixture was evaporated in vacuum to give the crude product, which was purified by preparative TLC (DCM:MeOH=7:1) to give the product (26 mg, 61%). 1 H NMR (400 MHz, DMSO ) δ 12.29 (s, 1H), 10.25 (s, 1H), 9.57 (d, J = 7.6 Hz, 1H), 8.85 (s, 1H), 7.60-7.46 (m, 2H), 7.27 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.98-6.87 (m, 2H), 6.82 (s, 1H), 6.77 (d, J = 8.4 Hz, 1H), 5.48-5.34 (m, 1H), 3.75-3.62 (m, 3H), 3.50-3.43 (m, 1H), 3.25 (s, 4H), 2.73-2.61 (m, 4H), 2.58-2.53 (m, 2H), 2.46 (s, 3H), 2.29-2.16 (m, 2H), 2.10 (s, 3H), 1.94-1.89 (m, 2H), 1.89-1.76 (m, (2H), 1.76-1.66 (m, 1H), 1.61-1.53 ​​(m, 3H), 1.44 (s, 9H), 1.25-1.19 (m, 2H); + = 856.7.

[0194] Examples 25 and 26: 3-(tert-butyl)-N-((R)-1-(4-(7-(4-(3-(4-((S)))-2,6-dioxopiperidine-3-yl)phenyl)cyclobutyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide and 3-(tert-butyl)-N-((R)-1-(4-(7-(4-(3-(4-((R)-2,6-dioxopiperidine-3 -yl)phenyl)cyclobutyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indolaid-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0195] Step 1: 2,6-Bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine TIFF2025503463000164.tif1128 A solution of 2,6-bis(benzyloxy)-3-bromopyridine (40.00 g, 108.036 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (41.15 g, 162.054 mmol) in dioxane (800.00 mL) was diluted with KOAc (31.81 g, 324.109 mmol) and Pd(dppf)Cl 2 (6.32 g, 8.643 mmol) is added. After stirring at 100° C. for 16 h under nitrogen atmosphere, the resulting mixture is concentrated under reduced pressure. The reaction mixture is used in the next step. [M+H] + =418.1.

[0196] Step 2: 3-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)cyclobutan-1-one TIFF2025503463000165.tif1451 A solution of 3-(4-bromophenyl)cyclobutan-1-one (22.50 g, 99.962 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (37.54 g, 89.966 mmol) in dioxane (200 mL) and water (40 mL) was added to the reaction mixture. 2 CO 3 (16.58 g, 119.955 mmol) and Pd(dppf)Cl 2 (7.31 g, 9.996 mmol) is added. After stirring at 90° C. for 16 h under nitrogen atmosphere, the resulting mixture is concentrated under reduced pressure. The residue is purified by silica gel column chromatography eluted with 1-20% EtOAc in PE to give the product (30.1 g, 38.89%). [M+H] + =436.1.

[0197] Step 3: 3-(4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)-2,6-bis(benzyloxy)pyridine TIFF2025503463000166.tif1139To a solution of 3-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)cyclobutan-1-one (26.00 g, 59.698 mmol) in toluene (500.00 mL), 4-toluene-1-sulfonic acid hydrate (1.14 g, 5.970 mmol) and 2-dihydroxyethane (14.82 g, 238.793 mmol) are added under nitrogen atmosphere. The mixture is refluxed in a Dean-Stark for 16 h to separate the water. The resulting mixture is concentrated under reduced pressure. The residue is dissolved in EtOAc (500 mL). The combined organic layers are washed with NaHCO 3 Wash with aqueous solution (3x200mL) of anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with 1-40% EtOAc in PE to give the product (25.2 g, 88.02%). [M+H] + =480.1.

[0198] Step 4: 3-(4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)piperidine-2,6-dione TIFF2025503463000167.tif2332Add Pd / C (5.55 g) to a solution of 3-(4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)-2,6-bis(benzyloxy)pyridine (25.00 g, 52.129 mmol) in THF (600.00 mL) and EtOH (200.00 mL) under nitrogen atmosphere. Stir the mixture under hydrogen atmosphere with hydrogen tyre for 16 h. Filter the resulting mixture through a Celite pad and wash the filter cake with MeOH (3x20 mL). Concentrate the filtrate under reduced pressure. Concentrate the resulting mixture under reduced pressure. The residue was purified by silica gel column chromatography eluting with 10-40% EtOAc in PE to give the product (14.4 g, 91.67%). [M+H] + =302.2.

[0199] Step 5: 3-(4-(3-oxocyclobutyl)phenyl)piperidine-2,6-dione TIFF2025503463000168.tif2330To a stirred solution of 3-(4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)piperidine-2,6-dione (13.5 g, 44.8 mmol) in THF (100 mL) and water (80 mL) is added 2 M hydrochloric acid (20 mL) at room temperature. The resulting mixture is stirred at 55 °C under nitrogen atmosphere for 4 h. The desired product is detected by LCMS. The reaction is cooled to 0 °C with NaHCO 3 The mixture was quenched with aqueous solution (10 mL). The resulting mixture was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (3 x 100 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with 10-60% EtOAc in PE to give the product (8.2 g, 72%). [M+H] + =258.1.

[0200] Step 6: (R)-3-(4-(3-oxocyclobutyl)phenyl)piperidine-2,6-dione and (S)-3-(4-(3-oxocyclobutyl)phenyl)piperidine-2,6-dione TIFF2025503463000169.tif21733-(4-(3-oxocyclobutyl)phenyl)piperidine-2,6-dione (8.20 g, 31.9 mmol) is separated by Prep-Chiral-SFC under the following conditions: Column: CHIRALPAK IH, 5*25 cm, 5 um, Mobile phase A: CO 2 , Mobile phase B: MeOH, Flow rate: 200 mL / min, Gradient: 50% B, Column temperature: Back pressure: 100 bar, Detector: 220 nm, RT 1 :3.99min, RT 2 : 5.53 min, injection volume: 5 mL, number of runs: 30, (3R)-3-[4-(3-oxocyclobutyl)phenyl]piperidine-2,6-dione (3.30 g, 40%) (obtained in 3.99 min). 1 H NMR (400 MHz, DMSO) δ 10.84 (s, 1H), 7.36-7.32 (m, 2H), 7.21-7.19 (m, 2H), 3.86 (dd, J = 11.6, 5.2 Hz, 1H), 3.84-3.83 (m, 1H), [M+H] + = 258.1. (3S)-3-[4-(3-oxocyclobutyl)phenyl]piperidine-2,6-dione (3.23 g, 40%) was obtained in 5.53 min. 1H NMR (400 MHz, DMSO) δ 10.84 (s, 1H), 7.38-7.31 (m, 2H), 7.23-7.13 (m, 2H), 3.85 (dd, J = 11.6, 4.8 Hz, 1H), 3.71-3.58 (m, 1H), [M+H] + = 258.1.

[0201] Step 7: 3-(tert-butyl)-N-((R)-1-(4-(7-(4-(3-(4-((S)))-2,6-dioxopiperidine-)3-yl)phenyl)cyclobutyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000170.tif5380To a solution of (R)-3-(tert-butyl)-N-(1-(5-fluoro-2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (120 mg, crude) in dichloromethane (4 mL) and MeOH (4 mL), NaOAc (53 mg, 0.636 mmol) is added. The mixture is stirred at room temperature for 5 min. Then, (R)-3-(4-(3-oxocyclobutyl)phenyl)piperidine-2,6-dione (81.7 mg, 0.318 mmol) and HOAc (0.06 mL) are added. The mixture is stirred at room temperature overnight. Then, NaBH(OAc) 3 (224.7 mg, 1.06 mmol) and stir at room temperature overnight. Then, NaBH 3Add CN (135 mg, 0.636 mmol) and stir at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (elution with a gradient of DCM:MeOH=100%:0% to 90%:10%) to give the crude product, which was further purified by preparative TLC (DCM:MeOH=10:1) to give the desired product (17.7 mg, 10%). 1 H NMR (500 MHz, DMSO) δ 12.20 (s, 1H), 10.81 (s, 1H), 9.53 (d, J = 10.0 Hz, 1H), 8.86 (s, 1H), 7.56-7.50 (m, 2H), 7.31-7.24 (m, 2H), 7.23-7.19 (m, 2H), 7.18-7.12 (m, 2H), 6.93 (s, 2H), 5.46-5.35 (m, 1H), 3.85-3.77 (m, 1H), 3.30-3.21 (m, 4H), 3.15 (s, 1H), 2.75 (s, 1H), 2.70-2.60 (m, 2H), 2.49-2.42 (m, 9H), 2.23-2.12 (m, 2H), 2.06-1.98 (m, 1H), 1.94-1.84 (m, 2H), 1.56 (d, J = 5.0 Hz, 3H), 1.43 (d, J = 9.4 Hz, 9H); [M+H] + = 798.6.

[0202] Step 8: 3-(tert-butyl)-N-((R)-1-(4-(7-(4-(3-(4-((R)-2,6-dioxopiperidin-3) -yl)phenyl)cyclobutyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indolaid-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000171.tif5380 To a solution of (R)-3-(tert-butyl)-N-(1-(5-fluoro-2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (120 mg, crude) in dichloromethane (4 mL) and MeOH (4 mL) is added NaOAc (53 mg, 0.636 mmol). The mixture is stirred at room temperature for 5 min. Then (S)-3-(4-(3-oxocyclobutyl)phenyl)piperidine-2,6-dione (81.7 mg, 0.318 mmol) and HOAc (0.06 mL) are added. The mixture is stirred at room temperature overnight. Then NaBH(OAc) 3 (224.7 mg, 1.06 mmol) and stir at room temperature overnight. Then, NaBH 3 Add CN (135 mg, 0.636 mmol) and stir at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (elution with a gradient of DCM:MeOH=100%:0% to 90%:10%) to give the crude product, which was further purified by preparative TLC (DCM:MeOH=10:1) to give the desired product (6.75 mg, 4%). 1 H NMR (500 MHz, DMSO) δ 12.20 (s, 1H), 10.82 (s, 1H), 9.53 (d, J = 10.0 Hz, 1H), 8.86 (s, 1H), 7.62-7.50 (m, 2H), 7.25-7.4 (m, 2H), 7.20-7.09 (m, 4H), 6.93 (s, 2H), 5.44-5.31 (m, 1H), 3.90-3.74 (m, 1H), 3.25 (s, 3H), 3.15 (s, 1H), 2.75 (s, 1H), 2.68-2.59 (m, 2H), 2.49-2.42 (m, 8H), 2.17 (d, J = 7.7 Hz, 2H), 2.06-1.97 (m, 2H), 1.96-1.85 (m, 1H), 1.56 (d, J = 7.0 Hz, 4H), 1.44 (s, 10H); [M+H] + = 798.5.

[0203] Example 27: (R)-5-(tert-butyl)-N-(1-(4-(7-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1)(2H)-yl))phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide

[0204] Step 1: (R)-4-(4-(4-(1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)ethyl)-2-fluoro-3-methylphenyl)-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate benzyl TIFF2025503463000172.tif35341,4-Benzyl 4-(4-chloro-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate (420 mg, 1.0 mmol), (R)-5-(tert-butyl)-N-(1-(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide (540 mg, 1.25 mmol), Pd(dppf)Cl in 20 mL of dioxane and 5 mL of water. 2 (73 mg, 0.10 mmol) and Cs 2 CO 3 (1000 mg, 3.07 mmol) in a round-bottom flask and stir at 105 °C overnight. The mixture was evaporated in vacuum to give the crude product, which was further purified by silica gel column chromatography (elution with a gradient of PE:EA = 30:70 to 0:100) to give the product (298 mg, 43%). [M+H] + =691.3.

[0205] Step 2: (R)-5-(tert-butyl)-N-(1-(3-fluoro-2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide TIFF2025503463000173.tif3430A solution of (R)-4-(4-(4-(1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)ethyl)-2-fluoro-3-methylphenyl)-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate (298 mg, 0.43 mmol) in MeOH (10 mL) was added to CH at 0 °C. 3 Add 33% HBr in COOH (8 mL). Stir the mixture at 25° C. for 18 h. Evaporate the mixture in vacuum to give the crude product, which was further purified by C18 column chromatography (elution with a gradient of 0.1% FA:ACN in water = 75:25 to 45:55) to give the title product (50 mg, 21%). [M+H] + =557.3.

[0206] Step 3: (R)-5-(tert-butyl)-N-(1-(4-(7-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1)(2H)-yl))phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide TIFF2025503463000174.tif3554 A mixture of (R)-5-(tert-butyl)-N-(1-(3-fluoro-2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide (25 mg, 0.045 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (24 mg, 0.079 mmol) in dichloromethane (10 mL) and MeOH (2 mL) is placed in a round-bottom flask and stirred at room temperature for 1 h. The mixture is added with NaBH(OAc) 3 (106 mg, 0.50 mmol) was added and stirred at room temperature in a round bottom flask overnight. The mixture was evaporated in vacuum to give the crude product, which was purified by preparative TLC (DCM:MeOH=9:1) to give the product (26 mg, 61%). 1 H NMR (400 MHz, DMSO) δ 12.21 (s, 1H), 10.25 (s, 1H), 9.75-9.45 (m, 1H), 8.85 (s, 1H), 7.62-7.45 (m, 2H), 7.29-7.05 (m, 3H), 6.97-6.88 (m, 4H), 5.52-5.32 (m, 1H), 3.76-3.64 (m, 5H), 3.28-3.17 (m, 4H), 2.78-2.61 (m, 5H), 2.40 (s, 4H), 2.27-2.14 (m, 2H), 1.88-1.65 (m, 4H), 1.61-1.51 (m, 3H), 1.43 (s, 9H), 1.31-1.14 (m, 3H); [M+H] + = 842.8.

[0207] Example 28: (R)-5-(tert-butyl)-N-(1-(4-(7-(4-(1-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxa 1,2,4-oxadiazole-3-carboxamide The title compound TIFF2025503463000175.tif3755 was synthesized in a similar manner to Example 27. 1 H NMR (400 MHz, DMSO) δ 12.26 (s, 1H), 10.23 (s, 1H), 9.61 (d, J = 7.6 Hz, 1H), 8.85 (s, 1H), 7.59-7.45 (m, 2H), 7.27-7.18 (m, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.98-6.88 (m, 2H), 6.86-6.75 (m, 2H), 5.50-5.39 (m, 1H), 3.74-3.62 (m, 4H), 3.27-3.18 (m, 5H), 2.75-2.64 (m, 4H), 2.40 (s, 3H), [M+H] 2.27-2.19 (m, 2H), 2.15-2.07 (m, 3H), 1.83-1.74 (m, 6H), 1.62-1.53 ​​(m, 3H), 1.43 (s, 9H), 1.28-1.16 (m, 4H) + = 856.8.

[0208] Example 29: 5-(tert-butyl)-N-((1R)-1-(4-(7-(4-(1-(4-(2,6-dioxopiperidin-3-yl))phenyl)piperidine)-4-yl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide

[0209] Step 1: 2,6-Bis(benzyloxy)-3-(4-bromophenyl)pyridine TIFF2025503463000176.tif16282,6-Bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (36 g, 86.3 mmol), 1-bromo-4-iodobenzene (24.3 g, 86.3 mmol) and K 2 CO 3 (23.8 g, 172.6 mmol) was dissolved in dioxane (500 mL) and water (100 mL) and the resulting solution was treated with Pd(dppf)Cl 2 (6.32 g, 8.63 mmol) is added. The mixture is stirred at 80° C. for 16 h and cooled to rt. The mixture is washed with water and extracted with EtOAc. The organic layers are combined and diluted with Na 2 SO 4 The residue was purified by silica gel column chromatography (PE: EtOAc = 100 / 1) to give the product (30 g, 78%). [M+H] + =446.1.

[0210] Step 2: 8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-1,4-dioxa-8-azaspiro[4.5]decane TIFF2025503463000177.tif21422,6-Bis(benzyloxy)-3-(4-bromophenyl)pyridine (0.89 g, 2.0 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (0.29 g, 2.0 mmol), Cs 2 CO 3 (1.3 g, 4.0 mmol) and Xantphos (0.23 g, 0.4 mol) were dissolved in dioxane (25 mL), and the resulting solution was added to Pd 2 dba 3 (0.18 g, 0.2 mmol) is added. The mixture is stirred at 90° C. for 16 h and cooled to rt. The solution is washed with water and extracted with EtOAc. The organic layers are combined and diluted with Na 2 SO 4 The residue was purified by silica gel column chromatography (PE: EtOAc = 4 / 1) to give the product (300 mg, 30%). [M+H]+ =509.3.

[0211] Step 3: 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-one TIFF2025503463000178.tif1939H 2 To a solution of 8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-1,4-dioxa-8-azaspiro[4.5]decane (300 mg, 0.59 mmol) in 2H2O (5 mL) is added HCl / dioxane (4N, 5 mL) dropwise. The mixture is stirred at 60 °C for 16 h. The mixture is washed with water and extracted with DCM. The organic layers are combined and washed with Na 2 SO 4 The mixture was filtered and the filtrate was concentrated in vacuo to give the product (0.2 g, 73%). [M+H] + =465.2.

[0212] Step 4: 3-(4-(4-oxopiperidin-1-yl)phenyl)piperidine-2,6-dione TIFF2025503463000179.tif2137To a mixture of 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-one (0.2 g, 0.43 mmol) dissolved in THF / MeOH, add Pd / C (40 mg, 20% w / w). The reaction is stirred under hydrogen atmosphere at rt for 16 h. The mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to give the product (105 mg, 85%). [M+H] + =287.3.

[0213] Step 5: 5-(tert-butyl)-N-((1R)-1-(4-(7-(4-(1-(4-(2,6-dioxopiperidin-3-yl))phenyl)piperidine)-4-yl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide TIFF2025503463000180.tif4189To a solution of (R)-5-(tert-butyl)-N-(1-(3-fluoro-2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide (100 mg, crude) in dichloromethane (5 mL) and MeOH (5 mL), add NaOAc (44.3 mg, 0.540 mmol). The mixture is stirred at room temperature for 5 min. Then 3-(4-(4-oxopiperidin-1-yl)phenyl)piperidine-2,6-dione (61.7 mg, 0.216 mmol) and HOAc (0.06 mL) are added. The mixture is stirred at room temperature overnight. Then NaBH(OAc) 3 (191 mg, 0.9 mmol) and stir at room temperature overnight. Then, NaBH 3 Add CN (113 mg, 1.8 mmol) and stir at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (elution with a gradient of DCM:MeOH=100%:0% to 90%:10%) to give the crude product, which was further purified by preparative TLC (DCM:MeOH=10:1) to give the desired product (20.16 mg, 14%). 1H NMR (500 MHz, DMSO) δ 12.27 (d, J = 70.0 Hz, 1H), 10.78 (s, 1H), 9.62 (s, 1H), 8.87 (d, J = 20.0 Hz, 1H), 7.60-7.45 (m, 2H), 7.24 (d, J = 30.0 Hz, 1H), 7.12-6.99 (m, 3H), 6.99-6.86 (m, 3H), 5.51-5.40 (m, 1H), 3.99 (d, J = 10.0 Hz, 1H), 3.89 (d, J = 10.0 Hz, 1H), 3.80-3.65 (m, 3H), 3.26-3.07 (m, 4H), 2.74-2.60 (m, 5H), 2.54 (s, 1H), 2.48-2.43 (m, 1H), 2.40 (s, 3H), 2.23-2.09 (m, 2H), 2.05-1.95 (m, 1H), 1.92-1.84 (m, 1H), 1.75 (s, 1H), 1.56 (d, J = 5.0 Hz, 3H), 1.43 (s, 9H); [M+H] + = 827.6.

[0214] Example 30: 5-(tert-butyl)-N-((1R)-1-(4-(7-(4-(3-(4-(2,6-dioxopiperidin-3-yl)phenyl)cyclobutyl)methyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide

[0215] Step 1: (3-(4-bromophenyl)cyclobutyl)methanol TIFF2025503463000181.tif1030A solution of 3-(4-bromophenyl)cyclobutane-1-carboxylic acid (510 mg, 2 mmol) in THF was treated with BH 3 (2.6 mL, 1N in THF) is added dropwise. The mixture is stirred at rt for 16 h. The reaction is quenched with 1N HCl at 0° C. and extracted with EtOAc. The organic layers are combined and washed with Na 2 SO 4Dry at 40° C. The mixture is filtered and the filtrate is concentrated to give the product (470 mg, 98%). 1 H NMR (400 MHz, DMSO) δ 7.48 (t, J = 9.2 Hz, 2H), 7.21 (dd, J = 25.4, 10.6 Hz, 2H), 6.52 (s, 1H), 3.38 (d, J = 16.9 Hz, 4H), 2.41-2.26 (m, 2H), 2.14 (dd, J = 21.7, 10.3 Hz, 1H), 1.85-1.74 (m, 1H).

[0216] Step 2: (3-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)cyclobutyl)methanol TIFF2025503463000182.tif1241Dioxane / H 2 (3-(4-bromophenyl)cyclobutyl)methanol (470 mg, 1.95 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (813 mg, 1.95 mmol) and Pd(PPh) dissolved in 20 3 ) 4 (116 mg, 0.1 mmol) of Na 2 CO 3 (413 mg, 3.9 mmol) is added. The mixture is stirred at 105° C. overnight. The solvent is removed by vacuum. The mixture is washed with water and extracted with EtOAc. The organic layers are combined and diluted with Na 2 SO 4 The residue was purified by silica gel column chromatography (PE: EtOAc = 4 / 1) to give the product (600 mg, 68%). [M+H] + =452.1.

[0217] Step 3: 3-(4-(3-(hydroxymethyl)cyclobutyl)phenyl)piperidine-2,6-dione TIFF2025503463000183.tif1239To a solution of (3-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)cyclobutyl)methanol (600 mg, 1.33 mmol) dissolved in THF / MeOH is added Pd / C (60 mg, 10% w / w). The reaction is stirred under hydrogen atmosphere at rt for 16 h. The mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to give the product (340 mg, 94%). [M+H] + =274.2.

[0218] Step 4: 3-(4-(2,6-dioxopiperidin-3-yl)phenyl)cyclobutane-1-carbaldehyde TIFF2025503463000184.tif1237To a mixture of 3-(4-(3-(hydroxymethyl)cyclobutyl)phenyl)piperidine-2,6-dione (340 mg, 1.24 mmol) dissolved in DMSO, IBX (444 mg, 1.59 mmol) is added. The mixture is stirred at room temperature for 4 h. The mixture is then washed with water and extracted with DCM. The organic layers are combined and washed with brine. The mixture is diluted with Na 2 SO 4 Dry with 500 ml and filter. Concentrate the filtrate in vacuo. The residue was purified by silica gel column chromatography to give the product (302 mg, 90%). [M+H] + =272.3.

[0219] Step 5: 5-(tert-butyl)-N-((1R)-1-(4-(7-(4-(3-(4-(2,6-dioxopiperidin-3-yl)phenyl)cyclobutyl)methyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide TIFF2025503463000185.tif5337To a solution of (R)-5-(tert-butyl)-N-(1-(3-fluoro-2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide (100 mg, crude) in dichloromethane (5 mL) and MeOH (5 mL), add NaOAc (44.3 mg, 0.540 mmol). The mixture is stirred at room temperature for 5 min. Then, 3-(4-(2,6-dioxopiperidin-3-yl)phenyl)cyclobutane-1-carbaldehyde (58.8 mg, 0.216 mmol) and HOAc (0.06 mL) are added. The mixture is stirred at room temperature overnight. Then, NaBH(OAc) 3 (191 mg, 0.9 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (elution with a gradient of DCM:MeOH=100%:0% to 90%:10%) to give the crude product, which was further purified by preparative TLC (DCM:MeOH=10:1) to give the desired product (28.04 mg, 19%). 1 H NMR (500 MHz, DMSO) δ 12.27 (d, J = 70.0 Hz, 1H), 10.82 (s, 1H), 9.61 (s, 1H), 8.89 (s, 1H), 7.65-7.43 (m, 2H), 7.29-7.06 (m, 5H), 7.05-6.87 (d, J = 47.3 Hz, 2H), 5.51-5.34 (m, 1H), 3.94 (s, 1H), 3.82 (d, J = 5.0 Hz, 1H), 3.63-3.49 (m, 1H), 3.48-3.39 (s, 1H), 3.30 (s, 3H), 3.25-3.09 (m, 4H), 2.72-2.62 (m, 1H), 2.54 (s, 1H), 2.48-2.43 (m, 2H), 2.40 (s, 3H), 2.23-2.13 (m, 1H), 2.05-1.97 (m, 1H), 1.95-1.87 (s, 1H), 1.75 (s, 1H), 1.56 (d, J = 5.0 Hz, 3H), 1.43 (s, 9H); [M+H]+ = 812.3.

[0220] Example 31: 5-(tert-butyl)-N-((R)-1-(4-(7-(4-(3-((S)-2,6-dioxopiperidin-3-yl)phenyl)cyclobutyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide TIFF2025503463000186.tif4159To a solution of (R)-5-(tert-butyl)-N-(1-(3-fluoro-2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide (100 mg, crude) in dichloromethane (5 mL) and MeOH (5 mL), add NaOAc (44 mg, 0.540 mmol). The mixture is stirred at room temperature for 5 min. Then, add (S)-3-(4-(3-oxocyclobutyl)phenyl)piperidine-2,6-dione (46 mg, 0.180 mmol) and HOAc (0.06 mL). The mixture is stirred at room temperature overnight. Then, add NaBH(OAc) 3 (190 mg, 0.9 mmol) and stir at room temperature overnight. Then, NaBH 3 Add CN (226 mg, 3.6 mmol) and stir at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (elution with a gradient of DCM:MeOH=100%:0% to 90%:10%) to give the crude product, which was further purified by preparative TLC (DCM:MeOH=10:1) to give the desired product (55.99 mg, 39%). 1H NMR (500 MHz, DMSO) δ 12.27 (d, J = 70.0 Hz, 1H), 10.83 (s, 1H), 9.61 (d, J = 5.0 Hz, 1H), 8.87 (d, J = 15.0 Hz, 1H), 7.64-7.46 (m, 2H), 7.37 (s, 1H), 7.33-7.13 (m, 4H), 6.98 (d, J = 45.0 Hz, 2H), 5.48-5.41 (m, 1H), 3.98 (d, J = 10.0 Hz, 1H), 3.89-3.69 (m, 2H), 3.50 (s, 1H), 3.28-3.14 (m, 4H), 3.07 (s, 1H), 2.74-2.61 (m, 2H), 2.47 (s, 3H), 2.40 (s, 3H), 2.19 (d, J = 10.0 Hz, 1H), 2.06-1.99 (m, 1H), 1.93-1.83 (m, 1H), 1.57 (d, J = 5.0 Hz, 3H), 1.43 (s, 9H); [M+H] + = 796.5.

[0221] Example 32: 5-(tert-butyl)-N-((R)-1-(4-(7-(3-(4-((R)-2,6-dioxopiperidin-3-yl)phenyl)cyclobutyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide To a solution of (R)-5-(tert-butyl)-N-(1-(3-fluoro-2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide (100 mg, crude) in dichloromethane (5 mL) and MeOH (5 mL) is added NaOAc (44 mg, 0.540 mmol). The mixture is stirred at room temperature for 5 min. Then (R)-3-(4-(3-oxocyclobutyl)phenyl)piperidine-2,6-dione (46 mg, 0.180 mmol) and HOAc (0.06 mL) are added. The mixture is stirred at room temperature overnight. Then NaBH(OAc)3 (190 mg, 0.9 mmol) and stir at room temperature overnight. Then, NaBH 3 Add CN (226 mg, 3.6 mmol) and stir at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (elution with a gradient of DCM:MeOH=100%:0% to 90%:10%) to give the crude product, which was further purified by preparative TLC (DCM:MeOH=10:1) to give the desired product (50.86 mg, 35%). 1 H NMR (500 MHz, DMSO) δ 12.27 (d, J = 70.0 Hz, 1H), 10.83 (s, 1H), 9.61 (d, J = 10.0 Hz, 1H), 8.87 (d, J = 20.0 Hz, 1H), 7.61-7.42 (m, 2H), 7.37 (s, 1H), 7.28-7.12 (s, 4H), 7.05-6.88 (m, 2H), 5.46-5.33 (m, 1H), 3.97 (s, 1H), 3.88-33.69 (m, 2H), 3.50 (s, 1H), 3.25 (s, 3H), 3.08 (s, 2H), 2.69-2.61 (m, 2H), 2.46-2.43 (m, 3H), 2.40 (s, 3H), 2.18 (d, J = 5.0 Hz, 1H), 2.05-1.97 (m, 1H), 1.90-1.82 (m, 1H), 1.56 (d, J = 5.0 Hz, 3H), 1.43 (s, 9H); [M+H] + = 796.6.

[0222] Example 33: (R)-5-(tert-butyl)-N-(1-(4-(7-(4-(4-(2,4-dioxo-tetrahydropyrimidin-1(2H)-yl)phenyl)cyclobutyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide

[0223] Step 1: 1-(4-chlorobenzoyl)pyrimidine-2,4(1H,3H)-dione TIFF2025503463000187.tif2321To a suspension of pyrimidine-2,4(1H,3H)-dione (9 g, 0.080 mol) in DMF (60 mL), pyridine (12.9 mL) and 4-chlorobenzoyl chloride (11.1 mL, 0.081 mol) are added. The mixture is stirred at room temperature overnight. Then the mixture is filtered. The residue is washed with PE:EA=10:1 and filtered to give the product (15.16 g, 82%). [M+Na] + =273.0.

[0224] Step 2: 3-((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(1H,3H)-dione TIFF2025503463000188.tif1614To a suspension of 1-(4-chlorobenzoyl)pyrimidine-2,4(1H,3H)-dione (15 g, 0.060 mol) in DMF (60 mL) is added NaH (3 g, 0.075 mol) and 2-(trimethylsilyl)ethoxymethyl chloride (12 g, 0.072 mol) at 0 °C. The mixture is stirred at room temperature overnight. The resulting solution is extracted with EtOAc (2x200.0 mL) and the organic layers are combined. The organic layers are dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is dissolved in MeOH (200 mL) and diluted with K. 2 CO 3 (22.3 g, 0.162 mol) is added. The mixture is stirred at room temperature for 2 h and concentrated in vacuo. Saturated NH 4 Add aqueous Cl and extract the product with EtOAc (2x200.0 mL). 2 SO 4 The crude product was purified by high performance chromatography (PE:EA=100%:0% to 80%:20%) to give the product (10.9 g, 75%). [M+Na] + =265.0.

[0225] Step 3: 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutan-1-one TIFF2025503463000189.tif11323-(4-bromophenyl)cyclobutan-1-one (1 g, 0.0044 mol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.69 g, 0.0066 mol), Pd(dppf)Cl in 1,4-dioxane (20 mL). 2 (0.16g, 0.00022mol) and K 2 CO 3 A mixture of (0.86 g, 0.0088 mol) was stirred in a round-bottom flask at 93 °C overnight. The mixture was evaporated in vacuum to give the crude product, which was further purified by silica gel column chromatography (elution with a gradient of PE:EA = 100:0 to 75%:25%) to give the product (5 g, 70%). [M+H] + =273.2.

[0226] Step 4: (4-(3-oxocyclobutyl)phenyl)boronic acid TIFF2025503463000190.tif1028A solution of 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutan-1-one (1 g, 0.00368 mol) in THF (16 mL) and water (4 mL) was diluted with NaIO 4 (2.3 g, 0.0110 mol) is added. The mixture is stirred at room temperature for 30 min. Then HCl (2M, 2 mL) is added. The mixture is stirred at room temperature overnight. The resulting solution is extracted with DCM (2x20 mL) and the organic layers are combined. The organic layers are dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (eluted with a gradient of DCM:MeOH=100%:0% to 90%:10%) to give the product (0.5 g, 72%). [M+H] + =191.0.

[0227] Step 5: 1-(4-(3-oxocyclobutyl)phenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(1H,3H)-dione TIFF2025503463000191.tif1135(4-(3-oxocyclobutyl)phenyl)boronic acid (1.78 g, 0.00937 mol), 3-((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(1H,3H)-dione (3.4 g, 0.0140 mol), Cu(OAc) in DMA (50 mL). 2 A mixture of 4A MS (5.1 g, 0.028 mol), pyridine (3.7 g, 0.0468 mol) and 4A MS (2 g) is stirred in a round bottom flask at 80 °C for 3 h. The mixture is filtered and the filtrate is extracted with EA (2x100 mL). The organic layers are combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography (DCM:MeOH=100%:0%) to give the product (3.27 g, crude). [M+Na] + =409.2.

[0228] Step 6: 1-(4-(3-oxocyclobutyl)phenyl)pyrimidine-2,4(1H,3H)-dione TIFF2025503463000192.tif1135To a solution of 1-(4-(3-oxocyclobutyl)phenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(1H,3H)-dione (3.2 g, 0.0083 mol) in DCM (10 mL) is added TFA (10 mL). The mixture is stirred at room temperature for 2 h. The mixture is concentrated in vacuo and diluted with MeOH (20 mL). NH 3 (7M in MeOH, 3 mL) is added. The mixture is stirred at room temperature for 1 h and concentrated under vacuum. The residue is purified by silica gel column chromatography (eluted with a gradient of DCM:MeOH=100%:0% to 90%:10%) to give the product (1.1 g, 50%). [M+H] + =257.0.

[0229] Step 7: 1-(4-(3-oxocyclobutyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione TIFF2025503463000193.tif1137To a solution of 1-(4-(3-oxocyclobutyl)phenyl)pyrimidine-2,4(1H,3H)-dione (300 mg, 1.167 mmol) in THF (10 mL), add Pd / C (50 mg, 10%). The mixture is heated to 37° C. for 1 h. 2 The mixture was stirred overnight at room temperature under atmospheric pressure. The mixture was then filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with a gradient of DCM:MeOH = 100%:0% to 90%:10%) to give the product (40 mg, 13%). [M+H] + =259.1.

[0230] Step 13: (R)-5-(tert-butyl)-N-(1-(4-(7-(4-(4-(2,4-dioxo-tetrahydropyrimidin-1(2H)-yl)phenyl)cyclobutyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide TIFF2025503463000194.tif3960To a solution of (R)-5-(tert-butyl)-N-(1-(3-fluoro-2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide (70 mg, crude) in dichloromethane (5 mL) and MeOH (5 mL), add NaOAc (31 mg, 0.375 mmol). The mixture is stirred at room temperature for 5 min. Then, add 1-(4-(3-oxocyclobutyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (40 mg, 0.125 mmol) and HOAc (0.06 mL). The mixture is stirred at room temperature overnight. Then, add NaBH(OAc) 3 (133 mg, 0.630 mmol) and stir at room temperature overnight. Then, NaBH 3Add CN (80 mg, 1.25 mmol) and stir at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (elution with a gradient of DCM:MeOH=100%:0% to 90%:10%) to give the crude product, which was further purified by preparative TLC (DCM:MeOH=10:1) to give the desired product (7.3 mg, 5%). 1 H NMR (500 MHz, DMSO) δ 12.19 (s, 1H), 10.33 (s, 1H), 9.59 (d, J = 5.0 Hz, 1H), 8.85 (s, 1H), 7.58-7.48 (m, 2H), 7.38-7.16 (m, 5H), 6.94 (s, 2H), 5.48-5.39 (m, 1H), 3.76 (t, J = 5.0 Hz, 2H), 3.3-3.12 (m, 6H), 2.75 (s, 1H), 2.69 (d, J = 5.0 Hz, 3H), 2.62-2.52 (m, 4H), 2.48-2.44 (m, 1H), 2.40 (s, 3H), 1.89 (s, 1H), 1.56 (d, J = 6.8 Hz, 3H), 1.43 (s, 9H); [M+H] + = 799.6.

[0231] Example 34: 5-(tert-butyl)-N-((1R)-1-(4-(7-(4-(1-(3-(2,6-dioxopiperidin-3-yl))phenyl)piperidine)-4-yl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide

[0232] Step 1: 8-(3-bromophenyl)-1,4-dioxa-8-azaspiro[4.5]decane TIFF2025503463000195.tif2121K 2 CO 3(2.76 g, 20 mmol) is added to a solution of 1-bromo-3-iodobenzene (2.83 g, 10 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (1.43 g, 10 mmol), CuI (0.389 g, 2 mmol) and L-proline (0.23 g, 2 mmol) dissolved in NMP. The mixture is stirred at 110 °C for 16 h. The mixture is cooled to rt. The mixture is washed with water and extracted with EtOAc. The organic layers are combined and washed with brine. The mixture is diluted with Na 2 SO 4 The residue was purified by silica gel column chromatography (PE: EtOAc = 4 / 1) to give the product (1.01 g, 33%). [M+H] + =298.1.

[0233] Step 2: 1-(3-bromophenyl)piperidin-4-one TIFF2025503463000196.tif1818HCl (4 M, 6.8 mL, 27.2 mmol) was added to H 2 Add dropwise to a solution of 8-(3-bromophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (1.01 g, 3.4 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (0.29 g, 2.0 mmol) in 200. Stir the mixture at 50° C. for 16 h. Cool the mixture to rt. Wash the solution with water and extract with EtOAc. Combine the organic layers and dilute with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give the product (822 mg, 96%). [M+H] + =254.1.

[0234] Step 3: 1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-one TIFF2025503463000197.tif3021Dioxane / H 21-(3-bromophenyl)piperidin-4-one (254 mg, 1 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (419 mg, 1 mmol) and Pd(PPh) dissolved in 20 3 ) 4 (116 mg, 0.1 mmol) was added to a solution of K 2 CO 3 (276 mg, 2 mmol) is added. The mixture is stirred at 105° C. overnight. The mixture is washed with water and extracted with EtOAc. The organic layers are combined and diluted with Na 2 SO 4 The residue was purified by silica gel column chromatography (PE: EtOAc = 4 / 1) to give the product (0.28 g, 61%). [M+H] + =465.2.

[0235] Step 4: 3-(3-(4-oxopiperidin-1-yl)phenyl)piperidine-2,6-dione TIFF2025503463000198.tif2818To a mixture of 1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-one (0.28 g, 0.61 mmol) dissolved in THF / MeOH, add Pd / C (30 mg, 10% w / w). The reaction is stirred under hydrogen atmosphere at rt for 16 h. The mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to give the product (168 mg, 97%). [M+H] + =287.3.

[0236] Step 5: 5-(tert-butyl)-N-((1R)-1-(4-(7-(4-(1-(3-(2,6-dioxopiperidin-3-yl))phenyl)piperidine)-4-yl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide TIFF2025503463000199.tif3959 To a solution of (R)-5-(tert-butyl)-N-(1-(3-fluoro-2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide (67.8 mg, crude) and 3-(3-(4-oxopiperidin-1-yl)phenyl)piperidine-2,6-dione (35 mg, 0.122 mmol) in dichloromethane (5 mL) and MeOH (5 mL), add NaOAc (30 mg, 0.366 mmol). The mixture is stirred at room temperature for 5 min. Then, add HOAc (0.06 mL). The mixture is stirred at 30° C. overnight. Then NaBH(OAc) 3 (129 mg, 0.610 mmol) and stir at room temperature overnight. Then, NaBH 3 CN (78 mg, 1.22 mmol) was added and stirred overnight at 30° C. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (elution with a gradient of DCM:MeOH=100%:0% to 90%:10%) to give the crude product, which was further purified by preparative TLC (DCM:MeOH=10:1) to give the desired product (16.31 mg, 16%). 1H NMR (500 MHz, DMSO) δ 12.34 (s, 1H), 10.81 (s, 1H), 9.62 (s, 1H), 9.52 (s, 1H), 8.90 (s, 1H), 7.60-7.45 (m, 2H), 7.26 (d, J = 5.0 Hz,1H), 7.21-7.13 (m, 2H), 7.11-7.05 (m, 1H), 7.03 (s, 1H), 7.00-6.95 (m, 1H), 6.91-6.79 (m, 2H), 6.64 (d, J = 10.0 Hz, 1H), 5.49-5.38 (m, 1H), 4.00 (d, J = 10.0 Hz, 2H), 3.90 (d, J = 10.0 Hz, 2H), 3.80-3.74 (m, 1H), 3.72-3.64 (d, J = 10.0 Hz, 2H), 3.27-3.21 (m, 2H), 3.13-3.02 (m, 2H), 2.77-2.69 (m, 2H), 2.67-2.59 (m, 1H), 2.41 (s, 3H), 2.26-2.12 (m, 3H), 2.06-1.96 (m, 1H), 1.78-1.68 (m, 2H), 1.57 (d, J = 5.0 Hz, 3H), 1.44 (s, 9H); [M+H] + = 827.5.

[0237] Example 35: (R)—N-(1-(4-(7-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl))phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide

[0238] Step 1: Benzyl (R)-4-(4-(3-methyl-4-(1-(3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)phenyl)-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate TIFF2025503463000200.tif39411,4-Dioxane (20 mL) and H 2 Benzyl 4-(4-chloro-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate (0.2 g, 0.47 mmol), (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-oxadiazole-5-carboxamide (compound obtained in a similar manner to WO2021219070A) (191 mg, 0.47 mmol), Pd(dppf)Cl in O (40 mL). 2 (38 mg, 0.047 mmol) and Cs 2 CO 3 (0.305 g, 0.94 mmol) in a round-bottom flask and stir at 90 °C overnight. The mixture was evaporated in vacuum to give the crude product, which was further purified by silica gel column chromatography (elution with a gradient of PE:EA = 100:0 to 3:1) to give the product (0.2 g, 63.5%). [M+H] + =671.8.

[0239] Step 2: (R)-N-(1-(2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide trifluoroacetic acid TIFF2025503463000201.tif3448 A mixture of benzyl (R)-4-(4-(3-methyl-4-(1-(3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)phenyl)-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate (0.2 g, 0.3 mmol) in dichloromethane (20 mL) and trifluoroacetic acid (20 mL) is placed in a round-bottom flask and stirred overnight at room temperature. The mixture is evaporated in vacuum to give the crude product (0.13 mg, 67%), which is used in the next step without further purification. [M+H] + =537.6.

[0240] Step 3: (R)-N-(1-(4-(7-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl))phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000202.tif3964A mixture of (R)-N-(1-(2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide trifluoroacetic acid (130 mg, 0.243 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (467.52 mg, 0.291 mmol) in MeOH (10 mL) is stirred at room temperature for 30 min in a round-bottom flask. Then, NaBH(OAc) 3 (103 mg, 0.485 mmol) and stir at room temperature for 2 h. The reaction was quenched with water and the mixture was washed with saturated aqueous NaHCO 3 The organic layer was washed once with DCM and extracted with anhydrous Na 2 SO 4 Drying in vacuuo gave the crude product which was further purified by preparative HPLC to give the product (100 mg, 65%). 1H NMR (400 MHz, DMSO) δ 12.19 (s, 1H), 10.26 (s, 1H), 9.88 (d, J = 7.2 Hz, 1H), 8.90-8.80 (m, 1H), 7.90-7.60 (m, 4H), 7.20-7.10 (m, 1H), 7.0-6.88 (m, 4H), 5.45-5.35 (m, 1H), 3.97-3.85 (m, 1H), 3.80-3.60 (m, 5H), 3.45-3.35 (m, 1H), 3.30-3.05 (m, 4H), 2.80-2.60 (m, 4H), 2.30-2.20 (m, [M+H] + = 822.8.

[0241] Example 36: 5-(tert-butyl)-N-((1R)-1-(4-(7-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-1-yl)methyl)piperidin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide

[0242] Step 1: 7-Bromo-4-((2-(trimethylsilyl)ethoxy)methoxy)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-pyrimido[4,5-b]indole TIFF2025503463000203.tif1621To a stirred mixture of 7-bromo-3,9-dihydro-4H-pyrimido[4,5-b]indol-4-one (20.0 g, 75.734 mmol) and t-BuONa (18.2 g, 189.335 mmol) in DMF (400 mL) is added dropwise at 0 °C under nitrogen atmosphere with SEM-Cl (40 mL, 227.218 mmol). The resulting mixture is stirred at room temperature for 3 h. The reaction is quenched with water at room temperature. The resulting mixture is extracted with EtOAc (2x500 mL). The combined organic layers are washed with brine (3 x 500 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1 to 5:1) to give the product (18.1 g, 45%). [M+H] + =524.1.

[0243] Step 2: tert-Butyl 4-vinylpiperidine-1-carboxylate TIFF2025503463000204.tif197To a stirred mixture of methyltriphenylphosphine bromide (26.8 g, 75.020 mmol) in THF (80 mL) is added t-BuOK (9.2 g, 82.522 mmol) portionwise at 0 °C under nitrogen atmosphere. The resulting mixture is stirred at room temperature for 1 h under nitrogen atmosphere. To the above mixture is added tert-butyl 4-formylpiperidine-1-carboxylate (8.0 g, 37.510 mmol) in THF (80 mL) dropwise at 0 °C. The resulting mixture is further stirred at room temperature for 3 h. The reaction is quenched with water at 0 °C and concentrated under reduced pressure. The resulting mixture is extracted with EtOAc (2x500 mL). The combined organic layers are washed with brine (500 mL) and anhydrous Na 2 SO 4 Dry at 40° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1 to 4:1) to give the product (7 g, 88%).

[0244] Step 3: 4-Vinylpiperidine hydrochloride TIFF2025503463000205.tif1912To a stirred solution of tert-butyl 4-vinylpiperidine-1-carboxylate (9.5 g, 44.959 mmol) in DCM (90 mL) is added dropwise at room temperature to HCl (90 mL) in 1,4-dioxane (4 M). The resulting mixture is stirred at room temperature for 1 h and concentrated under reduced pressure. To the resulting mixture is added MTBE (100 mL) and filtered. The filter cake is washed with MTBE (3x50 mL). This afforded the product (6 g, 90%).

[0245] Step 4: 4-((2-(trimethylsilyl)ethoxy)methoxy)-9-((2-(trimethylsilyl)ethoxy)methyl)-7-(4-vinylpiperidin-1-yl)-9H-pyrimido[4,5-b]indole TIFF2025503463000206.tif1634A stirred mixture of 7-bromo-4-((2-(trimethylsilyl)ethoxy)methoxy)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-pyrimido[4,5-b]indole (9.2 g, 17.537 mmol) and 4-vinylpiperidine hydrochloride (3.8 g, 26.278 mmol) in dioxane (180 mL) was incubated at room temperature under a nitrogen atmosphere with Cs 2 CO 3 (17.1 g, 52.606 mmol), XPhos (1.2 g, 2.622 mmol) and XPhos Pd G 3 (3.3 g, 3.946 mmol) was added. The resulting mixture was stirred at 100° C. under nitrogen overnight and cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with MeOH (3×100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1 to 4:1) to give the product (4.5 g, 46%). [M+H] + =555.5.

[0246] Step 5: 7-(4-vinylpiperidin-1-yl)-3,9-dihydro-4H-pyrimido[4,5-b]indol-4-one TIFF2025503463000207.tif1637A solution of 4-((2-(trimethylsilyl)ethoxy)methoxy)-9-((2-(trimethylsilyl)ethoxy)methyl)-7-(4-vinylpiperidin-1-yl)-9H-pyrimido[4,5-b]indole (2.5 g, 4.505 mmol) in TFA (30 mL) is stirred at room temperature for 2 h. The resulting mixture is concentrated under reduced pressure. The residue is added with DCM (50 mL), MeOH (10 mL) and NH 3 H 2 The mixture was basified to pH 8 with 200. The resulting mixture was stirred at room temperature for 24 h and concentrated under reduced pressure. Water (20 mL) was added to the resulting mixture and filtered. The filter cake was washed with water (3x20 mL). The solid was dried under infrared light to give the product (1.1 g, 82%). [M+H] + =295.1.

[0247] Step 6: 4-Chloro-7-(4-vinylpiperidin-1-yl)-9H-pyrimido[4,5-b]indole TIFF2025503463000208.tif1935POCl 3 A solution of 7-(4-vinylpiperidin-1-yl)-3,9-dihydro-4H-pyrimido[4,5-b]indol-4-one (1.1 g, 3.737 mmol) in 1,2-dihydro-4H-pyrimido[4,5-b]indol-4-one (20 mL) is stirred at 110° C. for 2 h. The mixture is cooled to room temperature and concentrated under reduced pressure. The residue is added with EtOAc (50 mL) and saturated NaHCO 3 (aqueous) to pH 8. The resulting mixture is extracted with EtOAc (3x100 mL). The combined organic layers are washed with brine (100 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give the product (1.1 g, 94%). [M+H] + =313.1.

[0248] Step 7: tert-Butyl 4-chloro-7-(4-vinylpiperidin-1-yl)-9H-pyrimido[4,5-b]indole-9-carboxylate TIFF2025503463000209.tif1732A stirred solution of 4-chloro-7-(4-vinylpiperidin-1-yl)-9H-pyrimido[4,5-b]indole (1.1 g, 3.517 mmol), DIEA (1.2 mL, 7.062 mmol) and DMAP (42.96 mg, 0.352 mmol) in DMF (20 mL) was treated with Boc- 2 O (1.15 g, 5.28 mmol) is added. The resulting mixture is stirred at room temperature for 16 h and diluted with water (30 mL). The resulting mixture is extracted with EtOAc (3x50 mL). The combined organic layers are washed with brine (50 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1 to 5:1) to give the product (1.1 g, 82%). [M+H] + =413.1.

[0249] Step 8: tert-Butyl 4-chloro-7-(4-formylpiperidin-1-yl)-9H-pyrimido[4,5-b]indole-9-carboxylate TIFF2025503463000210.tif1834THF(20mL) and H 2 tert-Butyl 4-chloro-7-(4-vinylpiperidin-1-yl)-9H-pyrimido[4,5-b]indole-9-carboxylate (1.1 g, 2.616 mmol) in 2H2O (5 mL) and NaIO 4 A stirred mixture of (2.2 g, 10.473 mmol) was added at room temperature to 2 OsO 4 .2H 2 O (19 mg, 0.052 mmol) is added. The resulting mixture is stirred at room temperature for 1 h. Saturated Na 2 S 2 O 3 The reaction was quenched with (aqueous). The resulting mixture was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (100 mL) and anhydrous Na 2 SO 4Dry at 40° C. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography eluting with PE / EtOAc (10:1 to 2:1) to give the product (215 mg, 20%). 1 H NMR (400 MHz, CDCl 3 ) δ 9.77 (s, 1H), 8.87 (s, 1H), 8.25 (d, J = 8.7 Hz, 1H), 7.96 (d, J = 24.0 Hz, 1H), 7.20 (s, 1H), 3.91-3.74 (m, 2H), 3.15 (t, J = 11.4 Hz, 2H), 2.56 (s, 1H), 2.17 (s, 2H), 1.97-1.91 (m, 2H), 1.79 (s, 9H); [M+H] + = 415.1.

[0250] Step 9: (R)-5-(tert-butyl)-N-(1-(3-fluoro-4-(7-(4-formylpiperidin-1-yl))-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide TIFF2025503463000211.tif35441,4-Dioxane (10 mL) and water (2 mL) were mixed with tert-butyl 4-chloro-7-(4-formylpiperidin-1-yl)-9H-pyrimido[4,5-b]indole-9-carboxylate (100 mg, 0.241 mmol), (R)-5-(tert-butyl)-N-(1-(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide (103.5 mg, 0.241 mmol), Pd(dppf)Cl 2 (8.8 mg, 0.012 mmol) and K 2 CO 3(53 mg, 0.386 mmol) was stirred at 93° C. overnight. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (eluted with a gradient of PE:EA=100%:0% to 0%:100%) to give the title product (20 mg, 14%). [M+H] + =584.0.

[0251] Step 10: tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)piperidine-1-carboxylate TIFF2025503463000212.tif21334-(4-Bromophenyl)piperidine-1-carboxylate tert-Butyl (10 g, 29.5 mmol), (Bpin) 2 (11.3g, 44.3mmol), Pd(dppf)Cl 2 (3.2 g, 4.4 mmol), KOAc (5.8 g, 59 mmol) are dissolved in dioxane (400 mL). The resulting mixture is then heated at reflux for 2 h until LC-MS indicates all starting material has been consumed. The mixture is cooled to room temperature, the solids are filtered and concentrated to give the product (12 g, crude), which is used directly without further purification. [M+H] + =388.3.

[0252] Step 11: tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidine-1-carboxylate TIFF2025503463000213.tif21374-(tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)piperidine-1-carboxylate (12 g, crude), Pd(dppf)Cl 2 (3.2 g, 4.4 mmol), 2,6-bis(benzyloxy)-3-bromopyridine (16.2 g, 44.0 mmol), Cs 2 CO 3(28.7 g, 88 mmol) in dioxane / water (300 mL, 10:1) until LC-MS shows all starting material has been consumed and the mixture is stirred at 100 °C overnight. The reaction is cooled to room temperature and the solids are filtered. The filtrate is concentrated and purified by SiO 2 -Purification by gel column (eluted with 1:1 EtOAc / Hexane) gave the desired product (5 g, 30.8% over two steps). [M+H] + =551.3.

[0253] Step 12: tert-Butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-1-carboxylate TIFF2025503463000214.tif21324-(tert-Butyl 4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidine-1-carboxylate (5 g, 9.1 mmol) is dissolved in MeOH (50 mL) and Pd / C (10%, w / w, 0.5 g) is added portionwise to the solution. The resulting mixture is heated to 37° C. for 1 hour at 37° C. for 1 hour until LC-MS shows all starting material has been consumed. 2 Stir under atmosphere (1 atm) overnight. The mixture was filtered and concentrated to give the desired product (1.9 g, 56.1%). [M+H] + =373.1.

[0254] Step 13: 3-(4-(piperidin-4-yl)phenyl)piperidine-2,6-dione hydrochloride TIFF2025503463000215.tif2130 tert-Butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-1-carboxylate (1.9 g, 5.1 mmol) is dissolved in HCl-dioxane (4 M, 20 mL) and the mixture is stirred at room temperature for 2 h until LC-MS indicates all starting material has been consumed. The mixture is concentrated and slurried with MTBE to give the desired product (1.6 g, 100%). [M+H] + =273.2.

[0255] Step 14: 5-(tert-butyl)-N-((1R)-1-(4-(7-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-1-yl)methyl)piperidin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide TIFF2025503463000216.tif2875A mixture of (R)-5-(tert-butyl)-N-(1-(3-fluoro-4-(7-(4-formylpiperidin-1-yl))-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide (20 mg, 0.0343 mmol), 3-(4-(piperidin-4-yl)phenyl)piperidine-2,6-dione hydrochloride (18.7 mg, 0.0686 mmol) and NaOAc (8.4 mg, 0.103 mmol) in DCM / MeOH (3 mL / 3 mL) is stirred at room temperature for 30 min. Then HOAc (0.04 mL) is added. The mixture is stirred at room temperature overnight. Then, NaBH(OAc) 3 (36 mg, 0.172 mmol) and stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (elution with a gradient of DCM:MeOH=100%:0% to 90%:10%) to give the crude product, which was further purified by preparative TLC (DCM:MeOH=10:1) to give the desired product (8.09 mg, 28%). 1H NMR (500 MHz, DMSO) δ 12.19 (s, 1H), 10.84 (s, 1H), 9.62 (d, J = 10.0 Hz, 1H), 8.85 (s, 1H), 7.61-7.45 (m, 2H), 7.30-7.05 (m, 6H), 6.93 (s, 2H), 5.53-5.37 (m, 1H), 3.83 (d, J = 10.0 Hz, 4H), 3.62 (s, 1H), 3.31 (s, 2H), 3.05 (s, 3H), 2.81 (s, 3H), 2.71-2.63 (m, 2H), 2.47-2.45 (m, 2H), 2.40 (s, 3H), 2.22-2.14 (m, 2H), 2.07-1.98 (m, 3H), 1.87 (s, 2H), 1.56 (d, J = 5.0 Hz, 3H), 1.43 (s, 9H); [M+H] + = 840.6.

[0256] Example 37: (R)-3-(tert-butyl)-N-(5-(7-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H))-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2,3-dihydro-1H-inden-1-yl)-1,2,4-oxadiazole-5-carboxamide

[0257] Step 1: (R)-N-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000217.tif1925To a suspension of sodium 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate (500 mg, 2.01 mmol) in DCM (40 mL) is added DMF (0.06 mL). Then, (COCl) 2(5.6 mL, 1 M in DCM, 5.6 mmol) is added dropwise. The mixture is stirred at rt for 1.5 h. Then the mixture is filtered and the filtrate is concentrated in vacuum. The residue is diluted with DCM (10 mL). To a solution of (R)-5-bromo-2,3-dihydro-1H-inden-1-amine (540 mg, 2.8 mmol) in DCM (20 mL) is added triethylamine (1.01 g, 10.05 mmol). The above mixture is added dropwise and stirred at room temperature overnight. The mixture is evaporated in vacuum to give the crude product, which is further purified by silica gel column chromatography (elution with a gradient of PE:EA=100%:0%~50%:50%) to give the product (500 mg, 54%). [M+Na] + =386.1.

[0258] Step 2: (R)-3-(tert-butyl)-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-2,3-dihydro-1H-inden-1-yl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000218.tif2132 (R)-N-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide (180 mg, 0.467 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (178 mg, 0.701 mmol), Pd(dppf)Cl in 1,4-dioxane (10 mL). 2 A mixture of (34 mg, 0.0467 mmol) and KOAc (91.5 mg, 0.934 mmol) was stirred under nitrogen at 90 °C overnight. The mixture was evaporated in vacuum to give the crude product, which was further purified by silica gel column chromatography (elution with a gradient of PE:EA = 100%:0% to 0%:100%) to give the product (280 mg, crude). [M+H] + =412.0.

[0259] Step 3: (R)-4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)-2,3-dihydro-1H-inden-5-yl)-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate benzyl TIFF2025503463000219.tif3737Benzyl 4-(4-chloro-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate (286 mg, 0.679 mmol), (R)-3-(tert-butyl)-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-2,3-dihydro-1H-inden-1-yl)-1,2,4-oxadiazole-5-carboxamide (280 mg, crude), Pd(dppf)Cl in 1,4-dioxane (10 mL) and water (2 mL). 2 A mixture of (50 mg, 0.068 mmol) and KOAc (150 mg, 1.08 mmol) was stirred under nitrogen at 90 °C overnight. The mixture was evaporated in vacuum to give the crude product, which was further purified by silica gel column chromatography (PE:EA = 100%: 0% ~ 0%: 100% gradient elution) to give the product (120 mg, 26%). [M+H] + =671.0.

[0260] Step 4: (R)-3-(tert-butyl)-N-(5-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2,3-dihydro-1H-inden-1-yl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000220.tif3433 A solution of (R)-4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)-2,3-dihydro-1H-inden-5-yl)-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate benzyl (120 mg, 0.223 mmol) in trifluoroacetic acid (10 mL) is stirred at 85° C. for 2 h. The mixture is evaporated in vacuo to give the crude product (100 mg, crude), which is used in the next step without further purification. [M+H]+ =537.0.

[0261] Step 5: (R)-3-(tert-butyl)-N-(5-(7-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H))-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2,3-dihydro-1H-inden-1-yl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000221.tif3759 To a solution of (R)-3-(tert-butyl)-N-(5-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2,3-dihydro-1H-inden-1-yl)-1,2,4-oxadiazole-5-carboxamide (100 mg, crude) in dichloromethane (5 mL) and MeOH (5 mL), NaOAc (47 mg, 0.558 mmol) is added. The mixture is stirred at room temperature for 5 min. Then, 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (67.4 mg, 0.223 mmol) and HOAc (0.06 mL) are added. The mixture is stirred at room temperature overnight. Then NaBH(OAc) 3 (197 mg, 0.93 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (elution with a gradient of DCM:MeOH=100%:0% to 90%:10%) to give the product (50.27 mg, 32%). 1H NMR (500 MHz, DMSO) δ 12.17 (s, 1H), 10.25 (s, 1H), 9.86 (d, J = 5.0 Hz, 1H), 8.83 (s, 1H), 8.83 (s, 1H), 7.82 (s, 1H), 7.78 (d, J = 10.0 Hz, 1H), 7.69 (d, J = 10.0 Hz, 1H), 7.50 (d, J = 10.0 Hz, 1H), 7.13 (d, J = 10.0 Hz, 2H), 6.96-6.90 (m, 4H), 5.65 (q, J = 10.0 Hz, 1H), 3.73-3.65 (m, 4H), 3.25 (s, 4H), 3.20-3.12 (m, 1H), 3.04-2.95 (m, 1H), 2.71-2.62 (m, 4H), 2.54 (s, 5H), 2.23 (dd, J = 20.0 Hz, 10.0 Hz, 3H), 1.82 (d, J = 10.0 Hz, 2H), 1.72 (s, 1H), 1.37 (s, 9H), 1.23 (dd, J = 20.0 Hz, 10.0 Hz, 2H); [M+H] + = 822.6.

[0262] Example 38: (R)-3-(tert-butyl)-N-(1-(4-(7-(1-(((1-(4-(2,4-dioxotetrahydropyrimidin-1)(2H)-yl))phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0263] Step 1: 2-(5-bromo-3-nitropyridin-2-yl)-2-cyanoethyl acetate TIFF2025503463000222.tif2128To a stirred solution of ethyl cyanoacetate (24.3 g, 214.790 mmol) in t-BuOH (60 mL) and i-PrOH (100 mL, 0.17 mmol) is added portionwise at room temperature under nitrogen atmosphere to t-BuOK (42.5 g, 227.43 mmol). The resulting mixture is stirred at room temperature under nitrogen atmosphere for 0.5 h. Then, 5-bromo-2-chloro-3-nitropyridine (30 g, 126.35 mmol) is added portionwise to the above mixture at room temperature. The resulting mixture is stirred at 100 °C for 7 h and concentrated under reduced pressure. The resulting mixture is diluted with 1 M HCl (100 mL) and extracted with EA (3x100 mL). The combined organic layers are washed with brine (3 x 100 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with 1-30% EA in petroleum ether to give the product (24 g, 60%). [MH] - =312.0.

[0264] Step 2: Ethyl 2-amino-6-bromo-1H-pyrrolo[3,2-b]pyridine-3-carboxylate TIFF2025503463000223.tif2330To a stirred solution of ethyl 2-(5-bromo-3-nitropyridin-2-yl)-2-cyanoacetate (18 g, 57.31 mmol) in AcOH (200 mL) is added Fe (16 g, 286.54 mmol) portionwise at room temperature. The resulting mixture is stirred at room temperature for 2 h. The resulting mixture is filtered and the filter cake is washed with MeOH (3x50 mL). The filtrate is concentrated under reduced pressure. The resulting mixture is extracted with EA (3x100 mL). The combined organic layers are washed with brine (3x100 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with 1-100% EA in PE to give the product (20 g, 92%). [M+H] + =284.1.

[0265] Step 3: 7-Bromo-3,9-dihydro-4H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-4-one TIFF2025503463000224.tif21322-A solution of ethyl 2-amino-6-bromo-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (27 g, 95.03 mmol) and formamidine acetate (29.3 g, 281.58 mmol) in methoxyethanol (300 mL) is stirred at 125 °C overnight. The mixture is cooled to room temperature. The resulting mixture is diluted with water (300 mL). The precipitated solid is collected by filtration. The resulting solid is dried under infrared light to give the product (9 g, 35%). [M+H] + =264.9.

[0266] Step 4: tert-butyl 4-(4-oxo-4,9-dihydro-3H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate TIFF2025503463000225.tif2349Dioxane (120 mL) and H 2 To a stirred solution of 7-bromo-3,9-dihydro-4H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-4-one (8 g, 30.18 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (13.3 g, 45.26 mmol) in 24 mL of KCl was added 3 PO 4 (12.8 g, 60.36 mmol) and Pd(dppf)Cl 2 (2.2 g, 3.02 mmol) is added. The resulting mixture is stirred overnight at 80° C. under nitrogen atmosphere. The residue is purified by silica gel column chromatography and 2 Cl 2 Elution with 5:1 MeOH / MeOH (0.1% TEA) gave the product (7 g, 63%). [M+H] + =368.1.

[0267] Step 5: tert-Butyl 4-(4-oxo-4,9-dihydro-3H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate TIFF2025503463000226.tif2349To a stirred solution of tert-butyl 4-(4-oxo-4,9-dihydro-3H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (10.7 g, 29.12 mmol) in DMF (30 mL), EtOH (120 mL) and EA (120 mL), Pd / C (5 g) and Pd(OH) were added. 2 Add / C (5.00 g). Stir the resulting mixture at 50° C. for 16 h under 20 atm hydrogen atmosphere. Cool the mixture to room temperature. Purify the residue by silica gel column chromatography and elute with DCM / MeOH (5:1) to give the product (5.7 g, 53%). [M+H] + =370.2.

[0268] Step 6: 4-Chloro-7-(piperidin-4-yl)-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidine TIFF2025503463000227.tif2341POCl 3 A solution of butyl 4-(4-oxo-4,9-dihydro-3H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-tert-carboxylate (1.60 g, 4.33 mmol) in butyl 4-(4-oxo-4,9-dihydro-3H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-tert-carboxylate (30.00 mL, 321.84 mmol) is stirred at 110° C. for 2 h. The resulting mixture is concentrated in vacuo. The residue is dissolved in toluene (3×15 mL). The resulting mixture is concentrated in vacuo. The crude is used in the next step without further purification. [M+H] + =288.1.

[0269] Step 7: tert-Butyl 4-(4-chloro-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate TIFF2025503463000228.tif2346A solution of 4-chloro-7-(piperidin-4-yl)-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidine (1.8 g, 6.26 mmol) in DMF (50 mL, 646.09 mmol) is stirred at room temperature for 5 min. Saturated NaHCO 3 Neutralize the mixture to pH 7 with (aqueous). 2 2H2O (13.6 g, 62.54 mmol) is added to the above mixture at room temperature. The resulting mixture is further stirred at room temperature for 16 h. The resulting mixture is extracted with EA (2x200 mL). The combined organic layers are washed with brine (2x100 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:1) to give the product (1 g, 41%). [M+H] + =388.1.

[0270] Step 8: tert-Butyl 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-chloro-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidine-9-carboxylate TIFF2025503463000229.tif2546To a stirred solution of tert-butyl 4-(4-chloro-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate (1 g, 2.58 mmol) and DIEA (2.94 mL, 16.88 mmol) in DCM (30 mL) at room temperature was added DMF (9 mL) and Boc 2 O (1 g, 5.18 mmol) is added. The resulting mixture is stirred at room temperature for 16 h and concentrated in vacuo. The residue is purified by silica gel column chromatography eluted with PE / EA (3:1) to give the product (166 mg, 13%). [M+H] + =488.2.

[0271] Step 9: (R)-7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-(4-(1-(3-(tert-butyl))-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidine-9-carboxylate tert-butyl TIFF2025503463000230.tif4646 At room temperature, dioxane (5 mL) and H 2 To a stirred solution of tert-butyl 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-chloro-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidine-9-carboxylate (166 mg, 0.34 mmol) and 3-tert-butyl-N-[(1R)-1-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide (169 mg, 0.41 mmol) in 20O (1 mL) was added 1 mL of KCl. 3 PO 4 (144 mg, 0.68 mmol) and Pd(dppf)Cl 2 (25 mg, 0.034 mmol) is added. The resulting mixture is stirred at 80 °C under nitrogen atmosphere for 2 h and concentrated in vacuo. The residue is purified by silica gel column chromatography and purified with CH 2 Cl 2 Elution with 100% ethanol / EA (3:1) gave the product (87 mg, 34%). [M+H] + =739.5.

[0272] Step 10: (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(7-(piperidin-4-yl))-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000231.tif4641 To a stirred solution of (R)-7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-(4-(1-(3-(tert-butyl))-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidine-9-carboxy tert-butyl acid ester (87 mg, 0.12 mmol) in DCM (5 mL) at room temperature is added dropwise in portions TFA (1 mL). The resulting mixture is stirred at room temperature for 1 h and concentrated in vacuo. The residue was purified by reversed phase flash chromatography under the following conditions: Column: spherical C18, 20-40um, 40g, mobile phase A: water (add 5mM FA), mobile phase B: ACN, flow rate: 80mL / min, gradient: 5%-5%B in 10min, 10%B-30%B gradient in 30min, detector: 220nm. The fraction containing the desired product was collected at 29%B and concentrated under reduced pressure to give the product (31mg, 49%). 1 H NMR (400 MHz, DMSO) δ 9.95 (d, J = 8.0 Hz, 1H), 9.04 (s, 1H), 8.61 (d, J = 8.4 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.47 (d, J = 2.0 Hz, 1H), 8.36 (s, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 5.42 (t, J = 7.2 Hz, 1H), 3.22 (d, J = 12.0 Hz, 2H), 2.99 (t, J = 12.0 Hz, 1H), 2.81 (t, J = 12.0 Hz, 2H), 2.53 (s, 3H), 1.91 (d, J = 12.4 Hz, 2H), 1.78 (d, J = 12.4 Hz, 2H), 1.57 (d, J = 6.8 Hz, 3H), 1.38 (s, 9H), 1.24 (s, 1H); [M+H] + = 538.9.

[0273] Step 12: (R)-3-(tert-butyl)-N-(1-(4-(7-(1-(((1-(4-(2,4-dioxotetrahydropyrimidin-1)(2H)-yl))phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000232.tif4474 To a mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(7-(piperidin-4-yl))-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (7 mg, 0.013 mmol) in dichloromethane (10 mL) and MeOH (2 mL), add 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (7 mg, 0.023 mmol). The mixture is then stirred at room temperature in a round-bottom flask for 1 h. NaBH(OAc) 3 (14 mg, 0.065 mmol) was added to the mixture and stirred at room temperature overnight. The mixture was evaporated in vacuum to give the crude product, which was purified by preparative TLC (DCM:MeOH=9:1) to give the product (2 mg, 18%). 1H NMR (400 MHz, DMSO ) δ 12.79 (s, 1H), 11.06-10.36 (m, 1H), 10.27 (s, 1H), 9.95 (d, J = 7.6 Hz, 1H), 9.04 (s, 1H), 8.69-8.51 (m, 2H), 8.46 (s, 1H), 7.87 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 5.53-5.28 (m, 1H), 3.78-3.60 (m, 5H), 3.42-3.35 (m, 1H), 3.19-2.95 (m, 4H), 2.77-2.64 (m, 4H), 2.58-2.51 (m, 6H), 2.13-1.95 (m, 4H), 1.57 (d, J = 6.8 Hz, 3H), 1.43-1.31 (m, 9H), 1.23 (s, 2H); [M+H] + = 824.7.

[0274] Example 39: (R)-3-(tert-butyl)-N-(1-(4-(7-(1-(((1-(4-(2,4-dioxotetrahydropyrimidin-1)(2H)-yl))phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-9H-pyrido[3',2':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound TIFF2025503463000233.tif3951 was synthesized in a similar manner to Example 38. 1H NMR (400 MHz, DMSO) δ 12.93 (s, 1H), 10.25 (s, 1H), 9.94 (d, J = 7.6 Hz, 1H), 8.14 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.79 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 5.49-5.37 (m, 1H), 3.76-3.62 (m, 4H), 3.00-2.92 (m, 2H), 2.79 (brs, 1H), 2.73-2.60 (m, 4H), 2.26-2.16 (m, 2H), 2.09-1.96 (m, 2H), 1.94-1.76 (m, 6H), 1.70 (brs, 1H), 1.58 (d, J = 6.8 Hz, 3H), 1.37 (s, 9H), 1.27-1.20 (m, 2H); [M+H] + = 824.7.

[0275] Example 40: (R)-3-(tert-butyl)-N-(1-(4-(7-(4-(((1-(4-(2,4-dioxotetrahydropyrimidin-1)(2H)-yl))phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-6-methyl-9H-pyrimido[4,5-b]indol-4-yl)-5-fluoro-2-(hydroxymethyl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0276] Step 1: (R)-4-(4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-5-(((tert-butyldiphenylsilyl))oxy)methyl)-2-fluorophenyl)-6-methyl-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate benzyl TIFF2025503463000234.tif4643 Dioxane (10 mL) and H 2Benzyl 4-(4-chloro-6-methyl-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate (169.3 mg, 0.39 mmol), (R)-3-(tert-butyl)-N-(1-(2-(((tert-butyldiphenylsilyl)oxy)methyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (compound obtained in a similar manner to WO2021219070A) (320 mg, 0.47 mmol), Pd(PPh 3 ) 4 (45 mg, 0.04 mmol) and K 2 CO 3 (107.4 mg, 0.78 mmol) was stirred at 95° C. for 16 h under nitrogen atmosphere. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with EA / PE (2:1) to give the product (260 mg, 69.7%). [M+H] + =959.5.

[0277] Step 2: (R)-3-(tert-butyl)-N-(1-(5-fluoro-2-(hydroxymethyl)-4-(6-methyl-7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide trifluoroacetic acid TIFF2025503463000235.tif3932A mixture of (R)-4-(4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-5-(((tert-butyldiphenylsilyl))oxy)methyl)-2-fluorophenyl)-6-methyl-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate benzyl (100 mg, 0.104 mmol) in TFA (5 mL) is refluxed for 2 h. The mixture is concentrated in vacuo to give the product (90 mg, crude) which is used as is in the next step. [M+H] + =587.3.

[0278] Step 3: (R)-3-(tert-butyl)-N-(1-(4-(7-(4-(((1-(4-(2,4-dioxotetrahydropyrimidin-1)(2H)-yl))phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-6-methyl-9H-pyrimido[4,5-b]indol-4-yl)-5-fluoro-2-(hydroxymethyl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000236.tif5453A mixture of (R)-3-(tert-butyl)-N-(1-(5-fluoro-2-(hydroxymethyl)-4-(6-methyl-7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide trifluoroacetic acid (90 mg, 0.15 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (91 mg, 0.20 mmol) and AcOH (0.02 mL) in MeOH (5 mL) and DCM (5 mL) is stirred at rt for 16 h. STAB (63.6 mg, 0.3 mmol) is then added to the above mixture and stirred at rt for 5 h. The resulting mixture is diluted with water (50 mL) and extracted with DCM (3x100 mL). The combined organic layers are washed with anhydrous Na 2 SO 4 The residue was purified by silica gel column chromatography eluting with MeOH / DCM (1:9) to give the product (59.48 mg, 44.4%). 1H NMR (400 MHz, DMSO) δ 12.30 (s, 1H), 10.26 (s, 1H), 9.93 (d, J = 8.0 Hz, 1H), 8.91 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 12.0 Hz, 1H), 7.23-7.10 (m, 4H), 6.93 (d, J = 8.0 Hz, 2H), 5.51-5.42 (m, 1H), 5.41-5.35 (m, 1H), 4.88-4.78 (m, 1H), 4.76-4.65 (m, 1 H), 3.75-3.65 (m, 4H), 3.00-2.88 (m, 4H), 2.74-2.61 (m, 4H), 2.61-2.53 (m, 3H), 2.30-2.23 (m, 2H), 2.20 (s, 3H), 1.86-1.78 (m, 2H), 1.76-1.67 (m, 1H), 1.61 (d, J = 4.0 Hz, 3H), 1.37 (s, 9H), 1.31-1.18 (m, 3H); [M+H] + = 872.4.

[0279] Example 41: 3-(tert-butyl)-N-((1R)-1-(4-(7-(1-(3-(4-(2,6-dioxopiperidin-3-yl)phenyl))cyclobutyl)piperidin-4-yl)-9H-pyrido[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0280] Step 1: 3-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)cyclobutan-1-one TIFF2025503463000237.tif1137Dioxane / H 2 A solution of 3-(4-bromophenyl)cyclobutan-1-one (4.0 g, 17.7 mmol) in 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (7.4 g, 17.7 mmol), K 2CO 3 (7.3 g, 53 mmol) and Pd(dppf)Cl 2 Add DCM (1.4 g, 1.77 mmol). Stir the reaction at 100° C. for 6 h. Evaporate the organic phase and extract with EA (50 mL*2). Combine the organic phases and purify by high performance chromatography with PE / EA (100:1 to 3:1) to give the product (3.2 g, 41.6%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.60 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H),7.48-7.20 (m, 12H), 6.48 (d, J = 8.0 Hz, 1H), 5.44 (s, 2H), 5.37 (s, 2H), 3.78-3.64 (m, 1H), 3.55-3.48 (m, 2H), 3.32-3.26 (m, 2H).

[0281] Step 2: 3-(4-(3-oxocyclobutyl)phenyl)piperidine-2,6-dione TIFF2025503463000238.tif1134To a solution of 3-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)cyclobutan-1-one (0.5 g, 1.1 mmol) in THF (30 mL), add Pd / C (50 mg). The reaction mixture is heated at 60 °C and heated to 40 °C. 2 The mixture was stirred under (1 atm) for 18 h. After filtration, the filtrate was concentrated and used directly in the next step.

[0282] Step 3: 3-(tert-butyl)-N-((1R)-1-(4-(7-(1-(3-(4-(2,6-dioxopiperidin-3-yl)phenyl))cyclobutyl)piperidin-4-yl)-9H-pyrido[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000239.tif3059To a solution of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(7-(piperidin-4-yl)-9H-pyrido[3',4':4,5]pyrrolo) [2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (a compound obtained in a manner similar to Example 38) (160 mg, 0.3 mmol) and 3-(4-(3-oxocyclobutyl)phenyl)piperidine-2,6-dione (77 mg, 0.3 mmol) in DCM / EtOH (20 mL), add NaOAc (74 mg, 0.9 mmol). After stirring for 3 h, add NaBH(OAc) 3 (191 mg, 0.9 mmol) is added. The reaction mixture is stirred for another 3 h. The solvent is evaporated and purified by preparative TLC with DCM / MeOH (10:1) to give the product (48.7 mg, 20.8%). 1 H NMR (400 MHz, DMSO) δ 11.22 (brs, 1H), 10.83 (s, 1H), 9.99 (d, J = 8.0 Hz, 1H), 9.17 (s, 1H), 9.00 (s, 1H), 7.99-7.82 (m, 2H), 7.77 (d, J = 8.0 Hz, 1H), 7.67 (brs, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.20 (t, J = 7.6 Hz, 2H), 5.51-5.29 (m, 1H), 3.85-3.83 (m, 1H), 3.66-3.17 (m, 18H), 2.66 (d, J = [M+H] + = 780.7.

[0283] Example 42: (R)-3-(tert-butyl)-N-(1-(4-(7-(1-((1-(4-(2,4-dioxotetrahydropyrimidine)-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-9H-pyrido[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-(yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000240.tif3941To a solution of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(7-(piperidin-4-yl)-9H-pyrido[3',4':4,5]pyrrolo)[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (90 mg, 0.17 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (50 mg, 0.17 mmol) in DCM / EtOH (30 mL) was added NaOAc (42 mg, 0.51 mmol). After stirring for 0.5 h, NaBH(OAc) 3 (108 mg, 0.51 mmol) is added. The reaction mixture is stirred for an additional 18 h. The solvent is evaporated and purified by preparative TLC using DCM / MeOH (10:1) to give the product (85.2 mg, 60.8%). 1 H NMR (400 MHz, DMSO) δ 10.30 (s, 1H), 9.99 (d, J = 7.2 Hz, 2H), 9.17 (s, 1H), 9.00 (s, 1H), 8.01-7.82 (m, 2H), 7.77 (d, J = 8.0 Hz, 1H), 7.66 (brs, 1H), 7.30-6.80 (m, 4H), 5.50-5.31 (m, 1H), 3.81-3.65 (m, 8H), 3.25-3.08 (m, 5H), 2.69 (t, J = 6.8 Hz, 2H), 2.55 (s, 3H), 2.33 (brs, 3H), 2.23-1.89 (m, 6H), 1.59 (d, J = 6.4 Hz, 3H), 1.37 (s, 9H); [M+H] + = 824.7.

[0284] Example 43: (R)-3-(tert-butyl)-N-(1-(4-(7-(4-((1-(4-(2,4-dioxotetrahydropyrimidine)-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-6-methyl-9H-pyrimido[4,5-b]indol-4-yl)-2-methyl((phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0285] Step 1: Benzyl 4-(4-chloro-2-methylphenyl)piperazine-1-carboxylate TIFF2025503463000241.tif1130To a stirred mixture of 1-bromo-4-chloro-2-toluene (50 g, 243.3 mmol) and benzylpiperazine-1-carboxylate (64.3 g, 292 mmol) in toluene (1 L) at room temperature under a nitrogen atmosphere, t-BuONa (46.77 g, 486.6 mmol), BINAP (30.3 g, 48.7 mmol) and Pd 2 (dba) 3 (22.3 g, 24.3 mmol) is added. The resulting mixture is stirred at 95 °C under nitrogen atmosphere for 2 h. The reaction is quenched with water at room temperature. The resulting mixture is extracted with EtOAc (3x1 L). The combined organic layers are washed with brine (2x800 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with EtOAc in PE (0% to 30%) to give the product (51.3 g, 61.1%). [M+H] + =345.1.

[0286] Step 2: 1-(4-chloro-2-methyl-5-nitrophenyl)piperazine TIFF2025503463000242.tif1425DarkH 2 SO 4A stirred solution of benzyl 4-(4-chloro-2-methylphenyl)piperazine-1-carboxylate (15 g, 43.5 mmol) in 10 mL of ethyl acetate (60 mL) was added to a nitrogen atmosphere at 0 °C with concentrated HNO 3 (27.6 mL) is added dropwise in portions. The resulting mixture is stirred at 0 °C for 0.5 h. The reaction is cooled to 0 °C with Na 2 CO 3 The mixture was extracted with EtOAc (3x1 L). The combined organic layers were washed with brine (2x800 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give the product (26.5 g, crude). [M+H] + =256.2.

[0287] Step 3: Benzyl 4-(4-chloro-2-methyl-5-nitrophenyl)piperazine-1-carboxylate TIFF2025503463000243.tif1430To a stirred solution of 1-(4-chloro-2-methyl-5-nitrophenyl)piperazine (26.5 g, 103.6 mmol) in DCM (280 mL), Cbz-Cl (35.4 g, 207.3 mmol) and DIEA (72.2 mL, 558.7 mmol) are added at room temperature. The resulting mixture is stirred at room temperature for 16 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (0%-30%) to give the product (36.6 g, 57.8%). [M+H] + =391.1.

[0288] Step 4: 4-(4-(1-cyano-2-ethoxy-2-oxyethyl)-2-methyl-5-nitrophenyl)piperazine-1-carboxylate benzyl TIFF2025503463000244.tif1435Cs in DMF (200 mL) 2 CO 3To a stirred mixture of (91.8 g, 281.6 mmol) is added dropwise in portions at room temperature under nitrogen atmosphere, ethyl cyanoacetate (15.0 mL, 132.5 mmol) in DMF (100 mL). The resulting mixture is stirred at room temperature under nitrogen atmosphere for 0.5 h. To the above mixture is added benzyl 4-(4-chloro-2-methyl-5-nitrophenyl)piperazine-1-carboxylate (36.6 g, 93.9 mmol) in DMF (100 mL) at 0 °C. The resulting mixture is stirred at 70 °C for 16 h. The mixture is cooled to room temperature. The mixture is acidified with HCl (aq) (1 M) to pH = 6. The resulting mixture is extracted with EtOAc (3x800 mL). The combined organic layers are washed with brine (3x300 mL) and anhydrous Na 3 SO 4 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 (52.3 g, crude). [M+H] + =467.3.

[0289] Step 5: Ethyl 2-amino-6-(4-((benzyloxy)carbonyl)piperazin-1-yl)-5-methyl-1H-indole-3-carboxylate TIFF2025503463000245.tif2133EtOH (600 mL) and H 2 Benzyl 4-(4-(1-cyano-2-ethoxy-2-oxyethyl)-2-methyl-5-nitrophenyl)piperazine-1-carboxylate (52.3 g, 112.1 mmol), NH 4 A mixture of Cl (18.0 g, 336.4 mmol) and Fe (62.6 g, 1121.1 mmol) is stirred at 80 °C for 32 h. The mixture is cooled to room temperature and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography eluted with EtOAc in PE (1% to 30%) to give the product (6.8 g, 13.9%). [M+H] + =437.1.

[0290] Step 6: Benzyl 4-(6-methyl-4-oxo-4,9-dihydro-3H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate TIFF2025503463000246.tif1634A mixture of ethyl 2-amino-6-(4-((benzyloxy)carbonyl)piperazin-1-yl)-5-methyl-1H-indole-3-carboxylate (6.8 g, 15.6 mmol) and formamidine acetate (16.2 g, 155.8 mmol) in 2-methoxyethan-1-ol (68 mL) is stirred at 125° C. for 24 h. The mixture is cooled to room temperature. Water is added to the resulting mixture and it is filtered. The filter cake is washed with water (3×200 mL). The solid is dried under infrared light to give the product (5.4 g, 83%). [M+H] + =418.2.

[0291] Step 7: 4-(4-chloro-6-methyl-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate benzyl TIFF2025503463000247.tif1632POCl 3 Stir a solution of benzyl 4-(6-methyl-4-oxo-4,9-dihydro-3H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate (3.4 g, 8.2 mmol) in dioxane (34 mL) at 90 °C for 2 h. Concentrate the resulting mixture under reduced pressure and extract with EtOAc (3x300 mL). Wash the combined organic layers with brine (2x80 mL) and anhydrous NaCl. 2 SO 4 The mixture was dried at 75° C. 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 (1.5 g, 42.2%). [M+H] + =436.2.

[0292] Step 8: (R)-4-(4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-6-methyl-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate benzyl TIFF2025503463000248.tif3341Under a nitrogen atmosphere, at room temperature, 2 To a stirred mixture of 3-tert-butyl-N-[(1R)-1-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-methyl)phenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide (2.3 g, 5.5 mmol) and benzyl 4-(4-chloro-6-methyl-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate (2 g, 4.6 mmol) in 2H2O (8 mL) was added Pd(dppf)Cl 2 (335 mg, 0.46 mmol) and K 3 PO 4 (1.95 g, 9.2 mmol) is added. The resulting mixture is stirred at 80 °C under nitrogen atmosphere for 16 h. The mixture is cooled to room temperature and extracted with EtOAc (3x300 mL). The combined organic layers are washed with brine (2x80 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in PE (20%-90%) to give the product. [M+H] + =687.4

[0293] Step 9: (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-methyl-7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol)-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000249.tif3441 A solution of (R)-4-(4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-6-methyl-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate benzyl (1 g, 1.5 mmol) in TFA (100 mL) is refluxed under nitrogen atmosphere for 16 h. The resulting mixture is concentrated under reduced pressure. The residue was purified by reversed phase flash chromatography with the following conditions: Column: C18, Mobile phase: MeCN in water (0.1% FA), 5% to 40% gradient in 20 min, Detector: UV 254 nm. This gave the product (1.4 g, 99.27%). [M+H] + =553.3.

[0294] Step 10: (R)-3-(tert-butyl)-N-(1-(4-(7-(4-((1-(4-(2,4-dioxotetrahydropyrimidine)-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-6-methyl-9H-pyrimido[4,5-b]indol-4-yl)-2-methyl((phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000250.tif4455A mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-methyl-7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol)-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (200 mg, 0.36 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (120 mg, 0.39 mmol) and AcOH (0.02 mL) in MeOH (10 mL) and DCM (10 mL) is stirred at rt overnight. Then, STAB (154 mg, 0.72 mmol) is added to the above mixture and stirred at rt for 5 h. The resulting mixture is diluted with water (100 mL) and extracted with DCM (3x100 mL). The combined organic layers are washed with anhydrous Na 2 SO 4The residue was purified by silica gel column chromatography eluting with MeOH / DCM (1:7) to give the product (164.9 mg, 54.3%). 1 H NMR (400 MHz, DMSO) δ 12.24 (s, 1H), 10.26 (s, 1H), 9.43 (d, J = 8.0 Hz, 1H), 8.86 (s, 1H), 7.84-7.69 (m, 3H), 7.65 (s, 1H), 7.18-7.09 (m, 3H), 6.93 (d, J = 12.0 Hz, 2H), 5.48-5.39 (m, 1H), 3.75-3.64 (m, 4H), 3.03-2.87 (m, 4H), 2.76-2.61 (m, 5H), 2.60-2.54 (m, 3H), 2.52 (s, 3H), 2.26 (s, 5H), 1.83 (d, J = 8.0 Hz, 2H), 1.77-1.66 (m, 1H), 1.59 (d, J = 8.0 Hz, 3H), 1.37 (s, 9H), 1.31-1.19 (m, 2H); [M+H] + = 838.4.

[0295] Example 44: (R)-5-(tert-butyl)-N-(1-(4-(7-(4-((1-(4-(2,4-dioxotetrahydropyrimidine)-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-6-methyl-9H-pyrimido[4,5-b]indol-4-yl)-5-fluoromethyl-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide The title compound TIFF2025503463000251.tif3355 was synthesized in a similar manner to Example 43. 1H NMR (400 MHz, DMSO) δ 12.30 (s, 1H), 11.97 (s, 1H), 10.26 (s, 1H), 9.54 (d, J = 8.0 Hz, 1H), 8.90 (s, 1H), 7.62-7.46 (m, 2H), 7.25-7.09 (m, 4H), 6.93 (d, J = 8.0 Hz, 1H), 5.48-5.34 (m, 1H), 3.82-3.64 (m, 4H), 3.02-2.87 (m, 4H), 2.75-2.61 (m, 5H), 2.61-2.53 (m, 3H), 2.47 (s, 3H), [M+H] + = 856.4.

[0296] Example 45: (R)-5-(tert-butyl)-N-(1-(4-(7-(4-((1-(4-(2,4-dioxotetrahydropyrimidine)-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-6-methyl-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoromethyl-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide

[0297] Step 1: (R)-N-(1-(4-bromo-3-fluoro-2-methylphenyl)ethyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide TIFF2025503463000252.tif2521To a stirred solution of (1R)-1-(4-bromo-2,3-dimethylphenyl)ethanolamine hydrochloride (2.50 g, 9.5 mmol) and sodium 5-tert-butyl-1,2,4-oxadiazole-3-carboxylate (2.18 g, 11.3 mmol) in DMF (30 mL) is added dropwise at room temperature to DIEA (4.94 mL, 38.2 mmol). The resulting mixture is stirred at room temperature for 5 h. T3P (17.98 g, 28.251 mmol) is added dropwise to the above mixture at room temperature. The resulting mixture is stirred for 2 h. The reaction is quenched with water (50 mL). The resulting mixture is extracted with EtOAc (2x100 mL). The combined organic layers are washed with brine (1x50 mL) and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EtOAc (2:1) to give the product (2 g, 55%). [M+H] + =386.1.

[0298] Step 2: (R)-5-(tert-butyl)-N-(1-(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide TIFF2025503463000253.tif1939To a stirred solution of (R)-N-(1-(4-bromo-3-fluoro-2-methylphenyl)ethyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide (800 mg, 2.08 mmol) and bis(pinacolide)diboron (793.05 mg, 3.12 mmol) in 1,4-dioxane (20 mL) at room temperature, KOAc (612.99 mg, 6.246 mmol) and Pd(dppf)Cl 2(152.34 mg, 0.21 mmol) is added. The resulting mixture is stirred at 100 °C for 16 h. The mixture is cooled to room temperature. The reaction is quenched with water (20 mL). The resulting mixture is extracted with EtOAc (3x20 mL). The combined organic layers are washed with brine (1x20 mL) and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, (0.1% NH 4 HCO 3 ) in ACN, 50% to 80% gradient in 20 min, UV 254 nm. This gave the product (75.4 mg, 9%). [M+H] + =432.2.

[0299] Step 3: (R)-4-(4-(4-(1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)ethyl)-2-fluoro-3-methylphenyl)-6-methyl-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate benzyl TIFF2025503463000254.tif3735Dioxane (10 mL) and H 2 Benzyl 4-(4-chloro-6-methyl-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate (250 mg, 0.57 mmol), (R)-5-(tert-butyl)-N-(1-(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide (296.1 mg, 0.68 mmol), Pd(dppf)Cl in O (2 mL). 2 (41.7 mg, 0.057 mmol), K 3 PO 4 A mixture of (243.7 mg, 1.15 mmol) was stirred overnight at 80° C. under nitrogen atmosphere. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with EtOAc to give the product (140 mg, 34.6%). [M+H]+ =705.3.

[0300] Step 4: (R)-5-(tert-butyl)-N-(1-(3-fluoro-2-methyl-4-(6-methyl-7-(piperazin-1-yl))-9H-pyrimidine and [4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide TIFF2025503463000255.tif3530 A mixture of (R)-4-(4-(4-(1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)ethyl)-2-fluoro-3-methylphenyl)-6-methyl-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate benzyl (140 mg, 0.19 mmol) in TFA (5 mL) is refluxed for 2 h. The mixture is concentrated in vacuo to give the product (120 mg, crude) which is used as is in the next step. [M+H] + =571.3.

[0301] Step 5: (R)-5-(tert-butyl)-N-(1-(4-(7-(4-((1-(4-(2,4-dioxotetrahydropyrimidine)-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-6-methyl-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoromethyl-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide TIFF2025503463000256.tif3759A mixture of (R)-5-(tert-butyl)-N-(1-(3-fluoro-2-methyl-4-(6-methyl-7-(piperazin-1-yl))-9H-pyrimidine and [4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide (214 mg, 0.37 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (136 mg, 0.45 mmol) and AcOH (0.02 mL) in MeOH (10 mL) and DCM (10 mL) is stirred at rt overnight. STAB (156.8 mg, 0.74 mmol) was then added to the above mixture and stirred at rt for 5 h. The resulting mixture was diluted with water (100 mL) and extracted with DCM (3x100 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was purified by silica gel column chromatography eluting with MeOH / DCM (1:7) to give the product (164.5 mg, 51.2%). 1 H NMR (400 MHz, DMSO) δ 12.29 (s, 1H), 10.27 (s, 1H), 9.61 (d, J = 8.0 Hz, 1H), 8.90 (s, 1H), 7.60-7.50 (m, 2H), 7.19-7.09 (m, 4H), 6.93 (d, J = 8.0 Hz, 2H), 5.52-5.41 (m, 1H), 3.75-3.64 (m, 4H), 3.01-2.87 (m, 4H), 2.74-2.61 (m, 5H), 2.60-2.51 (m, 2H), 2.41 (s, 3H), 2.30-2.18 (m, 5H), [M+H] + = 856.4.

[0302] Example 46: (R)-3-(tert-butyl)-N-(1-(4-(7-(4-((1-(4-(2,4-dioxotetrahydropyrimidine)-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-6-methoxy-9H-pyrimido[4,5-b]indol-4-yl)-2-methyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000257.tif3759A mixture of (R)-3-(tert-butyl)-N-(1-(4-(6-methoxy-7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indolindol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (130 mg, 0.23 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (82.7 mg, 0.27 mmol) and AcOH (0.02 mL) in MeOH (5 mL) and DCM (5 mL) is stirred at rt overnight. Then, STAB (97 mg, 0.46 mmol) is added to the above mixture and stirred at rt for 5 h. The resulting mixture is diluted with water (50 mL) and extracted with DCM (3x100 mL). The combined organic layers are washed with anhydrous Na 2 SO 4 The residue was purified by silica gel column chromatography eluting with MeOH / DCM (1:7) to give the product (100.13 mg, 51.2%). 1H NMR (400 MHz, DMSO) δ 12.16 (s, 1H), 10.26 (s, 1H), 9.94 (d, J = 8.0 Hz, 1H), 8.85 (s, 1H), 7.83-7.68 (m, 3H), 7.28 (s, 1H), 7.13 (d, J = 12.0 Hz, 2H), 7.02 (s, 1H), 6.93 (d, J = 8.0 Hz, 2H), 5.45-5.35 (m, 1H), 3.76-3.62 (m, 7H), 3.15-3.03 (m, 4H), 2.74-2.61 (m, 5H), 2.60-2.54 (m, 6H), [M+H] + = 854.4.

[0303] Example 47: 3-(tert-butyl)-N-((1R)-1-(4-(7-(4-((3-(4-(2,6-dioxopiperidin-3-yl))phenyl)cyclobutyl)methyl)piperazin-1-yl)-6-methoxy-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0304] Step 1: Benzyl 4-(4-chloro-2-methoxyphenyl)piperazine-1-carboxylate TIFF2025503463000258.tif1230A solution of 1-bromo-4-chloro-2-methoxybenzene (50.00 g, 225.7 mmol) and benzylpiperazine-1-carboxylate (59.67 g, 270.9 mmol) in toluene (1.0 L) was diluted with BINAP (28.11 g, 45.2 mmol), Pd 2 (dba) 3(20.67 g, 22.6 mmol) and t-BuONa (43.39 g, 451.5 mmol) are added. After stirring at 95 °C for 2 h under nitrogen atmosphere, the resulting mixture is filtered. The filter cake is washed with EA (3x200 mL). The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography eluted with PE / EtOAc (20:1 to 3:1) to give the product (50 g, 61.4%). [M+H] + =361.1.

[0305] Step 2: 1-(4-chloro-2-methoxy-5-nitrophenyl)piperazine TIFF2025503463000259.tif1625DarkH 2 SO 4 To a stirred solution of benzyl 4-(4-chloro-2-methoxyphenyl)piperazine-1-carboxylate (40.0 g, 110.8 mmol) in 1,2-dichloro-2,4-diphenyl-1,2-tetrafluoroethylene (200.0 mL, 3.75 mol) is added guanidine nitrate (16.24 g, 133.0 mmol) in portions at 0° C. under nitrogen atmosphere. The resulting mixture is stirred at 0° C. for 2 h under nitrogen atmosphere. At 0° C., add saturated Na 2 CO 3 The reaction is quenched by adding (aqueous). The resulting mixture is diluted with EtOAc (6x500 mL) and DCM (10% CH in DCM). 3 The combined organic layers were washed with brine (100 mL) and anhydrous NaOH (3x500 mL). 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give the product (30 g, crude). [M + H] + =272.1.

[0306] Step 3: 4-(4-chloro-2-methoxy-5-nitrophenyl)piperazine-1-carboxylate benzyl TIFF2025503463000260.tif1628To a stirred solution of 1-(4-chloro-2-methoxy-5-nitrophenyl)piperazine (37.0 g, 136.2 mmol) and DIEA (71.16 mL, 408.5 mmol) in DCM (400.0 mL) under nitrogen atmosphere, add Cbz-Cl (46.46 g, 272.4 mmol) dropwise at 0 °C. The resulting mixture is stirred at room temperature for 16 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EtOAc (15:1 to 3:1) to give the product (26.5 g, 47.9%). [M+H] + =406.1.

[0307] Step 4: 4-(4-(1-cyano-2-ethoxy-2-oxyethyl)-2-methoxy-5-nitrophenyl)piperazine-1-carboxylate benzyl TIFF2025503463000261.tif1635Cs in DMF (500.0 mL) 2 CO 3 To a stirred mixture of benzyl 4-(4-chloro-2-methoxy-5-nitrophenyl)piperazine-1-carboxylate (63.82 g, 195.9 mmol) is added dropwise at 0 °C under nitrogen atmosphere, and the resulting mixture is stirred at 0 °C for 0.5 h. A solution of benzyl 4-(4-chloro-2-methoxy-5-nitrophenyl)piperazine-1-carboxylate (26.50 g, 65.3 mmol) in DMF (30.0 mL) is added dropwise to the above mixture at 0 °C. The resulting mixture is further stirred at 80 °C for 16 h. The mixture is filtered and the filter cake is washed with EtOAc (3x500 mL). The solution is acidified to pH 5-6 with HCl (aq, 1.0 M). The resulting solution is extracted with EtOAc (3x500.0 mL). The combined organic layers are washed with brine (500 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (10:1 to 1:1) to give the product (28.2 g, 89.5%). [M+H] + =483.1.

[0308] Step 5: 2-amino-6-(4-((benzyloxy)carbonyl)piperazin-1-yl)-5-methoxy-1H-indole-3-carboxylate ethyl TIFF2025503463000262.tif1833To a stirred solution of benzyl 4-(4-(1-cyano-2-ethoxy-2-oxyethyl)-2-methoxy-5-nitrophenyl)piperazine-1-carboxylate (28.2 g, 58.4 mmol) in AcOH (282.0 mL) is added Fe (22.85 g, 0.41 mmol) at room temperature. The resulting mixture is stirred at room temperature for 16 h. The reaction is monitored by LCMS and concentrated under reduced pressure. The residue is purified by silica gel column chromatography and purified in CH 2 Cl 2 Elution with 20:1 hexane / MeOH gave the product (24.3 g, 91.9%). [M+H] + =453.1.

[0309] Step 6: 4-(6-Methoxy-4-oxo-4,9-dihydro-3H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate benzyl TIFF2025503463000263.tif1834To a stirred solution of ethyl 2-amino-6-(4-((benzyloxy)carbonyl)piperazin-1-yl)-5-methoxy-1H-indole-3-carboxylate (33.1 g, 73.1 mmol) in 2-methoxyethan-1-ol (330.0 mL), formyl acetate (76.1 g, 731.0 mmol) is added portionwise at room temperature under air atmosphere. The resulting mixture is stirred at 125° C. for 16 h under nitrogen atmosphere. The mixture is cooled to room temperature and diluted with water (800.0 mL). The precipitated solid is collected by filtration and washed with water (2×50.0 mL). The resulting solid is dried under infrared light to give the product (28 g, 88.3%). [M+H] + =434.1.

[0310] Step 7: 4-(4-chloro-6-methoxy-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate benzyl TIFF2025503463000264.tif1834To a stirred solution of benzyl 4-(6-methoxy-4-oxo-4,9-dihydro-3H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate (28.0 g, 64.6 mmol) in dioxane (560.0 mL), POCl was added. 3 (78.27 mL, 0.84 mol) is added at room temperature under air atmosphere. The resulting mixture is stirred at 90 °C under nitrogen atmosphere for 6 h. The mixture is cooled to room temperature and concentrated under reduced pressure. Saturated NaHCO 3 The residue is basified with (aqueous) to pH 7. The resulting mixture is extracted with EtOAc (2x1.0 L) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The precipitated solid was collected by filtration and washed with ether (3x100.0 mL) to give the product (30 g, 96.0%). 1 H NMR (400 MHz, DMSO) δ 12.52 (s, 1H), 8.66 (s, 1H), 7.68 (s, 1H), 7.42-7.29 (m, 5H), 7.07 (s, 1H), 5.13 (s, 2H), 3.93 (s, 3H), 3.61 (s, 4H), 3.09 (t, J = 5.1 Hz, 4H); [M+H] + = 452.3.

[0311] Step 8: (R)-4-(4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-6-methoxy-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate benzyl TIFF2025503463000265.tif3748Under nitrogen atmosphere, at room temperature, in DMF / H 2To a stirred mixture of benzyl 4-(4-chloro-6-methoxy-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate (1.1 g, 2.4 mmol) and 3-tert-butyl-N-[(1R)-1-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide (1.21 g, 2.9 mmol) in 20O (5 / 1, 20 mL) was added K 3 PO 4 (1.04 g, 4.9 mmol) and Pd(dppf)Cl 2 (0.18 g, 0.24 mmol) is added. The resulting mixture is stirred at 90° C. overnight under nitrogen atmosphere. The mixture is cooled to room temperature and diluted with water (250.0 mL). The resulting mixture is extracted with EtOAc (3×300.0 mL). The combined organic layers are washed with water (1×300.0 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified with CH 2 Cl 2 Elution with 20:1 hexane / MeOH gave the product (850 mg, 49.6%). [M+H] + =703.4.

[0312] Step 9: (R)-3-(tert-butyl)-N-(1-(4-(6-methoxy-7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indolindol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide formate TIFF2025503463000266.tif3744A solution of (R)-4-(4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-6-methoxy-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate benzyl (0.7 g, 0.996 mmol) in TFA (65.0 mL) is stirred overnight at 60 °C under nitrogen atmosphere. The resulting mixture is concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column: silica gel, mobile phase: 0.1% formic acid in water, 10% to 50% gradient in 30 min, detector: UV 254 nm. This gave the desired product (530 mg, 86.6%). 1 H NMR (400 MHz, DMSO) δ 12.25 (s, 1H), 9.97 (d, J = 7.6 Hz, 1H), 8.88 (s, 1H), 8.24 (s, 1H), 7.83-7.75 (m, 2H), 7.73 (d, J = 7.9 Hz, 1H), 7.30 (s, 1H), 7.05 (s, 1H), 5.44-5.34 (m, 1H) 3.67 (s, 3H), 3.19 (s, 8H), 2.53 (s, 3H), 1.58 (d, J = 7.0 Hz, 3H), 1.37 (s, 9H); [M+H] + = 569.1.

[0313] Step 10: 3-(tert-butyl)-N-((1R)-1-(4-(7-(4-((3-(4-(2,6-dioxopiperidin-3-yl))phenyl)cyclobutyl)methyl)piperazin-1-yl)-6-methoxy-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000267.tif3959A stirred solution of (R)-3-(tert-butyl)-N-(1-(4-(6-methoxy-7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide formic acid (0.1 g, 0.163 mmol), 3-(4-(2,6-dioxopiperidin-3-yl)phenyl)cyclobutane-1-carbaldehyde (50 mg, 0.184 mmol) and AcOH (0.5 mL) in DCM / MeOH (10.0 mL / 2.5 mL) was stirred at room temperature for 16 h, followed by addition of NaBH(OAc) 3 (173 mg, 0.815 mmol) is added and stirred at room temperature for 1 h. The resulting mixture is diluted with water (20.0 mL) and extracted with DCM (3 x 15.0 mL). The combined organic layers are concentrated under reduced pressure. The residue is purified by silica gel column chromatography and purified with CH 2 Cl 2 Elution with 10:1 hexane / MeOH gave the product (66 mg, 49.2%). 1 H NMR (500 MHz, DMSO) δ 12.15 (s, 1H), 10.82 (s, 1H), 9.95 (d, J = 7.7 Hz, 1H), 8.85 (s, 1H), 7.82-7.75 (m, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.20 (ddd, J = 24.4, 17.9, 9.9 Hz, 5H), 7.01 (s, 1H), 5.39 (q, J = 6.9 Hz, 1H), 3.87-3.76 (m, 1H), 3.65 (s, 3H), 3.42-3.33 (m, 1H), 3.07 (s, 4H), 2.73-2.51 (m, 9H), 2.50-2.40 (m, 4H), 2.25-2.11 (m, 2H), 2.02 (dt, J = 13.2, 4.6 Hz, 1H), 1.81-1.69 (m, 1H), 1.57 (d, J = 6.9 Hz, 3H), 1.37 (s, 9H); [M+H] + = 824.9.

[0314] Example 48: 3-(tert-butyl)-N-((1R)-1-(4-(7-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl))cyclohexyl)piperazin- 1-yl)-6-methoxy-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound was synthesized in a similar manner to Example 47. 1 H NMR (500 MHz, DMSO) δ 12.31 (s, 1H), 10.84 (s, 1H), 10.01 (d, J = 7.6 Hz, 1H), 8.93 (s, 1H), 7.88-7.80 (m, 2H), 7.78 (d, J = 7.9 Hz, 1H), 7.35 (s, 1H), 7.12 (d, J = 7.7 Hz, 3H), 7.00 (d, J = 6.0 Hz, 2H), 5.45 (q, J = 7.0 Hz, 1H), 4.02-3.84 (m, 2H), 3.84-3.76 (m, 2H), 3.77-3.66 (m, 5H), 3.46 (d, J = 26.8 Hz, 2H), 3.36-3.26 (m, 2H), 3.25-3.09 (m, 3H), 2.84-2.65 (m, 4H), 2.59 (d, J = 5.0 Hz, 3H), 2.23 (ddd, J = 23.8, 15.8, [M+H] + = 839.6.

[0315] Example 49: 3-(tert-butyl)-N-((R)-1-(4-(7-(4-(3-(4-((S))-2,6-dioxopiperidin-3-yl)phenyl)cyclobutyl)piperazin-1-yl)-6-methoxy-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound was synthesized in a similar manner to that of Example 47. 1 H NMR (500 MHz, DMSO) δ 12.15 (s, 1H), 10.83 (s, 1H), 9.95 (d, J = 7.7 Hz, 1H), 8.85 (s, 1H), 7.84-7.75 (m, 2H), 7.72 (d, J = 7.9 Hz, 1H), 7.28 (s, 1H), 7.25-7.12 (m, 4H), 7.02 (s, 1H), 5.39 (q, J = 7.0 Hz, 1H), 3.82 (dd, J = 11.3, 4.8 Hz, 1H), 3.66 (s, 3H), 3.20-2.99 (m, 5H), 2.84-2.73 (m, 1H), 2.67 (ddd, J = 17.0, 13.4, 7.6 Hz, 1H), 2.53 (s, 4H), 2.46 (t, J = 11.7 Hz, 6H), 2.18 (dt, J = 20.2, 9.9 Hz, 1H), 2.07-1.98 (m, 1H), 1.95-1.82 (m, 2H), 1.58 (d, J = 6.9 Hz, 3H), 1.37 (s, 9H); [M+H] + = 810.6.

[0316] Example 50: 3-(tert-butyl)-N-((R)-1-(4-(7-(4-(3-(4-((R)))-2,6-dioxopiperidin-3-yl)phenyl)cyclobutyl)piperazin-1-yl)-6-methoxy-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound was synthesized in a similar manner to Example 47. 1H NMR (500 MHz, DMSO) δ 12.16 (s, 1H), 10.83 (s, 1H), 9.96 (d, J = 7.7 Hz, 1H), 8.85 (s, 1H), 7.83-7.76 (m, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.19 (dd, J = 28.3, 7.4 Hz, 4H), 7.02 (s, 1H), 5.43-5.36 (m, 1H), 3.82 (dd, J = 11.5, 4.9 Hz, 1H), 3.66 (s, 3H), 3.20-3.04 (m, 4H), 2.78 (dt, J = 15.0, 7.6 Hz, 1H), 2.71-2.61 (m, 1H), 2.53 (s, 4H), 2.47 (d, J = 4.3 Hz, 6H), 2.22-2.11 (m, 1H), 2.06-1.99 (m, 1H), 1.95-1.83 (m, 2H), 1.57 (d, J = 6.9 Hz, 3H), 1.37 (s, 9H); [M+H] + = 810.6.

[0317] Example 51: 3-(tert-butyl)-N-((1R)-1-(4-(7-(4-(1-(3-(2,6-dioxopiperidin-3-yl)phenyl))pyrrolidin-3-yl)piperazin-1-yl)-6-methoxy-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0318] Step 1: 1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)pyrrolidin-3-ol TIFF2025503463000271.tif2728To a stirred mixture of 2,6-bis(benzyloxy)-3-(3-bromophenyl)pyridine (4.1 g, 9.21 mmol) and pyrrolidin-3-ol hydrochloride (1.36 g, 11.06 mmol) in DME (80.0 mL), BINAP (573 mg, 0.921 mmol), Pd 2 (dba) 3(422 mg, 0.46 mmol) and t-BuONa (2.65 g, 27.63 mmol) are added. After stirring at 100 °C for 6 h under nitrogen atmosphere, the resulting mixture is concentrated under reduced pressure. The residue is purified by silica gel column chromatography and eluted with PE / EtOAc (10:1 to 3:1) to give the product (3.2 g, 76.9%). [M+H] + =453.3.

[0319] Step 2: 3-(3-(3-hydroxypyrrolidin-1-yl)phenyl)piperidine-2,6-dione TIFF2025503463000272.tif2623 A solution of 1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)pyrrolidin-3-ol (2.9 g, 33.606 mmol) and Pd / C (2.9 g) in methanol (80.0 mL) is stirred under hydrogen atmosphere at room temperature for 16 h. The mixture is filtered and concentrated under reduced pressure to give the product (1.7 g, 97%). [M+H] + =275.2.

[0320] Step 3: 3-(3-(3-oxopyrrolidin-1-yl)phenyl)piperidine-2,6-dione TIFF2025503463000273.tif2821To a stirred mixture of DMSO (1.48 g, 19 mmol) in DCM (10.0 mL) is added oxalyl chloride (9.5 mL, 9.5 mmol) at -78 °C. After stirring at -78 °C for 1 h under nitrogen atmosphere, 3-(3-(3-hydroxypyrrolidin-1-yl)phenyl)piperidine-2,6-dione (1.3 g, 4.74 mmol) in DCM (10.0 mL) is added at -78 °C. The resulting mixture is stirred at -78 °C for 1 h, then TEA (2.4 g, 23.7 mmol) is added and stirred at room temperature for 30 min. The resulting mixture is diluted with DCM (3x50.0 mL) and H 2 The combined organic layers were washed with brine (50 mL) and anhydrous NaCl. 2 SO 4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM / MeOH (20:1) to give the product (1.1 g, 84.6%). [M+H] + =273.

[0321] Step 4: 3-(tert-butyl)-N-((1R)-1-(4-(7-(4-(1-(3-(2,6-dioxopiperidin-3-yl)phenyl))pyrrolidin-3-yl)piperazin-1-yl)-6-methoxy-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide TIFF2025503463000274.tif3466A solution of (R)-3-(tert-butyl)-N-(1-(4-(6-methoxy-7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide formate (120 mg, 0.195 mmol), 3-(3-(3-oxopyrrolidin-1-yl)phenyl)piperidine-2,6-dione (106 mg, 0.39 mmol) and HOAc (1.0 mL) in MeOH (3.0 mL) and DCM (12.0 mL) is stirred at 35° C. for 72 h. Then, NaBH(OAc) 3 (413.4 mg, 1.95 mmol) is added and stirred at room temperature for 24 h. The resulting mixture is diluted with water (20.0 mL) and extracted with DCM (3x15.0 mL). The combined organic layers are concentrated under reduced pressure. The residue is purified by silica gel column chromatography and purified with CH 2 Cl 2 Elution with 100% methanol / MeOH (20:1) on preparative HPLC afforded the product (10 mg, 6.2%). 1H NMR (500 MHz, MeOD) δ 8.80 (s, 1H), 7.76-7.69 (m, 3H), 7.24 (s, 1H), 7.21-7.14 (m, 2H), 6.57-6.49 (m, 2H), 6.47 (s, 1H), 5.53 (q, J = 7.0 Hz, 1H), 3.80 (dd, J = 9.3, 5.6 Hz, 1H), 3.68 (s, 3H), 3.58 (t, J = 7.5 Hz, 1H), 3.47 (dd, J = 18.0, 9.4 Hz, 1H), 3.24-3.12 (m, 6H), 2.95-2.77 (m, 4H), 2.73-2.55 (m, 6H), 2.38-2.32 (m, 1H), 2.30-2.18 (m, 2H), 2.06-1.95 (m, 1H), 1.66 (d, J = 7.0 Hz, 3H), 1.42 (s, 9H); [M+H] + = 825.6.

[0322] Example 52: (R)-N-(1-(4-(7-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl))phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-6-methoxy-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide The title compound TIFF2025503463000275.tif4258 was synthesized in a similar manner to Example 47. 1H NMR (500 MHz, DMSO) δ 12.10 (s, 1H), 10.19 (s, 1H), 9.80 (d, J = 7.7 Hz, 1H), 8.78 (s, 1H), 7.74-7.68 (m, 2H), 7.63 (d, J = 7.9 Hz, 1H), 7.20 (s, 1H), 7.07 (d, J = 8.9 Hz, 2H), 6.95 (s, 1H), 6.86 (d, J = 9.0 Hz, 2H), 5.30 (q, J = 7.0 Hz, 1H), 3.62 (dd, J = 11.9, 5.2 Hz, 4H), 3.58 (s, 3H), 3.09-2.93 (m, 4H), 2.60 (dd, J = 16.5, 9.6 Hz, 4H), 2.51-2.46 (m, 4H), 2.45 (s, 3H), 2.17 (d, J = 7.0 Hz, 2H), 1.83 (s, 2H), 1.75 (d, J = 11.4 Hz, 2H), 1.70-1.60 (m, 1H), 1.49 (d, J = 6.9 Hz, 3H), 1.42 (s, 3H), 1.19-1.11(m, 6H), 0.92 (d, J = 2.5 Hz, 2H); + = 852.6.

[0323] Example 53: (R)-N-(1-(4-(7-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl))phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-6-methoxy-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylbenzene(ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide The title compound TIFF2025503463000276.tif4255 was synthesized in a similar manner to Example 47. 1H NMR (500 MHz, DMSO) δ 12.18 (s, 1H), 10.25 (s, 1H), 9.93 (d, J = 6.9 Hz, 1H), 8.88 (s, 1H), 7.62-7.45 (m, 2H), 7.13 (d, J = 7.4 Hz, 2H), 7.01 (s, 1H), 6.93 (d, J = 7.7 Hz, 2H), 6.72 (s, 1H), 5.43-5.31 (m, 1H), 3.74-3.64 (m, 4H), 3.56 (s, 3H), 3.13-3.02 (m, 4H), 2.71-2.63 (m, 4H), 2.41 (s, 4H), 2.29-2.19 (m, 2H), 1.87-1.77 (m, 2H), 1.75-1.66 (m, 1H), 1.57 (d, J = 5.5 Hz, 3H), 1.49 (s, 3H), 1.30-1.16 (m, 4H), 1.11 (s, 3H), 1.04-0.94 (m, 2H); [M+H] + = 870.5.

[0324] Example 54: (R)-3-(tert-butyl)-N-(1-(4-(7-(4-((1-(4-(2,4-dioxotetrahydropyrimidine)-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-6-methoxy-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound TIFF2025503463000277.tif3958 was synthesized in a similar manner to Example 47. 1H NMR (500 MHz, DMSO) δ 12.19 (s, 1H), 10.26 (s, 1H), 10.01 (d, J = 7.5 Hz, 1H), 8.89 (s, 1H), 7.56 (q, J = 8.1 Hz, 2H), 7.13 (d, J = 8.9 Hz, 2H), 7.01 (s, 1H), 6.93 (d, J = 9.0 Hz, 2H), 6.72 (s, 1H), 5.40 (q, J = 7.0 Hz, 1H), 3.69 (t, J = 6.7 Hz, 4H), 3.56 (s, 3H), 3.19-2.95 (m, 4H), 2.67 (dd, J = 17.5, 10.5 Hz, 4H), 2.53 (dd, J = 31.1, 14.9 Hz, 4H), 2.42 (d, J = 1.4 Hz, 3H), 2.23 (d, J = 6.7 Hz, 2H), 1.82 (d, J = 11.9 Hz, 2H), 1.76-1.65 (m, 1H), 1.58 (d, J = 6.9 Hz, 3H), 1.37 (s, 9H), 1.23 (dd, J = 21.3, 11.3 Hz, 2H); [M+H] + = 872.6.

[0325] Example 55: 3-(tert-butyl)-N-((R)-1-(4-(7-(4-(3-(4-((S))-2,6-dioxopiperidin-3-yl)phenyl)cyclobutyl)piperazin-1-yl)-6-methoxy-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound JPEG2025503463000278.jpg3266 was synthesized in a similar manner to Example 47. 1H NMR (500 MHz, DMSO) δ 12.17 (s, 1H), 10.82 (s, 1H), 10.00 (d, J = 7.1 Hz, 1H), 8.89 (s, 1H), 7.61-7.50 (m, 2H), 7.24-7.13 (m, 4H), 7.02 (s, 1H), 6.73 (s, 1H), 5.49-5.32 (m, 1H), 3.82 (dd, J = 11.7, 4.8 Hz, 1H), 3.56 (s, 3H), 3.10 (ddd, J = 19.2, 16.1, 10.6 Hz, 4H), 2.78 (dt, J = 16.0, 11.4 Hz, 1H), 2.71-2.62 (m, 1H), 2.61-2.51 (m, 3H), 2.50-2.34 (m, 8H), 2.23-2.13 (m, 1H), 2.07-1.99 (m, 1H), 1.93-1.84 (m, 2H), 1.59 (d, J = 6.5 Hz, 3H), 1.38 (d, J = 1.2 Hz, 9H); [M+H] + = 828.5.

[0326] Example 56: 3-(tert-butyl)-N-((R)-1-(4-(7-(4-(3-(4-((R)))-2,6-dioxopiperidin-3-yl)phenyl)cyclobutyl)piperazin-1-yl)-6-methoxy-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound JPEG2025503463000279.jpg3363 was synthesized in a similar manner to Example 47. 1H NMR (500 MHz, DMSO) δ 12.17 (s, 1H), 10.82 (s, 1H), 10.00 (d, J = 7.4 Hz, 1H), 8.89 (s, 1H), 7.56 (q, J = 8.0 Hz, 2H), 7.23-7.13 (m, 4H), 7.01 (s, 1H), 6.73 (s, 1H), 5.44-5.36 (m, 1H), 3.82 (dd, J = 11.4, 4.8 Hz, 1H), 3.56 (s, 3H), 3.16-3.11 (m, 4H), 2.85-2.73 (m, 1H), 2.65-2.61 (m, 1H), 2.60-2.52 (m, 3H), 2.50-2.40 (m, 8H), 2.23-2.13 (m, 1H), 2.06-1.99 (m, 1H), 1.92-1.83 (m, 2H), 1.58 (d, J = 6.9 Hz, 3H), 1.37 (s, 9H); [M+H] + = 828.5.

[0327] Example 57: 3-(tert-butyl)-N-((1R)-1-(4-(7-(4-(1-(3-(2,6-dioxopiperidin-3-yl)phenyl))pyrrolidin-3-yl)piperazin-1-yl)-6-methoxy-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylbenzene(ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound JPEG2025503463000280.jpg3466 was synthesized in a similar manner to that described in Example 47. 1H NMR (500 MHz, DMSO) δ 12.17 (s, 1H), 10.78 (s, 1H), 10.00 (d, J = 7.5 Hz, 1H), 8.89 (s, 1H), 7.56 (q, J = 8.1 Hz, 2H), 7.11 (t, J = 7.8 Hz, 1H), 7.02 (s, 1H), 6.73 (s, 1H), 6.45 (t, J = 6.9 Hz, 2H), 6.41 (s, 1H), 5.40 (q, J = 6.8 Hz, 1H), 3.73 (dd, J = 10.9, 4.9 Hz, 1H), 3.57 (s, 3H), 3.49 (dd, J = 15.7, 7.3 Hz, 1H), 3.36 (dd, J = 14.0, 7.8 Hz, 1H), 3.29 (s, 1H), 3.23 (ddd, J = 12.9, 9.7, 3.9 Hz, 1H), 3.16-3.03 (m, 4H), 3.00 (dd, J = 15.1, 7.3 Hz, 1H), 2.73-2.59 (m, 5H), 2.47-2.39 (m, 4H), 2.27-2.15 (m, 2H), 2.09-2.00 (m, 1H), 1.91-1.82 (m, 1H), 1.58 (d, J = 7.0 Hz, 3H), 1.38 (s, 9H); [M+H] + = 843.5.

[0328] Example 58: (R)-5-(tert-butyl)-N-(1-(4-(7-(4-((1-(4-(2,4-dioxotetrahydropyrimidine)-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-6-methoxy-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide The title compound JPEG2025503463000281.jpg3955 was synthesized in a similar manner to that of Example 47. 1H NMR (500 MHz, DMSO) δ 12.19 (s, 1H), 10.27 (s, 1H), 9.62 (d, J = 7.3 Hz, 1H), 8.89 (s, 1H), 7.58-7.49 (m, 2H), 7.13 (d, J = 8.4 Hz, 2H), 7.01 (s, 1H), 6.93 (d, J = 8.5 Hz, 2H), 6.73 (s, 1H), 5.50-5.33 (m, 1H), 3.73-3.65 (m, 4H), 3.57 (s, 3H), 3.15-2.98 (m, 4H), 2.67 (dd, J = 17.0, 9.8 Hz, 4H), 2.64-2.57 (m, 4H), 2.42 (s, 3H), 2.23 (d, J = 5.9 Hz, 2H), 1.82 (d, J = 10.6 Hz, 2H), 1.76-1.66 (m, 1H), 1.56 (d, J = 6.7 Hz, 3H), 1.43 (s, 2H), 1.23 (dd, J = 22.2, 11.2 Hz, 2H); [M+H] + = 872.6.

[0329] Example 59: 5-(tert-butyl)-N-((R)-1-(4-(7-(4-(3-(4-((S))-2,6-dioxopiperidin-3-yl)phenyl)cyclobutyl)piperazin-1-yl)-6-methoxy-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide The title compound JPEG2025503463000282.jpg3469 was synthesized in a similar manner to that described in Example 47. 1H NMR (500 MHz, DMSO) δ 12.17 (s, 1H), 10.82 (s, 1H), 9.60 (d, J = 7.6 Hz, 1H), 8.89 (s, 1H), 7.58-7.51 (m, 2H), 7.24-7.13 (m, 4H), 7.02 (s, 1H), 6.73 (s, 1H), 5.45-5.37 (m, 1H), 3.82 (dd, J = 11.2, 4.6 Hz, 1H), 3.57 (s, 3H), 3.19-3.04 (m, 4H), 2.83-2.74 (m, 1H), 2.69-2.62 (m, 1H), 2.60-2.50 (m, 3H), 2.48-2.35 (m, 8H), 2.23-2.13 (m, 1H), 2.06-1.99 (m, 1H), 1.91-1.81 (m, 2H), 1.56 (d, J = 6.9 Hz, 3H), 1.43 (s, 9H); [M+H] + = 828.6.

[0330] Example 60: 5-(tert-butyl)-N-((R)-1-(4-(7-(4-(3-(4-((R)))-2,6-dioxopiperidin-3-yl)phenyl)cyclobutyl)piperazin-1-yl)-6-methoxy-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide JPEG2025503463000283.jpg3569 The title compound was synthesized in a similar manner to that of Example 47. 1H NMR (500 MHz, DMSO) δ 12.17 (s, 1H), 10.82 (s, 1H), 9.60 (d, J = 7.6 Hz, 1H), 8.89 (s, 1H), 7.58-7.51 (m, 2H), 7.25-7.13 (m, 4H), 7.01 (s, 1H), 6.73 (s, 1H), 5.44-5.37 (m, 1H), 3.82 (dd, J = 11.2, 4.4 Hz, 1H), 3.57 (s, 3H), 3.19-3.04 (m, 4H), 2.83-2.75 (m, 1H), 2.68-2.63 (m, 2H), 2.60-2.56 (m, 3H), 2.48-2.35 (m, 8H), 2.21-2.13 (m, 1H), 2.07-1.99 (m, 1H), 1.91-1.82 (m, 2H), 1.56 (d, J = 6.9 Hz, 3H), 1.43 (s, 9H); [M+H] + = 828.7.

[0331] Example 61: 5-(tert-butyl)-N-((1R)-1-(4-(7-(4-(1-(3-(2,6-dioxopiperidin-3-yl)phenyl))pyrrolidin-3-yl)piperazin-1-yl)-6-methoxy-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylbenzene(ethyl)-1,2,4-oxadiazole-3-carboxamide The title compound JPEG2025503463000284.jpg3264 was synthesized in a similar manner to Example 47. 1H NMR (500 MHz, MeOD) δ 8.84 (s, 1H), 7.53 (s, 2H), 7.17 (t, J = 7.9 Hz, 2H), 6.82 (s, 1H), 6.57-6.51 (m, 2H), 6.47 (s, 1H), 5.54 (dd, J = 13.0, 6.2 Hz, 1H), 3.80 (dd, J = 9.3, 5.6 Hz, 1H), 3.68-3.55 (m, 4H), 3.51-3.43 (m, 1H), 3.27-3.10 (m, 6H), 2.93-2.76 (m, 4H), 2.71-2.57 (m, 3H), 2.51 (d, J = 1.9 Hz, 3H), 2.36 (dt, J = 12.0, 6.2 Hz, 1H), 2.29-2.19 (m, 2H), 1.99 (dq, J = 18.9, 9.4 Hz, 1H), 1.65 (d, J = 7.0 Hz, 3H), 1.49 (s, 9H); [M+H] + = 843.6.

[0332] Example 62: (R)-3-(tert-butyl)-N-(1-(4-(7-(4-((1-(4-(2,4-dioxotetrahydropyrimidine)-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-6-methoxy-9H-pyrimido[4,5-b]indol-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide JPEG2025503463000285.jpg4258 The title compound was synthesized in a similar manner to that of Example 47. 1H NMR (500 MHz, DMSO) δ 12.12 (s, 1H), 10.19 (s, 1H), 9.48 (d, J = 7.8 Hz, 1H), 8.82 (d, J = 5.2 Hz, 1H), 7.48 (dd, J = 9.3, 3.6 Hz, 2H), 7.06 (d, J = 9.0 Hz, 2H), 6.95 (s, 1H), 6.86 (d, J = 9.1 Hz, 2H), 6.72 (d, J = 1.7 Hz, 1H), 5.30 (q, J = 7.1 Hz, 1H), 3.62 (dd, J = 12.8, 6.0 Hz, 4H), 3.49 (s, 3H), 3.00 (s, 4H), 2.62-2.56 (m, 5H), 2.44 (dt, J = 3.6, 1.8 Hz, 3H), 2.41 (s, 3H), 2.17 (d, J = 7.1 Hz, 2H), 1.75 (d, J = 11.4 Hz, 2H), 1.68-1.59 (m, 1H), 1.47 (d, J = 7.0 Hz, 3H), 1.37 (s, 9H), 1.19-1.12 (m, 2H); [M+H] + = 872.5.

[0333] Example 63: (R)-5-(tert-butyl)-N-(1-(4-(7-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H))-yl)phenyl)azetidin-3-yl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide

[0334] Step 1: 3,3'-((4-hydroxyphenyl)azadiyl)dipropionic acid JPEG2025503463000286.jpg1928A solution of 4-aminophenol (250 g, 2.29 mol) and acrylic acid (363 g, 5.04 mol) in water (1.25 L) is stirred at 80-85 °C for 16 h. The reaction mixture is filtered and the filter cake is separated by H 2Wash with O (2.00 L). Concentrate the filtrate in vacuo to give the title product (552 g, 95.1%). 1 H NMR (400 MHz, DMSO) δ 12.18 (brs, 2H), 8.67 (brs, 1H), 6.48-6.88 (m, 4H), 3.38 (s, 5H), 2.36 (t, J = 7.06 Hz, 4H).

[0335] Step 2: 1-(4-hydroxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione JPEG2025503463000287.jpg1623 Urea (106 g, 1.76 mol) was added to a solution of 3,3'-((4-hydroxyphenyl)azadiyl)dipropionic acid (300 g, 1.18 mol) in AcOH (1.50 L) at 20-30 °C. After addition, the mixture is stirred at 120-130 °C for 12 h. LCMS showed that the starting material was completely consumed and the desired product was observed. 10.0% hydrochloric acid (1.00 L) was added to the reactor at 120-130 °C. After addition, the mixture is stirred at 120-130 °C for 1 h. The reaction mixture is cooled to 10-20 °C and filtered. The filter cake was washed with petroleum ether (2.00 L) to give the title product (185 g, crude). 1 H NMR (400 MHz, DMSO) δ 10.3 (s, 1H), 9.45 (s, 1H), 7.00-7.26 (m, 2H), 6.67-6.86 (m, 2H), 3.67 (t, J = 6.72 Hz, 2H), 2.67 (t, J = 6.72 Hz, 2H).

[0336] Step 3: 1-(4-((tert-butyldimethylsilyl)oxy)phenyl)dihydropyrimidine-2,4(1H,3H)-dione JPEG2025503463000288.jpg1628To a solution of 1-(4-hydroxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (80.0 g, 0.380 mol) and imidazole (52.8 g, 0.770 mol) in DCM (400 mL) is added TBSCl (64.3 g, 0.420 mol) at 10-15 °C. The mixture is subsequently stirred at 25 °C for 12 h. The reaction mixture is partitioned between DCM (400 mL) and water (500 mL). The aqueous layer is extracted with DCM (200 mL). The combined organic layers are washed with brine (200 mL) and anhydrous NaCl. 2 SO 4 and concentrated in vacuo to give the title product (120 g, 96.1%). 1 H NMR (400 MHz, DMSO) δ 10.31 (s, 1H), 7.07-7.40 (m, 2H), 6.67-6.95 (m, 2H), 3.72 (t, J = 6.73 Hz, 2H), 2.68 (t, J = 6.73 Hz, 2H), 0.95 (s, 9H), 0.20 (s, 6H).

[0337] Step 4: 1-(4-((tert-butyldimethylsilyl)oxy)phenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione JPEG2025503463000289.jpg2335To a solution of 1-(4-((tert-butyldimethylsilyl)oxy)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (85.0 g, 0.260 mol) and DIEA (137 g, 1.06 mol) in ACN (425 mL), SEMCl (88.4 g, 0.530 mol) is added at 20-25 °C. The mixture is subsequently stirred at 80-85 °C for 12 h. TLC (petroleum ether:ethyl acetate = 1:R f (starting material) = 0.6, R f(Product) = 0.9) indicates consumption of starting material. The reaction mixture is cooled to 20-25 °C and water (500 mL) is added. The mixture is filtered and concentrated under reduced pressure at 45 °C. The residue is purified with activated charcoal and then adsorbed onto silica gel to give the product (124 g, 68.6%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.03-7.21 (m, 2H), 6.85 (d, J = 8.60 Hz, 2H), 5.29 (s, 2H), 3.78 (t, J = 6.62 Hz, 2H), 3.61-3.72 (m, 2H), 2.89 (t, J = 6.62 Hz, 2H), 0.98 (s, 9H), 0.72-0.93 (m, 1H), 0.20 (s, 5H), 0.03-0.04 (m, 10H).

[0338] Step 5: 1-(4-hydroxyphenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione JPEG2025503463000290.jpg23301-(4-((tert-butyldimethylsilyl)oxy)phenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (124 g, 0.270 mol) and NH 4 A solution of F (20.3 g, 0.550 mol) was stirred at 15-20 °C for 1 h. The mixture was filtered and concentrated under reduced pressure at 45 °C. The crude product was wet-triturated with petroleum ether:ethyl acetate = 10:1 (200 mL) at 15 °C for 45 min to give the desired product (65.0 g, 68.6%). 1 H NMR (400 MHz, DMSO) δ 6.96-7.15 (m, 2H), 6.63-6.84 (m, 2H), 5.31 (s, 2H), 5.93 (s, 1H), 3.76 (t, J = 6.80 Hz, 2H), 3.66-3.73 (m, 2H), 2.90 (t, J = 6.58 Hz, 2H), 0.87-1.16 (m, 2H), 0.02 (s, 9H).

[0339] Step 6: 4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)ectohydropyrimidin-1(2H)-yl)phenyl triflate JPEG2025503463000291.jpg2130A mixture of 1-(4-hydroxyphenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (4 g, 11.9 mmol) and pyridine (1.88 g, 23.8 mmol) in DCM (30 mL) was treated with Tf 2 Add 2H2O (4.03 g, 14.28 mmol) dropwise. Stir the mixture at rt for 3 h. Dilute the resulting mixture with water (100 mL) and extract with DCM (3x100 mL). Wash the combined organic layers with anhydrous Na 2 SO 4 The residue was purified by silica gel column chromatography eluted with EA / PE (2:3) to give the product (5.1 g, 91.5%). [M+H] + =469.1.

[0340] Step 7: 1-(4-(3-hydroxyazetidin-1-yl)phenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione JPEG2025503463000292.jpg18324-4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyl trifluoromethanesulfonic acid (1.25 g, 0.00267 mol), azetidin-3-ol hydrochloride (582 mg, 0.00534 mol), Pd in ​​1,4-dioxane (20 mL). 2 (dba) 3 (250mg, 0.00267mol), Ruphos (125mg, 0.00027mol) and Cs 2 CO 3(2.6 g, 0.00810 mol) in a round-bottom flask and stir overnight at 100 °C under nitrogen atmosphere. The mixture was evaporated in vacuum to give the crude product, which was further purified by silica gel column chromatography (elution with a gradient of PE:EA = 100:0 to 0:100) to give the title product (600 mg, 57%). [M+H] + =392.3.

[0341] Step 8: 1-(4-(3-oxazetidin-1-yl)phenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione JPEG2025503463000293.jpg1833(COCl) in DCM (10 mL) 2 To a solution of (2.76 mL, 1.38 mmol, 1 M in DCM) at -60 °C, add DMSO (430 mg, 5.52 mmol, dissolved in 2 mL DCM) dropwise. The mixture is stirred at -60 °C for 1 h. Then, 1-(4-(3-hydroxyazetidin-1-yl)phenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (540 mg, 1.38 mmol, dissolved in 2 mL DCM) is added. The mixture is stirred at -60 °C for 1 h. Then, triethylamine (836 mg, 8.28 mmol) is added and the mixture is stirred from -60 °C to room temperature. The mixture is evaporated in vacuum to give the crude product, which is further purified by silica gel column chromatography (elution with a gradient of PE:EA = 100:0 to 90:10) to give the title product (400 mg, 74%). [M+H] + =390.2.

[0342] Step 9: (R)-5-(tert-butyl)-N-(1-(4-(7-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H))-yl)phenyl)azetidin-3-yl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide JPEG2025503463000294.jpg3957 To a solution of (R)-5-(tert-butyl)-N-(1-(3-fluoro-2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide (100 mg, crude) in dichloromethane (4 mL) and MeOH (4 mL), add NaOAc (44.3 mg, 0.540 mmol). The mixture is stirred at room temperature for 5 min. Then, 1-(4-(3-oxazetidin-1-yl)phenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (84 mg, 0.216 mmol) and HOAc (0.06 mL) are added. The mixture is stirred at room temperature overnight. Then, NaBH(OAc) 3 (190 mg, 0.9 mmol) and stir at room temperature overnight. Then, NaBH 3 Add CN (114 mg, 1.8 mmol) and stir at room temperature overnight. Concentrate the reaction mixture in vacuo and purify the residue by silica gel column chromatography (elution with a gradient of DCM:MeOH=100%:0% to 90%:10%) to obtain the crude product, dilute with DCM (3 mL) and add TFA (3 mL). Stir the mixture at room temperature for 2 h and concentrate in vacuo. Dissolve the residue in DCM (3 mL) and add NH 3 H 2 O (0.5 mL) is added. The mixture is stirred for 30 min, concentrated in vacuo, and further purified by preparative HPLC to give the desired product (2.48 mg, 1.6%). 1H NMR (500 MHz, DMSO) δ 12.19 (s, 1H), 10.23 (s, 1H), 9.60 (d, J =10.0 Hz, 1H), 8.85 (s, 1H), 7.59-7.45 (m, 2H), 7.22 (s, 1H), 7.11 (d, J =10.0 Hz, 2H), 6.93 (s, 2H), 6.45 (d, J = 5.0 Hz, 2H), 5.50-5.38 (m, 1H), 3.95 (s, 2H), 3.67 (s, 4H), 3.28-3.24 (m, 6H), 2.72-2.64 (m, 3H), 2.42-2.35 (m, 5H), 1.60-1.55 (m, 3H), 1.43 (s, 9H); [M+H] + = 800.5.

[0343] Example 64: (R)-N-(1-(4-(7-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl))phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide

[0344] Step 1: 1-(4-bromo-3-fluoro-2-methylphenyl)ethan-1-one JPEG2025503463000295.jpg1811To a stirred solution of 1-bromo-2-fluoro-4-iodo-3-toluene (25.00 g, 79.384 mmol) and tributyl(1-ethoxyvinyl)stannane (34.40 g, 95.261 mmol) in DMF (500 mL) at room temperature, Pd(PPh 3 ) 2 Cl 2(5.57 g, 7.938 mmol) is added. The resulting mixture is stirred at 80 °C under nitrogen overnight. The mixture is cooled to room temperature. The resulting mixture is diluted with water (800 mL) and extracted with PE (3x600 mL). The organic layer is washed with 2x200 mL of brine. The resulting mixture is concentrated under reduced pressure and diluted with THF (600 mL). The mixture is acidified to pH 3 with hydrochloric acid (aq). The resulting mixture is stirred at room temperature for 1 h, extracted with EtOAc (3x500 mL) and washed with 2x500 mL of brine. The organic layer is washed with anhydrous Na 2 SO 4 Dry at 40° C. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give 1-(4-bromo-3-fluoro-2-methylphenyl)ethanone (16.65 g, 90.8%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.48 (ddd, J = 8.4, 6.5, 0.7 Hz, 1H), 7.35 (dd, J = 8.4, 1.3 Hz, 1H), 2.58 (s, 3H), 2.46 (d, J = 2.7 Hz, 3H).

[0345] Step 2: (R,E)-N-(1-(4-bromo-3-fluoro-2-methylphenyl)ethylene)-2-methylpropane-2-sulfinamide JPEG2025503463000296.jpg2512 1-(4-bromo-3-fluoro-2-methylphenyl)ethan-1-one (30.00 g, 129.834 mmol) and Ti(Oi-Pr) in THF (600 mL). 4To a stirred solution of (184.50 g, 649.171 mmol) is added (R)-2-methylpropane-2-sulfinamide (39.34 g, 324.585 mmol) portionwise at room temperature. The resulting mixture is stirred at 80 °C for 4 h. The mixture is cooled to 15 °C. The reaction is quenched with ice / water (400 mL) and EA (600 mL) at 15 °C. The resulting mixture is filtered and the filter cake is washed with EtOAc (3x2 L). The filtrate is concentrated under reduced pressure. The resulting mixture is diluted with EtOAc (600 mL). The organic layer is washed with 2x300 mL of brine. The residue was purified by silica gel column chromatography eluting with hexane / EtOAc (20:1) to give the product (40.0 g, 83.8%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.50-7.38 (m, 1H), 7.05-6.96 (m, 1H), 2.70 (s, 3H), 2.36 (d, J = 2.7 Hz, 3H), 1.31 (s, 9H); [M+H] + = 336.0.

[0346] Step 3: (R)-N-((R)-1-(4-bromo-3-fluoro-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide JPEG2025503463000297.jpg2514To a stirred solution of (R,E)-N-(1-(4-bromo-3-fluoro-2-methylphenyl)ethylene)-2-methylpropane-2-sulfinamide (40.00 g, 119.671 mmol) in THF / MeOH (1 / 1, 800 mL) at -60 °C under nitrogen atmosphere, was added NaBH 4 (4.53 g, 119.671 mmol) is added in portions. The resulting mixture is stirred overnight at room temperature under nitrogen. At 0° C., saturated NH 4 The reaction was quenched with Cl(aq). The aqueous layer was washed with CH 2 Cl 2 (3x300mL). The organic layer is washed with brine (2x200mL) and anhydrous Na 2 SO 4Dry at 40° C. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (50:1 to 10:1) to give the product (27.3 g, 67.9%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.43-7.35 (m, 1H), 7.08 (dd, J = 8.4, 1.3 Hz, 1H), 4.80 (qd, J = 6.7, 3.5 Hz, 1H), 3.29 (d, J = 2.8 Hz, 1H), 2.35 (d, J = 2.4 Hz, 3H), 1.51 (d, J = 6.7 Hz, 3H), 1.22 (s, 9H); [M+H] + 336.0.

[0347] Step 4: (R)-N-((R)-1-(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane)-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide JPEG2025503463000298.jpg1433To a stirred mixture of (R)-N-((R)-1-(4-bromo-3-fluoro-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (14.00 g, 41.634 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (21.15 g, 83.269 mmol) in 1,4-dioxane (280 mL) at room temperature was added KOAc (8.17 g, 83.269 mmol) and Pd(dppf)Cl. 2 (1.83 g, 2.498 mmol) is added in portions. The resulting mixture is stirred overnight at 80° C. under nitrogen atmosphere and concentrated in vacuo. The residue is purified by silica gel column chromatography eluted with PE / EtOAc (3:1) to give the product (11.95 g, 74.89%). 1H NMR (400 MHz, DMSO) δ 7.50-7.38 (m, 1H), 7.24 (d, J = 7.8 Hz, 1H), 5.40 (d, J = 5.2 Hz, 1H), 4.68-4.55 (m, 1H), 2.19 (d, J = 2.3 Hz, 3H), 1.42 (d, J = 6.7 Hz, 3H), 1.28 (s, 12H), 1.09 (s, 9H); [M+H] + = 384.1.

[0348] Step 5: (R)-1-(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)ethyl-1-amine hydrochloride JPEG2025503463000299.jpg12331,4-Add 4 M HCl in dioxane (200.00 mL) dropwise to a stirred solution of (R)-N-((R)-1-(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane)-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (21.70 g, 56.609 mmol) in DCM (200 mL) at room temperature. Stir the resulting mixture at room temperature for 1 h. Concentrate the resulting mixture under reduced pressure and dilute with MTBE (450 mL). Collect the precipitated solid by filtration and dilute with MTBE (2x200 mL) and Et 2 O (2x300 mL) to give the product (12.2 g, 68.50%). 1 H NMR (400 MHz, DMSO) δ 8.63 (s, 3H), 7.52 (dd, J = 7.8, 6.0 Hz, 1H), 7.43 (d, J = 7.9 Hz, 1H), 4.57 (q, J = 6.7 Hz, 1H), 2.23 (d, J = 2.2 Hz, 3H), 1.46 (d, J = 6.8 Hz, 3H), 1.29 (s, 12H); [M+H] + = 280.1.

[0349] Step 6: (R)-N-(1-(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide JPEG2025503463000300.jpg2834To a solution of (R)-1-(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)ethyl-1-amine hydrochloride (1.5 g, 4.7 mmol) in DCM (20 mL), was added NH 3 (7M in MeOH, 3 mL) is added. The mixture is stirred at room temperature for 20 min and extracted with DCM (2*20 mL). The organic layers are combined and washed with Na 2 SO 4 Dry with 500 ml and concentrate under vacuum. Dilute the residue with EtOH (10 mL) and add ethyl 3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxylate (0.924 g, 0.0047 mol). Stir the mixture at reflux overnight. Concentrate the mixture in vacuum and purify the residue by silica gel column chromatography (eluted with a gradient of PE:EA=100:0 to 0:100) to give the title product (950 mg, 48%). [M+H] + =430.2.

[0350] Step 6: (R)-4-(4-(2-fluoro-3-methyl-4-(1-(3-(1-methylcyclopropyl))-1,2,4-oxadiazole-5-carboxamido)ethyl)phenyl)-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate benzyl JPEG2025503463000301.jpg30331,4-Benzyl 4-(4-chloro-9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate (930 mg, 2.21 mmol), (R)-N-(1-(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide (950 mg, 2.21 mmol), Pd(dppf)Cl in 20 mL of dioxane and 4 mL of water. 2 (160 mg, 0.22 mmol) and Cs 2 CO 3 (1.29 g, 3.99 mmol) was stirred at 93 °C overnight. The mixture was evaporated in vacuum to give the crude product, which was further purified by silica gel column chromatography (elution with a gradient of PE:EA = 100:0 to 0:100) to give the title product (830 mg, 54%). [M+H] + =689.6.

[0351] Step 7: (R)-N-(1-(3-fluoro-2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-(yl)phenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide JPEG2025503463000302.jpg3028 A mixture of (R)-4-(4-(2-fluoro-3-methyl-4-(1-(3-(1-methylcyclopropyl))-1,2,4-oxadiazole-5-carboxamido)ethyl)phenyl)- 9H-pyrimido[4,5-b]indol-7-yl)piperazine-1-carboxylate benzyl (830 mg, 1.2 mmol) in trifluoroacetic acid (10 mL) is stirred at reflux at 85 °C for 2 h. The mixture is evaporated in vacuo to give the product (1.8 g, crude), which is used in the next step without further purification. [M+H] + =555.6.

[0352] Step 8: (R)-N-(1-(4-(7-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl))phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide JPEG2025503463000303.jpg3559To a solution of (R)-N-(1-(3-fluoro-2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-(yl)phenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide (140 mg, crude) in dichloromethane (4 mL) and MeOH (4 mL), was added NaOAc (62 mg, 0.758 mmol). The mixture is stirred at room temperature for 5 min. Then, 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (76 mg, 0.252 mmol) and HOAc (0.06 mL) are added. The mixture is stirred at room temperature overnight. Then, NaBH(OAc) 3 (267 mg, 1.264 mmol) and stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (elution with a gradient of DCM:MeOH=100%:0% to 90%:10%) to give the crude product, which was further purified by preparative TLC (DCM:MeOH=10:1) to give the desired product (43.91 mg, 20%). 1H NMR (500 MHz, DMSO) δ 12.20 (s, 1H), 10.25 (s, 1H), 9.92 (d, J = 5.0 Hz, 1H), 8.85 (s, 1H), 7.60-7.46 (m, 2H), 7.21 (d, J = 5.0 Hz, 1H), 7.13 (d, J = 5.0 Hz, 2H), 6.93 (d, J = 5.0 Hz, 4H), 5.51-5.19 (m, 1H), 3.73-3.60 (m, 4H), 3.24 (s, 5H), 2.75-2.61 (m, 5H), 2.57-2.51 (m, 3H), 2.39 (s, [M+H] + = 840.6.

[0353] Example 65: N-((R)-1-(4-(7-(4-(3-(4-((S)-2,6-dioxopiperidin-3-yl)phenyl)cyclobutyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide JPEG2025503463000304.jpg3453To a solution of (R)-N-(1-(3-fluoro-2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-(yl)phenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide (140 mg, crude) in dichloromethane (4 mL) and MeOH (4 mL), add NaOAc (62 mg, 0.758 mmol). The mixture is stirred at room temperature for 5 min. Then, add (R)-3-(4-(3-oxocyclobutyl)phenyl)piperidine-2,6-dione (64 mg, 0.252 mmol) and HOAc (0.06 mL). The mixture is stirred at room temperature overnight. Then, add NaBH(OAc) 3(267 mg, 1.264 mmol) and stir at room temperature overnight. Then, NaBH 3 Add CN (164 mg, 2.52 mmol) and stir at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (elution with a gradient of DCM:MeOH=100%:0% to 90%:10%) to give the crude product, which was further purified by preparative TLC (DCM:MeOH=10:1) to give the desired product (23.98 mg, 11%). 1 H NMR (500 MHz, DMSO) δ 12.19 (s, 1H), 10.81 (s, 1H), 9.92 (d, J = 10.0 Hz, 1H), 8.85 (s, 1H), 7.58-7.47 (m, 2H), 7.32-7.10 (m, 5H), 6.96-6.87 (m, 2H), 5.50-5.29 (m, 1H), 3.82 (dd, J = 10.0, 5.0 Hz, 1H), 3.30-3.21 (m, 5H), 3.20-3.08 (m, 1H), 2.69-2.60 (m, 3H), 2.59-2.54 (m, 3H), 2.41-2.34 (m, 4H), 2.25-2.12 (m, 2H), 2.07-1.99 (m, 1H), 1.90 (d, J = 10.0 Hz, 1H), 1.57 (d, J = 6.9 Hz, 3H), 1.49 (s, 3H), 1.24-1.18 (m, 2H), 0.99 (d, J = 2.6 Hz, 2H); [M+H] + = 796.5.

[0354] Example 66: N-((R)-1-(4-(7-(4-(3-(4-((R)-2,6-dioxopiperidin-3-yl)phenyl)cyclobutyl))piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-3-fluoro-2-methylphenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide JPEG2025503463000305.jpg3755To a solution of (R)-N-(1-(3-fluoro-2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-(yl)phenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide (140 mg, crude) in dichloromethane (4 mL) and MeOH (4 mL), add NaOAc (62 mg, 0.758 mmol). The mixture is stirred at room temperature for 5 min. Then, add (S)-3-(4-(3-oxocyclobutyl)phenyl)piperidine-2,6-dione (64 mg, 0.252 mmol) and HOAc (0.06 mL). The mixture is stirred at room temperature overnight. Then, add NaBH(OAc) 3 (267 mg, 1.264 mmol) and stir at room temperature overnight. Then, NaBH 3 Add CN (164 mg, 2.52 mmol) and stir at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (elution with a gradient of DCM:MeOH=100%:0% to 90%:10%) to give the crude product, which was further purified by preparative TLC (DCM:MeOH=10:1) to give the desired product (15.95 mg, 8%). 1H NMR (500 MHz, DMSO) δ 12.19 (s, 1H), 10.81 (s, 1H), 9.92 (d, J = 10.0 Hz, 1H), 8.85 (s, 1H), 7.58-7.44 (m, 2H), 7.30-7.09 (m, 5H), 6.98-6.84 (m, 2H), 5.42 (dd, J = 14.3, 7.1 Hz, 1H), 3.82 (dd, J = 10.0, 5.0 Hz, 1H), 3.25 (s, 5H), 3.19-3.09 (m, 1H), 2.80-2.72 (m, 1H), 2.70-2.59 (m, 1H), 2.48-2.45 (m, 4H), 2.41-2.34 (m, 5H), 2.23-2.13 (m, 2H), 2.05-1.98 (m, 1H), 1.94-1.85 (m, 1H), 1.57 (d, J = 6.9 Hz, 3H), 1.49 (s, 3H), 1.23-1.18 (m, 2H), 0.99 (d, J = 2.5 Hz, 2H); [M+H] + = 796.5.

[0355] Example 67: N-((R)-1-(4-(7-(4-(3-(4-((S)-2,6-dioxopiperidin-3-yl)phenyl)cyclobutyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide JPEG2025503463000306.jpg3452To a solution of (R)-N-(1-(2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide (120 mg, crude) in dichloromethane (4 mL) and MeOH (4 mL), add NaOAc (55 mg, 0.672 mmol). The mixture is stirred at room temperature for 5 min. Then, add (R)-3-(4-(3-oxocyclobutyl)phenyl)piperidine-2,6-dione (69 mg, 0.268 mmol) and HOAc (0.06 mL). The mixture is stirred at room temperature overnight. Then, add NaBH(OAc) 3 (237 mg, 1.12 mmol) and stir at room temperature overnight. Then, NaBH 3 Add CN (143 mg, 2.24 mmol) and stir at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (elution with a gradient of DCM:MeOH=100%:0% to 90%:10%) to give the crude product, which was further purified by preparative HPLC to give the desired product (40.14 mg, 23%). 1 H NMR (400 MHz, DMSO) δ 12.76 (s, 1H), 10.35 (s, 1H), 9.99 (s, 1H), 8.88 (s, 1H), 8.15 (s, 2H), 8.06 (d, J = 6.8 Hz, 2H), 7.55 (s, 1H), 7.45 (s, 3H), 7.21 (d, J = 7.2 Hz, 2H), 7.01 (d, J = 7.8 Hz, 2H), 4.64 (s, 2H), 3.77 (d, J = 5.6 Hz, 4H), 3.41 (s, 2H), 3.04 (s, 2H), 2.76-2.74 (m, 4H), 2.53-2.42 (m, 3H), 2.28 (s, 3H), 2.08 (s, 2H), 1.93-1.70 (m, 8H), 1.45 (s, 9H), 1.35-1.20 (m, 3H); [M+H] + = 778.6.

[0356] Example 68: N-((R)-1-(4-(7-(4-(3-(4-((S)-2,6-dioxopiperidin-3-yl)phenyl)cyclobutyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide JPEG2025503463000307.jpg3755To a solution of (R)-N-(1-(2-methyl-4-(7-(piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)phenyl)ethyl)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide (120 mg, crude) in dichloromethane (4 mL) and MeOH (4 mL), add NaOAc (55 mg, 0.672 mmol). The mixture is stirred at room temperature for 5 min. Then, add (S)-3-(4-(3-oxocyclobutyl)phenyl)piperidine-2,6-dione (69 mg, 0.268 mmol) and HOAc (0.06 mL). The mixture is stirred at room temperature overnight. Then, add NaBH(OAc) 3 (237 mg, 1.12 mmol) and stir at room temperature overnight. Then, NaBH 3 Add CN (143 mg, 2.24 mmol) and stir at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (elution with a gradient of DCM:MeOH=100%:0% to 90%:10%) to give the crude product, which was further purified by preparative HPLC to give the desired product (42 mg, 24%). 1H NMR (500 MHz, DMSO) δ 12.09 (s, 1H), 10.75 (s, 1H), 9.79 (d, J = 10.0 Hz, 1H), 8.75 (s, 1H), 7.76-7.54 (m, 4H), 7.23-7.01 (m, 4H), 6.87 (s, 2H), 5.38-5.28 (m, 1H), 3.75 (dd, J = 10.0, 5.0 Hz, 1H), 3.19 (s, 5H), 3.10-3.04 (m, 2H), 2.73-2.64 (m, 1H), 2.63-2.58 (m, 2H), 2.29 (s, 3H), 2.15-2.03 (m, 3H), 2.00-1.90 (m, 2H), 1.86-1.75 (m, 3H), 1.49 (d, J = 6.9 Hz, 3H), 1.42 (s, 3H), 1.15-1.12 (m, 1H), 0.92 (d, J = 2.6 Hz, 2H); [M+H] + = 778.6.

[0357] Example 69: 3-(tert-butyl)-N-((1R)-1-(4-(7-(4-((1-(2,6-dioxopiperidin-3-yl))-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperazin-1-yl)-6-methoxy-9H-pyrimido[4,5-b]indol-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound JPEG2025503463000308.jpg3459 was synthesized in a similar manner to that described in Example 47. 1H NMR (500 MHz, DMSO) δ 12.14 (s, 1H), 11.10 (s, 1H), 9.93 (d, J = 7.7 Hz, 1H), 8.85 (s, 1H), 7.81-7.75 (m, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.27 (s, 1H), 7.17 (s, 1H), 7.08 (s, 1H), 7.04 (s, 1H), 7.01 (s, 1H), 5.43-5.33 (m, 2H), 3.65 (s, 3H), 3.57 (s, 1H), 3.36 (s, 3H), 3.29 (s, 2H), 3.16-3.00 (m, 3H), 2.96-2.86 (m, 1H), 2.75-2.70 (m, 1H), 2.65-2.54 (m, 4H), 2.52 (s, 3H), 2.05-1.99 (m, 1H), 1.57 (d, J = 6.9 Hz, 3H), 1.37 (s, 9H); [M+H] + = 840.5.

[0358] Example 70: 3-(tert-Butyl)-N-((1-(7-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl))phenyl)(Din-4-yl))methyl)piperazin-1-yl)-9H-pyrimido[4,5-b]indol-4-yl)piperidin-4-yl)methyl)-1,2,4-oxadiazole-5-carboxamide

[0359] Step 1: tert-Butyl 4-((3-(tert-butyl)-1,...

Claims

1. Compounds of formula (I) or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, During the ceremony, Cy1 is a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered saturated ring containing 0-3 heteroatoms selected from nitrogen, oxygen, and sulfur; Cy2 is a compound represented by the structure of formula (I) a ring fused to, said ring being an aromatic ring or a non-aromatic ring (preferably an aromatic ring); Cy3 is a saturated or unsaturated ring (preferably an aromatic ring); L ａ , L ｂ and L ｃ each independently represents a single bond, —O—, —S—, —C(O)—, or —(CR ｃ R ｄ ) ｎ -or-NR ｃ - and The above The part is and wherein the E3 ubiquitin ligase portion is selected from L １ and L ２ each independently represents a single bond, —O—, —S—, —C(O)—, or —(CR ｃ R ｄ ) ｎ -or-NR ｃ - and Z １ is part of a double bond in a ring, Z １ is N or CR ｚａ or Z １ is not part of a double bond in the ring, Z １ is NR ｚａ Or C(R ｚａ ) ２ and Z ２ is part of a double bond in a ring, Z ２ is N or CR ｚａ or Z ２ is not part of a double bond in the ring, Z ２ is NR ｚａ Or C(R ｚａ ) ２ and Z ３ is part of a double bond in a ring, Z ３ is N or CR ｚａ or Z ３ is not part of a double bond in the ring, Z ３ is NR ｚａ Or C(R ｚａ ) ２ and Z ４ is part of a double bond in a ring, Z ４ is N or CR ｚａ or Z ４ is not part of a double bond in the ring, Z ４ is NR ｚａ Or C(R ｚａ ) ２ where Z １ , Z ２ , Z ３ and Z ４ Not all of the are =N-, Z ５ is part of a double bond in a ring, Z ５ is C, or Z ５ is not part of a double bond in the ring, Z ５ is N or CR ｚａ and Z ６ and Z ７ are each independently ｚａ or N, X ａ , X ｂ , X ｃ , X ｄ and X ｅ are each independently １３ or N, R １ , R ２ , R ３ , R ４ , R ７ , R ８ , R ９ , R １１ , R １３ and R ｚａ 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, -CN, -NO ２ , -OR ａ , -SO ２ R ａ , -COR ａ , -CO ２ R ａ , -CONR ａ R ｂ , -C(=NR ａ ) N.R. ｂ R ｃ , -NR ａ R ｂ , -NR ａ C.O.R. ｂ , -NR ａ C.O.N.R. ｂ R ｃ , -NR ａ CO ２ R ｂ , -NR ａ SONR ｂ R ｃ , -NR ａ SO ２ N.R. ｂ R ｃ Or -NR ａ SO ２ R ｂ and said -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Each of alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally selected from halogen, hydroxy, -haloC １－８ Alkyl, -C １－８ optionally substituted with alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; Or, R １ and R ３ is R １ and R ３ forms a 3- to 12-membered ring together with the atom to which it is attached, said ring containing 0, 1 or 2 additional heteroatoms as ring members independently selected from nitrogen, oxygen or optionally oxidized sulfur, said ring optionally containing halogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ２ , -OR ａ , -SO ２ R ａ , -COR ａ , -CO ２ R ａ , -CONR ａ R ｂ , -C(=NR ａ ) N.R. ｂ R ｃ , -NR ａ R ｂ , -NR ａ C.O.R. ｂ , -NR ａ C.O.N.R. ｂ R ｃ , -NR ａ CO ２ R ｂ , -NR ａ SONR ｂ R ｃ , -NR ａ SO ２ N.R. ｂ R ｃ Or -NR ａ SO ２ R ｂ and wherein the -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Each of alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally selected from halogen, hydroxy, -haloC １－８ Alkyl, -C １－８ substituted with alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R ５ , R ６ 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 selected from halogen, hydroxy, -haloC １－８ Alkyl, -C １－８ substituted with alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; R １０ is a 5- or 6-membered aromatic ring containing 0 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, the aromatic ring optionally being 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 ａ , -SO ２ R ａ , -COR ａ , -CO ２ R ａ , -CONR ａ R ｂ , -C(=NR ａ ) N.R. ｂ R ｃ , -NR ａ R ｂ , -NR ａ C.O.R. ｂ , -NR ａ C.O.N.R. ｂ R ｃ , -NR ａ CO ２ R ｂ , -NR ａ SONR ｂ R ｃ , -NR ａ SO ２ N.R. ｂ R ｃ Or -NR ａ SO ２ R ｂ 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; Or, R ５ and R １０ is R ５ and R １０ forms a 3- to 12-membered ring together with the atom to which it is attached, said ring containing 0, 1 or 2 additional heteroatoms as ring members independently selected from nitrogen, oxygen or optionally oxidized sulfur, said ring optionally containing halogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ２ , -OR ａ , -SO ２ R ａ , -COR ａ , -CO ２ R ａ , -CONR ａ R ｂ , -C(=NR ａ ) N.R. ｂ R ｃ , -NR ａ R ｂ , -NR ａ C.O.R. ｂ , -NR ａ C.O.N.R. ｂ R ｃ , -NR ａ CO ２ R ｂ , -NR ａ SONR ｂ R ｃ , -NR ａ SO ２ N.R. ｂ R ｃ Or -NR ａ SO ２ R ｂ and wherein the -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Each of alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally selected from halogen, hydroxy, -haloC １－８ Alkyl, -C １－８ substituted with alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; m1, m2, m3, m4, p1, p2, p3, p4 and p5 each independently represent 0, 1, 2, 3 or 4; n is 0, 1, 2, 3, 4, 5 or 6; r is 0 or 1; s is 0 or 1; R ａ and R ｂ are each independently hydrogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; or R ａ and R ｂ is R ａ and R ｂ forms a 3- to 12-membered ring together with the atom to which it is attached, said ring containing 0, 1 or 2 additional heteroatoms as ring members independently selected from nitrogen, oxygen or optionally oxidized sulfur, said ring optionally containing 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 and R ｄ 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 is R ｃ and R ｄ forms a 3- to 12-membered ring together with the atom to which it is attached, said ring containing 0, 1 or 2 additional heteroatoms as ring members independently selected from nitrogen, oxygen or optionally oxidized sulfur, said ring optionally containing 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 compound is selected from formula (II) and formula (III): However, Cy1, Cy2, Cy3, L ａ , L ｂ , L ｃ , , Z １ , Z ２ , Z ３ , Z ４ , Z ５ , X ａ , X ｂ , X ｃ , X ｄ , R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ 2. The compound according to claim 1, wherein m1, m2, m3, m4, p1, p2, p3, p4, r and s are as defined in claim 1.

3. The compound is selected from formula (IV) and formula (V): However, Cy1, Cy2, Cy3, L ａ , L ｂ , L ｃ , , Z １ , Z ２ , Z ３ , Z ４ , Z ５ , X ａ , X ｂ , X ｃ , X ｄ , R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ 2. The compound according to claim 1, wherein m1, m2, m3, m4, p1, p2, p3, p4, r and s are as defined in claim 1.

4. Cy1 is where X ｆ and X ｇ are each independently CR １１ or N, ＊ 1 is refers to the position at which the molecule is attached to the ＊＊ 1 is The compound of claim 1 , wherein the moiety is a carboxyl group.

5. Cy1 is 2. The compound of claim 1,

6. Cy1 is 2. The compound of claim 1 , selected from:

7. p2 is 0, 1, or 2, and each R ７ are independently hydrogen, -F, -Br, -Cl, -I, -CH ３ , -C ２ H ５ , -C ３ H ７ , -C ４ H ９ , -C ５ H １１ , -C ６ H １３ , -C ７ H １５ , -C ８ H １７ , -OCH ３ , -OC ２ H ５ , -OC ３ H ７ , -OC ４ H ９ , -OC ５ H １１ , -OC ６ H １３ , -OC ７ H １５ , -OC ８ H １７ , -C ２－８ Alkenyl, -C ２－８ Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, heteroaryl, -CN, -NO ２ , -OR ａ , -SO ２ R ａ , -COR ａ , -CO ２ R ａ , -CONR ａ R ｂ , -C(=NR ａ ) N.R. ｂ R ｃ , -NR ａ R ｂ , -NR ａ C.O.R. ｂ , -NR ａ C.O.N.R. ｂ R ｃ , -NR ａ CO ２ R ｂ , -NR ａ SONR ｂ R ｃ , -NR ａ SO ２ N.R. ｂ R ｃ Or -NR ａ SO ２ R ｂ and said -CH ３ , -C ２ H ５ , -C ３ H ７ , -C ４ H ９ , -C ５ H １１ , -C ６ H １３ , -C ７ H １５ , -C ８ H １７ , -OCH ３ , -OC ２ H ５ , -OC ３ H ７ , -OC ４ H ９ , -OC ５ H １１ , -OC ６ H １３ , -OC ７ H １５ , -OC ８ H １７ , -C ２－８ Alkenyl, -C ２－８ Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl, and heteroaryl is optionally selected from -F, -Br, -Cl, -I, hydroxy, -haloC １－８ Alkyl, -C １－８ substituted with alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; R ａ , R ｂ and R ｃ The compound according to claim 1, wherein:

8. p2 is 0, 1, or 2, and each R ７ are independently hydrogen, -F, -Br, -Cl, -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 or cyclohexyl.

9. The above The part is is selected from R １１ is hydrogen, -F, -Br, -Cl, -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 or cyclohexyl; R ｃ Sum R ｄ , each independently represents hydrogen, —CH ３ , -C ２ H ５ , -C ３ H ７ , -C ４ H ９ , -C ５ H １１ , -C ６ H １３ , -C ２－８ Alkenyl, -C ２－８ selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclyl, aryl or heteroaryl; or R ｃ and R ｄ is R ｃ and R ｄ forms a 3- to 12-membered ring together with the atom to which it is attached, said ring containing 0, 1 or 2 additional heteroatoms as ring members independently selected from nitrogen, oxygen or optionally oxidized sulfur, said ring optionally containing 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 and p5 is 0 or 1.

10. The above The part is 7. The compound of claim 6, selected from:

11. The above The part is 7. The compound of claim 6, selected from:

12. L ａ , L ｂ and L ｃ each independently represents a single bond, —O—, —S—, —C(O)—, or —(CR ｃ R ｄ ) ｎ -or-NR ｃ - selected from n is 1, 2, 3, 4, 5 or 6; R ｃ and R ｄ are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, aryl or heteroaryl, R ｃ and R ｄ is R ｃ and R ｄ together with the atom to which it is attached form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 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 -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 of claim 1 , substituted with at least one substituent independently selected from:

13. L ａ , L ｂ and L ｃ each independently represents a single bond, —O—, —CO—, or —(CH ２ ) ｎ -, -[CH(CH ３ ) ] ｎ -, -[C(CH ３ ) ２ ] ｎ - or -NH-, where n is 1, 2, 3, 4 or 5.

14. R １３ is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

15. 2. The compound according to claim 1, wherein m1, m2, m3 and m4 are each independently selected from 0 or 1.

16. p3 and p4 are each independently 0 or 1; R ８ and R ９ are each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

17. The above The part is is selected from however, ＊ A is refers to the position at which the molecule is attached to the ＊＊ b is The compound of claim 1 , wherein the moiety is a carboxyl group.

18. The above The part is is selected from however, ＊ A is refers to the position at which the molecule is attached to the ＊＊ b is The compound of claim 1 , wherein the moiety is a carboxyl group.

19. The above The part is is selected from however, ＊ A is refers to the position at which the molecule is attached to the ＊＊ b is The compound of claim 1 , wherein the moiety is a carboxyl group.

20. The above The part is is selected from however, ＊ A is refers to the position at which the molecule is attached to the ＊＊ b is The compound of claim 1 , wherein the moiety is a carboxyl group.

21. The above The moiety is -CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ -, -(CH ２ ) ４ --, is selected from ＊ L is refers to the position at which the molecule is attached to the ＊＊ L is The compound of claim 1 , wherein the moiety is a carboxyl group.

22. Z １ and Z ４ are each independently ｚａ or N, R ｚａ is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C ２－８ Alkenyl, -C ２－８ The compound of claim 1, which is alkynyl, heterocyclyl, aryl, heteroaryl or -CN.

23. Z ２ and Z ３ one of them is C and is bonded to Cy1, and Z ２ and Z ３ The other is CR ｚａ or N, R ｚａ is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C ２－８ Alkenyl, -C ２－８ The compound of claim 1, which is alkynyl, heterocyclyl, aryl, heteroaryl or -CN.

24. Z １ , Z ２ , Z ３ and Z ４ The compound of claim 1, wherein a maximum of two of are N.

25. Z １ , Z ２ , Z ３ and Z ４ The compound of claim 1 , wherein at most one of is N.

26. R １ is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -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 or -CH ２ CH ２ CF ３ 2. The compound of claim 1,

27. R １ and R ３ is R １ and R ３ together with the atom to which it is attached forms a 3-, 4-, 5-, 6-, 7- or 8-membered ring, said ring containing 0, 1 or 2 additional N atoms as ring members, said ring being optionally -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or -CH ２ The compound of claim 1 , substituted with at least one substituent independently selected from OH.

28. R ２ The compound of claim 1, wherein is H, -F, -Cl, -Br, -I, methyl, ethyl or propyl, and p1 is 0, 1 or 2.

29. R ３ and R ４ The compound of claim 1 , wherein each is independently -H, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

30. The above The part is where: ＊ 3 is indicates the position of attachment to the moiety, and ＊＊ 3 is The compound of claim 1 , wherein the moiety is a carboxyl group.

31. R ５ and R ６ The compound according to claim 1 , wherein each is independently -H, methyl, ethyl, or propyl.

32. R １０ teeth, And Y １ , Y ２ , Y ３ and Y ４ is selected from CH, O, S or N; R １４ is 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 ａ , -SO ２ R ａ , -COR ａ , -CO ２ R ａ , -CONR ａ R ｂ , -C(=NR ａ ) N.R. ｂ R ｃ , -NR ａ R ｂ , -NR ａ C.O.R. ｂ , -NR ａ C.O.N.R. ｂ R ｃ , -NR ａ CO ２ R ｂ , -NR ａ SONR ｂ R ｃ , -NR ａ SO ２ N.R. ｂ R ｃ Or -NR ａ SO ２ R ｂ 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 selected from halogen, hydroxy, -haloC １－８ Alkyl, -C １－８ alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; R ａ , R ｂ Sum R ｃ are each independently hydrogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ 2. The compound of claim 1, wherein p6 is 0, 1, 2, 3 or 4;

33. 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.

34. 26. The compound of claim 25, selected from:

35. R １４ 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 at least one halogen, hydroxy, -haloC １－８ Alkyl, -C １－８ 26. The compound of claim 25, substituted with alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl.

36. R １４ teeth, 26. The compound of claim 25, selected from:

37. The compound is 2. The compound of claim 1 , selected from:

38. A pharmaceutical composition comprising a compound according to any one of claims 1 to 32, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier or excipient.

39. 34. A method of inhibiting BTK activity comprising administering to a subject a compound according to any one of claims 1 to 32, including a compound of formula (I) or the specific compounds exemplified herein, or a pharma- ceutically acceptable salt thereof.

40. A method of treating a disease or disorder in a patient, comprising administering to said patient a therapeutically effective amount of a compound according to any one of claims 1 to 32, or a pharma- ceutically acceptable salt thereof, as a BTK kinase inhibitor, wherein said disease or disorder is associated with inhibition of BTK, preferably said disease or disorder is cancer.

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