Degradation of bruton's tyrosine kinase (BTK) by conjugation of BTK inhibitors with e3 ligase ligand and methods of use

Abstract

To provide a proteolysis targeting chimera (PROTAC) compound by conjugating a BTK inhibitor with an E3 ligase ligand, and methods of preparation and use thereof.SOLUTION: The invention provides a compound of formula (I) and methods of preparation and use thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Disclosed herein are novel bifunctional compounds formed by the conjugation of a BTK inhibitor moiety and an E3 ligase ligand moiety, which function to recruit targeted proteins to an E3 ubiquitin ligase for degradation, as well as methods for their preparation and use. [Background technology]

[0002] Proteolysis-inducing chimeric molecules (PROTACs) are a novel strategy for selectively knocking down target proteins using small molecules (Sakamoto KM et al., Proc Natl Acad Sci 2001, 98:8554-9; Sakamoto KMet al., Methods Enzymol. 2005, 399:833-847). PROTACs utilize the ubiquitin-protease system to target specific proteins in cells and induce their degradation (Zhou P. et al., Mol Cell. 2000, 6(3):751-756; Neklesa TK et al., Pharmacol Ther. 2017, 174:138-144; Lu M. et al., Eur J Med Chem. 2018, 146:251-259). The normal physiological function of the ubiquitin-protease system is responsible for the clearance of denatured, mutated, or harmful proteins in cells. The ubiquitin-proteasome system (UPS), also known as the ubiquitin-proteasome pathway (UPP), is a common post-translational regulatory mechanism responsible for 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 GL et al., Cell Rep. 2015, 12, 545-553; Swatek KN et al., Cell Res. 2016, 26, 399-422). Ubiquitin, highly conserved in eukaryotic cells, is a 76-amino acid modification molecule that covalently attaches to target substrates through a cascade of enzymatic reactions involving E1, E2, and E3 enzymes. The modified substrates are then recognized by the 26S proteasome complex for ubiquitination-mediated degradation. To date, two E1 enzymes have been discovered, designated UBA1 and UBA6. On the other hand, there are approximately 40 E2 enzymes and over 600 E3 enzymes that provide functional diversity and control the activity of many downstream protein substrates.However, only a limited number of E3 ubiquitin ligases have been successfully hijacked for use by small molecule PROTAC technology: von Hippel-Lindau disease tumor suppressor protein (VHL), mouse double minute 2 homolog (MDM2), cellular inhibitor of apoptosis (cIAP), and cereblon (Philipp O. et al., Chem. Biol. 2017, 12, 2570-2578).

[0003] Bifunctional compounds composed of a target protein-binding moiety and an E3 ubiquitin ligase-binding moiety have been shown to induce proteasome-mediated degradation of selected proteins. These drug-like molecules offer the possibility of temporally controlling protein expression and could be useful as biochemical reagents for treating diseases.In recent years, this newly developed method has been widely used in anti-tumor research (Lu J. et al., Chem Biol. 2015;22(6):755-763; Ottis P. et al., Chem Biol. 2017;12(4):892-898; Crews CM et al., J Med Chem. 2018;61(2):403-404; Neklesa TK et al., Pharmacol Ther. 2017,174:138-144; Cermakova K. et al., Molecules, 2018.23(8); An S. et al., BioMedicine, 2018; Lebraud H. et al., Essays Biochem. 2017;61(5):517-527; Sun YH et al., Cell Res.2018;28:779-81;Toure M.et al.,Angew Chem Int Ed Engl.2016;55(6):1966-1973;Yonghui Sun et al.,Leukemia,volume 33,pages2105-2110(2019);Shaodong Liu et al.,Medicinal Chemistry Research,volume 29, pages 802-808 (2020); Patent publications, such as US20160045607, US20170008904, US20180050021, US20180072711, WO2002020740, WO2014108452, WO2016146985, WO2016149668, WO2016149989, WO2016197032, WO20 16197114, WO2017011590, WO2017030814, WO2017079267, WO2017182418, WO2017197036, WO2017197046, WO2017197051, WO2017197056, WO2017201449, WO2017211924, WO2018033556, and WO2018071606.

[0004] Bruton's tyrosine kinase (Btk) belongs to the Tec tyrosine kinase family (Vetrie et al., Nature 361:226-233, 1993; Bradshaw, Cell Signal. 22:1175-84, 2010). Btk is primarily expressed in many hematopoietic cells, such as B cells, mast cells, and macrophages (Smith et al., J. Immunol. 152:557-565, 1994), and is localized in bone marrow, spleen, and lymph node tissues. Btk plays an important role in the B cell receptor (BCR) and FcR signaling pathways involved in B cell development and differentiation (Khan, Immunol. Res. 23:147, 2001). Btk is activated by upstream Src family kinases. Upon activation, Btk then phosphorylates PLC gamma, resulting in effects on B cell function and survival (Humphries et al., J. Biol. Chem. 279:37651, 2004). These signaling pathways must be tightly regulated. Mutations in the gene encoding Btk cause a hereditary B cell-specific immunodeficiency disease known as X-linked agammaglobulinemia (XLA) in humans (Conley et al., Annu. Rev. Immunol. 27:199-227, 2009). Aberrant BCR-mediated signaling can result in dysregulated B cell activation, leading to several 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 that depletes mature B cells, have revealed the important role of B cells in several inflammatory diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis (Gurcan et al., Int. Immunopharmacol. 9:10-25, 2009). Therefore, Btk inhibitors can be used to treat autoimmune and / or inflammatory diseases.

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

[0006] WO2019 / 186343A1 discloses N-(3-(7H-pyrrolo[2,3-D]pyrimidin-4yl)phenyl)-benzamide derivatives as BTK depredators of formula (A): [ka] [In the formula, R 1 , R 1a , R 2 and R 2a is independently selected for each occurrence from H and F; R 6 is H or F; R 7 is selected from H, F, Cl, —CH3, —OCH3, and —OCH2CH3; and X 1 is a linker group]

[0007] WO2019 / 186358A1 discloses 3-hydroxy-N-(3-(7H-pyrrolo[2,3-D]pyrimidin-4yl)phenyl)-benzamide derivatives as BTK decomposers of formula (B): [ka] [In the formula, R 1 is isobutyl; R 1a is H;R 2 is H or F; R 2a is H or F; R 6 is H or F; R 7 is selected from H, F, Cl, —CH3, —OCH3, and —OCH2CH3; and X 1 is a linker group]

[0008] There is a need for new BTK inhibitors or degraders that are more potent than known inhibitors of BTK and that inhibit BTK through alternative strategies, e.g., by degradation of BTK. This application addresses that need. Summary of the Invention [Problem to be solved by the invention]

[0009] One object of the present invention is to provide proteolysis targeting chimeric molecules (PROTACs) compounds by conjugating a BTK inhibitor with an E3 ligase ligand, which function to recruit targeted proteins to an E3 ubiquitin ligase for degradation, as well as methods for their preparation and use. In particular, the present disclosure provides PROTAC compounds having Formula I: [Means for solving the problem]

[0010] Aspect 1: A compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. [In formula: [ka] is a 5- or 6-membered aromatic ring containing 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur; [ka] teeth, [ka] an E3 ubiquitin ligase moiety selected from: L1, L2, L3, L4 and L5 each independently represent a bond, -O-, -CO-, -(CR c R d ) n2 -or-NR c - and; L6 is independently -(CR a R b ) n1 -, -CO-(CR a R b ) n1 -NH-(CR e R f ) n3 -, -CO-(CR a R b ) n1 -NH-, or -(CR a R b ) n1 -NH-(CR e R f ) n3 - and; Z1, Z2 and Z3 are each independently CR 12 or N; X a , X b , X c , X d and X e are independently, CR 12 or N; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R7 , R 8 and R 10 are each independently hydrogen, halogen, or -C 1~8 Alkyl, -C 1~8 Alkoxy, -C 2~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR a , -SO2R a , -COR a , -CO2R 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 CO2R b , -NR a SONR b R c , -NR a SO2NR b R c , or -NR a SO2R b and -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be selected from halogen, hydroxy, -haloC 1~8 Alkyl, -C 1~8 optionally substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or R 4 and R at the ortho position of the phenyl ring 2 and forming a five- or six-membered carbocyclic ring; or X a and either one of the two adjacent carbon atoms forms a double bond, provided that Xa is CR 12 and R12 Is it conditional on the absence of or [ka] Two non-adjacent R on 8 forms a bridge containing one, two, or three CH2; Each R 12 are independently hydrogen or -C 1~8 is alkyl; R 9 is a 5- or 6-membered aromatic ring containing 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur; each of said aromatic rings is selected from halogen, —C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C 1~8 Alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR a , -SO2R a , -COR a , -CO2R 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 CO2R b , -NR a SONR b R c , -NR a SO2NR b R c , or -NR a SO2R b and wherein said -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8Each of alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be selected from halogen, hydroxy, -haloC 1~8 Alkyl, -C 1~8 optionally substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; n1, n2, n3, m1, m2, m3, m4, m5, p1, p2, p3, p4 and p5 are each independently 0, 1, 2, 3 or 4; R a , R b , R c , R d , R e and R f are each independently hydrogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl]

[0011] Aspect 2: A compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. [In formula: [ka] is a 5- or 6-membered aromatic ring containing 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur; [ka] teeth, [ka] an E3 ubiquitin ligase moiety selected from: L1, L2, L3, L4 and L5 each independently represent a bond, -O-, -CO-, -(CR c R d ) n2 -or-NR c - and; Z1, Z2 and Z3 are each independently CR 12 or N; X a , X b , X c , X d and X e are independently, CR 12 or N; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 10 are each independently hydrogen, halogen, or -C 1~8 Alkyl, -C 1~8 Alkoxy,-C 2~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR a , -SO2R a , -COR a , -CO2R 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 CO2R b , -NR a SONR b R c , -NR a SO2NR b R c , or -NR a SO2R b and -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8Each of alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be selected from halogen, hydroxy, -haloC 1~8 Alkyl, -C 1~8 optionally substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; Each R 12 are independently hydrogen or -C 1~8 is alkyl; R 9 is a 5- or 6-membered aromatic ring containing 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur; each of said aromatic rings is selected from halogen, —C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkynyl, -C 1~8 Alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR a , -SO2R a , -COR a , -CO2R 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 CO2R b , -NR a SONR b R c , -NR a SO2NR b R c , or -NR a SO2R b and wherein said -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be selected from halogen, hydroxy, -haloC 1~8Alkyl, -C 1~8 optionally substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; n1, n2, m1, m2, p1, p2, p3, p4, and p5 are each independently 0, 1, 2, 3, or 4; R a , R b , 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]

[0012] Aspect 3: [ka] but, [ka] and; wherein Z4, Z5, Z6, and Z7 are each independently selected from CH or N; * 1, [ka] and ** A compound according to embodiment 1 or 2, wherein 1 refers to the position at which L1 is attached.

[0013] Aspect 4: [ka] but, [ka] wherein Z4, Z5, and Z7 are each independently selected from CH or N.

[0014] Aspect 5: [ka] but, [ka] 5. The compound according to embodiment 3 or 4, selected from:

[0015] Aspect 6: p3 is 0, 1, or 2, and each R 7 are independently halogen, -C 1~8 Alkyl, or -C 1~8 The compound according to any one of embodiments 3 to 5, wherein the alkoxy is preferably selected from F, Cl, Br, I, CH 3 , or —OCH 3 .

[0016] Aspect 7: [ka] but, [ka] 3. A compound according to embodiment 1 or 2, selected from:

[0017] Aspect 8: [ka] but, [ka] Selected from R 10 A compound according to embodiment 7, wherein is selected from hydrogen or halogen; and p5 is 0 or 1.

[0018] Aspect 9: [ka] but, [ka] Selected from R 10is selected from hydrogen, F, Cl, Br, and I.

[0019] Aspect 10: [ka] but, [ka] where R 10 But hydrogen, halogen, -C 1~8 Alkyl, -OR a and;R a is hydrogen or -C 1~8 A compound according to embodiment 1 or 2, wherein p5 is 0 or 1.

[0020] Aspect 11: [ka] but, [ka] where R is selected from 10 But hydrogen, halogen, -C 1~8 Alkyl, or -C 1~8 A compound according to embodiment 10, wherein alkoxy is fluoro, chloro, methyl, or methoxy.

[0021] Aspect 12: [ka] but, [ka] 12. The compound according to embodiment 11, selected from:

[0022] Embodiment 13: A compound according to embodiment 1 or 2, wherein L1 is a bond or -O-, and L2 is a bond.

[0023] Aspect 14:Ra and R b A compound according to embodiment 1 or 2, wherein is independently selected from hydrogen or CH3; and n1 is 1 or 2.

[0024] Aspect 15:X a is selected from CH or N; X b is N;X c is CH and X d A compound according to any one of the preceding embodiments, wherein

[0025] Embodiment 16: A compound according to embodiment 1 or 2, wherein m1, m2, m3, m4 and m5 are each independently selected from 0, 1 or 2, preferably 1.

[0026] Embodiment 17: p4 is 0 or 1 and R 8 But halogen, OH, or -C 1~8 A compound according to embodiment 1 or 2, wherein alkyl is selected from CH3.

[0027] Aspect 18: [ka] but, [ka] (wherein m3 and m4 are each independently 0, 1, 2, 3, or 4), or [ka] A compound according to embodiment 1 or 2, wherein m3 is 1, 2, 3 or 4, and m4 is 0, 1, 2, 3 or 4.

[0028] Embodiment 19: p4 is 2 and two non-adjacent R 8 forms a bridge containing 1 or 2 or 3 CH2.

[0029] Aspect 20: [ka] but, [ka] 2. The compound according to embodiment 1, selected from:

[0030] Aspect 21: [ka] but, [ka] 3. The compound according to embodiment 2, selected from:

[0031] Embodiment 22: A compound according to any of embodiments 1 to 21, wherein Z1 is CH or N; and p2=0.

[0032] Aspect 23:R 1 is methyl, -CHOH, -OCH, -CHOCH or halogen; p1 is 0 or 1, and R 2 A compound according to any of embodiments 1-22, wherein is halogen.

[0033] Aspect 24:R 3 is hydrogen; R 4 and R 5 A compound according to any of embodiments 1-23, wherein is selected from hydrogen or methyl.

[0034] Aspect 25:R 9 but, [ka] Y1, Y2, Y3 and Y4 are selected from CH, O, S or N; R 11 But hydrogen, halogen, -C 1~8 Alkyl, -C 1~8 Alkoxy,-C 2~8 Alkenyl, -C 2~8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR a , -SO2R a , -COR a , -CO2R 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 CO2R b , -NR a SONR b R c , -NR a SO2NR b R c , or -NR a SO2R b -C is selected from 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of halogen, hydroxy, -haloC 1~8 Alkyl, -C 1~8 optionally substituted with alkyloxy, 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 A compound according to any of embodiments 1-24, wherein p6 is alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and p6 is 0, 1, 2, 3, or 4.

[0035] Embodiment 26: A compound according to embodiment 25, wherein Y 1 is CH, S, N or O; Y 2 is CH, O or N; Y 3 is O, S or N; and Y 4 is S, CH or N.

[0036] Aspect 27: [ka] but, [ka] 27. A compound according to embodiment 25 or 26, selected from:

[0037] Aspect 28:R 11 but, [ka] 28. The compound according to embodiment 27, selected from:

[0038] Aspect 29: [ka] 29. A compound according to any one of embodiments 1 to 28, wherein:

[0039] In one embodiment, the compound is [ka] [Wherein, R 2a and R 2b are each independently hydrogen, halogen, or -C 1~8 Alkyl, -C 1~8 Alkoxy,-C 2~8 Alkenyl, -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR a , -SO2R a , -COR a , -CO2R 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 CO2R b , -NR a SONR b R c , -NR a SO2NR b R c , or -NR a SO2R b and -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be selected from halogen, hydroxy, -haloC 1~8 Alkyl, -C 1~8 optionally substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0040] Embodiment 30: A compound according to embodiment 1, selected from compounds 1 to 192.

[0041] In a second aspect, disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0042] In a third aspect, disclosed herein is a method of inhibiting BTK activity comprising administering to an individual a compound disclosed herein, including a compound of Formula (I) or the specific compounds exemplified herein, or a pharmaceutically acceptable salt thereof.

[0043] In a fourth aspect, disclosed herein is a method of treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, as a BTK kinase inhibitor, wherein the compound disclosed herein comprises a compound of Formula (I) or a specific compound exemplified herein. In some embodiments, the disease or disorder is associated with inhibition of BTK. Preferably, the disease or disorder is cancer.

[0044] In a fifth aspect, disclosed herein are methods for reducing BTK activity by inhibition and / or proteolysis, comprising administering to an individual a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION

[0045] definition The following terms have the indicated meanings throughout this specification:

[0046] As used in this specification, including the appended claims, the singular forms of words such as "a," "an," and "the" include their corresponding plural references unless the context clearly dictates otherwise.

[0047] The term "or" is used to mean, and is used interchangeably with, the term "and / or," unless context clearly dictates otherwise.

[0048] The term "alkyl" refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups containing 1 to 18, for example, 1 to 12, further for example, 1 to 10, and even further for example, 1 to 8, or 1 to 6, or 1 to 4 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms (i.e., C 1~6Examples 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 s-butyl ("s-Bu"), 1,1-dimethylethyl or t-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 groups.

[0049] The term "propyl" refers to 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr").

[0050] The term "butyl" refers to 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu").

[0051] 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.

[0052] The term "hexyl" refers to 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.

[0053] The term "halogen" refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I).

[0054] The term "haloalkyl" refers to an alkyl group in which one or more hydrogens have been replaced by one or more halogen atoms, such as fluoro, chloro, bromo, and iodo. Examples of haloalkyl include, but are not limited to, haloC 1~8 Alkyl, HaloC 1~6 Alkyl or haloC 1~4 Alkyl, for example, -CF3, -CH2Cl, -CH2CF3, -CHCl2, -CF3, and the like are included.

[0055] The term "alkenyl" refers to a hydrocarbon group selected from straight-chain and branched hydrocarbon groups containing at least one C=C double bond and 2 to 18, for example, 2 to 8, further for example, 2 to 6 carbon atoms. Alkenyl groups, for example, C 2~6 Examples of alkenyl include, but are not limited to, 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 groups.

[0056] 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, such as 2 to 8, further such as 2 to 6 carbon atoms. Alkynyl groups, such as C 2~6 Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0057] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (eg, bicyclic and tricyclic) groups, including fused, bridged, or spirocycloalkyls.

[0058] For example, the cycloalkyl group may contain 3 to 12, such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Still further for example, the cycloalkyl may be selected from monocyclic groups containing 3 to 12, such as 3 to 10, further such as 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 groups. In particular, saturated monocyclic cycloalkyl groups, such as C 3~8 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In a preferred embodiment, cycloalkyl is a monocyclic ring (C) containing 3 to 6 carbon atoms, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3~6 Examples of bicyclic cycloalkyl groups 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 as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Further examples of bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5,6] and [6,6] ring systems.

[0059] 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.

[0060] The term "fused cycloalkyl" refers to a bicyclic cycloalkyl group, as defined herein, that is saturated and is formed by two or more rings that share two adjacent atoms.

[0061] 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.

[0062] The term "cycloalkenyl" refers to a non-aromatic cyclic alkyl group of 3 to 10 carbon atoms having single or multiple rings and at least one double bond, preferably one to two 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.

[0063] The term "fused cycloalkenyl" refers to a bicyclic cycloalkyl group, as defined herein, that contains at least one double bond and is formed by two or more rings that share two adjacent atoms.

[0064] The term "cycloalkynyl" refers to a non-aromatic cycloalkyl group of from 5 to 10 carbon atoms having single or multiple rings and at least one triple bond.

[0065] The term "fused cycloalkynyl" refers to a bicyclic cycloalkyl group, as defined herein, which contains at least one triple bond and is formed by two or more rings that share two adjacent atoms.

[0066] 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 [ka] where the wavy lines indicate the points of attachment.

[0067] 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.

[0068] 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.

[0069] Examples of fused cycloalkyl, fused cycloalkenyl, or fused cycloalkynyl include, but are not limited to, 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, as well as 3-8 membered benzocycloalkyl, benzoC 4~6 Included are cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, 1,4-dihydronaphthyl, etc. Preferred embodiments are 8-9 membered fused rings, which refer to cyclic structures containing 8-9 ring atoms within the scope of the above examples.

[0070] The term "aryl" used alone or in combination with other terms, a) 5- and 6-membered carbocyclic aromatic rings, for example, phenyl; b) bicyclic ring systems, for example, 7-12 membered bicyclic ring systems, where at least one ring is carbocyclic and aromatic, for example, naphthyl and indanyl; and c) tricyclic ring systems, for example, 10-15 membered tricyclic ring systems (wherein at least one ring is carbocyclic and aromatic, for example, fluorenyl); It refers to the group selected from:

[0071] 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.

[0072] Specifically, the term "bicyclic fused aryl" refers to a bicyclic aryl ring as defined herein. An exemplary bicyclic fused aryl is naphthalene.

[0073] 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, and in some embodiments, 1 to 2 heteroatoms, with the remaining ring atoms being carbon; b) a 7-12 membered bicyclic ring containing at least one heteroatom selected from N, O, and S, for example, 1 to 4, or in some embodiments, 1 to 3, or in other embodiments, 1 or 2 heteroatoms, and the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and c) 11-14 membered tricyclic rings containing at least one heteroatom selected from N, O, and S, for example, 1 to 4, or in some embodiments, 1 to 3, or in other embodiments, 1 or 2 heteroatoms, and the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is in the aromatic ring. refers to a group selected from

[0074] When the total number of S and O atoms in the heteroaryl group exceeds 1, the heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is 1 or less. When a heteroaryl group contains more than one heteroatom ring member, the heteroatoms can be the same or different. Nitrogen atoms in the ring(s) of a heteroaryl group can be oxidized to form an N-oxide.

[0075] Specifically, the term "bicyclic fused heteroaryl" refers to a 7- to 12-membered, preferably 7- to 10-membered, and more preferably a 9- or 10-membered fused bicyclic heteroaryl ring, as defined herein. Typically, a bicyclic fused heteroaryl is a 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered, or 6-membered / 7-membered bicyclic. The group may be attached to the remainder of the molecule via either ring.

[0076] Representative examples of bicyclic fused heteroaryls include, but are not limited to, the following groups: benzisoxazolyl, benzodiazolyl, benzofuranyl, benzofurazanyl, benzofuryl, benzimidazolyl, benzisothiazolyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl, benzotriazolyl, benzoxadiazolyl, benzoxazolyl, furopyridinyl, furopyrrolyl, imidazopyridinyl, imidazopyridyl, imidazothiazolyl, indazolyl, indolizinyl, indophenyl, and benzotriazolyl. aryl, isobenzofuryl, isoindolyl, isoquinolinyl (or isoquinolyl), naphthyridinyl, phthalazinyl, pteridinyl, purinyl, pyrazinopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridyl, pyrazolotriazinyl, pyridazolopyridyl, pyrrolopyridinyl, quinazolinyl, quinolinyl (or quinolyl), quinoxalinyl, thiazolopyridyl, thienopyrazinyl, thienopyrazolyl, thienopyridyl, thienopyrrolyl, thienothienyl, or triazolopyridyl.

[0077] 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.

[0078] The terms "aromatic heterocyclic ring" and "heteroaryl" are used interchangeably throughout this disclosure. In some embodiments, a monocyclic or bicyclic aromatic heterocyclic ring has 5, 6, 7, 8, 9, or 10 ring members, wherein 1, 2, 3, or 4 heteroatom ring members are independently selected from nitrogen (N), sulfur (S), and oxygen (O), and the remaining ring members are carbon. In some embodiments, a monocyclic or bicyclic aromatic heterocyclic ring is a monocyclic or bicyclic ring containing 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, a monocyclic or bicyclic aromatic heterocyclic ring is a 5- to 6-membered heteroaryl ring that is monocyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is a bicyclic 8-10 membered heteroaryl ring having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

[0079] Examples of heteroaryl groups or monocyclic or bicyclic aromatic heterocyclic rings include, but are not limited to (numbered from the 1-position assigned attachment position), pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), 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 ... aryl, or 1,3,4-thiadiazolyl), tetrazolyl, thienyl (e.g., thien-2-yl, thien-3-yl), triazinyl, benzothienyl, furyl or furanyl, benzofuryl, 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-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl aryl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, furazanyl (e.g., furazan-2-yl, furazan-3-yl), benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (e.g., benzo[d]thiazol-6-yl), and indazolyl (e.g., 1H-indazol-5-yl).

[0080] "Heterocyclyl," "heterocycle," or "heterocyclic" are used interchangeably and refer to a non-aromatic heterocyclyl group containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spiro rings, i.e., including monocyclic heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, and fused heterocyclic groups.

[0081] As used herein, the term "optionally oxidized sulfur" refers to S, SO, or SO.

[0082] 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 heteroatom(s)) is a heteroatom selected from nitrogen, oxygen, or optionally oxidized sulfur. The heterocycle can be saturated or partially saturated.

[0083] Exemplary monocyclic 4- to 9-membered heterocyclyl groups include, but are not limited to, 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, aziridin-1-yl, aziridin-2-yl, azocan-1-yl, azocan-2-yl, azocan-3-yl, azocan-4-yl, azocan-5-yl, thiiranyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl dithiepanyl, thiazepanyl, 1,4-thienyl, 1,4-azathienyl, 1,4-thienyl, 1,4-azazepinyl, 1,4-thien ... pyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl, or 1,1-dioxo-thiomorpholinyl.

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

[0085] The term "fused heterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl group, in which each ring in the system shares an adjacent atom pair (carbon and carbon atoms or carbon and nitrogen atoms) with another ring and contains 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 the fused heterocyclic group may contain one or more double bonds, but the fused heterocyclic group 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. Depending on the number of membered rings, the fused heterocyclyl could be a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl. The group may be attached to the rest of the molecule via any ring.

[0086] Specifically, the term "bicyclic fused heterocyclyl" refers to a 7- to 12-membered, preferably 7- to 10-membered, more preferably 9- or 10-membered fused heterocyclyl, as defined herein, containing two fused rings and containing from 1 to 4 heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members. Typically, 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, octahydro-benzo[b][1,4]dioxin, indolinyl, isoindolinyl, benzopyranyl, dihydrothiazolopyrimidinyl, tetrahydroquinolyl, tetrahydroisoquinolyl (or tetrahydroisoquinolinyl), dihydrobenzofuranyl, dihydrobenzoxazinyl, dihydrobenzimidazolyl, tetrahydrobenzothienyl, and the like. benzoyl, tetrahydrobenzofuranyl, benzodioxolyl, benzodioxonyl, chromanyl, chromenyl, octahydrochromenyl, dihydrobenzodioxinyl, dihydrobenzoxedinyl, dihydrobenzodioxepinyl, dihydrothienodioxinyl, dihydrobenzoxazepinyl, tetrahydrobenzoxazepinyl, dihydrobenzazepinyl, tetrahydrobenzazepinyl, isochromanyl, chromanyl, or tetrahydropyrazolopyrimidinyl (e.g., 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl).

[0087] 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.

[0088] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic alkyl group in which every two rings in the system share two non-consecutive atoms and contain 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 in a bridged heterocyclyl group may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably, the bridged heterocyclyl has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of ring members, the bridged heterocyclyl can be a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl, and is preferably a bicyclic, tricyclic, or tetracyclic bridged heterocyclyl, more preferably a bicyclic or tricyclic bridged heterocyclyl. Representative examples of bridged heterocyclyl include, but are not limited to, the following groups: 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.2]octyl, and 2-azabicyclo[3.3.2]decyl.

[0089] The term "at least one substituent" disclosed herein includes, for example, 1 to 4, for example, 1 to 3, further for example, 1 or 2 substituents, provided that valence theory is satisfied. For example, the term "at least one substituent R" disclosed herein includes, for example, 1 to 4, for example, 1 to 3, further for example, 1 or 2 substituents, provided that valence theory is satisfied. 6d " includes R as disclosed herein. 6d The group includes 1 to 4, such as 1 to 3, further such as 1 or 2, substituents selected from the list below.

[0090] 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 compounds disclosed herein have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers fall within a broad group of stereoisomers. All such possible stereoisomers are intended to be included, including substantially pure resolved enantiomers, racemic mixtures thereof, and even mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and / or pharmaceutically acceptable salts thereof are intended to be included. Unless specifically stated otherwise, reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is not specified, all possible isomers are included.

[0091] The term "substantially pure," as used herein, means that the target stereoisomer contains 35% by weight or less, such as 30% by weight or less, further such as 25% by weight or less, and even further such as 20% by weight or less, of any other stereoisomer(s). In some embodiments, the term "substantially pure" means that the target stereoisomer contains 10% by weight or less, such as 5% by weight or less, e.g., 1% by weight or less, of any other stereoisomer(s).

[0092] When compounds disclosed herein contain olefinic double bonds, unless otherwise specified, such double bond is intended to include both E and Z geometric isomers.

[0093] When the compounds disclosed herein contain a disubstituted cyclic ring system, the substituents found on such ring systems can adopt cis and trans configurations. Cis configuration means that both substituents are found on the top of the two substituents arrangement on the carbon, while trans means that they are on opposite sides. For example, the disubstituted cyclic ring system can be a cyclohexyl or cyclobutyl ring.

[0094] It may be advantageous to separate reaction products from one another and / or from starting materials. The desired products of each step or series of steps are separated and / or purified (hereinafter "separated") to the desired degree of homogeneity by techniques common in the art. Typically, such separation involves multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography may involve any number of methods, including, for example: reverse-phase and normal-phase; size exclusion; ion exchange; high-pressure, medium-pressure, and low-pressure liquid chromatography methods and devices; small-scale analytical; simulated moving bed ("SMB") and preparative thin- or thick-layer chromatography, as well as small-scale thin-layer and flash chromatography techniques. Those skilled in the art will apply the technique most likely to achieve the desired separation.

[0095] "Diastereomers" refer 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 or chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into 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 using chiral HPLC columns.

[0096] Single stereoisomers, e.g., substantially pure enantiomers, can be obtained by resolving racemic mixtures using methods such as forming diastereomers with optically active resolving agents (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C.H. et al., "Chromatographic resolution of enantiomers: Selective review," J. Chromatogr., 113(3) (1975): pp. 283-302). Racemic mixtures of chiral compounds of the present invention can be separated and isolated by any suitable method, including (1) forming ionic diastereomeric salts with chiral compounds and separating them by fractional crystallization or other methods, (2) forming diastereomeric compounds with chiral derivatizing agents, separating the diastereomers, and converting them to pure stereoisomers, and (3) directly separating 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.

[0097] "Pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately, by reacting a free base function with a suitable organic acid, or by reacting an acidic group with a suitable base.

[0098] In addition, if a compound disclosed herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize a variety of synthetic methods that can be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

[0099] As defined herein, "a pharmaceutically acceptable salt thereof" includes salts of at least one compound of formula (I), and salts of stereoisomers, e.g., enantiomeric and / or diastereomeric salts, of compounds of formula (I).

[0100] 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 pharmaceutical, therapeutic, or diagnostic agent or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent with a cell, as well as contact of a reagent with a fluid, where the fluid contacts the cell. The terms "administration" and "treatment" also refer to in vitro and ex vivo treatments of a cell, for example, with a reagent, diagnostic agent, binding compound, or with another cell. As used herein, the term "subject" includes any living organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0101] The term "effective amount" or "therapeutically effective amount" refers to an amount of an active ingredient, e.g., a compound, that, when administered to a subject to treat a disease or at least one clinical symptom of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or condition. A "therapeutically effective amount" may vary with 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 for any given situation will be apparent to one of ordinary skill in the art or can be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound disclosed herein and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof, effective to "treat" a disease or disorder, as defined herein, in a subject. In the example of a combination therapy, a "therapeutically effective amount" refers to the total amount of the combined components to effectively treat a disease, disorder, or condition.

[0102] The pharmaceutical composition comprising the compound disclosed herein can be administered to a subject in need thereof via oral, inhalation, rectal, parenteral or topical route.For oral administration, pharmaceutical composition can be a conventional solid preparation, such as tablet, powder, granule, capsule, etc., or a liquid preparation, such as aqueous or oily suspension or other liquid preparation, such as syrup, solution, suspension or similar;For parenteral administration, pharmaceutical composition can be a liquid, aqueous solution, oily suspension concentrate, freeze-dried powder or similar.Preferably, the pharmaceutical composition formulation is selected from tablet, coated tablet, capsule, suppository, nasal spray or injection, more preferably tablet or capsule.Pharmaceutical composition can be a single unit administration with precise dosage.In addition, pharmaceutical composition can further comprise additional active ingredients.

[0103] All formulations of the pharmaceutical compositions disclosed herein can be produced by conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more additives to produce the desired formulation. "Pharmaceutically acceptable additives" refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, such as diluents, vehicles such as water, various organic solvents, fillers such as starch, sucrose, binders such as cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone (PVP); wetting agents such as glycerol; disintegrating agents such as agar, calcium carbonate, and sodium bicarbonate; absorption enhancers such as quaternary ammonium compounds; surfactants such as hexadecanol; absorption carriers such as kaolin and soap clay; lubricants such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical composition may further comprise other pharmaceutically acceptable additives, such as decentralized agents, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, flavors, sweeteners, dyes, and the like.

[0104] The term "disease" refers to any disease, ailment, illness, symptom or indication, and may be interchangeable with the term "disorder" or "condition."

[0105] Throughout this specification and the claims that follow, unless the context otherwise requires, the term "comprise," and variations such as "comprises" and "comprising," are intended to specify the presence of the subsequent feature but do not exclude the presence or addition of one or more other features. As used herein, the term "comprising" can be replaced with the terms "containing," "including," or sometimes "having."

[0106] Throughout this specification and the claims that follow, "C n~m" denotes an inclusive range where n and m are integers and indicate the number of carbons. Examples include C 1~8 , C 1~6 These include:

[0107] Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0108] General reaction scheme for preparing compounds The subject compounds and their pharmaceutically acceptable salts can be prepared from (a) commercially available starting materials, (b) known starting materials that can be prepared as described in literature procedures, and (c) new intermediates described in the schemes and experimental procedures herein. In making the compounds of the present invention, the order of synthetic steps can be varied to increase the yield of the desired product. Some of the compounds of the present invention can be produced by the methods shown in the following reaction schemes and accompanying descriptions.

[0109] Scheme A [ka] wherein X3 corresponds to Z2 in formula (I), and X4 corresponds to Z3 in formula (I). A-2 can be synthesized from A-1 and piperidin-4-ylmethanol under basic conditions, followed by reduction of the nitro group in A-2 to form A-3, which is mixed with acrylic acid to give a mixture of A-4a and A-4b. A-4a and A-4b are then heated in the presence of urea to give A-5, which is hydrolyzed under acidic conditions to give A-6. The final intermediate A is obtained from oxidation of A-6 using an oxidation reagent such as IBX.

[0110] Scheme B [ka] wherein n corresponds to n1 in formula (I), X3 corresponds to Z2 in formula (I), and X4 corresponds to Z3 in formula (I). B-3 can be synthesized from B-1 and B-2 by using Pd as a catalyst, and then B-3 is coupled with B-4 in the presence of a metal catalyst to give B-5. The ester group in B-5 can be reduced to alcohol B-6 by using a reducing agent such as LiAlH4. B-6 can be further reduced with Pd / C in the presence of hydrogen to give B-7, which can then be oxidized to intermediate B by using an oxidizing agent such as IBX.

[0111] Scheme C [ka] wherein n corresponds to n1 in Formula (I), X3 corresponds to Z2 in Formula (I), and X4 corresponds to Z3 in Formula (I). C-2 can be synthesized from C-1 and (BOC)2O, and then C-2 and C-3 are coupled using Pd as a catalyst to give intermediate C-4. The Boc group can be removed under acidic conditions to form C-5, which is mixed with acrylic acid and heated to give C-6. C-7 can be synthesized from C-6 and urea under heating conditions, and then the TBS group in C-7 can be removed with TBAF or CsF to give intermediate C-8, which is oxidized to intermediate C by using an oxidation reagent such as IBX.

[0112] Scheme D [ka] wherein X3 corresponds to Z2 in formula (I), and X4 corresponds to Z3 in formula (I). D-1 and D-2 can be coupled in a metal catalyst (such as CuI or Pd) to give D-3, which can be coupled with D-4 using Pd as a catalyst to give D-5. The bis(benzyloxy)pyridine group in D-5 can be reduced to piperidine-2,6-dione in D-6 with hydrogen using Pd / C as a catalyst, and the final intermediate D can then be oxidized with an oxidizing reagent such as IBX.

[0113] Scheme E [ka] E-3 can be synthesized from E-1 and E-2 under basic conditions, and the hydroxy group can be protected with THP under acidic conditions to give E-4. The isobenzofuran-1(3H)-one in E-4 can be hydrolyzed with NaOH / HO to give E-5, which can be mixed with TBSCl and base to form intermediate E-6. E-6 can be coupled with 3-aminopiperidine-2,6-dione using HATU to give E-7, and the TBS group can be removed with TBAF or CsF to form E-8. E-9 can be synthesized from E-8 and TsCl under basic conditions, and the THP group can then be removed under acidic conditions, which can be oxidized with an oxidizing agent to give the final intermediate E.

[0114] Scheme F [ka] In the formula, R 1 , R 3 , R 4 , R 5 , R 9 , X a , X c , X d , X e, Z2, Z3, Z4, and Z5 are defined as in formula (I), (II), or (III). F-2 is synthesized from F-1 and SEMCl under basic conditions, which is further coupled with F-3 in catalytic Pd to form F-4. F-4 is coupled with F-5 in catalytic Pd to give F-6, and the Boc and SEM groups are removed under acidic or basic conditions to give F-7, which is mixed with an aldehyde in the presence of a reducing reagent such as NaBH(OAc) to form F.

[0115] Scheme G [ka] In the formula, R 1 , R 3 , R 4 , R 9 , X a , X c , X d , X e , Z2, Z3, Z4, and Z5 are defined as in formula (I). G-1 and G-2 are mixed with CoCl2 as a catalyst to form G-3, which is then coupled with G-4 using Pd as a catalyst to give G-5. The Boc group can be removed in acid to form G-6, which is mixed with an aldehyde in the presence of a reducing reagent such as NaBH(OAc)3 to form G. [Example]

[0116] The following examples are intended to be purely illustrative and should not be construed as limiting in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Temperatures are in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI and used without further purification unless otherwise indicated. Unless otherwise indicated, reactions described below were carried out under a positive pressure of nitrogen or argon, or in anhydrous solvents using drying tubes; reaction flasks were equipped with rubber septa for the introduction of substrates and reagents via syringe; and glassware was oven-dried and / or heat-dried.

[0117] 1 1 H NMR spectra were recorded on an Agilent instrument operating at 400 MHz or a Bruker instrument operating at 500 MHz.

[0118] 1 H NMR spectra were obtained using CDCl3, CD2Cl2, CD3OD, DO, d6-DMSO, d6-acetone, or (CD3)2CO as solvents, and tetramethylsilane (0.00 ppm) or residual solvent (CDCl3: 7.25 ppm; CD3OD: 3.31 ppm; DO: 4.79 ppm; d6-DMSO: 2.50 ppm; d6-acetone: 2.05; (CD3)3CO: 2.05) as reference standards. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextet), m (multiplet), br (broadened), dd (double doublet), and dt (double triplet). Where given, coupling constants are reported in Hertz (Hz).

[0119] LCMS-1: LC-MS spectrometer (Agilent 1260 Infinity) Detector: MWD (190-400 nm), Mass Detector: 6120 SQ Mobile phase: A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid, Column: Poroshell 120 EC-C18, 4.6 x 50 mm, 2.7 pm Gradient method: Flow rate: 1.8 mL / min, Time (min) A (%) B (%) [Table 1]

[0120] LCMS, LCMS-3: LC-MS spectrometer (Agilent 1260 Infinity II) Detector: MWD (190-400 nm), Mass Detector: G6125C SQ Mobile phase: A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid, Column: Poroshell 120 EC-C18, 4.6 x 50 mm, 2.7 pm Gradient method: Flow rate: 1.8 mL / min, Time (min) A (%) B (%) [Table 2]

[0121] LCMS-2: LC-MS spectrometer (Agilent 1290 Infinity II) Detector: MWD (190-400 nm), Mass Detector: G6125C SQ Mobile phase: A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid, Column: Poroshell 120 EC-C18, 4.6 x 50 mm, 2.7 pm Gradient method: Flow rate: 1.2 mL / min, Time (min) A (%) B (%) [Table 3]

[0122] Preparative HPLC was performed on a column (150×21.2 mm id, 5 pm, Gemini NXC 18) at a flow rate of 20 ml / min, injection volume of 2 ml, at room temperature and UV detection at 214 nm and 254 nm.

[0123] In the following examples, the following abbreviations are used: [Table 4-1] [Table 4-2] [Table 4-3]

[0124] Example 1: 3-(tert-butyl)-N-(4-(6-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] Step 1: tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate [ka] A mixture of tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate (10 g, 29.4 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (9 g, 5.0 mmol), Pd(dppf)Cl2 (2.12 g, 10.6 mmol), and KOAc (4.55 g, 22.75 mmol) in 1,4-dioxane (200 mL) was stirred in a round-bottom flask at 100 °C overnight. The mixture was evaporated in vacuo to give the crude product, which was further purified by silica gel column chromatography (PE:EA = 100:0 to 90:10 gradient elution) to give the title product (11 g, 90%). [M+H] + = 388.0.

[0125] Step 2: (1-(4-nitrophenyl)piperidin-4-yl)methanol [ka] To a solution of 1-fluoro-4-nitrobenzene (100.0 g, 710.0 mmol) and 4-piperidinemethanol (98.0 g, 850 mmol) in DMF (1400.0 mL) was added K2CO3 (196.0 g) at 25 °C. The mixture was stirred at 80 °C for 15 hours. The reaction was monitored by HPLC. The reaction was cooled to room temperature, and the mixture was poured into ice water (6000.0 mL) and stirred for 20 minutes. The solid was filtered, washed with water (500.0 mL × 2), and dried to give the product (140.0 g, 83.8%). 1 H NMR (400 MHz, DMSO) δ H 8.03 (d, J = 9.4 Hz, 2H), 7.01-6.98 (m, 2H), 4.54 (t, J = 5.3 Hz, 1H), 4.07-4.04 (m, 2H), 3.29-3.26 (m, 2H), 3.00-2.93 (m, 2H), 1.76-1.67 (m, 3H), 1.21-1.11 (m, 2H);[M+H] + = 237.2.

[0126] Step 3: (1-(4-aminophenyl)piperidin-4-yl)methanol [ka] To a solution of (1-(4-nitrophenyl)piperidin-4-yl)methanol (140.0 g, 592.7 mmol) in MeOH (1680.0 mL) under N was added 10% Pd / C (28.0 g) at 25° C., and the mixture was then exchanged with H twice and stirred under H atmosphere at 25° C. for 15 h. The reaction was monitored by HPLC. The mixture was filtered through a pad of Celite and washed with MeOH (140.0 mL). The filtrate was concentrated in vacuo to give the product (113.0 g, 92.0%). 1 H NMR (400 MHz, DMSO) δH 6.77-6.61 (m, 2H), 6.54-6.38 (m, 2H), 4.53 (brs, 2H), 4.45 (t, J = 5.3 Hz, 1H), 3.32-3.27 (m, 2H), 2.46-2.41 (m, 2H), 1.76-1.62 (m, 2H), 1.50-1.31 (m, 1H), 1.27-1.08 (m, 2H);[M+H] + = 207.2.

[0127] Steps 4 and 5: (1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl acetate [ka] To a solution of (1-(4-aminophenyl)piperidin-4-yl)methanol (25.0 g, 121.2 mmol) in PhMe (183.0 mL) was added acrylic acid (13.0 g, 181.8 mmol) at 25° C. The mixture was stirred at 90° C. for 15 hours. The reaction was monitored by HPLC. The reaction was cooled to 25° C., and then HOAc (183.0 mL) and urea (36.4 g, 606.2 mmol) were added. The mixture was stirred at 110° C. for 24 hours. The reaction was monitored by HPLC. The reaction was cooled to 25° C. and concentrated in vacuo. The residue was dissolved in EtOAc (500.0 mL) and then adjusted to pH=7 with saturated NaHCO3. The resulting solution was extracted with 2×200.0 mL of EtOAc, and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate, concentrated under vacuum, and the residue was purified on silica gel (PE: EtOAc = 1:1) to give the product (17.5 g, 74%). 1 H NMR (400 MHz, DMSO) δ H10.32 (s, 1H), 7.20 (d, J = 8.9 Hz, 2H), 6.99 (d, J = 9.0 Hz, 2H), 3.98 (d, J = 6.2 Hz, 2H), 3.80-3.66 (m, 4H), 2.74-2.72 (m, 4H), 2.09 (s, 3H), 1.80 (d, J = 13.8 Hz, 4H), 1.37 (dd, J = 12.1, 2.8 Hz, 3H);[M+H] + = 346.2.

[0128] Step 6: 1-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] (1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl acetate (35.0 g, 121.2 mmol) was added to 2N HCl (260.0 mL) at 25° C. The mixture was stirred at 100° C. for 15 hours. The reaction was monitored by HPLC. The reaction was cooled to 10° C. and then adjusted to pH=7 with saturated NaHCO. The solid was collected by filtration, washed with water (50.0 mL), and dried to give the product (16.9 g, 55%). 1 H NMR (400 MHz, DMSO) δ H 10.26 (s, 1H), 7.13 (d, J = 8.9 Hz, 2H), 6.92 (d, J = 9.0 Hz, 2H), 4.49 (s, 1H), 3.78-3.61 (m, 4H), 3.30-3.28 (m, 2H), 2.70-2.66 (m, 4H), 1.75-1.72 (m, 2H), 1.52-1.49 (m, 1H), 1.28-1.18 (m, 2H);[M+H] + = 304.2.

[0129] Step 7: 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde [ka] To a solution of 1-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (15.0 g, 46.8 mmol) in DMSO (120.0 mL) was added IBX (32.7 g, 117.1 mmol) portionwise at 25° C. (Caution: exotherm to 40° C.). The mixture was stirred at 25° C. for 15 hours. The reaction was monitored by HPLC. Water (300.0 mL) was added to the reaction at 25° C. The solid was filtered and washed with water (100.0 mL) and then with EtOAc (100.0 mL). The resulting solution was extracted with 4×200.0 mL of EtOAc. The combined organic layers were dried over NaSO and concentrated under vacuum to give the crude residue. The crude product was purified by column chromatography to give the product (3.1 g, 22.1%). 1 H NMR (300 MHz, DMSO) δ H 10.26 (s, 1H), 9.63 (s, 1H), 7.15-7.10 (m, 2H), 6.95-6.89 (m, 2H), 3.71-3.51 (m, 4H), 2.86-2.57 (m, 4H), 1.94-1.91 (m, 1H), 1.77-1.73 (m, 1H), 1.64-1.51 (m, 2H), 1.38-1.30 (m, 1H);[M+H] + = 302.1.

[0130] Step 8: 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine [ka] To a mixture of 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (50 g, 179.2 mmol) in DMF (1 L) was added NaH (8.6 g, 215 mmol). The mixture was stirred at 0 °C for 20 min. Then, SEM-Cl (62 g, 232 mmol) was added. LCMS showed the reaction was complete. The reaction was concentrated to give a residue, which was partitioned with DCM and H2O. The combined organic layers were dried over Na2SO4, and MTBE (300 mL) was added to give the product (55 g, 80%). [M+H] + = 410.0.

[0131] Step 9: tert-butyl 4-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperidine-1-carboxylate [ka] A mixture of 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (6.42 g, 11.8 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (5.18 g, 4.5 mmol), Pd(dppf)Cl (0.862 g, 0.75 mmol) and KCO (3.25 g, 23.6 mmol) in 1,4-dioxane (20 mL) and HO (4 mL) was stirred at 80 °C overnight in a round-bottom flask. The mixture was evaporated in vacuo to give the crude product, which was further purified by silica gel column chromatography (PE:EA = 100:0 to 3:1 gradient elution) to give the product (5 g, 70%). [M+H] + = 543.4.

[0132] Step 10: tert-butyl 4-(4-(4-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperidine-1-carboxylate [ka] A mixture of tert-butyl 4-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperidine-1-carboxylate (6.42 g, 11.8 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 (5.18 g, 4.5 mmol), Pd(dppf)Cl (0.862 g, 0.75 mmol) and KCO (3.25 g, 23.6 mmol) in 1,4-dioxane (100 mL) and HO (20 mL) was stirred at 100 °C overnight in a round-bottom flask. The mixture was evaporated in vacuo to give the crude product, which was further purified by silica gel column chromatography (PE: EtOAc = 100:0 to 3:1 gradient elution) to give the product (5 g, 70%). [M+H] + = 780.4.

[0133] Step 11: 3-(tert-butyl)-N-(4-(7-(hydroxymethyl)-6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of tert-butyl 4-(4-(4-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperidine-1-carboxylate (7 g, 8.9 mmol) in dichloromethane (20 mL) and trifluoroacetic acid (20 mL) was stirred in a round-bottom flask at room temperature overnight. The mixture was evaporated in vacuo to give the crude product (5 g, 81%), which was used for the next step without further purification. [M+H] + =580.4.

[0134] Step 12: 3-(tert-butyl)-N-(2-methyl-4-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka] To a stirred solution of 3-(tert-butyl)-N-(4-(7-(hydroxymethyl)-6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide (5.0 g, 8.6 mmol) in MeOH (20 mL) was added NH3 / HO (25%-30%, 10 mL). The mixture was stirred at 0 °C for 30 min. LCMS showed the reaction was complete. The mixture was evaporated in vacuo to give the crude product, which was further purified by silica gel column chromatography (DCM:MeOH = 10:1-2:1 gradient elution) to give the product (3 g, 60%). [M+H] + = 550.4.

[0135] Step 13: 3-(tert-butyl)-N-(4-(6-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of 3-(tert-butyl)-N-(2-methyl-4-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (3 g, 5.45 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (1.64 g, 5.45 mmol) in 1,2-dichloromethane (150 mL) and MeOH (30 mL) was stirred in a round-bottom flask at room temperature for 1 hour. The mixture was added to NaBH(OAc) (2.3 g, 10.84 mmol) and stirred in a round-bottom flask at room temperature overnight. The mixture was then evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH=100:0 to 80:20 gradient elution) to give the product (3.2 g, 82%). 1 H NMR (400 MHz, DMSO) δ H12.76 (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] + = 835.5.

[0136] Example 2: 3-(tert-butyl)-N-(4-(6-(4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized in a similar manner to Example 1. 1 H NMR (400 MHz, DMSO) δ H12.68 (s, 1H), 11.13 (s, 1H), 9.93 (s, 1H), 8.80 (s, 1H), 8.07 (s, 2H), 7.98 (d, J = 7.7 Hz, 2H), 7.72 (d, J = 11.4 Hz, 1H), 7.46 (s, 2H), 7.38 (d, J = 8.3 Hz, 3H), 5.11 (d, J = 7.3 Hz, 1H), 4.56 (d, J = 5.5 Hz, 2H), 3.62 (d, J = 12.2 Hz, 2H), 2.98-2.90 (m, 6H), 2.57 (t, J = 15.0 Hz, 2H), 2.22 (s, 2H), 2.02 (s, 4H), 1.88-1.65 (m, 8H), 1.38 (s, 9H), 1.34-1.17 (m, 3H);[M+H] + = 921.8.

[0137] Example 3: 3-(tert-butyl)-N-(4-(6-(4-(1-(2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)ethyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized in a similar manner to Example 1. 1 H NMR (400 MHz, DMSO) δ H12.72 (s, 1H), 10.28 (s, 1H), 9.93 (s, 1H), 8.82 (s, 1H), 8.07 (s, 2H), 8.02 (d, J = 7.9 Hz, 2H), 7.48 (d, J = 8.2 Hz, 1H), 7.39 (s, 3H), 7.14 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 8.5 Hz, 2H), 4.56 (d, J = 5.4 Hz, 2H), 3.78-3.63 (m, 4H), 3.38 (s, 3H), 2.95 (s, 2H), 2.80 (s, 2H), 2.73-2.65 (m, 4H), 2.49-2.48 (s, 3H), 1.95 (s, 4H), 1.78 (d, J = 11.3 Hz, 2H), 1.63 (s, 2H), 1.51 (d, J = 17.4 Hz, 1H), 1.38 (s, 9H), 1.30-1.28 (m, 2H);[M+H] + = 849.9.

[0138] Example 4: 3-(tert-butyl)-N-(4-(6-(4-(1-(2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide Step 1: 2,6-Bis(benzyloxy)-3-(4-bromophenyl)pyridine [ka] To a stirred mixture of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (25 g, 59.908 mmol) and 4-bromoiodobenzene (20.3 g, 71.897 mmol) in dioxane (250 mL) and HO (50 mL) was added KCO (16.6 g, 119.822 mmol) and Pd(dppf)Cl (4.4 g, 5.986 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give the product (23 g, 86%). [M+H] + = 446.2.

[0139] Step 2: Ethyl 2-(1-[4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl]piperidin-4-yl)acetate [ka] To a stirred solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (15 g, 33.606 mmol) and ethyl 2-(piperidin-4-yl)acetate (8.6 g, 50.410 mmol) in 2-methyl-THF (150 mL) and HO (15 mL) was added CsCO (32.9 g, 100.819 mmol), DavePhos (2.7 g, 6.721 mmol), and Pd(dba) (3.1 g, 3.361 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (500 mL) and washed with water (3 × 200 mL) and brine (200 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give the product (14 g, 78%). [M+H] + = 537.3.

[0140] Step 3: 2-(1-[4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl]piperidin-4-yl)ethanol [ka] To a stirred solution of ethyl 2-(1-[4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl]piperidin-4-yl)acetate (13 g, 24.223 mmol) in THF (130 mL) was added LiAlH (1 g, 26.646 mmol) portionwise at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched at 0 °C by the addition of water / ice (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:2) to give the product (11 g, 92%). [M+H] + = 495.3.

[0141] Step 4: 3-[4-[4-(2-hydroxyethyl)piperidin-1-yl]phenyl]piperidine-2,6-dione [ka] To a stirred solution of 2-(1-[4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl]piperidin-4-yl)ethanol (10.5 g, 21.228 mmol) in EtOH (100 mL), EtOAc (100 mL), and DCM (20.00 mL) was added Pd / C (wet, 10%) (5 g, 46.984 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The resulting mixture was filtered, and the filter cake was washed with DCM / CHOH (10:1, 200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:10) to give the product (5.1 g, 76%). [M+H] + = 317.1.

[0142] Step 5: 2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetaldehyde [ka] A mixture of 3-[4-[4-(2-hydroxyethyl)piperidin-1-yl]phenyl]piperidine-2,6-dione (100 mg, 0.32 mmol) and IBX (132 mg, 0.47 mmol) in DMSO (10 mL) was stirred overnight at room temperature in a round-bottom flask. The reaction was quenched with water, and the mixture was extracted with EtOAc and washed three times with saturated aqueous NaCl and twice with saturated aqueous NaHCO. The organic layer was dried over anhydrous NaSO and evaporated in vacuo to give the product (70 mg, 70%). [M+H] + = 315.2.

[0143] Step 6: 3-(tert-butyl)-N-(4-(6-(4-(1-(2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of 3-(tert-butyl)-N-(2-methyl-4-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (20 mg, 0.036 mmol) and 2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetaldehyde (14 mg, 0.044 mmol) in MeOH (5 mL) was stirred at room temperature for 30 minutes in a round-bottom flask. NaBH(AcO) (15 mg, 0.073 mmol) was then added and stirred at room temperature for 2 hours. The reaction was quenched with water, and the mixture was washed once with saturated aqueous NaHCO and then extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to give the crude product, which was further purified by preparative HPLC to give the product (13.3 mg, 43%). 1 H NMR (400 MHz, DMSO) δ H12.80 (s, 1H), 10.81 (s, 1H), 9.96-9.92 (m, 1H), 9.16 (brs, 1H), 8.84 (s, 1H), 8.03-8.01 (m, 4H), 7.52-7.36 (m, 4H), 7.25-7.23 (m, 1H), 7.10-7.06 (m, 2H), 6.99-6.95 (m, 1H), 4.57 (d, J = 5.5 Hz, 2H), 3.79-3.61 (m, 5H), 3.38-3.36 (m, 1H), 3.20-3.18 (m, 2H), 3.10-3.04 (m, 3H), 2.91-2.89 (m, 2H), 2.73-2.71 (m, 1H), 2.66-2.64 (m, 1H), 2.54 (s, 3H), 2.23-2.02 (m, 3H), 2.03-1.99 (m, 1H), 1.88 (d, J = [M+H] + = 848.8.

[0144] Example 5: 3-(tert-butyl)-N-(4-(6-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidin-3-yl)methyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide Step 1: (1-(4-nitrophenyl)azetidin-3-yl)methanol [ka] A mixture of azetidin-3-ylmethanol HCl salt (8.00 g, 65.041 mmol), 4-fluoronitrobenzene (9.17 g, 65.041 mmol), and Na2CO3 (17.95 g, 130.082 mmol) in DMSO (40 mL) was stirred at 60 °C for 2 h. The reaction was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was used in the next step without further purification.

[0145] Step 2: (1-(4-aminophenyl)azetidin-3-yl)methanol [ka] To a stirred mixture of (1-(4-nitrophenyl)azetidin-3-yl)methanol (15.20 g, 73.001 mmol) in MeOH (50.00 mL) was added Pd / C (10% wt, 8.00 g). The resulting mixture was stirred for 1 hour at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to give the product (12.5 g, 96.07%). The crude product was used directly in the next step without further purification.

[0146] Step 3: 4-(3-(((tert-butyldiphenylsilyl)oxy)methyl)azetidin-1-yl)aniline [ka] To a stirred mixture of (1-(4-aminophenyl)azetidin-3-yl)methanol (12.50 g, 70.132 mmol) and imidazole (9.55 g, 140.264 mmol) in DMF (50.00 mL) was added TBDPSCl (45.59 mL, 165.875 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give the product (21.5 g, 73.58%).

[0147] Step 4: Methyl 3-((4-(3-(((tert-butyldiphenylsilyl)oxy)methyl)azetidin-1-yl)phenyl)amino)propanoate [ka] A mixture of 4-(3-(((tert-butyldiphenylsilyl)oxy)methyl)azetidin-1-yl)aniline (10.00 g, 24.002 mmol) and methyl acrylate (2.07 g, 24.002 mmol) in HO (50.00 mL) and THF (50.00 mL) was stirred overnight at 50° C. The reaction was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give the product (2.1 g, 17.40%).

[0148] Step 5: Methyl 3-(1-(4-(3-(((tert-butyldiphenylsilyl)oxy)methyl)azetidin-1-yl)phenyl)ureido)propanoate [ka] A mixture of methyl 3-((4-(3-(((tert-butyldiphenylsilyl)oxy)methyl)azetidin-1-yl)phenyl)amino)propanoate (2.10 g, 4.177 mmol) and sodium cyanate (543.09 mg, 8.354 mmol) in AcOH (20.00 mL) and HO (4.00 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. The crude product (2.7 g) was used directly in the next step without further purification.

[0149] Step 6: 1-(4-(3-(((tert-butyldiphenylsilyl)oxy)methyl)azetidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] A mixture of methyl 3-(1-(4-(3-(((tert-butyldiphenylsilyl)oxy)methyl)azetidin-1-yl)phenyl)ureido)propanoate (2.70 g, 4.947 mmol) and TMSOK (0.76 g, 5.937 mmol) in THF (30.00 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo to give the product (1.1 g, 43.28%). The crude product was used directly in the next step without further purification.

[0150] Step 7: 1-(4-(3-(hydroxymethyl)azetidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] A mixture of 1-(4-(3-(((tert-butyldiphenylsilyl)oxy)methyl)azetidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (3.00 g, 5.840 mmol) and CsF (2.66 g, 17.520 mmol) in DMF (30.00 mL) was stirred at room temperature for 4 hours. The resulting mixture was filtered, and the filter cake was washed with DMF. The filtrate was concentrated under reduced pressure. The residue was purified by slurrying in water. The resulting mixture was filtered, and the filter cake was washed with water. The filter cake was dried in vacuo to give the product (1.1 g, 68.42%).

[0151] Step 8: (1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidin-3-yl)methyl 4-methylbenzenesulfonate [ka] To a stirred mixture of 1-(4-(3-(hydroxymethyl)azetidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (2.2 g, 7.991 mmol), TEA (2.77 mL), and TsCl (4.57 g, 23.973 mmol) in DCM (20.00 mL) was added DMAP (3.9 g, 31.884 mmol). The resulting mixture was stirred at 50° C. for 4 hours. The reaction was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with citric acid (aq) and brine, then dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (12:1) to give the product (995.4 mg, 29.00%). 1 H NMR (400 MHz, DMSO) δ H10.23 (s, 1H), 7.94-7.72 (m, 2H), 7.61-7.39 (m, 2H), 7.32-6.94 (m, 2H), 6.50-6.26 (m, 2H), 4.25 (d, J = 4 Hz, 2H), 3.83 (t, J = [M+H] + = 430.0.

[0152] Step 9: 3-(tert-butyl)-N-(4-(6-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidin-3-yl)methyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of (1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidin-3-yl)methyl 4-methylbenzenesulfonate (50.00 mg, 0.116 mmol), 3-(tert-butyl)-N-(2-methyl-4-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (63.99 mg, 0.116 mmol) and DIEA (0.06 mL, 0.471 mmol) in DMSO (1.00 mL) was stirred at 80° C. for 3 hours. The reaction was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: mobile phase, water (10 mmol / L NH4HCO3) and ACN (from 46% to 52% of phase B in 8 min); detector, UV 254 mm. This gave the product (2.6 mg, 2.77%). 1 H NMR (400 MHz, DMSO) δ H 10.22 (s, 1H), 9.89 (d, J = 4 Hz, 1H), 8.81 (s, 1H), 8.09 (d, J = 4 Hz, 2H), 7.99 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8 Hz, 1H), 7.38-7.36 (m, 4H), 7.11 (d, J = 8 Hz, 2H), 6.43 (d, J = 8 Hz, 2H), 4.57 (d, J = 4 Hz, 2H), 3.96 (t, J = 8 Hz, 1H), 3.68 (t, J = 8 Hz, 2H), 3.63 (s, 2H), 2.97 (d, J = 12 Hz, 3H), 2.70 (t, J = 8.0 Hz, 2H), 2.61 (d, J = 8.0 Hz, 2H), 2.08-2.05 (m, 3H), 1.77 (s, 1H), 1.71 (d, J = 16 Hz, 3H), 1.40-1.38 (m, 12H), 1.24 (s, 1H), 0.88 (s, 4H);[M+H] + = 807.0.

[0153] Example 6: 3-(tert-butyl)-N-(4-(6-(4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)propyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide Step 1: 3-(azetidin-3-yl)propan-1-ol [ka] A 25 mL round-bottom flask was charged with tert-butyl 3-(3-hydroxypropyl)azetidine-1-carboxylate (950.00 mg, 4.413 mmol), DCM (4.0 mL), and TFA (2.0 mL, 2.693 mmol). The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo to give the product (1.4 g, crude).

[0154] Step 2: 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-hydroxypropyl)azetidin-1-yl)isoindoline-1,3-dione [ka] A 50 mL round-bottom flask was charged with 3-(azetidin-3-yl)propan-1-ol (1.40 g, 3.647 mmol), DMSO (10.00 mL), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (1.21 g, 4.376 mmol), and DIEA (2.83 g, 21.880 mmol). The resulting solution was stirred at 80 °C for 1 hour. The reaction mixture was cooled to room temperature. The resulting solution was diluted with EtOAc. The resulting solution was extracted with H2O, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied to a silica gel column with dichloromethane / methanol (8:1) to give the product (550 mg, 40.61%).

[0155] Step 3: 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)propyl 4-methylbenzenesulfonate [ka] A 25 mL round-bottom flask was charged with 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-hydroxypropyl)azetidin-1-yl)isoindoline-1,3-dione (480.00 mg, 1.292 mmol), DCM (10.00 mL), TEA (262.00 mg, 2.589 mmol), and TsCl (493.00 mg, 2.586 mmol). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with dichloromethane / methanol (7:1) to give the product (400 mg, 58.89%).

[0156] Step 4: 3-(tert-butyl)-N-(4-(6-(4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)propyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] A 25 mL round-bottom flask was charged with 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)propyl 4-methylbenzenesulfonate (50.00 mg, 0.095 mmol), ACN (5.00 mL), 3-(tert-butyl)-N-(2-methyl-4-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (52.00 mg, 0.095 mmol), KI (3.00 mg, 0.018 mmol), and DIEA (0.05 mL, 0.385 mmol). The resulting solution was stirred overnight at 70 °C in an oil bath. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was loaded onto a silica gel column with dichloromethane / methanol (10:1). The crude product (35 mg) was purified by preparative HPLC under the following conditions: mobile phase, water (10 mmol / L NH4HCO3) and ACN (phase B from 40% to 52% in 8 min); detector, UV 254 nm. This resulted in the product (5.3 mg, 6.17%). 1 H NMR (300 MHz, DMSO) δ H 12.66 (s, 1H), 11.05 (s, 1H), 8.80 (s, 1H), 8.06 (s, 3H), 7.98 (d, J = 7.8 Hz, 2H), 7.64 (d, J = 8.3 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.37 (d, J = 8.6 Hz, 4H), 6.77 (s, 1H), 6.63 (d, J = 5.9 Hz, 1H), 5.07-5-05 (m, 1H), 4.56 (s, 2H), 4.15 (t, J = 7.8 Hz, 3H), 3.68 (d, J = 7.5 Hz, 2H), 2.57 (d, J = 16.3 Hz, 10H), 2.04-1.37 (m, 18H), 1.23 (s, 2H);[M+H] + = 903.42.

[0157] Example 7: (R)-3-(tert-butyl)-N-(1-(4-(6-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized in a similar manner to Example 1. 1 H NMR (400 MHz, DMSO) δ H 12.68 (s, 1H), 10.27 (s, 1H), 9.98 (d, J = 8.0 Hz, 1H), 8.80 (s, 1H), 8.17-7.96 (m, 4H), 7.67 (d, J = 8.1 Hz, 1H), 7.38 (s, 3H), 7.14 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.5 Hz, 2H), 5.38 (s, 1H), 3.74-3.64 (m, 4H), 3.05 (s, 2H), 2.67 (dd, J = 14.9, 8.6 Hz, 5H), 2.54 (s, 3H), 2.32 (s, 2H), 2.13 (s, 2H), 1.66-1.86 (m, 7H), 1.55 (d, J = 6.6 Hz, 3H), 1.37 (s, 9H), 1.18-1.28 (m, 2H);[M+H] + = 849.5.

[0158] Example 8: (S)-3-(tert-butyl)-N-(1-(4-(6-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized in a similar manner to Example 1. 1 H NMR (400 MHz, DMSO) δ H 12.68 (s, 1H), 10.27 (s, 1H), 9.97 (d, J = 7.6 Hz, 1H), 8.80 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 7.99 (d, J = 7.6 Hz, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.38 (s, 3H), 7.14 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 5.38 (s, 1H), 3.69 (s, 4H), 3.01 (s, 2H), 2.72-2.61 (m, 4H), 2.54 (s, 3H), 2.25 (s, 2H), 2.05 (s, 2H), 1.91 (s, 2H), 1.85-1.65 (m, 7H), 1.55 (d, J = 6.0 Hz, 3H), 1.37 (s, 10H), 1.30-1.15 (m, 3H);[M+H] + =849.8.

[0159] Example 9: 1-(4-(4-((4-(4-(4-(3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperidin-1-yl)methyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The title compound was synthesized in a similar manner to Example 1. 1 H NMR (400 MHz, DMSO) δ H12.71 (s, 1H), 10.28 (s, 1H), 8.83 (s, 1H), 8.20 (s, 1H), 7.90 (d, J = 6.9 Hz, 2H), 7.47 (d, J = 17.7 Hz, 3H), 7.36 (d, J = 6.9 Hz, 2H), 7.13 (d, J = 7.5 Hz, 2H), 6.93 (d, J = 7.6 Hz, 2H), 6.78 (s, 1H), 6.51 (s, 1H), 4.19 (s, 3H), 3.85 (s, 1H), 3.69 (d, J = 6.7 Hz, 4H), 2.97 (d, J = 8.6 Hz, 3H), 2.72-2.62 (m, 5H), 2.17 (d, J = 19.8 Hz, 6H), 1.87-2.10 (m, 3H), 1.85-1.63 (m, 8H), 1.15-1.25 (m, 9H);[M+H] + = 856.5.

[0160] Example 10: 1-(4-(4-((4-(5-(4-(3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] The title compound was synthesized in a similar manner to Example 1. 1 H NMR (400 MHz, DMSO) δ H12.62 (s, 1H), 10.27 (s, 1H), 8.79 (s, 1H), 8.73 (s, 1H), 8.10 (d, J = 9.0 Hz, 1H), 7.46 (d, J = 18.9 Hz, 3H), 7.13 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 7.9 Hz, 3H), 6.69 (s, 1H), 6.50 (s, 1H), 4.17 (d, J = 8.7 Hz, 3H), 3.85 (s, 1H), 3.68 (d, J = 6.8 Hz, 4H), 3.58 (s, 4H), 2.67 (dd, J = 13.8, 9.1 Hz, 4H), 2.56 (s, 2H), 2.46 (s, 4H), 2.41 (s, 2H), 2.22 (d, J = 6.3 Hz, 2H), 2.14 (s, 3H), 1.82 (d, J = 12.3 Hz, 2H), 1.73 (s, 1H), 1.21 (s, 8H);[M+H] + = 858.4.

[0161] Example 11: 1-(4-(4-((4-(4-(4-(3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Step 1: tert-butyl 4-(4-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate [ka] To a solution of 4-chloro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 14.4 mmol) in dioxane (35 mL) and HO (7 mL) was added tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (1.6 g, 4.2 mmol), KCO (1.6 g, 12 mmol), and Pd(dppf)Cl.CHCl (0.3 g, 0.4 mmol). The mixture was stirred at 80 °C for 6 h. The mixture was concentrated, dissolved in HO (30 mL), and extracted with EtOAc (30 mL × 2). The organic phase was concentrated and purified by flash chromatography with PE / EA (100:1 to 7:3) to give the product (1.9 g, 86.4%).

[0162] Step 2: tert-butyl 4-(4-(4-(3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-2-methylphenyl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(4-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate (1.9 g, 3.4 mmol) in dioxane (30 mL) and HO (6 mL) was added 7,7-dimethyl-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one (1.4 g, 3.4 mmol), KCO (1.4 g, 10.0 mmol), and Pd(dppf)Cl.CHCl (0.3 g, 0.3 mmol). The mixture was stirred at 100° C. under N for 18 h. The solvent was evaporated, added to HO (30 mL), and extracted with EtOAc (50 mL×2). The organic phases were combined, concentrated, and purified by flash chromatography using PE / EA (100:1 to 1:100) to give the product (1.1 g, crude).

[0163] Step 3: 7,7-dimethyl-2-(2-methyl-3-(6-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one hydrochloride [ka] To a solution of tert-butyl 4-(4-(4-(3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-2-methylphenyl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate (1.1 g, 1.4 mmol) in THF (10 mL) was added NaOH in MeOH (4%, 3 mL). The mixture was stirred at 20-30 °C for 1 h, concentrated, and slurried with HO (30 mL). The solid was filtered and washed with HO (30 mL). The filter cake was dried under reduced pressure. The solid was transferred to a flask, and HCl / MeOH (4 N, 30 mL) was added. The mixture was stirred at 20-30° C. for 3 h. The solvent was evaporated, slurried with MeOH, filtered, and the filter cake was washed with MeOH (30 mL) and MTBE (20 mL). The filter cake was dried and used as is for the next step. 1 H NMR (400 MHz, DMSO) δ H 12.54 (s, 1H), 8.77 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.57-7.39 (m, 3H), 6.99 (d, J = 8.4 Hz, 2H), 6.62 (s, 1H), 6.50 (s, 1H), 4.18 (br, 3H), 3.84 (br, 1H), 3.15 (s, 4H), 2.84 (s, 4H), 2.56 (s, 2H), 2.50 (br, 2H), 2.41 (s, 2H), 2.11 (s, 3H), 1.21 (s, 6H). [M+H] + = 572.3.

[0164] Step 4: 1-(4-(4-((4-(4-(4-(3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] To a solution of 7,7-dimethyl-2-(2-methyl-3-(6-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one (114 mg, 0.2 mmol) in DCM / EtOH (5:1, 30 mL) was added 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (60 mg, 0.2 mmol), HOAc (1 drop), and NaOAc (32.8 mg, 0.4 mmol). After stirring at 20-30°C for 60 min, NaBH(OAc)3 (127 mg, 0.6 mmol) was added. The mixture was stirred at 20-30°C for 3 h. The solvent was evaporated, HO (30 mL) was added, and extracted with DCM / iPrOH (10:1, 30 mL × 3). The organic phases were combined, concentrated, and purified by preparative TLC using DCM / MeOH (10:1) to give the product (53 mg, 31%). 1 H NMR (400 MHz, DMSO) δ H12.55 (s, 1H), 10.27 (s, 1H), 8.77 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.51-7.36 (m, 3H), 7.13 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.63 (s, 1H), 6.50 (s, 1H), 4.18 (br, 3H), 3.84 (br, 1H), 3.74-3.67 (m, 4H), 3.24 (br, 4H), 2.69-2.64 (m, 4H), 2.56 (s, 2H), 2.55-2.50 (m, 3H), 2.41 (s, 2H), 2.30-2.06 (m, 5H), 1.87-1.65 (m, 3H), 1.21 (s, 9H);[M+H] + = 857.5.

[0165] Example 12: 3-(tert-butyl)-N-(4-(6-(4-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid (26 mg, 0.1 mmol) and HATU (38 mg, 0.1 mmol) in DMF (1 mL) was stirred in a round-bottom flask at room temperature for 1 hour. 3-(tert-butyl)-N-(2-methyl-4-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (62 mg, 0.1 mmol) and DIPEA (39 mg, 0.3 mmol) were added to the mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was purified by C18 column chromatography (0.1% FA in water:acetonitrile = 60:40 to 20:80 gradient elution) to give the product (40 mg, 50%). 1 H NMR (400 MHz, DMSO) δ H 12.69 (s, 1H), 10.36 (s, 1H), 9.92 (s, 1H), 8.81 (s, 1H), 8.10-8.05 (m, 2H), 8.00 (d, J = 7.6 Hz, 2H), 7.50-7.35 (m, 6H), 7.18 (d, J = 8.4 Hz, 1H), 4.56 (d, J = 4.8 Hz, 2H), 3.85 (s, 3H), 3.65-3.58 (m, 2H), 3.33 (s, 2H), 2.96-2.81 (m, 2H), 2.73-2.65 (m, 2H), 1.91-1.76 (m, 2H), 1.75-1.63 (m, 2H), 1.38 (s, 10H);[M+H] + = 796.4.

[0166] Example 13: 3-(tert-butyl)-N-(4-(6-(4-(1-(2-(1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-6-methylpyridin-2-yl)piperidin-4-yl)ethyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide Step 1: 6-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-methyl-3-nitropyridine [ka] A mixture of 4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidine (5.00 g, 3.601 mmol), 6-fluoro-2-methyl-3-nitropyridine (2123.40 g, 13.601 mmol), and DIEA (5.27 g, 40.804 mmol) in DMSO (60 mL) was stirred for 1 h at 60 °C under an air atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give the product (5.6 g, 81.74%).

[0167] Step 2: 6-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-methylpyridin-3-amine [ka] To a stirred mixture of 6-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-methyl-3-nitropyridine (5.40 g, 10.720 mmol) and 10% Pd / C (2.00 g) in DCM (25 mL) and MeOH (25 mL) was added AcOH (0.20 mL, 3.490 mmol) and stirred for 5 hours at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to give the product (5 g, 98.45%).

[0168] Step 3: 3-((6-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-methylpyridin-3-yl)amino)propanoic acid [ka] A mixture of 6-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-methylpyridin-3-amine (5.00 g, 10.554 mmol) and acrylic acid (988.76 mg, 13.721 mmol) in toluene (100 mL) was stirred for 12 hours at 90° C. under a nitrogen atmosphere. LCMS and TLC showed that most of the starting material was converted to the product. The mixture (6.1 g, 105.89%) was used directly for the next step after concentration.

[0169] Step 4: 1-(6-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-methylpyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] A mixture of 3-((6-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-methylpyridin-3-yl)amino)propanoic acid (6.10 g, 11.176 mmol) and urea (2.01 g, 33.529 mmol) in AcOH (30 mL) and toluene (100 mL) was stirred for 12 hours at 105° C. under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 1:3) to give the product (3 g, 47.03%).

[0170] Step 5: 1-(6-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methylpyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione [ka] A mixture of 1-(6-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-methylpyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (3.00 g, 5.256 mmol) and CsF (3.19 g, 21.023 mmol) in DMF was stirred overnight at 35 °C under air atmosphere. The resulting mixture was extracted with CHCl. The combined organic layers were washed with water and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc 1:3) to give the product (1.08 g, 61.82%). 1 H NMR (300 MHz, DMSO) δ H 10.27 (s, 1H), 7.34 (d, J = 9 Hz, 1H), 6.64 (d, J = 9 Hz, 1H), 4.26 (d, J = 15 Hz, 3H), 3.64 (s, 1H), 3.51-3.41 (m, 3H), 2.73 (t, J = 15Hz, 4H), 2.19 (s, 3H), 1.98 (s, 1H), 1.70 (d, J = 12 Hz, 2H), 1.61 (s, 1H), 1.37 (q, J = 6 Hz, 2H), 1.23 (s, 1H), 1.17-1.03 (m, 2H);[M+H] + = 333.0.

[0171] Step 6: 3-(tert-butyl)-N-(4-(6-(4-(1-(2-(1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-6-methylpyridin-2-yl)piperidin-4-yl)ethyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized in a similar manner to Example 1. 1 H NMR (400 MHz, DMSO) δ H12.73 (s, 1H), 10.32 (s, 1H), 9.92 (s, 1H), 9.83 (s, 1H), 8.82 (s, 1H), 8.07 (s, 2H), 8.03 (d, J = 7.2 Hz, 2H), 7.48 (d, J = 8.4 Hz, 1H), 7.39 (s, 4H), 6.70 (d, J = 8.0 Hz, 1H), 4.60-4.52 (m, 2H), 4.40-4.25 (m, 2H), 3.70-3.55 (m, 3H), 3.54-3.45 (m, 1H), 3.20-3.10 (m, 2H), 3.09-2.98 (m, 3H), 2.95-2.63 (m, 6H), 2.21 (s, 3H), 2.08-1.95 (m, 4H), 1.81-1.55 (m, 6H), 1.38 (s, 9H), 1.25-1.10 (m, 3H);[M+H] + = 865.5.

[0172] Example 14: (R)-3-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide Step 1: tert-Butyl 4-(5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)piperazine-1-carboxylate [ka] A mixture of 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (3 g, 10.73 mmol), tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (4.18 g, 10.73 mmol), NaCO (1.25 g, 11.80 mmol), and Pd(dppf)Cl (0.39 g, 0.537 mmol) in dioxane (120 mL) and HO (20 mL) was stirred in a sealed tube at 85 °C overnight. After cooling, the reaction mixture was filtered, and the solid was washed with 20 mL of MeOH and dried under vacuum to give the product (4.05 g, 91%). [M+H] + = 415.0.

[0173] Step 2: tert-butyl (R)-4-(5-(4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)piperazine-1-carboxylate [ka] A mixture of tert-butyl 4-(5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)piperazine-1-carboxylate (0.9 g, 2.17 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 (0.94 g, 2.28 mmol), NaCO (0.46 g, 4.34 mmol), and Pd(dppf)Cl (79.3 mg, 0.108 mmol) in dioxane (60 mL) and HO (10 mL) was stirred at 100 °C overnight in a sealed tube. After cooling, the reaction mixture was filtered, and the solid was washed with 5 mL of MeOH and dried under vacuum to give the product (1.02 g, 70.6%). [M+H] + = 666.0.

[0174] Step 3: (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(6-(piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide, hydrochloride salt [ka] To a solution of tert-butyl (R)-4-(5-(4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)piperazine-1-carboxylate (1.02 g, 1.53 mmol) in DCM (50 mL) in a round-bottom flask was added HCl in dioxane (4 N, 35 mL) at 0° C. The mixture was stirred at 20° C. for 2 hours. The precipitate was collected by filtration and dried in vacuo to give the product (0.92 g, 100%). 1 H NMR (400 MHz, DMSO) δ H 13.53 (s, 1H), 10.06 (d, J = 7.5 Hz, 1H), 9.33 (s, 2H), 9.00 (s, 1H), 8.93 (s, 1H), 8.35 (d, J = 8.7 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.99 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.12 (d, J = 8.9 Hz, 1H), 5.50-5.28 (m, 1H), 3.89 (s, 4H), 3.20 (s, 4H), 2.57 (s, 3H), 1.56 (d, J = 6.9 Hz, 3H), 1.38 (s, 9H). [M+H] + = 566.3.

[0175] Step 4: (R)-3-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(6-(piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide, hydrochloride (0.06 g, 0.1 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (0.033 g, 0.11 mmol) and NaOAc (8.2 mg, 0.1 mmol) in DCM / EtOH (30 mL / 10 mL) was stirred in a round-bottom flask for 1 hour at 20° C. Then, NaBHCN (12.6 mg, 0.2 mmol) was added. The mixture was stirred overnight at 20° C. The mixture was concentrated to dryness and purified by silica gel column chromatography (0% to 12% MeOH in DCM gradient elution) to give the product (0.049 g, 57.8%). 1 H NMR (400 MHz, DMSO) δ H12.60 (s, 1H), 10.27 (s, 1H), 9.97 (d, J = 6.1 Hz, 1H), 8.79 (d, J = 18.7 Hz, 2H), 8.18 (d, J = 7.8 Hz, 1H), 8.09 (d, J = 7.0 Hz, 1H), 8.04 (s, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.30 (s, 1H), 7.13 (d, J = 6.9 Hz, 2H), 6.97-6.92 (m, 3H), 5.41-5.34 (m, 1H), 3.71-3.68 (m, 4H), 3.64-3.56 (m, 4H), 2.70-2.64 (m, 4H), 2.53 (s, 3H), 2.47-2.43 (m, 4H), 2.25-2.19 (m, 2H), 1.84-1.81 (m, 2H), 1.75-1.70 (m, 1H), 1.56 (t, J = 9.1 Hz, 3H), 1.37 (s, 9H), 1.28-1.18 (m, 2H).

[0176] Example 15: 3-(tert-butyl)-N-(4-(6-(4-(1-(2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide Step 1: tert-butyl (4-bromo-2-fluorophenyl)carbamate [ka] To a 500 mL round-bottom flask, 4-bromo-2-fluoroaniline (20.00 g) and (Boc)2O (49.80 g) in t-BuOH (250.00 mL) were added at 50° C. overnight. The resulting mixture was stirred overnight at 50° C. under an air atmosphere. The aqueous layer was extracted with EtOAc. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (50:1) to give the product (20 g, 65.7%).

[0177] Step 2: tert-butyl (4-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-fluorophenyl)carbamate [ka] To a 500 mL round-bottom flask containing a mixture of tert-butyl (4-bromo-2-fluorophenyl)carbamate (5.00 g) and 4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidine (10.00 g), Xphos (1.65 g), CsCO (16.90 g), dioxane (300.00 mL), and Pd(dba) (1.80 g) were added at room temperature. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give the product (8.0 g, 80.6%).

[0178] Step 3: 4-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-fluoroaniline [ka] To a stirred mixture of tert-butyl (4-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-fluorophenyl)carbamate (8.00 g) in DCM (40.00 mL) was added TFA (10.00 mL) dropwise at room temperature. The resulting mixture was stirred for 2 hours at room temperature under an air atmosphere. The resulting mixture was concentrated in vacuo. The crude product was used directly in the next step without further purification.

[0179] Step 4: 3-((4-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-fluorophenyl)amino)propanoic acid [ka] A stirred mixture of 4-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-fluoroaniline (3.80 g) and acrylic acid (2.00 g) in toluene (100.00 mL) was degassed in vacuo and flushed with nitrogen three times, then the mixture was heated in an oil bath at 100° C. for 12 hours. The mixture was used directly for the next step.

[0180] Step 5: 1-(4-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] To a mixture of 3-((4-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-fluorophenyl)amino)propanoic acid was added urea (1.17 g) and AcOH (30.00 mL), and the reaction was then heated at 105° C. under a nitrogen atmosphere for 12 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (20:1) to give the product (3 g, 65.6%).

[0181] Step 6: 1-(2-fluoro-4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] To a 50 mL round-bottom flask was added 1-(4-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (1 g) and CsF (1 g) in DMF (20.00 mL) at 35° C. The final reaction mixture was stirred overnight at 35° C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl / MeOH=8:1) to give the product (206.7 mg, 35.5%). 1 H NMR (300 MHz, DMSO) δ H 10.35 (s, 1H), 7.18 (d, J = 9 Hz, 1H), 6.76 (m, 2H), 4.36 (t, J = 5 Hz, 1H), 3.70 (m, 2H), 3.62 (m, 2H), 3.58 (m, 2H), 2.69 (m, 3H), 1.99 (m, 1H), 1.72 (m, 2H), 1.58 (m, 1H), 1.45 (m, 2H), 1.24 (m, 2H);[M+H] + = 336.0.

[0182] Step 7: 2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)piperidin-4-yl)acetaldehyde [ka] To a solution of 1-(2-fluoro-4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg, 0.6 mmol) in DMSO (10 mL) was added IBX (338 mg, 1.2 mmol). The mixture was stirred in a round-bottom flask at room temperature overnight. After the reaction was determined to be complete by LCMS, the mixture was extracted with EA (30 mL x 3), dried over anhydrous NaSO, and evaporated in vacuo to give the crude product (100 mg, crude), which was used for the next step without further purification. [M+H]+ = 334.1.

[0183] Step 8: 3-(tert-butyl)-N-(4-(6-(4-(1-(2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] To a solution of 3-(tert-butyl)-N-(2-methyl-4-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (100 mg, 0.182 mmol) in DCM (20 mL) and MeOH (5 mL) was added 2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)piperidin-4-yl)acetaldehyde (61 mg, 0.182 mmol) and AcOH (3 drops). The mixture was stirred overnight at room temperature. To the mixture was added HO (30 mL) and extracted with DCM (30 mL × 2). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was further purified by preparative HPLC to give the product (22 mg, 13.9%). 1 H NMR (400 MHz, DMSO) δ H12.69 (s, 1H), 10.38 (s, 1H), 9.93-9.91 (m, 1H), 8.80 (s, 1H), 8.37 (s, 2H), 8.07 (s, 2H), 7.98 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 1H), 7.38-7.36 (m, 3H), 7.20-7.16 (m, 1H), 6.83-6.75 (m, 2H), 4.56 (d, J = 8.0 Hz, 2H), 3.75-3.72 (m, 2H), 3.62-3.60 (m, 2H), 3.02-2.99 (m, 5H), 2.70-2.67 (m, 4H), 2.39-2.37 (m, 2H), 2.01-1.96 (m, 2H), 1.77-1.67 (m, 6H), 1.46-1.44 (m, 4H), 1.38 (s, 9H), 1.24-1.21 (m, 2H);[M+H] + = 867.5.

[0184] Example 16: 3-(tert-butyl)-N-(4-(6-(1-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide Step 1: tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate [ka] A mixture of tert-butyl 4-(4-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate (1 g, 3.03 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.54 g, 6.06 mmol), Pd(dppf)Cl2 (0.25 g, 0.303 mmol), and KOAc (0.89 g, 9.09 mmol) in dioxane (20 mL) was stirred in a round-bottom flask at 90 °C under N2 overnight. The mixture was evaporated in vacuo to give the crude product, which was further purified by silica gel column chromatography (PE:EA = 100:0 to 90:10 gradient elution) to give the product (1.01 g, 90%). [M+H] + = 378.2.

[0185] Step 2: tert-butyl 4-(4-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate [ka] A mixture of 4-chloro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (0.6 g, 1.43 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.01 g, 1.72 mmol), Pd(dppf)Cl (0.12 g, 0.14 mmol), and KCO (0.393 g, 2.86 mmol) in a mixture of dioxane (20 mL) and water (4 mL) was stirred in a round-bottom flask at 80 °C overnight. The mixture was evaporated in vacuo to give the crude product, which was further purified by silica gel column chromatography (PE:EA = 100:0 to 1:1 gradient elution) to give the product (0.7 g, 90%). [M+H] + = 543.1.

[0186] Step 3: tert-butyl 4-(4-(4-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate [ka] A mixture of tert-butyl 4-(4-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.7 g, 1.29 mmol), 3-(tert-butyl)-N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (0.521 g, 1.28 mmol), Pd(dppf)Cl (0.105 g, 0.13 mmol) and KCO (0.357 g, 2.58 mmol) in a mixture of dioxane (20 mL) and water (7 mL) was stirred at 90 °C overnight in a round-bottom flask. The mixture was evaporated in vacuo to give the crude product, which was further purified by silica gel column chromatography (PE:EA = 100:0 to 0:100 gradient elution) to give the product (0.12 g, 15%). [M+H] + = 644.0.

[0187] Step 4: 3-(tert-butyl)-N-(2-fluoro-4-(6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of tert-butyl 4-(4-(4-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.12 g, 0.18 mmol) and trifluoroacetic acid (1.25 mL) in dichloromethane (5 mL) was stirred in a round-bottom flask at room temperature for 1 hour. The mixture was evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (0.052 g, 53.1%). [M+H] + =544.0.

[0188] Step 5: 3-(tert-butyl)-N-(4-(6-(1-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of 3-(tert-butyl)-N-(2-fluoro-4-(6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (0.025 g, 0.046 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (0.018 g, 0.060 mmol) in dichloromethane (2.5 mL) and MeOH (0.5 mL) was stirred in a round-bottom flask at room temperature for 1 hour. NaBH(OAc) (0.005 g, 0.069 mmol) was added to the mixture, and the mixture was stirred in a round-bottom flask at room temperature overnight. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative TLC (DCM:MeOH=15:1 gradient elution) to give the product (0.0283 g, 74.3%). 1H NMR (400 MHz, DMSO) δ H 12.59 (s, 1H), 10.27 (s, 1H), 9.98 (s, 1H), 8.78 (s, 1H), 8.47 (s, 1H), 8.13 (s, 1H), 8.06 (d, J = 7.5 Hz, 1H), 7.96 (d, J = 11.4 Hz, 1H), 7.62 (s, 1H), 7.14 (d, J = 8.6 Hz, 3H), 6.95 (s, 2H), 4.62 (d, J = 5.3 Hz, 2H), 4.21 (s, 1H), 3.75-3.65 (m, 5H), 3.21-2.85 (m, 4H), 2.72-2.65 (m, 5H), 2.20-1.75 (m, 9H), 1.37 (s, 9H);[M+H] + = 829.5.

[0189] Example 17: 3-(tert-butyl)-N-(4-(6-(4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide Step 1: 5-(4-(hydroxymethyl)piperidin-1-yl)isobenzofuran-1(3H)-one [ka] A solution of 5-fluoroisobenzofuran-1(3H)-one (5.0 g, 33 mmol), piperidin-4-ylmethanol (5.0 g, 43 mmol), and DIPEA (10.0 g, 78 mmol) in DMSO (60 mL) was heated at 130° C. for 3 hours. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous NaSO and evaporated in vacuo to give the crude product, which was further purified by silica gel column chromatography to give the product (7.0 g, 85%). [M+H] + = 248.0.

[0190] Step 2: 5-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)piperidin-1-yl)isobenzofuran-1(3H)-one [ka] A solution of 5-(4-(hydroxymethyl)piperidin-1-yl)isobenzofuran-1(3H)-one (6.0 g, 24 mmol), pyridinium toluene-4-sulfonate (700 mg, 2.8 mmol), and 3,4-dihydro-2H-pyran (6.5 g, 77 mmol) in DCM (150 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous NaSO, and evaporated in vacuo to give the crude product, which was further purified by silica gel column chromatography to give the product (7.1 g, 87%). [M+H] + = 332.3.

[0191] Step 3: 2-(hydroxymethyl)-4-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)piperidin-1-yl)benzoic acid [ka] A solution of 5-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)piperidin-1-yl)isobenzofuran-1(3H)-one (7.1 g, 21 mmol) and NaOH (2.5 g, 62.5 mmol) in MeOH (100 mL) / HO (100 mL) / THF (100 mL) was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the pH value of the residue was adjusted to 6 with 1N HCl. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, and evaporated in vacuo to give the crude product (6.6 g). [M+H] + = 350.4.

[0192] Step 4: 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)piperidin-1-yl)benzoic acid [ka] A mixture of 2-(hydroxymethyl)-4-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)piperidin-1-yl)benzoic acid (6.6 g, 19 mmol), TBSCl (5.0 g, 33 mmol), and imidazole (5.0 g, 74 mmol) in DCM (200 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated in vacuo to give the crude product, which was further purified by silica gel column chromatography to give the product (8.0 g, 89%). [M+H] + = 464.5.

[0193] Step 5: 2-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,6-dioxopiperidin-3-yl)-4-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)piperidin-1-yl)benzamide [ka] A solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)piperidin-1-yl)benzoic acid (8.0 g, 17 mmol), HATU (7.6 g, 20 mmol), 3-aminopiperidine-2,6-dione hydrochloride (3.7 g, 22 mmol), and DIPEA (14 mL, 80 mmol) in DMF (100 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to give the crude product, which was further purified by silica gel column chromatography to give the product (5.6 g, 57%). [M+H] + = 574.4.

[0194] Step 6: N-(2,6-dioxopiperidin-3-yl)-2-(hydroxymethyl)-4-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)piperidin-1-yl)benzamide [ka] A solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,6-dioxopiperidin-3-yl)-4-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)piperidin-1-yl)benzamide (5.6 g, 9.8 mmol) and TBAF (1 M in THF, 2.5 mmol) in THF (100 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to give the crude product, which was further purified by silica gel column chromatography to give the product (2.5 g, 55%). [M+H] + = 460.4.

[0195] Step 7: 3-(1-oxo-5-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione [ka] A solution of N-(2,6-dioxopiperidin-3-yl)-2-(hydroxymethyl)-4-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)piperidin-1-yl)benzamide (2.5 g, 5.4 mmol), TsCl (1.5 g, 7.9 mmol), and EtN (6 mL, 43 mmol) in DCM (100 mL) was stirred at 40° C. for 16 h. The reaction was quenched with water and extracted with DCM. The organic layer was dried over anhydrous NaSO and evaporated in vacuo to give the crude product, which was further purified by silica gel column chromatography to give the product (1.9 g, 80%). [M+H] + = 442.2.

[0196] Step 8: 3-(5-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] A solution of 3-(1-oxo-5-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (1.8 g, 4.1 mmol) in HCl / dioxane (4N, 5 mL) / DCM (100 mL) / MeOH (100 mL) was stirred at room temperature for 1 hour. The mixture was evaporated in vacuo to give the crude product (1.7 g). [M+H] + = 358.3.

[0197] Step 9: 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-4-carbaldehyde [ka] A mixture of 3-(5-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (200 mg, 0.51 mmol) and IBX (200 mg, 0.71 mmol) in DMSO (8 mL) was stirred at room temperature for 1 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to give the crude product (180 mg). [M+H] + = 356.2.

[0198] Step 10: 3-(tert-butyl)-N-(4-(6-(4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-4-carbaldehyde (180 mg, 0.51 mmol), 3-(tert-butyl)-N-(2-methyl-4-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (50 mg, 0.091 mmol), and NaBH(OAc) (100 mg, 0.47 mmol) in dichloroethane (10 mL) was stirred at room temperature for 16 hours. The mixture was then evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography to give the product (15 mg, 10%). 1 H NMR (400 MHz, DMSO) δ H 12.69 (s, 1H), 10.71 (s, 1H), 9.92 (s, 1H), 8.81 (s, 1H), 8.07 (s, 2H), 8.00 (d, J = 7.5 Hz, 2H), 7.55-7.44 (m, 2H), 7.38 (s, 3H), 7.06 (d, J = 8.5 Hz, 1H), 7.00 (s, 1H), 5.31 (s, 2H), 4.57 (s, 3H), 3.90 (d, J = 11.1 Hz, 2H), 2.85 (t, J = 11.7 Hz, 3H), 2.72-2.57 (m, 4H), 2.05-1.94 (m, 3H), 1.89-1.78 (m, 5H), 1.38 (s, 9H);[M+H] + =889.5.

[0199] Example 18: 3-(tert-butyl)-N-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide Step 1: tert-butyl 4-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(4-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate (0.6 g, 1.1 mmol) in THF (20 mL) was added NaOH in MeOH (4%, 3 mL). The mixture was stirred at 20-30 °C for 1 h. The solvent was evaporated and HO (20 mL) was added. The mixture was filtered and washed with HO. The filter cake was dried under reduced pressure and used as is for the next step.

[0200] Step 2: tert-butyl 4-(4-(4-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate (120 mg, 0.3 mmol) in dioxane (15 mL) and HO (3 mL) was added 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 (120 mg, 0.3 mmol), KCO (124 mg, 0.9 mmol), and Pd(dppf)Cl.CHCl (22 mg, 0.03 mmol). The mixture was stirred at 90 °C under N for 5 h. The solvent was evaporated, HO (20 mL) was added, and extracted with DCM / iPrOH (20:1, 30 mL × 3). The organic phases were combined, washed with brine, concentrated, and purified by preparative TLC with DCM / MeOH (DCM:MeOH = 20:1) to give the product (110 mg, crude).

[0201] Step 3: 3-(tert-butyl)-N-(2-methyl-4-(6-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride [ka] To a solution of tert-butyl 4-(4-(4-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate (110 mg, 0.17 mmol) in dioxane (3 mL) was added HCl / dioxane (4 N, 20 mL). The mixture was stirred at 20-30 °C for 4 h, concentrated to 5 mL, and filtered. The filter cake was washed to give the crude product, which was used directly for the next step. 1 H NMR (400 MHz, DMSO) δ H13.53 (s, 1H), 9.99 (s, 1H), 9.38 (s, 2H), 9.00 (s, 1H), 8.04-8.02 (m, 4H), 7.57 (d, J = 8.4 Hz, 1H), 7.48 (s, 1H), 7.14 (d, J = [M+H] + = 551.3.

[0202] Step 4: 3-(tert-butyl)-N-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] To a solution of 3-(tert-butyl)-N-(2-methyl-4-(6-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride (140 mg, 0.24 mmol) in DCM / EtOH (10:1, 33 mL) was added 1-(4-(4-oxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (71 mg, 0.24 mmol), HOAc (1 drop), and NaOAc (40 mg, 0.48 mmol). After stirring at 20-30 °C for 60 min, NaBH(OAc) (102 mg, 0.48 mmol) was added. The mixture was stirred at 20-30°C for 5 h. The solvent was evaporated, HO (30 mL) was added, and extracted with DCM / iPrOH (20:1, 30 mL x 3). The organic phases were combined, concentrated, and purified by preparative TLC with DCM / MeOH (10:1) to give the product (100 mg, 49.8%). 1H NMR (400 MHz, DMSO) δ H 12.53 (s, 1H), 10.27 (s, 1H), 9.91 (br, 1H), 8.75 (s, 1H), 8.06 (s, 2H), 7.91 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.22 (s, 1H), 7.13 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 4.56 (d, J = 5.6 Hz, 2H), 3.77-3.60 (m, 4H), 3.26 (s, 4H), 2.70-2.64 (m, 4H), 2.23 (d, J = 6.0 Hz, 2H), 1.89-1.64 (m, 3H), 1.37 (s, 9H), 1.29-1.17 (m, 3H);[M+H] + =836.5.

[0203] Example 19: (R)-3-(tert-butyl)-N-(1-(4-(6-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide Step 1: tert-Butyl 4-(6-(trimethylstannyl)pyridin-3-yl)piperazine-1-carboxylate [ka] A mixture of tert-butyl 4-(6-bromopyridin-3-yl)piperazine-1-carboxylate (1.71 g, 5 mmol), 1,1,1,2,2,2-hexamethyldistannane (1.8 g, 5.5 mmol), and Pd(PPh3)4 (0.289 g, 0.25 mmol) in dioxane (50 mL) was stirred in a sealed tube at 100 °C for 6 h. LCMS showed complete conversion of the starting material to the target product. The resulting mixture was used directly in the next step. [M+H] + = 428.1.

[0204] Step 2: tert-butyl 4-(6-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-3-yl)piperazine-1-carboxylate [ka] To a mixture of tert-butyl 4-(6-(trimethylstannyl)pyridin-3-yl)piperazine-1-carboxylate in dioxane from the previous step was added a solution of 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (2.05 g, 5 mmol) and Pd(PPh3)2Cl2 (0.178 g, 0.25 mmol) in 30 mL of dioxane. The resulting mixture was stirred in a sealed tube at 100 °C for 24 h. After cooling, the solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (0% to 60% EtOAc in DCM gradient elution) to give the product (0.31 g, 11.4%). [M+H] + = 545.3.

[0205] Step 3: tert-butyl (R)-4-(6-(4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-3-yl)piperazine-1-carboxylate [ka] tert-Butyl 4-(6-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-3-yl)piperazine-1-carboxylate (0.31 g, 0.569 mmol), (R)-3-(tert-butyl)-N-(1-(2-methyl- A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (0.235 g, 0.569 mmol), Na2CO3 (90 mg, 0.853 mmol), and Pd(dppf)Cl2 (20.8 mg, 0.028 mmol) was stirred in a sealed tube at 100 °C overnight. After cooling, the reaction was quenched with water, and the mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to give the crude product, which was further purified by silica gel column chromatography (0% to 60% EtOAc in DCM gradient elution) to give the product (0.28 g, 61.9%). [M+H] + = 796.0.

[0206] Step 4: (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(5-(piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide, hydrochloride [ka] To a solution of tert-butyl (R)-4-(6-(4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-3-yl)piperazine-1-carboxylate (0.28 g, 0.352 mmol) in DCM (50 mL) in a round-bottom flask was added HCl in dioxane (4 N, 20 mL) at 0° C. The mixture was stirred at 20° C. for 48 hours. The solvent was removed under vacuum. The residue was recrystallized from MeOH / acetonitrile to give the product (0.15 g, 67%). 1 H NMR (400 MHz, DMSO) δ H 12.65 (s, 1H), 9.97 (d, J = 7.7 Hz, 1H), 8.80 (s, 1H), 8.44 (s, 1H), 8.09 (dd, J = 16.1, 8.6 Hz, 2H), 8.02 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 9.2 Hz, 1H), 7.45 (d, J = 9.2 Hz, 2H), 7.40 (s, 1H), 7.34 (s, 1H), 5.38 (s, 1H), 3.54 (s, 4H), 3.26 (s, 4H), 2.53 (s, 3H), 1.55 (d, J = 6.8 Hz, 3H), 1.37 (s, 9H); [M+H] + = 566.3.

[0207] Step 5: (R)-3-(tert-butyl)-N-(1-(4-(6-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(5-(piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide, hydrochloride (0.06 g, 0.094 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (0.033 g, 0.1 mmol) and NaOAc (16.4 mg, 0.2 mmol) in DCM / EtOH (50 mL / 10 mL) was stirred in a round-bottom flask for 1 hour at 20° C. Then NaBHCN (12.6 mg, 0.2 mmol) was added. The mixture was stirred for 8 hours at 20° C. The mixture was concentrated to dryness and purified by silica gel column chromatography (0% to 10% MeOH in DCM gradient elution) to give the product (0.028 g, 35.0%). 1 H NMR (400 MHz, DMSO) δ H 12.61 (s, 1H), 10.27 (s, 1H), 9.96 (d, J = 7.3 Hz, 1H), 8.78 (s, 1H), 8.39 (s, 1H), 8.10-8.12 (m, 3H), 7.68 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 9.2 Hz, 1H), 7.40 (s, 1H), 7.13 (d, J = 8.2 Hz, 2H), 6.93 (d, J = 8.1 Hz, 2H), 5.40-5.34 (m, 1H), 3.72-3.66 (m, 4H), 3.32-3.28 (m, 4H), 2.73-2.66 (m, 4H), 2.54-2.52 (m, 7H), 2.24 (d, J = 5.9 Hz, 2H), 1.92-1.79 (m, 2H), 1.75-1.71 (m, 1H), 1.55 (d, J = 6.4 Hz, 3H), 1.37 (s, 9H), 1.27-1.20 (m, 2H);[M+H] + = 851.5.

[0208] Example 20: (R)-3-(tert-butyl)-N-(1-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide Step 1: tert-butyl 4-(4-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate [ka] To a solution of 4-chloro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 14.4 mmol) in dioxane (35 mL) and HO (7 mL) was added tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (1.6 g, 4.2 mmol), KCO (1.6 g, 12 mmol), and Pd(dppf)Cl.CHCl (0.3 g, 0.4 mmol). The mixture was stirred at 80 °C for 6 h and concentrated to dryness. Water (30 mL) was added to the residue and extracted with EtOAc (30 mL × 2). The organic phase was concentrated and purified by flash chromatography with PE / EtOAc (100:1 to 7:3) to give the product (1.9 g, 86.4%).

[0209] Step 2: tert-Butyl 4-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(4-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate (4.0 g, 7.2 mmol) in THF (30 mL) was added NaOH in MeOH (4%, 5 mL). After stirring at 20-30 °C for 1 h, the solvent was evaporated and HO (20 mL) was added. The mixture was filtered, and the filter cake was washed with HO. The product (3 g, crude) was isolated after drying under reduced pressure and used as is for the next step.

[0210] Step 3: tert-butyl (R)-4-(4-(4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate (413 mg, 1 mmol) in dioxane / HO (5:1, 45 mL) was added (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 (413 mg, 1.0 mmol), KCO (414 mg, 3.0 mmol), and Pd(dppf)Cl.CHCl (82 mg, 0.1 mmol). The mixture was stirred at 100 °C under N for 6 h. After evaporation of the solvent, water (20 mL) was added. The mixture was extracted with DCM (30 mL x 2). The combined organic phases were concentrated and purified by preparative TLC with DCM / MeOH (100:1 to 20:1) to give the product (600 mg, 90.2%).

[0211] Step 4: (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride [ka] To a solution of tert-butyl (R)-4-(4-(4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate (1.1 g, 1.6 mmol) in dioxane (3 mL) was added HCl / dioxane (4 N, 30 mL). The mixture was stirred at 20-30° C. for 3 h and then concentrated to 10 mL. The solid was separated by filtration and washed with dioxane (10 mL). The product (1 g, 100%) was isolated after drying under reduced pressure. 1 H NMR (400 MHz, DMSO) δ H 13.43 (s, 1H), 10.06 (d, J = 7.2 Hz, 1H), 9.34 (s, 2H), 8.98 (s, 1H), 8.19-7.92 (m, 4H), 7.75 (d, J = 8.4 Hz, 1H), 7.48 (s, 1H), 7.13 (d, J = 8.8 Hz, 2H), 5.38 (t, J = 7.2 Hz, 1H), 3.55 (s, 4H), 3.22 (s, 4H), 2.57 (s, 3H), 1.56 (d, J = 6.8 Hz, 3H), 1.38 (s, 9H);[M+H] + = 565.3.

[0212] Step 5: (R)-3-(tert-butyl)-N-(1-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] To a solution of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride (0.8 g, 1.33 mmol) in DCM / EtOH (5:1, 60 mL) was added 1-(4-(4-oxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (0.4 g, 1.33 mmol) and NaOAc (0.33 g, 4.0 mmol). After stirring at 20-30 °C for 60 min, NaBH(OAc) (0.85 g, 4.0 mmol) was added. The mixture was stirred for another 2 h at 20-30° C. The solvent was evaporated and directly purified by chromatography on silica gel with DCM / MeOH (100:1 to 20:1) to give the product (400 mg, 35.4%). 1 H NMR (400 MHz, DMSO) δ H12.52 (s, 1H), 10.27 (s, 1H), 9.97 (d, J = 7.6 Hz, 1H), 8.75 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.23 (s, 1H), 7.13 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.38 (br, 1H), 3.69 (t, J = 6.8 Hz, 4H), 3.26 (s, 4H), 2.69-2.67 (m, 5H), 2.60-2.50 (m, 5H), 2.24 (br, 2H), 1.89-1.67 (m, 3H), 1.55 (d, J = 7.2 Hz, 3H), 1.37 (s, 9H), 1.24 (br, 3H);[M+H] + = 850.4.

[0213] Example 21: (R)-3-(tert-butyl)-N-(1-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-fluorophenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that of Example 19. 1 H NMR (400 MHz, DMSO) δ H12.61 (s, 1H), 10.27 (s, 1H), 10.03 (d, J = 7.2 Hz, 1H), 8.78 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 12.0 Hz, 1H), 7.93 (d, J = 7.2 Hz, 2H), 7.71 (t, J = 8.0 Hz, 1H), 7.30 (s, 1H), 7.13 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 7.6 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 5.58-5.38 (m, 1H), 3.71-3.66 (m, 4H), 3.26 (s, 4H), 2.72-2.65 (m, 5H), 2.60-2.50 (m, 2H), 2.22 (br, 2H), 1.87-1.69 (m, 3H), 1.59 (d, J = 6.8 Hz, 3H), 1.38 (s, 9H), 1.24 (br, 3H);[M+H] + = 854.4.

[0214] Example 22: 3-(tert-butyl)-N-(4-(6-(4-(1-(2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)ethyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide Step 1: 4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidine [ka] A 1000 mL round-bottom flask was charged with 4-piperidineethanol (20.00 g, 154.795 mmol), DMF (300.00 mL), tert-butyl(chloro)diphenylsilane (85.10 g, 309.612 mmol), and imidazole (26.35 g, 386.988 mmol). The resulting solution was stirred at room temperature for 1 hour. The resulting solution was diluted with HO. The resulting solution was extracted with ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:7) to give the product (22 g, 38.66%).

[0215] Step 2: 4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-1-(3-methyl-4-nitrophenyl)piperidine [ka] A 100 mL round-bottom flask was charged with 4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidine (5.00 g, 13.601 mmol), DMSO (50.00 mL), 4-fluoro-2-methyl-1-nitrobenzene (2.11 g, 13.601 mmol), and DIEA (6.80 mL, 39.040 mmol). The resulting solution was stirred at 60 °C for 1 hour. The reaction mixture was cooled to room temperature. The resulting solution was diluted with HO. The resulting solution was extracted with ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:8) to give the product (5.2 g, 76.05%).

[0216] Step 3: 4-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-methylaniline [ka] A 100 mL round-bottom flask was charged with 4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-1-(3-methyl-4-nitrophenyl)piperidine (5.20 g, 10.344 mmol), methanol (50.00 mL), acetic acid (0.20 mL), and Pd / C (1.00 g, 9.397 mmol). To the above mixture was introduced H2(g). The resulting solution was stirred at room temperature for 3 hours. The solid was filtered off. The resulting mixture was concentrated under vacuum to give the product (5 g, crude).

[0217] Step 4: 3-((4-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-methylphenyl)amino)propanoic acid [ka] A 100 mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with 4-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-methylaniline (2.50 g, 5.288 mmol), toluene (20.00 mL), and acrylic acid (0.65 mL). The resulting solution was stirred overnight at 100° C. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum to provide the product (2.85 g, 74.19%).

[0218] Step 5: 1-(4-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] A 100 mL round-bottom flask was charged with 3-((4-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-methylphenyl)amino)propanoic acid (2.85 g, 5.231 mmol), toluene (25.00 mL), AcOH (12.00 mL), and urea (1.00 g, 16.651 mmol). The resulting solution was stirred overnight at 105° C. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC with ethyl acetate / petroleum ether (3:1) to give the product (1.65 g, 55.35%).

[0219] Step 6: 1-(4-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] A 50 mL round-bottom flask was charged with 1-(4-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione (1.37 g, 2.404 mmol), DMF (10.00 mL), and CsF (1.82 g, 11.981 mmol). The resulting solution was stirred at 40° C. for 2 hours. The resulting solution was diluted with HO. The resulting solution was extracted with ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by preparative TLC with dichloromethane / methanol (10:1) to give the product (379.2 mg, 47.59%). 1 H NMR (300 MHz, DMSO) δ H10.22 (s, 1H), 7.02 (d, J = 8.5 Hz, 1H), 6.83-6.70 (m, 2H), 4.35 (t, J = 5.0 Hz, 1H), 3.73-3.58 (m, 3H), 3.52-3.38 (m, 3H), 2.80-2.64 (m, 2H), 2.61 (dd, J = 12.3, 9.8 Hz, 2H), 2.10 (s, 3H), 1.72 (d, J = 12.7 Hz, 2H), 1.38 (q, J = 6.6 Hz, 2H), 1.31-1.13 (m, 3H);[M+H] + = 332.19.

[0220] Step 7: 2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)acetaldehyde [ka] To a solution of 1-(4-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg, 0.6 mmol) in DMSO (10 mL) was added IBX (338 mg, 1.2 mmol). The mixture was stirred in a round-bottom flask at room temperature overnight. After the reaction was determined to be complete by LCMS, the mixture was extracted with EtOAc (30 mL x 3), dried over anhydrous NaSO, and evaporated in vacuo to give the crude product (100 mg, crude), which was used for the next step without further purification. [M+H] + = 330.1.

[0221] Step 8: 3-(tert-butyl)-N-(4-(6-(4-(1-(2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)ethyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] To a solution of 3-(tert-butyl)-N-(2-methyl-4-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (100 mg, 0.182 mmol) in DCM (20 mL) and MeOH (5 mL) was added 2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)acetaldehyde (60 mg, 0.182 mmol) and AcOH (3 drops). The mixture was stirred overnight at room temperature. To the mixture was added HO (30 mL) and extracted with DCM (30 mL × 2). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was further purified by preparative HPLC to give the product (32 mg, 20.4%). 1 H NMR (400 MHz, DMSO) δ H 12.68 (s, 1H), 10.25 (s, 1H), 9.93-9.91 (m, 1H), 8.80 (s, 1H), 8.22 (s, 2H), 8.07 (s, 2H), 7.98 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 1H), 7.38-7.37 (m, 3H), 7.40 (d, J = 8.0 Hz, 1H), 6.81-6.76 (m, 2H), 4.56 (d, J = 8.0 Hz, 2H), 3.47-3.44 (m, 2H), 3.04-3.01 (m, 2H), 2.72-2.61 (m, 5H), 2.40-2.39 (m, 2H), 2.12 (s, 3H), 2.05-2.00 (m, 2H), 1.77-1.68 (m, 6H), 1.47-1.45 (m, 3H), 1.37 (s, 9H), 1.26-1.24 (m, 2H);[M+H] + = 863.5.

[0222] Example 23: 3-(tert-butyl)-N-(4-(6-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 22. 1 H NMR (400 MHz, DMSO) δ H 12.79 (s, 1H), 10.29 (s, 1H), 10.02 (s, 1H), 8.87-8.16 (m, 1H), 8.25-8.03 (m, 5H), 7.64 (s, 1H), 7.46-7.41 (m, 3H), 7.18-7.14 (m, 2H), 6.98-6.93 (m, 2H), 4.65 (s, 2H), 3.73-3.71 (m, 4H), 3.03-3.01 (m, 2H), 2.69-2.60 (m, 6H), 2.25-2.22 (m, 2H), 2.05-2.02 (m, 3H), 1.86-1.82 (m, 4H), 1.40 (s, 9H), 1.28-1.26 (m, 3H);[M+H] + = 839.5.

[0223] Example 24: 3-(tert-butyl)-N-(4-(6-(4-(1-(2-(1-(3-chloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)ethyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide Step 1: 2-(1-(3-chloro-4-nitrophenyl)piperidin-4-yl)ethan-1-ol [ka] To a solution of 2-chloro-4-fluoro-1-nitrobenzene (141.0 g, 0.8 mol) and K2CO3 (278 g, 2.01 mol) in DMF (300 mL) was added 2-(piperidin-4-yl)ethan-1-ol (147 g, 0.89 mol). The resulting mixture was then stirred at 25 °C for 5 hours. TLC (petroleum ether / ethyl acetate = 10 / 1) showed that the starting material was completely consumed. The mixture was poured into H2O (300 mL). The aqueous phase was extracted with ethyl acetate (300 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the product (255 g, crude).

[0224] Step 2: 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(3-chloro-4-nitrophenyl)piperidine [ka] To a solution of 2-(1-(3-chloro-4-nitrophenyl)piperidin-4-yl)ethan-1-ol (255.0 g, 0.90 mol) and imidazole (91.5 g, 1.343 mol) in THF (1280 mL) was added TBSCl (202 g, 1.343 mol). The resulting mixture was then stirred at 25 °C for 3 h. TLC (petroleum ether / ethyl acetate = 10 / 1) showed that the starting material was completely consumed. The mixture was poured into H O (765 mL). The aqueous phase was extracted with dichloromethane (765 mL). The organic layer was dried over anhydrous Na SO , filtered, and concentrated in vacuo to give the product (320 g, 89.5%).

[0225] Step 3: 4-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-1-yl)-2-chloroaniline [ka] To a solution of 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(3-chloro-4-nitrophenyl)piperidine (320.0 g, 0.8 mol) and Fe (224 g, 4.01 mol) in MeOH (1920 mL) was added HOAc (289 g, 4.81 mol) at 25 °C. The resulting mixture was then stirred at 65 °C for 3 h. TLC (petroleum ether / ethyl acetate = 2 / 1) showed that the starting material was completely consumed. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 50:1 to 10:1) to give the product (138.0 g, 46.6%).

[0226] Step 4: 3-((4-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-1-yl)-2-chlorophenyl)amino)propanoic acid [ka] To a solution of 4-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-1-yl)-2-chloroaniline (80.0 g, 0.217 mol) in toluene (400 mL) was added acrylic acid (80 mL), and the mixture was stirred at 110° C. under N for 5 hours. TLC (dichloromethane:methanol=10:1) showed that the starting material was completely consumed. The mixture was concentrated under reduced pressure to give the product (120.0 g, crude).

[0227] Step 5: 2-(1-(3-chloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)ethyl acetate [ka] To a solution of 3-((4-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-1-yl)-2-chlorophenyl)amino)propanoic acid (120.0 g, 0.272 mol) in HOAc (600 mL) was added urea (32.7 g, 0.544 mol) at 25° C. The resulting mixture was then stirred at 120° C. for 12 hours. TLC (dichloromethane:methanol=10:1) showed that the starting material was completely consumed. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate=10:1 to 1:1) to give the product (30.0 g, 28.0%). 1 H NMR (400 MHz, DMSO) δ H 7.23 (d, J = 8.80 Hz, 1H), 7.04 (d, J = 2.80 Hz, 1H), 6.94-6.92 (m, 1H), 4.17-4.15 (m, 2H), 3.73-3.71 (m, 4H), 2.83-2.81 (m, 4H), 2.03 (s, 3H), 1.82 (d, J = 0.80 Hz, 2H), 1.62-1.60 (m, 3H), 1.35-1.33 (m, 2H);[M+H] + =394.1.

[0228] Step 6: 1-(2-chloro-4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] To a solution of 2-(1-(3-chloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)ethyl acetate (40.0 g, 0.102 mol) in MeOH (120 mL) / THF (120 mL) was added K2CO3 (42.1 g, 0.305 mol) at 25 °C. The resulting mixture was then stirred at 25 °C for 2 h. TLC (dichloromethane:methanol = 10:1) showed that the starting material was completely consumed. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1 to 0:1) to give the product (30.0 g, 83.9%). 1 H NMR (400 MHz, DMSO) δ H 10.4 (s, 1H), 7.22 (d, J = 8.80 Hz, 1H), 7.00 (d, J = 2.40 Hz, 1H), 6.92 (t, J = 4.40 Hz, 1H), 4.37 (s, 1H), 3.73 (d, J = 12.8 Hz, [M+H] + =352.1.

[0229] Step 7: 2-(1-(3-chloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)acetaldehyde [ka] 1-(2-chloro-4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (1.5 g, 4.26 mmol) was dissolved in DMSO (15 mL), IBX (1.79 g, 6.39 mmol) was added, and the reaction was stirred at 25° C. overnight until LC-MS showed all starting material was consumed. The reaction was quenched by the addition of EtOAc (30 mL) and water (30 mL). The mixture was filtered to give the product (1 g, 70%), which was used directly without further purification. [M+H] + =350.2.

[0230] Step 8: 3-(tert-butyl)-N-(4-(6-(4-(1-(2-(1-(3-chloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)ethyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] To a solution of the compounds 3-(tert-butyl)-N-(2-methyl-4-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (0.15 g, 0.273 mmol) and 2-(1-(3-chloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)acetaldehyde (0.153 g, 0.436 mmol) in DCE / MeOH (18 mL, 5 / 1) was added one drop of HOAc. The mixture was stirred for 0.5 h. NaBH(OAc) (0.116 g, 0.546 mmol) was added and the reaction was stirred at room temperature overnight. The mixture was concentrated to dryness and purified by preparative HPLC to give the product (167.55 mg, 69.47%). 1 H NMR (400 MHz, DMSO) δ H12.72 (s, 1H), 10.38 (s, 1H), 9.92 (s, 1H), 8.82 (s, 1H), 8.07-8.04 (m, 5H), 7.48 (d, J = 7.2 Hz, 1H), 7.40-7.37 (m, 3H), 7.25 (d, J = 9.2 Hz, 1H), 7.05 (s, 1H), 6.96-6.94 (m, 1H), 4.57 (s, 2H), 3.79 (d, J = 10.7 Hz, 2H), 3.68-3.48 (m, 4H), 3.21-2.81 (m, 5H), 2.79-2.62 (m, 5H), 2.14-1.43 (m, 10H), 1.38 (s, 9H), 1.33-1.23 (m, 2H);[M+H] + = 883.5.

[0231] Example 25: (R)-3-(tert-butyl)-N-(1-(4-(8-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-9H-purin-6-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide Step 1: tert-butyl 4-(4-(6-chloro-9H-purin-8-yl)phenyl)piperazine-1-carboxylate [ka] A mixture of 6-chloropyrimidine-4,5-diamine (1 g, 6.9 mmol), tert-butyl 4-(4-formylphenyl)piperazine-1-carboxylate (2 g, 6.9 mmol), and CoCl (0.089 g, 0.69 mmol) in DMF (50 mL) was stirred at 85 °C overnight under an O atmosphere. After cooling, the reaction mixture was poured into 100 mL of ice water. The precipitate was collected by filtration and washed with water. The solid was dried under vacuum to give the product (2.64 g, 91.9%). [M+H] + = 415.0.

[0232] Step 2: tert-butyl (R)-4-(4-(6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-9H-purin-8-yl)phenyl)piperazine-1-carboxylate [ka] A mixture of tert-butyl 4-(4-(6-chloro-9H-purin-8-yl)phenyl)piperazine-1-carboxylate (0.415 g, 1 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 (0.413 g, 1 mmol), NaCO (0.212 g, 2 mmol), and Pd(dppf)Cl (36.5 mg, 0.05 mmol) in dioxane (50 mL) and HO (8 mL) was stirred in a sealed tube at 100 °C for 48 h. After cooling, the solvent was removed and the residue was purified on a silica gel column (EtOAc in DCM, 0% to 100%) to give the product (0.48 g, 72.2%). [M+H] + = 666.0.

[0233] Step 3: (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(8-(4-(piperazin-1-yl)phenyl)-9H-purin-6-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride [ka] To a solution of tert-butyl (R)-4-(4-(6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-9H-purin-8-yl)phenyl)piperazine-1-carboxylate (0.2 g, 0.3 mmol) in EtOAc (10 mL) was added HCl in dioxane (4 N, 20 mL) at 0° C. The mixture was stirred at 20° C. for 4 hours. The precipitate was collected by filtration and dried in vacuo to give the product (0.14 g, 77.8%).

[0234] Step 4: (R)-3-(tert-butyl)-N-(1-(4-(8-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-9H-purin-6-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(8-(4-(piperazin-1-yl)phenyl)-9H-purin-6-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride (0.14 g, 0.232 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (0.07 g, 0.232 mmol), and NaOAc (38 mg, 0.465 mmol) in DCM / EtOH (100 mL / 50 mL) was stirred in a round-bottom flask for 1 hour at 20° C. Then, NaBHCN (29 mg, 0.465 mmol) was added. The mixture was stirred overnight at 20° C. The mixture was concentrated to dryness and purified by silica gel column chromatography (0% to 10% MeOH in DCM gradient elution) to give the product (92.6 mg, 46.7%). 1 H NMR (400 MHz, DMSO) δ H13.76 (s, 1H), 10.28 (s, 1H), 9.94 (s, 1H), 8.83 (d, J = 18.7 Hz, 2H), 8.68 (s, 1H), 8.20 (s, 2H), 7.71 (s, 1H), 7.15 (s, 4H), 6.95 (s, 2H), 5.40 (s, 1H), 3.71 (s, 4H), 3.36 (s, 4H), 2.70 (s, 4H), 2.55 (s, 3H), 2.51-2.47 (m, 4H), 2.26 (s, 2H), 1.84 (s, 2H), 1.75 (s, 1H), 1.57 (s, 3H), 1.39 (d, J = 5.3 Hz, 9H), 1.26 (s, 2H);[M+H] + = 851.5.

[0235] Example 26: (R)-3-(tert-butyl)-N-(1-(4-(6-(6-(4-(2-(1-(3-chloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)ethyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 24. 1 H NMR (400 MHz, DMSO) δ H12.61 (s, 1H), 10.38 (s, 1H), 9.97 (s, 1H), 8.82 (s, 1H), 8.78 (s, 1H), 8.20 (s, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.69 (s, 1H), 7.31 (s, 1H), 7.23 (s, 1H), 7.03 (s, 1H), 6.95 (s, 2H), 5.39 (s, 1H), 3.75 (d, J = 11.5 Hz, 2H), 3.60 (s, 6H), 3.34 (s, 2H), 2.72 (s, 4H), 2.53 (s, 3H), 2.48-2.46 (m, 1H), 2.39 (s, 2H), 1.88 (s, 1H), 1.76 (s, 2H), 1.56 (s, 3H), 1.47 (s, 2H), 1.38 (s, 9H), 1.25 (s, 2H);[M+H] + = 899.5.

[0236] Example 27: 3-(tert-butyl)-N-(4-(6-(4-((1-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide Step 1: tert-butyl 4-((4-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenoxy)piperidin-1-yl)methyl)piperidine-1-carboxylate [ka] A mixture of 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (409 mg, 1.0 mmol), tert-butyl 4-((4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidin-1-yl)methyl)piperidine-1-carboxylate (550 mg, 1.1 mmol), Pd(dppf)Cl (73 mg, 0.1 mmol) and KCO (276 mg, 2.0 mmol) in dioxane (10 mL) and water (3 mL) was stirred in a round-bottom flask at 80 °C overnight. The mixture was used for the next step without further purification. [M+H] + = 656.6.

[0237] Step 2: tert-butyl 4-((4-(4-(4-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenoxy)piperidin-1-yl)methyl)piperidine-1-carboxylate [ka] To a solution of the mixture from the previous step was added 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 (399 mg, 1.0 mmol), Pd(dppf)Cl (73 mg, 0.1 mmol), and CsCO (650 mg, 2.0 mmol). The reaction mixture was stirred in a round-bottom flask at 110 °C overnight. The mixture was then evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE:EA = 100:0 to 20:80 gradient elution) to give the product (493 mg, 55%, 2 steps). [M+H] + = 893.5.

[0238] Step 3: 3-(tert-butyl)-N-(4-(7-(hydroxymethyl)-6-(4-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of tert-butyl 4-((4-(4-(4-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenoxy)piperidin-1-yl)methyl)piperidine-1-carboxylate (493 mg, 0.55 mmol) in dichloromethane (3 mL) and trifluoroacetic acid (3 mL) was stirred in a round-bottom flask at room temperature overnight. The mixture was then evaporated in vacuo to give the crude product (516 mg, crude), which was used for the next step without further purification. [M+H] + = 693.6.

[0239] Step 4: 3-(tert-butyl)-N-(2-methyl-4-(6-(4-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of 3-(tert-butyl)-N-(4-(7-(hydroxymethyl)-6-(4-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide (516 mg, 0.55 mmol) and ammonium hydroxide (2 mL) in methanol (10 mL) was stirred overnight at room temperature in a round-bottom flask. The mixture was then evaporated in vacuo to give the crude product, which was purified by C18 column chromatography (gradient elution: 0.1% FA in water:acetonitrile = 90:10 to 60:40) to give the product (303 mg, 80%). [M+H] + = 663.6.

[0240] Step 5: 3-(tert-butyl)-N-(4-(6-(4-((1-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid (37 mg, 0.15 mmol) and HATU (57 mg, 0.15 mmol) in DCM (10 mL) and DMF (1 mL) was stirred in a round-bottom flask at room temperature for 1 hour. Then, 3-(tert-butyl)-N-(2-methyl-4-(6-(4-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (100 mg, 0.14 mmol) and DIPEA (56 mg, 0.4 mmol) were added to the mixture and stirred at room temperature overnight. The reaction mixture was purified by C18 column chromatography (gradient elution: 0.1% FA in water: acetonitrile = 60:40 to 20:80) to give the product (57 mg, 45%). 1 H NMR (400 MHz, DMSO) δ H 12.62 (s, 1H), 10.36 (s, 1H), 9.92 (s, 1H), 8.79 (s, 1H), 8.14 (s, 1H), 8.07 (s, 2H), 7.99 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 13.8 Hz, 2H), 7.16 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H), 4.65-4.52 (m, 3H), 3.85 (s, 3H), 3.67-3.56 (m, 2H), 3.09-2.84 (m, 4H), 2.78-2.63 (m, 3H), 2.10-2.00 (m, 2H), 1.98-1.87 (m, 1H), 1.83-1.58 (m, 4H), 1.38 (s, 9H), 1.19-1.06 (m, 2H);[M+H] + = 909.8.

[0241] Example 28: N-(3-(6-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide Step 1: tert-butyl 4-(4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperidine-1-carboxylate (560 mg, 1.0 mmol) in dioxane (20 mL) and water (5 mL) was added 2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(2-hydroxypropan-2-yl)benzamide (480 mg, 1.1 mmol), Pd(dppf)Cl (73 mg, 0.1 mmol), and CsCO (850 mg, 2.6 mmol). The reaction mixture was stirred at 110 °C overnight in a round-bottom flask. The mixture was then evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE:EA = 100:0 to 0:100 gradient elution) to give the product (570 mg, 70%). [M+H] + = 812.5.

[0242] Step 2: 2-fluoro-N-(5-fluoro-2-methyl-3-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-4-(2-hydroxypropan-2-yl)benzamide and 2-fluoro-N-(5-fluoro-2-methyl-3-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-4-(prop-1-en-2-yl)benzamide [ka] A mixture of tert-butyl 4-(4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropan-2-yl)benzamido)-2-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperidine-1-carboxylate (570 mg, 0.70 mmol) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL) was stirred in a round-bottom flask at room temperature overnight. The mixture was then evaporated in vacuo to give the crude product. A mixture of the crude product and ammonium hydroxide (2 mL) in methanol (10 mL) was stirred in a round-bottom flask at room temperature overnight. The mixture was then evaporated in vacuo to give the crude product, which was purified by C18 column chromatography (0.1% FA in water:acetonitrile = 85:15 to 40:60 gradient elution) to give 2-fluoro-N-(5-fluoro-2-methyl-3-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-4-(2-hydroxypropan-2-yl)benzamide (160 mg, 39%), [M+H] + = 582.4 and 2-fluoro-N-(5-fluoro-2-methyl-3-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-4-(prop-1-en-2-yl)benzamide (100 mg, 25%), [M+H] + = 564.4.

[0243] Step 3: N-(3-(6-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide [ka] A mixture of 2-fluoro-N-(5-fluoro-2-methyl-3-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-4-(2-hydroxypropan-2-yl)benzamide (86 mg, 0.14 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (60 mg, 0.20 mmol) in dichloroethane (20 mL) was stirred in a round-bottom flask at room temperature for 1 hour. Then, NaBH(OAc) (212 mg, 1.0 mmol) was added to the mixture, and the mixture was stirred in a round-bottom flask at room temperature overnight. The mixture was evaporated in vacuo to give a crude product, which was purified by C18 column chromatography (gradient elution: 0.1% FA in water: acetonitrile = 80:20 to 40:60) to give the product (61 mg, 50%). 1 H NMR (400 MHz, DMSO) δ H12.74 (s, 1H), 10.27 (s, 1H), 9.95 (s, 1H), 8.90-8.75 (m, 1H), 8.24-8.04 (m, 1H), 7.98-7.84 (m, 2H), 7.78-7.59 (m, 2H), 7.47-7.30 (m, 4H), 7.27-7.19 (m, 1H), 7.13 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 6.85-6.75 (m, 1H), 5.31 (s, 1H), 3.75-3.58 (m, 4H), 3.33 (s, 4H), 3.08-2.91 (m, 3H), 2.77-2.61 (m, 5H), 2.26-2.09 (m, 5H), 2.08-1.95 (m, 2H), 1.86-1.58 (m, 7H), 1.54-1.30 (m, 6H), 1.28-1.13 (m, 2H);[M+H] + = 867.8.

[0244] Example 29: N-(3-(6-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(prop-1-en-2-yl)benzamide [ka] A mixture of 2-fluoro-N-(5-fluoro-2-methyl-3-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-4-(prop-1-en-2-yl)benzamide (10 mg, 0.17 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (60 mg, 0.20 mmol) in dichloroethane (10 mL) was stirred in a round-bottom flask at room temperature for 1 hour. Then, NaBH(OAc) (212 mg, 1.0 mmol) was added to the mixture, and the mixture was stirred in a round-bottom flask at room temperature overnight. The mixture was evaporated in vacuo to give the crude product, which was purified by C18 column chromatography (gradient elution: 0.1% FA in water: acetonitrile = 75:25 to 30:70) to give the product (50 mg, 34%). 1 H NMR (400 MHz, DMSO) δ H 12.76 (s, 1H), 10.28 (s, 1H), 10.01 (s, 1H), 8.86 (s, 1H), 7.93 (d, J = 7.6 Hz, 2H), 7.84-7.75 (m, 1H), 7.71-7.62 (m, 1H), 7.56-7.48 (m, 2H), 7.37 (d, J = 7.6 Hz, 2H), 7.26 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 6.82 (s, 1H), 5.64 (s, 1H), 5.29 (s, 1H), 3.76-3.61 (m, 4H), 3.04-2.93 (m, 2H), 2.75-2.63 (m, 4H), 2.26-2.11 (m, 8H), 2.08-1.97 (m, 2H), 1.85-1.63 (m, 7H), 1.30-1.16 (m, 2H);[M+H] + = 849.5.

[0245] Example 30: 5-(tert-butyl)-N-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 24. 1 H NMR (400 MHz, DMSO) δ H 12.54 (s, 1H), 10.28 (s, 1H), 9.53 (s, 1H), 8.77 (s, 1H), 8.08 (s, 2H), 7.93 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 1H), 7.24 (s, 1H), 7.15 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 4.57 (d, J = 5.2 Hz, 2H), 3.66 (t, J = 6.4 Hz, 4H), 3.28 (s, 4H), 2.71-2.65 (m, 2.55-2.45 (m, 5H), 2.26 (br, 2H), 1.84-1.70 (m, 3H), 1.46 (s, 9H), 1.25 (br, 3H) + = 836.5.

[0246] Example 31: (R)-5-(tert-butyl)-N-(1-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-fluorophenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 24. 1 H NMR (400 MHz, DMSO) δ H 12.62 (s, 1H), 10.28 (s, 1H), 9.64 (d, J = 8.0 Hz, 1H), 8.78 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 12.0 Hz, 1H), 7.95 (d, J = 7.6 Hz, 2H), 7.70 (t, J = 7.6 Hz, 1H), 7.32 (s, 1H), 7.14 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 7.6 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 5.47 (t, J = 7.6 Hz, 1H), 3.69 (t, J = 6.8 Hz, 4H), 3.30 (s, 4H), 2.70-2.55 (m, 7H), 2.29 (br, 2H), 1.85-1.70 (m, 3H), 1.57 (d, J = 6.4 Hz, 3H), 1.44 (s, 9H), 1.24 (br, 3H);[M+H] + = 854.9.

[0247] Example 32: 3-(tert-butyl)-N-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 24. 1 H NMR (400 MHz, DMSO) δ H12.62 (s, 1H), 10.28 (s, 1H), 10.01-9.98 (m, 1H), 8.79 (s, 1H), 8.14-8.13 (m, 1H), 8.04-8.01 (m, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.64-7.60 (m, 1H), 7.30 (s, 1H), 7.16-7.13 (m, 2H), 7.07-7.04 (m, 2H), 6.94 (d, J = 8.0 Hz, 2H), 4.64-4.63 (m, 2H), 3.72-3.70 (m, 4H), 3.28 (s, 4H), 2.71-2.65 (m, 4H), 2.25-2.22 (m, 2H), 1.86-1.74 (m, 4H), 1.39 (s, 9H), 1.26-1.24 (m, 3H);[M+H] + = 840.8.

[0248] Example 33: (R)-3-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-fluorophenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 24. 1 H NMR (400 MHz, DMSO) δ H12.66 (s, 1H), 10.25 (s, 1H), 10.00 (s, 1H), 8.79-8.77 (m, 2H), 8.19-8.11 (m, 2H), 7.99-7.97 (m, 1H), 7.71-7.69 (m, 1H), 7.34 (s, 1H), 7.11-7.10 (m, 2H), 6.95-6.91 (m, 3H), 5.45-5.43 (m, 1H), 3.67-3.58 (m, 8H), 2.68-2.65 (m, 7H), 2.22-2.20 (m, 2H), 1.81-1.71 (m, 3H), 1.59-1.56 (m, 3H), 1.36 (s, 9H), 1.23-1.21(m, 3H);[M+H] + = 855.5.

[0249] Example 34: (R)-5-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-fluorophenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 24. 1 H NMR (400 MHz, DMSO) δ H12.65 (s, 1H), 10.24 (s, 1H), 9.59 (d, J = 8.0Hz, 1H), 8.79-8.76 (m, 2H), 8.18 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.68-7.65 (m, 1H), 7.33 (s, 1H), 7.10 (d, J = 8.0 Hz, 2H), 6.95-6.89 (m, 3H), 5.46-5.42 (m, 1H), 3.66-3.58 (m, 8H), 2.67-2.65 (m, 4H), 2.47-2.44 (m, 3H), 1.81-1.78 (m, 2H), 1.70 (s, 1H), 1.54 (d, J = 8.0 Hz, 3H), 1.41 (s, 9H), 1.22-1.19 (m, 3H);[M+H] + = 855.5.

[0250] Example 35: 1-(tert-butyl)-N-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 24. 1 H NMR (400 MHz, DMSO) δ H12.49 (s, 1H), 10.24 (s, 1H), 8.72 (s, 1H), 8.50 (br, 1H), 8.33 (s, 1H), 8.03 (s, 2H), 7.94-7.85 (m, 3H), 7.41 (d, J = 7.6 Hz, 1H), 7.19 (s, 1H), 7.11 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 7.6 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 4.48 (br, 2H), 3.66 (t, J = 6.8 Hz, 4H), 3.23 (s, 4H), 2.70-2.60 (m, 2.60-2.40 (m, 5H), 2.22 (br, 2H), 1.85-1.65 (m, 3H), 1.51 (s, 9H), 1.21 (br, 3H) + = 834.5.

[0251] Example 36: N-(4-(6-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-fluoro-5-methylbenzyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide Step 1: tert-butyl 4-(4-(4-(5-fluoro-4-((2-fluoro-4-(2-hydroxypropan-2-yl)benzamido)methyl)-2-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperidine-1-carboxylate [ka] A solution of tert-butyl 4-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperidine-1-carboxylate (542 mg, 1.0 mmol) in dioxane (20 mL) and water (2 mL) was added to 2-fluoro-N-(2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-4-(2-hydroxypropan-2-yl)benzamide (445 mg, 1.0 mmol), Pd(dppf)Cl (73 mg, 0.1 mmol), and CsCO (650 mg, 2.0 mmol). The reaction mixture was stirred at 110 °C overnight in a round-bottom flask. The mixture was then evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE:EA = 100:0 to 0:100 gradient elution) to give the product (341 mg, 38%). [M+H] + = 826.4.

[0252] Step 2: 2-fluoro-N-(2-fluoro-5-methyl-4-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-4-(2-hydroxypropan-2-yl)benzamide [ka] A mixture of tert-butyl 4-(4-(4-(5-fluoro-4-((2-fluoro-4-(2-hydroxypropan-2-yl)benzamido)methyl)-2-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperidine-1-carboxylate (340 mg, 0.38 mmol) and trifluoroacetic acid (3 mL) in dichloromethane (12 mL) was stirred in a round-bottom flask at room temperature overnight. The mixture was then evaporated in vacuo to give the crude product. A mixture of the crude product and ammonium hydroxide (2 mL) in methanol (10 mL) was stirred in a round-bottom flask at room temperature overnight. The mixture was evaporated in vacuo to give the crude product, which was purified by C18 column chromatography (gradient elution: 0.1% HCl in water: acetonitrile = 85:15 to 40:60) to give the product (160 mg, 42%). [M+H] + = 596.6.

[0253] Step 3: N-(4-(6-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-fluoro-5-methylbenzyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide [ka] A mixture of 2-fluoro-N-(2-fluoro-5-methyl-4-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-4-(2-hydroxypropan-2-yl)benzamide (90 mg, 0.15 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (60 mg, 0.20 mmol) in dichloroethane (20 mL) was stirred in a round-bottom flask at room temperature for 1 hour. Then, NaBH(OAc) (212 mg, 1.0 mmol) was added to the mixture, and the mixture was stirred in a round-bottom flask at room temperature overnight. The mixture was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH=100:0 to 80:20 gradient elution) to give the product (49 mg, 37%). 1 H NMR (400 MHz, DMSO) δ H 12.72 (s, 1H), 10.27 (s, 1H), 8.95-8.79 (m, 2H), 7.94 (d, J = 7.2 Hz, 2H), 7.72-7.59 (m, 1H), 7.46-7.28 (m, 6H), 7.14 (d, J = 8.0 Hz, 2H), 7.01-6.81 (m, 3H), 5.28 (s, 1H), 4.59 (s, 2H), 3.77-3.63 (m, 4H), 3.15-3.01 (m, 2H), 2.73-2.62 (m, 3H), 2.29 (s, 3H), 2.23-2.09 (m, 2H), 1.96-1.89 (m, 2H), 1.87-1.67 (m, 5H), 1.44 (s, 6H), 1.32-1.15 (m, 4H);[M+H] + = 881.8.

[0254] Example 37: 1-(tert-butyl)-N-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 24. 1 H NMR (400 MHz, DMSO) δ H 12.49 (s, 1H), 10.24 (s, 1H), 9.04 (s, 1H), 8.71 (s, 2H), 8.03 (s, 2H), 7.88 (br, 2H), 7.40 (br, 1H), 7.26-6.82 (m, 7H), 4.52 (s, 2H), 3.67 (s, 4H), 3.25 (s, 4H), 2.70-2.50 (m, 10H), 2.30 (br, 2H), 1.82-1.70 (m, 3H), 1.63 (s, 9H), 1.20 (br, 3H). [M+H] + = 835.5.

[0255] Example 38: (R)-3-(tert-butyl)-N-(1-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide, formate [ka] The title compound was synthesized using a procedure similar to that described in Example 24. 1 H NMR (400 MHz, DMSO) δ H12.64 (s, 1H), 10.27 (s, 1H), 9.98 (s, 1H), 8.79 (s, 1H), 8.23 (s, 1H), 8.09 (s, 1H), 8.04 (s, 1H), 7.92 (d, J = 14.2 Hz, 1H), 7.81 (s, 1H), 7.68 (s, 1H), 7.41 (s, 1H), 7.12 (s, 3H), 6.94 (s, 2H), 5.38 (s, 1H), 3.70 (s, 4H), 3.12 (s, 4H), 2.67 (s, 4H), 2.54 (s, 7H), 2.24 (s, 2H), 1.82 (d, J = 12.1 Hz, 2H), 1.72 (s, 1H), 1.55 (s, 3H), 1.37 (s, 9H), 1.23 (d, J = 9.8 Hz, 2H);[M+H] + = 868.8.

[0256] Example 39: 3-(tert-butyl)-N-(4-(6-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide, formate [ka] The title compound was synthesized using a procedure similar to that described in Example 24. 1 H NMR (400 MHz, DMSO) δ H12.68 (s, 1H), 10.37 (s, 1H), 9.91 (s, 1H), 8.80 (s, 1H), 8.22 (s, 1H), 8.07 (s, 2H), 7.97 (s, 2H), 7.48 (s, 1H), 7.37 (s, 3H), 7.17 (d, J = 14.2 Hz, 1H), 7.05 (s, 2H), 4.56 (s, 2H), 3.73 (s, 4H), 2.98 (s, 2H), 2.68 (s, 4H), 2.52 (s, 3H), 2.23 (s, 2H), 2.02 (s, 2H), 1.75 (dd, J = 34.4, 12.2 Hz, 7H), 1.38 (s, 9H), 1.30 (s, 3H);[M+H] + = 853.8.

[0257] Example 40: 1-(tert-butyl)-N-(4-(6-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide Step 1: tert-butyl 4-(4-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperidine-1-carboxylate (166 mg, 0.4 mmol) in dioxane / HO (5:1, 50 mL) was added 1-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (150 mg, 0.4 mmol), KCO (166 mg, 1.2 mmol), and Pd(dppf)Cl.CHCl (33 mg, 0.04 mmol). The reaction mixture was stirred at 90 °C under N for 5 h. The solvent was evaporated, and HO (20 mL) was added. The mixture was extracted with DCM / iPrOH (20:1, 30 mL x 3), and the organic phases were combined. The organic phase was washed with brine, concentrated, and purified by preparative TLC with DCM / MeOH to give the product (160 mg, crude).

[0258] Step 2: 1-(tert-butyl)-N-(2-methyl-4-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] To a solution of tert-butyl 4-(4-(4-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperidine-1-carboxylate (230 mg, 0.29 mmol) in DCM (20 mL) was added TFA (20 mL). The mixture was stirred at 20-30 °C for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (30 mL) and KCO (230 mg) was added. After stirring at 20-30 °C for 2 h, the reaction mixture was concentrated. HO (30 mL) was added and the mixture was extracted with DCM / iPrOH (10:1, 30 mL). The organic phase was separated, concentrated and used as is for the next step.

[0259] Step 3: 1-(tert-butyl)-N-(4-(6-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide [ka] To a solution of 1-(tert-butyl)-N-(2-methyl-4-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (200 mg, 0.36 mmol) in DCM / EtOH (5:1, 30 mL) was added 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (109 mg, 0.36 mmol), HOAc (1 drop), and NaOAc (88 mg, 1.1 mmol). After stirring at 20-30 °C for 60 min, NaBH(OAc) (233 mg, 1.1 mmol) was added. After stirring at 20-30 °C for another 5 h, the mixture was evaporated. To the residue, HO (30 mL) was added, and the mixture was extracted with DCM / iPrOH (20:1, 30 mL × 3). The organic phases were combined and purified by preparative TLC with DCM / MeOH (10:1) to give the product (32 mg, 10.7%). 1 H NMR (400 MHz, DMSO) δ H 12.66 (s, 1H), 10.27 (s, 1H), 9.07 (s, 1H), 8.80 (s, 1H), 8.74 (s, 1H), 8.19 (s, 1H), 8.06 (s, 2H), 7.98 (d, J = 7.6 Hz, 2H), 7.44 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.0 Hz, 3H), 7.13 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 4.56 (s, 2H), 3.76-3.66 (m, 4H), 2.98 (d, J = 8.8 Hz, 2H), 2.75-2.52 (m, 7H), 2.22 (br, 2H), 2.07-1.95 (m, 2H), 1.88-1.58 (m, 16H), 1.25-1.15 (m, 2H);[M+H] + =834.6.

[0260] Example 41: (R)-5-(tert-butyl)-N-(1-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide Step 1: tert-butyl (R)-4-(4-(4-(4-(1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)ethyl)-3-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate (271 mg, 0.5 mmol) in dioxane (25 mL) and HO (5 mL) was added (R)-5-(tert-butyl)-N-(1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide (207 mg, 0.5 mmol), KCO (207 mg, 1.5 mmol), and Pd(dppf)Cl.CHCl (41 mg, 0.05 mmol). The mixture was stirred at 90 °C under N for 18 h. After evaporation of the solvent, water (20 mL) was added. The mixture was extracted with DCM / iPrOH (10:1, 20 mL x 2). The organic phases were combined, washed with brine, and purified by preparative TLC with DCM / MeOH to give the product (160 mg, crude).

[0261] Step 2: (R)-5-(tert-butyl)-N-(1-(2-methyl-4-(6-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride [ka] To a solution of tert-butyl (R)-4-(4-(4-(4-(1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)ethyl)-3-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate (160 mg, 0.24 mmol) in dioxane (3 mL) was added HCl / dioxane (4 N, 30 mL). The mixture was stirred at 20-30 °C for 3 h, concentrated to 5 mL, and filtered. The filter cake was washed to give the crude product, which was used directly for the next step. 1 H NMR (400 MHz, DMSO) δ H 13.41 (s, 1H), 9.64 (d, J = 6.8 Hz, 1H), 9.32 (s, 2H), 8.98 (s, 1H), 8.14-7.97 (m, 4H), 7.74 (d, J = 7.6 Hz, 1H), 7.48 (s, 1H), 7.13 (d, J = 7.6 Hz, 2H), 5.40 (br, 1H), 3.54 (s, 4H), 3.23 (s, 4H), 2.57 (s, 3H), 1.61-1.39 (m, 12H);[M+H] + = 565.4.

[0262] Step 3: (R)-5-(tert-butyl)-N-(1-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] To a solution of (R)-5-(tert-butyl)-N-(1-(2-methyl-4-(6-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride (150 mg, 0.25 mmol) in DCM / EtOH (5:1, 30 mL) was added 1-(4-(4-oxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (75 mg, 0.25 mmol) and NaOAc (62 mg, 0.75 mmol). After stirring at 20-30 °C for 60 min, NaBH(OAc) (160 mg, 0.75 mmol) was added. The mixture was stirred at 20-30 °C for 3 h. The solvent was evaporated, and HO (30 mL) was added. The mixture was extracted with DCM / iPrOH (20:1, 30 mL × 3). The organic phases were combined and concentrated. The residue was purified by preparative TLC with DCM / MeOH (10:1) to give the product (85.7 mg, 40.3%). 1 H NMR (400 MHz, DMSO) δ H 12.53 (s, 1H), 10.27 (s, 1H), 9.54 (d, J = 7.2 Hz, 1H), 8.75 (s, 1H), 8.08 (d, J = 7.2 Hz, 1H), 8.03 (s, 1H), 7.92 (d, J = 6.8 Hz, 2H), 7.65 (d, J = 7.2 Hz, 1H), 7.23 (s, 1H), 7.13 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 7.2 Hz, 2H), 5.39 (br, 1H), 3.70 (br, 4H), 3.26 (s, 4H), 2.68-2.50 (m, 10H), 2.24 (s, 2H), 1.85-1.69 (m, 3H), 1.54-1.39 (m, 12H), 1.24 (br, 3H);[M+H] + = 850.8.

[0263] Example 42: 3-(tert-butyl)-N-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 24. 1 H NMR (400 MHz, DMSO) δ H 12.70 (s, 1H), 10.27 (s, 1H), 9.99 (s, 1H), 8.82-8.79 (m, 2H), 8.31 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.03-8.00 (m, 1H), 7.63-7.60 (m, 1H), 7.35 (s, 1H), 7.13 (d, J = 8.0 Hz, 2H), 6.98-6.92 (m, 3H), 4.63 (s, 2H), 3.70-3.68 (m, 4H), 3.61-3.59 (m, 4H), 2.69-2.64 (m, 4H), 2.49-2.47 (m, 4H), 2.23-2.21 (m, 2H), 1.84-1.73 (m, 3H), 1.37 (s, 9H), 1.25-1.22 (m, 2H);[M+H] + = 841.8.

[0264] Example 43: (R)-3-(tert-butyl)-N-(1-(4-(6-(4-(4-((1-(2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide Step 1: (1-(5-fluoro-2-nitrophenyl)piperidin-4-yl)methanol [ka] To a solution of 2,4-difluoro-1-nitrobenzene (20.0 g, 142.0 mmol) and 4-piperidinemethanol (19.6 g, 170 mmol) in DMF (200.0 mL) was added K2CO3 (39.2 g, 284 mmol) at 25 °C. The mixture was stirred at 80 °C for 16 hours. The reaction was monitored by LC-MS. The reaction was cooled to room temperature, poured into ice water (600.0 mL), and stirred for 20 minutes. The solid was filtered, washed with water (500.0 mL x 2), and dried to give the product (28.0 g, 84.0%). [M+H] + = 255.1.

[0265] Step 2: (1-(2-amino-5-fluorophenyl)piperidin-4-yl)methanol [ka] To a solution of (1-(5-fluoro-2-nitrophenyl)piperidin-4-yl)methanol (28.0 g, 118.5 mmol) in MeOH (300.0 mL) under N2, 10% Pd / C (2.80 g) was added at 25°C. The mixture was then exchanged with H2 twice and stirred under H2 atmosphere at 25°C for 15 h. The reaction was monitored by LC-MS. The mixture was filtered through a pad of Celite and washed with MeOH (140.0 mL). The filtrate was concentrated under vacuum to give the product (22.6 g, 85.1%). [M+H] + = 225.1.

[0266] Step 3: (1-(2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluorophenyl)piperidin-4-yl)methyl acetate [ka] To a solution of (1-(2-amino-5-fluorophenyl)piperidin-4-yl)methanol (22.6 g, 101 mmol) in toluene (200 mL) was added acrylic acid (10.9 g, 151.5 mmol) at 25° C. The mixture was stirred at 90° C. for 15 hours. The reaction was monitored by LC-MS. The reaction was cooled to 25° C., and HOAc (200 mL) and urea (30.3 g, 505 mmol) were added. The mixture was then stirred at 110° C. for 24 hours. The reaction was monitored by LC-MS. The reaction was cooled to 25° C. and concentrated in vacuo. The residue was dissolved in EtOAc (500 mL) and then adjusted to pH=7 with saturated NaHCO3. The resulting solution was extracted with 2×200 mL of EtOAc, and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified on silica gel to give the product (12.5 g, 34.1%). [M+H] + = 364.2.

[0267] Step 4: 1-(4-fluoro-2-(4-(hydroxymethyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione [ka] (1-(2-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)-5-fluorophenyl)piperidin-4-yl)methyl acetate (12.5 g, 34.4 mmol) was added to 4N HCl (100.0 mL) at 25° C. The mixture reaction was stirred at 100° C. for 1 hour. The reaction was monitored by LC-MS. The reaction was cooled to 10° C. and then adjusted to pH=7 with saturated NaHCO3. The solid was collected by filtration, washed with water (50.0 mL), and dried to give the product. [M+H] + = 322.1.

[0268] Step 5: 1-(2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluorophenyl)piperidine-4-carbaldehyde [ka] A mixture of 1-(4-fluoro-2-(4-(hydroxymethyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (650 mg, 2.6 mmol) and IBX (2.3 g, 1.71 mmol) in DMSO (12 mL) was stirred at 55° C. for 1 h. After adding EtOAc (50 mL), the solution was washed three times with brine (50 mL). The organic layer was dried over NaSO, filtered, concentrated, and purified by silica gel column chromatography to give the product (350 mg, 54%).

[0269] Step 6: (R)-3-(tert-butyl)-N-(1-(4-(6-(4-(4-((1-(2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] To a solution of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride (100 mg, 0.17 mmol) in DCM / EtOH (5:1, 40 mL) was added 1-(2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluorophenyl)piperidine-4-carbaldehyde (53 mg, 0.17 mmol) and NaOAc (41 mg, 0.5 mmol). After stirring for 30 min, NaBH(OAc) (106 mg, 0.5 mmol) was added. The mixture was stirred at 20-30 °C for 2 h. After the solvent was evaporated under reduced pressure, the residue was purified by preparative TLC with DCM / MeOH to give the product (60 mg, 41.6%). 1H NMR (400 MHz, DMSO) δ H 12.52 (s, 1H), 10.38 (s, 1H), 9.97 (br, 1H), 8.75 (s, 1H), 8.08 (br, 1H), 8.03 (s, 1H), 7.91 (d, J = 6.4 Hz, 2H), 7.67 (s, 1H), 7.23 (br, 2H), 7.03 (d, J = 5.2 Hz, 2H), 6.94 (d, J = 10.8 Hz, 1H), 6.86 (br, 1H), 5.38 (s, 1H), 3.72 (br, 1H), 3.47 (br, 1H), 3.25-3.0 (m, 6H), 2.80-2.50 (m, 10H), 2.25 (s, 2H), 1.86-1.66 (m, 3H), 1.55 (s, 3H), 1.37-1.24 (m, 12H);[M+H] + = 868.8.

[0270] Example 44: (R)-3-(tert-butyl)-N-(1-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 24. 1 H NMR (400 MHz, DMSO) δ H12.52 (s, 1H), 10.25 (s, 1H), 9.97 (s, 1H), 8.75 (s, 1H), 8.08 (s, 1H), 8.03 (s, 1H), 7.92 (br, 2H), 7.67 (br, 1H), 7.23 (s, 1H), 7.03 (br, 3H), 6.86-6.72 (m, 2H), 5.38 (s, 1H), 3.68 (br, 3H), 3.48 (br, 1H), 3.25 (s, 4H), 2.78-2.55 (m, 10H), 2.23 (s, 2H), 2.12 (s, 3H), 1.85-1.65 (m, 3H), 1.55 (s, 3H), 1.37 (s, 9H), 1.28-1.15 (m, 3H);[M+H] + = 864.8.

[0271] Example 45: (R)-3-(tert-butyl)-N-(1-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 24. 1 H NMR (400 MHz, DMSO) δ H12.53 (s, 1H), 10.21 (s, 1H), 9.97 (d, J = 7.6 Hz, 1H), 8.75 (s, 1H), 8.09 (d, J = 7.6 Hz, 1H), 8.04 (s, 1H), 7.91 (d, J = 7.6 Hz, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.23 (s, 1H), 7.07-6.98 (m, 3H), 6.59 (s, 1H), 6.49 (d, J = 9.2 Hz, 1H), 5.38 (s, 1H), 3.81-3.72 (m, 5H), 3.50 (s, 2H), 3.26 (s, [M+H] + = 880.8.

[0272] Example 46: 2-(tert-butyl)-N-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)thiazole-4-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 24. 1 H NMR (400 MHz, DMSO) δ H12.51 (s, 1H), 10.27 (s, 1H), 8.78 (br, 1H), 8.74 (s, 1H), 8.19 (s, 1H), 8.06 (s, 2H), 7.91 (d, J = 7.6 Hz, 2H), 7.43 (d, J = 7.2 Hz, 1H), 7.23 (s, 1H), 7.13 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 7.6 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 4.57 (s, 2H), 3.80-3.65 (m, 4H), 3.25 (br, 4H), 2.67-2.55 (m, 10H), 2.24 (br, 2H), 1.88-1.65 (m, 3H), 1.44 (s, 9H), 1.24 (br, 3H);[M+H] + = 851.8.

[0273] Example 47: 2-(tert-butyl)-N-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)thiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 24. 1 H NMR (400 MHz, DMSO) δ H12.52 (s, 1H), 10.27 (s, 1H), 9.15 (s, 1H), 8.75 (s, 1H), 8.36 (s, 1H), 8.07 (s, 2H), 7.91 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 7.2 Hz, 1H), 7.22 (s, 1H), 7.13 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 7.2 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 4.54 (s, 2H), 3.75-3.60 (m, 4H), 3.25 (s, 4H), 2.72-2.50 (m, 10H), 2.24 (br, 2H), 1.85-1.61 (m, 3H), 1.40 (s, 9H), 1.24 (br, 3H);[M+H] + = 851.8.

[0274] Example 48: 3-(tert-butyl)-N-((1R)-1-(4-(6-(6-(4-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] 1-(4-(2,6-Dioxopiperidin-3-yl)phenyl)piperidine-4-carbaldehyde (100 mg, crude) and (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(6-(piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (93.1 mg, 0.17 mmol) were dissolved in DCM / MeOH (5 mL, 10:1), and then AcOH (1 drop) was added to the solution. The resulting mixture was stirred at room temperature for 1 hour, and sodium triacetoxyborohydride (180.2 mg, 0.85 mmol) was added to the mixture in one portion. The mixture was stirred for another hour until LC-MS showed that all the starting material was consumed. The solid was filtered off. The filtrate was concentrated and purified by preparative TLC to give the desired product (20 mg, 13.9%). 1 H NMR (400 MHz, DMSO) δ H 12.59 (s, 1H), 10.78 (s, 1H), 10.00-9.96 (m, 1H), 8.81 (s, 1H), 8.76 (s, 1H), 8.10-8.06 (m, 1H), 8.06-8.02 (m, 2H), 7.68-7.64 (m, 1H), 7.29 (s, 1H), 7.06-6.95 (m, 1H), 6.95-6.92 (m, 1H), 6.92-6.88 (m, 1H), 5.42-5.36 (m, 1H), 3.75-3.69 (m, 4H), 3.69-3.55 (m, 4H), 2.62-2.50 (m, 6H), 2.48 (s, 3H), 2.35-2.33 (m, 1H), 2.28-2.25 (m, 2H), 2.15-2.10 (m, 1H), 2.05-1.98 (m, 2H), 1.81-1.70 (m, 2H), 1.70-1.65 (m, 1H), 1.55 (d, J = 8.0 Hz, 3H), 1.37 (s, 9H), 1.25-1.20 (m, 2H);[M+H] + = 850.6.

[0275] Example 49: 3-(tert-butyl)-N-(4-(6-(4-((1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide Step 1: tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidine-1-carboxylate [ka] A mixture of tert-butyl 4-(4-bromophenoxy)piperidine-1-carboxylate (710 mg, 2.0 mmol), bis(pinacolato)diboron (508 mg, 2.0 mmol), Pd(dppf)Cl (146 mg, 0.2 mmol), and CHCOOK (300 mg, 3.0 mmol) in dioxane (20 mL) was stirred in a round-bottom flask at 110 °C for 4 hours. The mixture was then used for the next step without further purification. [M-99] + = 304.2.

[0276] Step 2: tert-butyl 4-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenoxy)piperidine-1-carboxylate [ka] A solution of the reaction mixture from the previous step was added to 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (818 mg, 2.0 mmol), Pd(dppf)Cl (146 mg, 0.1 mmol), and KCO (400 mg, 3.0 mmol) in dioxane (20 mL) and water (4 mL) and stirred overnight at 80 °C in a round-bottom flask. The mixture was then evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE:EA = 100:0 to 60:40 gradient elution) to give the product (538 mg, 48%, 2 steps). [M+H] + = 559.3.

[0277] Step 3: tert-butyl 4-(4-(4-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenoxy)piperidine-1-carboxylate [ka] A mixture of tert-butyl 4-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenoxy)piperidine-1-carboxylate (538 mg, 0.96 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 (384 mg, 0.96 mmol), Pd(dppf)Cl (70 mg, 0.096 mmol) and KCO (265 mg, 1.92 mmol) in dioxane (16 mL) and water (4 mL) in a round-bottom flask was stirred at 100 °C overnight. The mixture was then evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE: EtOAc = 100:0 to 20:80 gradient elution) to give the product (440 mg, 57%). [M+H] += 796.4.

[0278] Step 4: 3-(tert-butyl)-N-(2-methyl-4-(6-(4-(piperidin-4-yloxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of tert-butyl 4-(4-(4-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenoxy)piperidine-1-carboxylate (440 mg, 0.55 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) was stirred in a round-bottom flask at room temperature for 2 hours. The mixture was then evaporated in vacuo to give the crude product, which was used for the next step without further purification. To the crude was added ammonium hydroxide (2 mL) in methanol (10 mL) and stirred in a round-bottom flask at room temperature overnight. The mixture was evaporated in vacuo to give the crude product, which was purified by C18 column chromatography (gradient elution: 0.1% HCl in water: acetonitrile = 80:20 to 40:60) to give the product (216 mg, 61%). [M+H] + = 566.6.

[0279] Step 5: 3-(tert-butyl)-N-(4-(6-(4-((1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of 3-(tert-butyl)-N-(2-methyl-4-(6-(4-(piperidin-4-yloxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (100 mg, 0.15 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (60 mg, 0.20 mmol) in dichloroethane (20 mL) was stirred in a round-bottom flask at room temperature for 1 hour. Then, NaBH(OAc) (212 mg, 1.0 mmol) was added to the mixture, and the mixture was stirred in a round-bottom flask at room temperature overnight. The mixture was evaporated in vacuo to give a crude product, which was purified by C18 column chromatography (gradient elution: 0.1% FA in water: acetonitrile = 80:20 to 30:70) to give the product (78 mg, 61%). 1 H NMR (400 MHz, DMSO) δ H 12.62 (s, 1H), 10.27 (s, 1H), 9.91 (s, 1H), 8.78 (s, 1H), 8.07 (s, 2H), 7.98 (d, J = 7.6 Hz, 2H), 7.48 (d, J = 7.6 Hz, 1H), 7.29 (s, 1H), 7.17-7.01 (m, 4H), 6.92 (d, J = 8.4 Hz, 2H), 4.63-4.43 (m, 3H), 3.75-3.64 (m, 4H), 2.86-2.73 (m, 2H), 2.71-2.61 (m, 4H), 2.41-2.22 (m, 4H), 2.07-1.94 (m, 2H), 1.86-1.76 (m, 2H), 1.74-1.59 (m, 3H), 1.38 (s, 9H), 1.24-1.13 (m, 3H);[M+H] + = 851.8.

[0280] Example 50: N-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxamide Step 1: Ethyl 2-imino-2-(((3,3,3-trifluoro-2,2-dimethylpropanoyl)oxy)amino)acetate [ka] To a solution of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (24.5 g, 157 mmol) and HATU (60 g, 158 mmol) in DCM (500 mL) was added EtN (30 g, 300 mmol). The mixture was stirred at room temperature for 1 hour, and then ethyl 2-(hydroxyamino)-2-iminoacetate (21 g, 159 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with water (500 mL) and brine (500 mL). The organic layer was dried over NaSO, filtered, concentrated, and purified by silica gel column chromatography to give the product (35 g, 82%). [M+H] + = 271.1.

[0281] Step 2: Ethyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxylate [ka] A solution of ethyl 2-imino-2-(((3,3,3-trifluoro-2,2-dimethylpropanoyl)oxy)amino)acetate (13 g, 48 mmol) in DMF (100 mL) was heated to 90° C. for 16 h. After EtOAc (300 mL) was added, the reaction mixture was washed with water (300 mL) and brine (300 mL). The organic layer was dried over NaSO, filtered, concentrated, and purified by silica gel column chromatography to give the product (7.5 g, 62%). [M+H] + = 253.1.

[0282] Step 3: 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxylic acid [ka] A solution of ethyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxylate (7.0 g, 28 mmol) and LiOH·HO (1.7 g, 40 mmol) in MeOH / THF / HO (30 mL / 30 mL / 30 mL) was stirred at room temperature for 16 h. The mixture was concentrated, adjusted to pH 6 with 1N aqueous HCl, and filtered to give the product (8.5 g, crude). [M+H] + = 225.2.

[0283] Step 4: tert-butyl (4-bromo-2-methylbenzyl)carbamate [ka] To a solution of (4-bromo-2-methylphenyl)methanamine (26 g, 130 mmol) and EtN (20 mL, 145 mmol) in DCM (300 mL) was slowly added BocO (30 g, 138 mmol) at room temperature, followed by stirring at room temperature for 1 h. The reaction mixture was concentrated. EtOAc (200 mL) was added and washed with water (200 mL) and brine (200 mL). The organic phase was dried over NaSO, concentrated, and purified by silica gel column chromatography to give the product (42 g, crude). [M-55] = 244.1.

[0284] Step 5: tert-butyl (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate [ka] A mixture of tert-butyl (4-bromo-2-methylbenzyl)carbamate (42 g, 140 mmol), bis(pinacolato)diboron (33 g, 130 mmol), Pd(PPh)Cl (2.0 g, 2.8 mmol), and KOAc (30 g, 306 mmol) in dioxane (300 mL) was stirred at 100 °C for 16 h under N. After cooling, the solvent was evaporated. The crude residue was dissolved in EtOAc (500 mL) and washed with water (500 mL) and brine (500 mL). The organic phase was separated and purified by silica gel column chromatography to give the product (46 g, crude). [M+Na] + = 370.4.

[0285] Step 6: (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine [ka] To a solution of tert-butyl (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (46 g, 132 mmol) in dioxane (200 mL) was added 4N HCl / dioxane (200 ml) slowly. The reaction mixture was stirred at room temperature for 2 hours and then concentrated to remove dioxane. The residue was stirred with MTBE (400 mL) and the solid was collected and dried in vacuo to give the product (31 g, crude). [M-NH] + = 231.3.

[0286] Step 7: N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxamide [ka] To a mixture of 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxylic acid (1.3 g, 5.8 mmol) and DMF (1 drop) in DCM (50 mL) was added oxalyl dichloride (1.5 mL) dropwise. The reaction mixture was stirred at room temperature for 1 hour and then concentrated to give crude 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carbonyl chloride. To a solution of (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine (1.6 g, 5.6 mmol) and EtN (2 mL, 14.5 mmol) in DCM (40 mL) was added a solution of crude 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carbonyl chloride in DCM (40 mL). The reaction mixture was stirred at room temperature for 1 h and then quenched with 100 mL of water. The DCM layer was dried over NaSO, concentrated, and purified by silica gel column chromatography to give the product (1.7 g, 65%). [M+H] + = 454.4.

[0287] Step 8: tert-butyl 4-(4-(4-(3-methyl-4-((5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxamido)methyl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate [ka] tert-Butyl 4-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate (250 mg, 0.46 mmol), N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2 A mixture of (1,1,1-dioxaborolan-2-yl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxamide (250 mg, 0.55 mmol), Pd(dppf)Cl (30 mg, 0.041 mmol), and KCO (300 mg, 2.17 mmol) was stirred at 100° C. for 16 h. The solvent was evaporated. The crude residue was dissolved in EtOAc (50 mL) and washed with water (50 mL) and brine (50 mL). The organic phase was separated and purified by silica gel column chromatography to give the product (100 mg, 26%).

[0288] Step 9: N-(2-methyl-4-(6-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxamide [ka] A solution of tert-butyl 4-(4-(4-(3-methyl-4-((5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxamido)methyl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate (100 mg, 0.12 mmol) in TFA / DCM (2 mL / 2 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the crude product, which was stirred with NH3 / MeOH (1 M, 10 mL) for 30 minutes. The mixture was then concentrated to give the product (160 mg, crude). [M+H] + = 605.6.

[0289] Step 10: N-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxamide [ka] A mixture of N-(2-methyl-4-(6-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxamide (160 mg, crude), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (40 mg, 0.13 mmol), and NaBH(OAc) (100 mg, 0.47 mmol) in dichloroethane (20 mL) was stirred at room temperature for 2 hours. After adding EtOAc (100 mL), the solution was washed with saturated aqueous NaHCO (50 mL) and three times with 50 mL of brine. The organic layer was dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography to give the product (30 mg, 28%). 1 H NMR (400 MHz, DMSO) δ H 12.53 (s, 1H), 10.27 (s, 1H), 9.66 (s, 1H), 8.75 (s, 1H), 8.07 (s, 2H), 7.91 (d, J = 7.2 Hz, 2H), 7.45 (d, J = 8.0 Hz, 1H), 7.27-6.90 (m, 7H), 4.60-4.56 (m, 2H), 3.71-3.66 (m, 4H), 3.26 (s, 3H), 2.70-2.66 (m, 4H), 2.26-2.22 (m, 2H), 1.82 (d, J = 11.3 Hz, 2H), 1.72 (s, 6H), 1.32-1.17 (m, 2H); [M+H] + = 890.5.

[0290] Example 51: N-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-5-(1-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that of Example 50. 1 H NMR (400 MHz, DMSO) δ H 12.52 (s, 1H), 10.27 (s, 1H), 9.59 (s, 1H), 8.75 (s, 1H), 8.06 (s, 2H), 7.91 (d, J = 7.0 Hz, 2H), 7.44 (d, J = 8.1 Hz, 1H), 7.26-6.88 (m, 7H), 4.56 (s, 2H), 3.75-3.63 (m, 4H), 3.26 (s, 3H), 2.68 (s, 5H), 2.24 (s, 2H), 1.84 (s, 6H), 1.72 (s, 1H), 1.32-1.16 (m, 2H);[M+H] + = 888.5.

[0291] Example 52: (R)-3-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-fluorophenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 24. 1 H NMR (400 MHz, DMSO) δ H12.65 (s, 1H), 10.24 (s, 1H), 10.03-10.02 (m, 1H), 8.82-8.79 (m, 2H), 8.22-8.12 (m, 2H), 8.01-7.98 (m, 1H), 7.74-7.69 (m, 1H), 7.37 (s, 1H), 7.05-6.96 (m, 2H), 6.82-6.77 (m, 2H), 5.48-5.45 (m, 1H), 3.71-3.69 (m, 7H), 3.48-3.43 (m, 1H), 2.73-2.63 (m, 4H), 2.49-2.47 (m, 4H), 2.23-2.21 (m, 2H), 2.12 (s, 3H), 1.83-1.71 (m, 3H), 1.60-1.59 (m, 3H), 1.38 (s, 9H), 1.28-1.17 (m, 3H);[M+H] + = 869.8.

[0292] Example 53: 3-(tert-butyl)-N-((R)-1-(4-(6-(6-(4-(2-(1-(4-((R)-2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 24. 1 H NMR (400 MHz, DMSO) δ H12.59 (s, 1H), 10.78 (s, 1H), 9.97 (d, J = 7.4 Hz, 1H), 8.81 (s, 1H), 8.76 (s, 1H), 8.17 (s, 2H), 8.09 (d, J = 7.2 Hz, 1H), 8.04 (s, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.30 (s, 1H), 7.03 (d, J = 8.2 Hz, 2H), 6.96 (d, J = 8.5 Hz, 1H), 6.88 (d, J = 8.2 Hz, 2H), 5.38 (s, 1H), 3.75-3.55 (m, 8H), 3.45-3.21 (m, 3H), 2.69-2.38 (m, 9H), 2.18-1.96 (m, 2H), 1.77 (d, J = 11.7 Hz, 2H), 1.55 (d, J = 6.3 Hz, 3H), 1.46 (s, 3H), 1.37 (s, 9H), 1.32-1.20 (m, 2H);[M+H] + = 864.8.

[0293] Example 54: 3-(tert-butyl)-N-((R)-1-(4-(6-(6-(4-(2-(1-(4-((S)-2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)ethyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 24. 1 H NMR (400 MHz, DMSO) δ H12.60 (s, 1H), 10.78 (s, 1H), 9.97 (d, J = 7.8 Hz, 1H), 8.79 (d, J = 18.9 Hz, 2H), 8.10 (dd, J = 35.4, 27.5 Hz, 4H), 7.66 (d, J = 8.0 Hz, 1H), 7.30 (s, 1H), 7.03 (d, J = 8.3 Hz, 2H), 6.96 (d, J = 9.1 Hz, 1H), 6.88 (d, J = 8.2 Hz, 2H), 5.38 (s, 1H), 3.75-3.54 (m, 8H), 2.68-2.33 (m, 12H), 2.19-1.96 (m, 2H), 1.77 (d, J = 12.0 Hz, 2H), 1.55 (d, J = 6.6 Hz, 3H), 1.46 (s, 3H), 1.37 (s, 9H), 1.33-1.21 (m, 2H);[M+H] + = 864.8.

[0294] Example 55: (R)-3-(tert-butyl)-N-(1-(4-(6-(4-(4-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide Step 1: (1-(4-bromophenyl)piperidin-4-yl)methanol [ka] 1-Bromo-4-iodobenzene (2.0 g, 7.1 mmol), piperidin-4-ylmethanol (894.0 mg, 7.8 mmol), CuI (270.0 mg, 1.4 mmol), L-proline (163.0 mg, 1.4 mmol), and KPO (3.0 g, 14.2 mmol) were placed in DMSO (20 mL). The resulting mixture was then heated to 80 °C overnight until LC-MS showed that all starting material had been consumed. The mixture was cooled to room temperature, and the solid was filtered off, diluted with EtOAc (200 mL), and washed three times with brine. The organic layer was dried over NaSO and concentrated to give the crude product (2.8 g, crude), which was used as is without further purification. [M+H] + = 270.0.

[0295] Step 2: (1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)methanol [ka] (1-(4-Bromophenyl)piperidin-4-yl)methanol (2.8 g, crude), Pd(dppf)Cl (580.0 mg, 0.71 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.0 g, 7.1 mmol), and CsCO (4.6 g, 14.2 mmol) were placed in dioxane / water (300 mL, 10:1). The mixture was stirred at 100 °C overnight until LC-MS showed that all starting material had been consumed. The reaction was cooled to room temperature, and the solid was filtered off. The filtrate was concentrated and purified on a SiO gel column (eluted with EtOAc / hexane = 1:1) to give the title product (3.0 g, 88%, 2 steps). [M+H] + = 481.2.

[0296] Step 3: 3-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)piperidine-2,6-dione [ka] (1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)methanol (3.0 g, 6.3 mmol) was dissolved in MeOH (30 mL). Pd / C (10%, w / w, 0.3 g) was added to the solution in one portion. The resulting mixture was stirred under H atmosphere (1 atm) overnight until LC-MS showed that all starting material was consumed. The solid was filtered off and the filtrate was concentrated to give the crude product. The crude was slurried with MTBE to give the desired product (1.2 g, 63.5%). [M+H] + = 303.0.

[0297] Step 4: 1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbaldehyde [ka] 3-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)piperidine-2,6-dione (100.0 mg, 0.33 mmol) was dissolved in DMSO (2 mL). IBX (184.8 mg, 0.66 mmol) was added portionwise to the solution at 0° C., and the mixture was stirred at 0° C. for 30 minutes. The mixture was then warmed to room temperature for another hour until TLC showed that all starting material had been consumed. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated to give the crude desired product (100.0 mg, crude), which was used as is without further purification.

[0298] Step 5: (R)-3-(tert-butyl)-N-(1-(4-(6-(4-(4-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] 1-(4-(2,6-Dioxopiperidin-3-yl)phenyl)piperidine-4-carbaldehyde (100.0 mg, crude) and (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (93.1 mg, 0.17 mmol) were dissolved in DCM / MeOH (5 mL, 10:1), and then AcOH (1 drop) was added to the solution. The resulting mixture was stirred at room temperature for 1 hour, and sodium triacetoxyborohydride (180.2 mg, 0.85 mmol) was added to the mixture in one portion. The mixture was stirred for another 1 hour until LC-MS showed that all starting material had been consumed. The solid was filtered off, concentrated and purified by preparative TLC to give the desired product (20.7 mg, 14.3%). 1 H NMR (400 MHz, DMSO) δ H 12.52 (s, 1H), 10.78 (s, 1H), 9.97 (d, J = 8.0 Hz, 1H), 8.75 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.23 (s, 1H), 7.07-7.01 (m, 4H), 6.89 (d, J = 8.0 Hz, 2H), 5.42-5.33 (m, 1H), 3.76-3.64 (m, 3H), 3.30-3.22 (m, 3H), 3.10-2.90 (m, 2H), 2.68-2.57 (m, 5H), 2.48 (s, 3H), 2.30-2.20 (m, 2H), 2.15-2.08 (m, 1H), 2.05-1.96 (m, 1H), 1.85-1.77 (m, 2H), 1.77-1.70 (m, 1H), 1.55 (d, J = 8.0 Hz, 3H), 1.37 (s, 9H), 1.28-1.18 (m, 3H);[M+H] + = 849.9.

[0299] Example 56: 5-(tert-butyl)-N-((1R)-1-(4-(6-(6-(4-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0300] Example 57: 5-(tert-butyl)-N-((1R)-1-(4-(6-(5-(4-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0301] Example 58: (R)-3-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(6-(piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (50 mg, 0.083 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidine-4-carbaldehyde (30 mg, 0.095 mmol), and NaBH(OAc) (50 mg, 0.24 mmol) in dichloroethane (20 mL) was stirred at room temperature for 2 hours. After adding EtOAc (100 mL), the solution was washed three times with saturated aqueous NaHCO (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography to give the product (15 mg, 21%). 1 H NMR (400 MHz, DMSO) δ H 12.60 (s, 1H), 10.25 (s, 1H), 9.99-9.95 (m, 1H), 8.82-8.77 (m, 2H), 8.23-8.15 (m, 1H), 8.13-7.99 (m, 2H), 7.67 (d, J = 6.6 Hz, 1H), 7.30 (s, 1H), 7.09-6.91 (m, 2H), 6.87-6.71 (m, 2H), 5.41-5.36 (m, 1H), 3.76-3.55 (m, 7H), 3.52-3.41 (m, 1H), 3.19-2.88 (m, 2H), 2.78-2.62 (m, 4H), 2.24-2.20 (m, 2H), 2.12 (s, 3H), 1.86-1.68 (m, 3H), 1.58-1.49 (m, 3H), 1.37 (s, 9H), 1.29-1.16 (m, 2H);[M+H] + = 865.8.

[0302] Example 59: (R)-3-(tert-butyl)-N-(1-(4-(6-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka]

[0303] Example 60: (R)-3-(tert-butyl)-N-(1-(4-(6-(1-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide Step 1: tert-Butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate [ka] To a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (2 g, 9.93 mmol) and TEA (1.5 g, 14.89 mmol) in DCM (20 mL) was added methanesulfonyl chloride (1.37 g, 11.92 mmol) at 0° C., and the resulting mixture was stirred at 25° C. for 2 hours. The mixture was washed with brine, dried over NaSO, filtered, and evaporated in vacuo to give the product (3 g, 92%), which was used directly for the next step. [M+H] + = 280.2.

[0304] Step 2: tert-butyl 4-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate [ka] To a mixture of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.6 g, 2.70 mmol) in anhydrous DMF (10 mL) was added NaH (0.119 g, 3.0 mmol) at 0° C., and the resulting mixture was stirred at 0° C. for 1 hour. After tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (0.91 g, 3.0 mmol) was added to the mixture, the reaction was heated to 95° C. for 1 hour. The mixture was cooled and quenched with brine (20 mL) at 0-10° C., then extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine and evaporated in vacuo to give the crude product, which was further purified by silica gel column chromatography (PE:EA = 100:0 to 70:30 gradient elution) to give the product (0.41 g, 37.4%). [M+H] + = 406.1.

[0305] Step 3: tert-butyl 4-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,5-dimethyl-1H-pyrazol-1-yl)piperidine-1-carboxylate [ka] A mixture of 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (0.394 g, 0.96 mmol), tert-butyl 4-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.41 g, 1.01 mmol), Pd(dppf)Cl (0.077 g, 0.096 mmol) and KCO (0.265 g, 1.92 mmol) in a mixture of dioxane (10 mL) and water (2.5 mL) was stirred at 90 °C overnight in a round-bottom flask. The mixture was evaporated in vacuo to give the crude product, which was further purified by silica gel column chromatography (PE:EA = 100:0 to 1:1 gradient elution) to give the product (0.365 g, 67.7%). [M+H] + = 561.1.

[0306] Step 4: tert-butyl (R)-4-(4-(4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,5-dimethyl-1H-pyrazol-1-yl)piperidine-1-carboxylate [ka] tert-Butyl 4-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,5-dimethyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.365 g, 0.65 mmol), (R)-3-(tert-butyl)-N-(1 A mixture of -(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (0.284 g, 0.684 mmol), Pd(PhP) (0.074 g, 0.065 mmol), and KCO (0.18 g, 1.3 mmol) was stirred in a round-bottom flask at 100 °C overnight. The mixture was evaporated in vacuo to give the crude product, which was further purified by silica gel column chromatography (PE:EA = 100:0 to 0:100 gradient elution) to give the product (0.28 g, 53%). [M+H] + = 812.0.

[0307] Step 5: (R)-3-(tert-butyl)-N-(1-(4-(6-(3,5-dimethyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of tert-butyl (R)-4-(4-(4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,5-dimethyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.28 g, 0.345 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) was stirred in a round-bottom flask at room temperature for 1 hour. The mixture was evaporated in vacuo to give the crude product, which was used directly for the next step. [M+H] + =612.0.

[0308] Step 6: (R)-3-(tert-butyl)-N-(1-(4-(6-(3,5-dimethyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of (R)-3-(tert-butyl)-N-(1-(4-(6-(3,5-dimethyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (crude from Step 5) and aqueous ammonia (1 mL, 25%) in methanol (5 mL) was stirred in a round-bottom flask at room temperature for 12 hours. The mixture was evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (0.124 g, 59.7%, 2 steps). [M+H] + =582.1.

[0309] Step 7: (R)-3-(tert-butyl)-N-(1-(4-(6-(1-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of (R)-3-(tert-butyl)-N-(1-(4-(6-(3,5-dimethyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (0.112 g, 0.192 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (0.087 g, 0.288 mmol) in dichloromethane (10 mL) and MeOH (2 mL) was stirred in a round-bottom flask at room temperature for 0.5 h. To the mixture was added NaBH(OAc)3 (0.061 g, 0.288 mmol) and stirred in a round-bottom flask at room temperature for 1 h. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (0.093 g, 55.7%). 1 H NMR (400 MHz, DMSO) δ H12.14 (s, 1H), 10.27 (s, 1H), 9.94 (d, J = 6.4 Hz, 1H), 8.78 (s, 1H), 8.14 (s, 1H), 8.06-7.97 (m, 2H), 7.66 (d, J = 8.2 Hz, 1H), 7.14 (d, J = 7.6 Hz, 2H), 6.94 (d, J = 6.9 Hz, 2H), 6.75 (s, 1H), 5.42-5.33 (m, 1H), 4.20 (s, 1H), 3.72-3.68 (m, 4H), 3.07 (s, 2H), 2.69-2.67 (m, 4H), 2.52 (s, [M+H] + = 867.8.

[0310] Example 61: (R)-3-(tert-butyl)-N-(1-(4-(6-(1-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperidin-4-yl)-3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of (R)-3-(tert-butyl)-N-(1-(4-(6-(3,5-dimethyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (0.12 g, 0.206 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidine-4-carbaldehyde (0.097 g, 0.309 mmol) in dichloromethane (10 mL) and MeOH (2 mL) was stirred in a round-bottom flask at room temperature for 0.5 h. To the mixture was added NaBH(OAc)3 (0.066 g, 0.309 mmol) and stirred in a round-bottom flask at room temperature for 1 h. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (0.037 g, 20.4%). 1 H NMR (400 MHz, DMSO) δ H 12.13 (s, 1H), 10.25 (s, 1H), 9.94 (d, J = 7.5 Hz, 1H), 8.78 (s, 1H), 8.18 (s, 1H), 8.06-7.96 (m, 2H), 7.65 (d, J = 7.8 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 6.82-6.74(m, 3H), 5.42-5.33 (m, 1H), 4.14 (s, 1H), 3.69-3.67 (m, 3H), 3.49-3.47 (m, 1H), 2.99-2.95 (m, 2H), 2.68-2.66 (m, 4H), [M+H] + = 881.9.

[0311] Example 62: (R)-5-(tert-butyl)-N-(1-(4-(6-(1-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.14 (s, 1H), 10.27 (s, 1H), 9.52 (s, 1H), 8.78 (s, 1H), 8.14 (s, 1H), 7.99 (s, 2H), 7.64 (d, J = 7.8 Hz, 1H), 7.14 (d, J = 7.3 Hz, 2H), 6.94 (d, J = 7.4 Hz, 2H), 6.74 (s, 1H), 5.38 (s, 1H), 4.18 (s, 1H), 3.70 (s, 4H), 3.02 (s, 2H), 2.72-2.63 (m, 4H), 2.56-2.48 (m, 4H), 2.37 (s, 3H), 2.35-2.04 (m, 10H), 1.82 (d, J = 11.2 Hz, 4H), 1.71 (s, 1H), 1.52 (d, J = 5.0 Hz, 3H), 1.42 (d, J = 1.2 Hz, 9H), 1.29-1.16 (m, 2H);[M+H] + = 867.6.

[0312] Example 63: (R)-3-(tert-butyl)-N-(1-(4-(8-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-9H-purin-6-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka]

[0313] Example 64: (R)-3-(tert-butyl)-N-(1-(4-(8-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-9H-purin-6-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka]

[0314] Example 65: (R)-3-(tert-butyl)-N-(1-(4-(8-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-9H-purin-6-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H13.83 (s, 1H), 10.24 (s, 1H), 9.91 (s, 1H), 9.02 (s, 1H), 8.85 (s, 1H), 8.75 (s, 1H), 8.67 (s, 1H), 8.41-8.28 (m, 1H), 7.75-7.59 (m, 1H), 7.07-6.99 (m, 2H), 6.85-6.70 (m, 3H), 5.37 (s, 1H), 3.77-3.59 (m, 8H), 3.50-3.43 (m, 1H), 2.74-2.60 (m, 6H), 2.26-2.19 (m, 2H), 2.14-2.05 (m, 4H), 2.00-1.86 (m, 2H), 1.86-1.65 (m, 3H), 1.54 (s, 3H), 1.41-1.33 (m, 9H), 1.30-1.15 (m, 2H);[M+H] + = 866.5.

[0315] Example 66: (R)-3-(tert-butyl)-N-(1-(4-(8-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-9H-purin-6-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka]

[0316] Example 67: (R)-3-(tert-butyl)-N-(1-(4-(8-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-9H-purin-6-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1H NMR (400 MHz, DMSO) δ H 13.76 (s, 1H), 10.25 (s, 1H), 9.93 (d, J = 6.8 Hz, 1H), 8.84 (s, 1H), 8.79 (d, J = 7.6 Hz, 1H), 8.67 (s, 1H), 8.19 (s, 2H), 7.69 (d, J = 8.4 Hz, 1H), 7.14 (s, 2H), 7.05 (d, J = 7.2 Hz, 1H), 6.82-6.79 (m, 2H), 5.39-5.37 (m, 1H), 3.75-3.60 (m, 3H), 3.50-3.40 (m, 1H), 2.76-2.60 (m, 4H), 2.24 (s, 2H), 2.12 (s, 3H), 1.85-1.78 (m, 2H), 1.55 (d, J = 6.4 Hz, 3H), 1.37 (s, 9H), 1.35-1.16 (m, 2H);[M+H] + =865.8.

[0317] Example 68: (R)-5-(tert-butyl)-N-(1-(4-(8-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-9H-purin-6-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0318] Example 69: (R)-5-(tert-butyl)-N-(1-(4-(8-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-9H-purin-6-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0319] Example 70: (R)-5-(tert-butyl)-N-(1-(4-(8-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-9H-purin-6-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0320] Example 71: (R)-5-(tert-butyl)-N-(1-(4-(8-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-9H-purin-6-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H13.87 (s, 1H), 10.25 (s, 1H), 9.52 (d, J = 6.4 Hz, 1H), 9.04 (s, 1H), 8.85 (s, 1H), 8.76 (d, J = 7.6 Hz, 1H), 8.67 (s, 1H), 8.38 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.04 (d, J = 8.4 Hz, 2H), 6.85-6.72 (m, 2H), 5.45-5.32 (m, 1H), 3.75-3.61 (m, 7H), 3.53-3.41 (m, 1H), 2.77-2.60 (m, 4H), 2.57-2.52 (m, 2H), 2.29-2.17 (m, 2H), 2.12 (s, 3H), 1.93-1.87 (m, 1H), 1.87-1.63 (m, 3H), 1.53 (d, J = 5.2 Hz, 3H), 1.42 (s, 9H), 1.30-1.16 (m, 3H);[M+H] + = 866.5.

[0321] Example 72: (R)-5-(tert-butyl)-N-(1-(4-(8-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-9H-purin-6-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0322] Example 73: (R)-5-(tert-butyl)-N-(1-(4-(8-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-9H-purin-6-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H 13.85 (s, 1H), 10.26 (s, 1H), 9.57-9.46 (m, 1H), 8.89-8.83 (m, 1H), 8.82-8.74 (m, 1H), 8.70-8.63 (m, 1H), 8.27-8.15 (m, 2H), 7.73-7.61 (m, 1H), 7.27-7.19 (m, 1H), 7.18-7.11 (m, 1H), 7.09-7.01 (m, 2H), 6.82 (s, 3H), 5.45-5.35 (m, 1H), 4.11-3.98 (m, 1H), 3.82-3.59 (m, 5H), 3.55-3.41 (m, 2H), 3.24-3.07 (m, 5H), 2.82-2.61 (m, 5H), 2.56-2.53 (m, 3H), 2.37-2.20 (m, 2H), 2.13 (s, 3H), 1.91 (s, 2H), 1.90-1.75 (m, 1H), 1.53 (s, 3H), 1.43 (s, 9H);[M+H] + = 865.5.

[0323] Example 74: (R)-3-(tert-butyl)-N-(1-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.54 (s, 1H), 10.27 (s, 1H), 9.99 (d, J = 8.0 Hz, 1H), 8.76 (s, 1H), 8.27 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.23 (s, 1H), 7.13 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 5.46-5.36 (m, 2H), 4.95-4.72 (m, 2H), 3.74-3.64 (m, 4H), 3.26 (s, 4H), 2.72-2.62 (m, 5H), 2.23 (s, 2H), 1.82 (d, J = 12.0 Hz, 2H), 1.73 (s, 1H), 1.57 (d, J = 8.0 Hz, 3H), 1.37 (s, 9H), 1.27-1.21 (m, 3H);[M+H] + = 866.7.

[0324] Example 75: (R)-3-(tert-butyl)-N-(1-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(methoxymethyl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka]

[0325] Example 76: (R)-3-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(methoxymethyl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka]

[0326] Example 77: (R)-3-(tert-butyl)-N-(1-(4-(6-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(methoxymethyl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka]

[0327] Example 78: (R)-3-(tert-butyl)-N-(1-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 24. 1 H NMR (400 MHz, DMSO) δ H12.53 (s, 1H), 10.27 (s, 1H), 10.00 (d, J = 7.1 Hz, 1H), 8.77 (s, 1H), 8.21 (s, 1H), 7.85 (d, J = 7.7 Hz, 2H), 7.65 (s, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 7.9 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), 6.78 (s, 1H), 5.42-5.38 (m, 1H), 3.75-3.64 (m, 4H), 3.25 (s, 5H), 2.73-2.62 (m, 4H), 2.52 (s, 3H), 2.41 (s, 3H), 2.22 (d, J = 4.1 Hz, 2H), 1.81 (d, J = 11.9 Hz, 2H), 1.72 (s, 1H), 1.56 (d, J = 6.1 Hz, 3H), 1.37 (s, 9H), 1.29-1.17 (m, 2H);[M+H] + = 868.8.

[0328] Example 79: (R)-3-(tert-butyl)-N-(1-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 24. 1 H NMR (400 MHz, DMSO) δ H12.54 (s, 1H), 10.27 (s, 1H), 9.95 (d, J = 7.8 Hz, 1H), 8.78 (s, 1H), 8.22 (s, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 7.3 Hz, 1H), 7.50 (d, J = 12.1 Hz, 1H), 7.13 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 7.8 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 6.77 (s, 1H), 5.35 (s, 1H), 3.68 (d, J = 6.8 Hz, 4H), 3.24 (s, 4H), 2.72-2.61 (m, 5H), 2.52 (s, 3H), 2.46 (s, 3H), 2.22 (d, J = 6.0 Hz, 2H), 1.81 (d, J = 12.0 Hz, 2H), 1.72 (s, 1H), 1.55 (d, J = 6.8 Hz, 3H), 1.38 (s, 9H), 1.28-1.15 (m, 3H);[M+H] + = 868.8.

[0329] Example 80: 3-(tert-butyl)-N-((R)-1-(4-(6-(6-((S)-4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2-methylpiperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-fluorophenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide Step 1: tert-butyl (S)-4-(5-bromopyridin-2-yl)-3-methylpiperazine-1-carboxylate [ka] A mixture of 5-bromo-2-fluoropyridine (12.5 g, 0.0714 mol), tert-butyl (S)-3-methylpiperazine-1-carboxylate (15.7 g, 0.0786 mol), and DIEA (18.5 g, 0.143 mol) in DMF (80 mL) was stirred in a round-bottom flask at 110 °C for 2 days. The mixture was then cooled, extracted with EtOAc (200 mL × 3), and washed with brine (200 mL). The organic phase was dried over Na SO and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA = 100%:0% to 0%:100%) to give the product (2.81 g, 11%). [M+H] + = 356.3.

[0330] Step 2: (S)-(6-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)pyridin-3-yl)boronic acid [ka] A mixture of tert-butyl (S)-4-(5-bromopyridin-2-yl)-3-methylpiperazine-1-carboxylate (2.71 g, 0.00766 mol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.89 g, 0.0153 mol), Pd(dppf)Cl (560 mg, 0.0008 mmol), and KOAc (2.4 g, 0.0245 mol) in dioxane (50 mL) was stirred in a round-bottom flask overnight at 100 °C under an atmosphere of N. After the reaction was determined to be complete by LCMS, the reaction was cooled. The mixture was extracted with EtOAc (60 mL × 3). The organic layers were combined, washed with brine (100 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA = 100%:0% to 0%:100%) to give the product (2.2 g, crude). [M+H] + = 322.2.

[0331] Step 3: tert-Butyl (S)-4-(5-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)-3-methylpiperazine-1-carboxylate [ka] A mixture of 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.489 mmol), (S)-(6-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)pyridin-3-yl)boronic acid (157 mg, 0.489 mmol), Pd(dppf)Cl (20 mg, 0.0244 mmol), and KCO (108 mg, 0.782 mmol) in dioxane / water (10 mL / 3 mL) was stirred in a round-bottom flask overnight at 100 °C under an atmosphere of N. The mixture was then cooled. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE:EA=100%:0% to 50%:50%) to give the product (124 mg, 45%). [M+H] + = 559.3.

[0332] Step 4: tert-butyl (S)-4-(5-(4-(4-((R)-1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-fluorophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)-3-methylpiperazine-1-carboxylate [ka] tert-Butyl (S)-4-(5-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)-3-methylpiperazine-1-carboxylate (124 mg, 0.222 mmol), (R)-3-(tert-butyl)-N-(1-(2-fluoro-4-(4 A mixture of 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (107.1 mg, 0.255 mmol), Pd(dppf)Cl2 (11.4 mg, 0.0155 mmol), and K2CO3 (49 mg, 0.355 mmol) was stirred in a round-bottom flask overnight at 100 °C under an atmosphere of N2. After the reaction was determined to be complete by LCMS, the mixture was cooled and then concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA = 100%:0% to 70%:30%) to give the product (155 mg, 86%). [M+H] + = 814.5.

[0333] Step 5: 3-(tert-butyl)-N-((R)-1-(2-fluoro-4-(6-(6-((S)-2-methylpiperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] To a solution of tert-butyl (S)-4-(5-(4-(4-((R)-1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-fluorophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)-3-methylpiperazine-1-carboxylate (155 mg, 0.190 mmol) in DCM (6 mL) was added TFA (3 mL). The mixture was stirred at room temperature overnight. Then the mixture was concentrated in vacuo. The residue was dissolved in MeOH (10 mL) and the pH value was adjusted to 8 with NH3 (7 M in MeOH). The mixture was stirred for 30 minutes at room temperature and concentrated in vacuo. The residue was diluted with DCM:MeOH (50 mL:5 mL) and filtered. The filtrate was concentrated in vacuo to give the product (147 mg, crude), which was used for the next step without further purification. [M+H] + = 584.5.

[0334] Step 6: 3-(tert-butyl)-N-((R)-1-(4-(6-(6-((S)-4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2-methylpiperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-fluorophenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of 3-(tert-butyl)-N-((R)-1-(2-fluoro-4-(6-(6-((S)-2-methylpiperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (147 mg, 0.247 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (97 mg, 0.322 mmol) in DCM (4 mL) / MeOH (4 mL) was stirred in a round-bottom flask for 5 minutes, and HOAc was added dropwise (3 drops). The mixture was stirred at room temperature for 2 hours, and then NaBH(OAc) was added. The mixture was stirred at room temperature overnight. After the reaction was determined to be complete by LCMS, the reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM:MeOH=95%:5%) to give the product (50.88 mg, 23.6%). 1 H NMR (400 MHz, DMSO) δ H12.66 (s, 1H), 10.27 (s, 1H), 10.02 (d, J = 8.0 Hz, 1H), 8.80 (d, J = 12.0 Hz, 2H), 8.19 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 12.0 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.34 (s, 1H), 7.13 (d, J = 8.0 Hz, 2H), 6.98-6.86 (m, 3H), 5.46 (t, J = 8.0 Hz, 1H), 4.58 (s, 1H), 4.13 (d, J = 12.0 Hz, 1H), 3.75-3.65 (m, 4H), 3.08 (t, J = 12.0 Hz, 1H), 2.93 (d, J = 8.0 Hz, 1H), 2.82 (d, J = 8.0 Hz, 1H), 2.70-2.66 (m, 4H), 2.28-2.20 (m, 1H), 2.21-2.10 (m, 2H), 2.01 (t, J = 8.0 Hz, 1H), 1.84 (t, J = 12.0 Hz, 2H), 1.73 (s, 1H), 1.59 (d, J = 8.0 Hz, 3H), 1.38 (s, 9H), 1.27-1.17 (m, 5H); [M+H] + = 869.8.

[0335] Example 81: 5-(tert-butyl)-N-((R)-1-(4-(6-(6-((R)-4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2-methylpiperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-fluorophenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that of Example 80. 1 H NMR (400 MHz, DMSO) δ H12.67 (s, 1H), 10.27 (s, 1H), 10.02 (d, J = 8.0 Hz, 1H), 8.80 (d, J = 12.0 Hz, 2H), 8.19 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 12.0 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.35 (s, 1H), 7.14 (d, J = 8.0 Hz, 2H), 6.92 (dd, J = 14.9, 8.2 Hz, 3H), 5.46 (t, J = 8.0 Hz, 1H), 4.58 (s, 1H), 4.13 (d, J = 12.0 Hz, 1H), 3.70 (s, 4H), 3.15-3.02 (m, 1H), 2.93 (d, J = 8.0 Hz, 1H), 2.82 (d, J = 8.0 Hz, 1H), 2.68 (s, 4H), 2.28-2.21 (m, 1H), 2.20-2.11 (m, 2H), 2.06-1.97 (m, 1H), 1.84 (t, J = 12.0 Hz, 3H), 1.74 (s, 1H), 1.59 (d, J = 8.0 Hz, 3H), 1.38 (s, 9H), 1.26-1.18 (m, 5H);[M+H] + = 869.8.

[0336] Example 82: (R)-3-(tert-butyl)-N-(1-(4-(6-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka]

[0337] Example 83: (R)-3-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka]

[0338] Example 84: (R)—N-(1-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-5-(1-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0339] Example 85: (R)—N-(1-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0340] Example 86: (R)—N-(1-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-5-(1-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0341] Example 87: (R)—N-(1-(4-(6-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-5-(1-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0342] Example 88: (R)—N-(1-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0343] Example 89: (R)—N-(1-(4-(6-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0344] Example 90: (R)—N-(1-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.53 (s, 1H), 10.27 (s, 1H), 9.49 (d, J = 7.2 Hz, 1H), 8.75 (s, 1H), 8.11-7.99 (m, 2H), 7.91 (d, J = 7.6 Hz, 2H), 7.64 (d, J = 7.6 Hz, 1H), 7.23 (s, 1H), 7.13 (d, J = 7.6 Hz, 2H), 7.03 (d, J = 7.6 Hz, 2H), 6.93 (d, J = 7.6 Hz, 2H), 5.45-5.30 (m, 1H), 3.75-3.62 (m, 4H), 3.29-3.20 (m, 5H), 2.73-2.60 (m, 4H), 2.58-2.52 (m, 6H), 2.28-2.17 (m, 2H), 1.87-1.78 (m, 2H), 1.76-1.65 (m, 1H), 1.57-1.49 (m, 6H), 1.42-1.35 (m, 2H), 1.31-1.20 (m, 2H), 1.19-1.14 (m, 2H);[M+H] + = 848.5.

[0345] Example 91: (R)-3-(tert-butyl)-N-(1-(4-(6-(4-(4-((1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka]

[0346] Example 92: (R)-3-(tert-butyl)-N-(1-(4-(6-(4-(4-((1-(6-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka]

[0347] Example 93: (R)-3-(tert-butyl)-N-(1-(4-(6-(5-(4-((1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka]

[0348] Example 94: (R)-3-(tert-butyl)-N-(1-(4-(6-(5-(4-((1-(6-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka]

[0349] Example 95: (R)-3-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka]

[0350] Example 96: (R)-3-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(6-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-3-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka]

[0351] Example 97: (R)-3-(tert-butyl)-N-(1-(4-(6-(4-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka]

[0352] Example 98: (R)-3-(tert-butyl)-N-(1-(4-(6-(4-(4-((4-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka]

[0353] Example 99: (R)-3-(tert-butyl)-N-(1-(4-(6-(4-(4-((4-(6-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka]

[0354] Example 100: (R)-3-(tert-butyl)-N-(1-(4-(6-(6-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka]

[0355] Example 101: (R)-3-(tert-butyl)-N-(1-(4-(6-(5-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka]

[0356] Example 102: (R)-3-(tert-butyl)-N-(1-(4-(6-(6-(4-((4-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka]

[0357] Example 103: (R)-3-(tert-butyl)-N-(1-(4-(6-(5-(4-((4-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka]

[0358] Example 104: (R)-5-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 14. 1 H NMR (400 MHz, DMSO) δ H12.60 (s, 1H), 10.27 (s, 1H), 9.55 (d, J = 7.2 Hz, 1H), 8.82 (s, 1H), 8.76 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 7.2 Hz, 1H), 8.04 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.30 (s, 1H), 7.13 (d, J = 8.0 Hz, 2H), 7.00-6.93 (m, 3H), 5.39 (s, 1H), 3.70 (brs, 4H), 3.60 (brs, 4H), 2.68 (brs, [M+H] + = 851.6.

[0359] Example 105: 3-(tert-butyl)-N-((R)-1-(4-(6-(6-((R)-4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2-methylpiperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 14. 1 H NMR (400 MHz, DMSO) δ H12.58 (s, 1H), 10.26 (s, 1H), 9.96 (d, J = 8.0 Hz, 1H), 8.81 (s, 1H), 8.76 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.13 (d, J = 4.0 Hz, 2H), 6.97-6.85 (m, 3H), 5.37 (t, J = 8.0 Hz, 1H), 4.58 (s, 1H), 4.12 (d, J = 12.0 Hz, 1H), 3.69 (s, 4H), 3.07 (t, J = 16.0 Hz, 2H), 2.93 (d, J = 8.0 Hz, 2H), 2.82 (d, J = 12.0 Hz, 2H), 2.68 (s, 5H), 2.52 (s, 3H), 2.25-2.08 (m, 4H), 2.01 (t, J = 12.0 Hz, 1H), 1.84 (t, J = 12.0 Hz, 2H), 1.73 (s, 1H), 1.55 (d, J = 4.0 Hz, 4H), 1.37 (s, 9H);[M+H] + = 865.5.

[0360] Example 106: 3-(tert-butyl)-N-((R)-1-(4-(6-(6-((S)-4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2-methylpiperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 14. 1 H NMR (400 MHz, DMSO) δ H12.58 (s, 1H), 10.29 (s, 1H), 9.96 (d, J = 8.0 Hz, 1H), 8.81 (s, 1H), 8.76 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.14 (d, J = 8.0 Hz, 2H), 6.97-6.83 (m, 3H), 5.42-5.31 (m, 1H), 4.58 (s, 1H), 4.12 (d, J = 8.0 Hz, 1H), 3.70 (s, 4H), 3.12-3.03 (m, 2H), 2.93 (d, J = 8.0 Hz, 2H), 2.82 (d, J = 8.0 Hz, 2H), 2.68 (s, 6H), 2.19-2.12 (m, 3H), 2.05-1.97 (m, 2H), 1.88-1.80 (m, 3H), 1.73 (s, 1H), 1.55 (d, J = 8.0 Hz, 3H), 1.37 (s, 9H);[M+H] + =865.6.

[0361] Example 107: (R)-5-(tert-butyl)-N-(1-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 24. 1 H NMR (400 MHz, DMSO) δ H12.52 (s, 1H), 10.26 (s, 1H), 9.55 (s, 1H), 8.78 (s, 1H), 8.15 (s, 1H), 7.84 (d, J = 7.8 Hz, 2H), 7.63 (d, J = 6.7 Hz, 1H), 7.48 (d, J = 12.2 Hz, 1H), 7.13 (d, J = 8.1 Hz, 2H), 7.01 (d, J = 7.6 Hz, 2H), 6.93 (d, J = 7.7 Hz, 2H), 6.77 (s, 1H), 5.36 (s, 1H), 3.69 (d, J = 6.3 Hz, 4H), 3.28 (d, J = 30.9 Hz, 9H), 2.73-2.62 (m, 4H), 2.46 (s, 3H), 2.23 (d, J = 5.6 Hz, 2H), 1.87-1.66 (m, 3H), 1.53 (d, J = 5.9 Hz, 3H), 1.44 (s, 9H), 1.23 (q, J = 14.1 Hz, 2H);[M+H] + = 868.8.

[0362] Example 108: (R)-5-(tert-butyl)-N-(1-(4-(6-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-fluorophenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that of Example 19. 1 H NMR (400 MHz, DMSO) δ H12.70 (s, 1H), 10.27 (s, 1H), 9.26 (d, J = 8.0 Hz, 1H), 8.81 (s, 1H), 8.39 (m, 1H), 8.12-8.07 (m, 2H), 7.99-7.96 (m, 1H), 7.72-7.70 (m, 1H), 7.47-7.46 (m, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 5.48-5.46 (m, 1H), 3.69-3.68 (m, 4H), 2.69-2.66 (m, 4H), 2.52-2.51 (m, [M+H] + = 855.5.

[0363] Example 109: 3-(tert-butyl)-N-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide Step 1: (2-(aminomethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol hydrochloride [ka] To a solution of tert-butyl (2-(hydroxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (2 g, 0.0055 mol) in dioxane (20 mL) was added 4 M HCl in dioxane (20 mL). The mixture was stirred at room temperature for 2.5 hours. After the reaction was determined to be complete by LCMS, the mixture was concentrated in vacuo. The residue was then diluted with MTBE (30 mL) and stirred at room temperature for 30 minutes. The mixture was filtered and the filter cake was collected to give the product (1.6 g, crude), which was used directly without further purification. [M+H] + = 264.3.

[0364] Step 2: 3-(tert-butyl)-N-(2-(hydroxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of sodium 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate (340 mg, 2.0 mmol), HOBT (450.9 mg, 3.34 mmol), and EDCI (634.6 mg, 3.34 mmol) in DMF (10 mL) was stirred in a round-bottom flask at room temperature for 5 minutes. Then, (2-(aminomethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol hydrochloride (500 mg, 1.67 mmol) was added. The mixture was stirred at room temperature for 2.5 hours. After the reaction was determined to be complete by LCMS, the mixture was extracted with EtOAc (50 mL × 3), washed with brine (40 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA = 100%:0% to 50%:50%) to give the desired product (242 mg, 30%). [M+H-HO] + = 398.3.

[0365] Step 3: tert-butyl 4-(4-(4-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-(hydroxymethyl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate [ka] A mixture of tert-butyl 4-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate (100 mg, 0.184 mmol), 3-(tert-butyl)-N-(2-(hydroxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (160 mg, 0.386 mmol), KCO (81.2 mg, 0.588 mmol), and Pd(dppf)Cl (13.4 mg, 0.0184 mmol) in dioxane:water (10 mL:3 mL) was stirred at 90 °C overnight in a round-bottom flask. The mixture was then cooled and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA = 100%:0% to 0%:100%) to give the target product (57 mg, 39%). [M+H] + = 797.5.

[0366] Step 4: 3-(tert-butyl)-N-(2-(hydroxymethyl)-4-(6-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka] To a solution of tert-butyl 4-(4-(4-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-(hydroxymethyl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate (56 mg, 0.170 mmol) in DCM (10 mL) was added TFA (10 mL). The mixture was stirred at room temperature overnight. Then, the mixture was concentrated in vacuo. The residue was dissolved in MeOH (10 mL) and the pH value was adjusted to 8 with NH3 (7 M in MeOH). The mixture was stirred for 30 min at room temperature and concentrated in vacuo to give the desired product (50 mg, crude), which was used for the next step without further purification. [M+H] + = 567.5.

[0367] Step 5: 3-(tert-butyl)-N-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of 3-(tert-butyl)-N-(2-(hydroxymethyl)-4-(6-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (50 mg, 0.088 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (32 mg, 0.106 mmol) in DCM (5 mL):MeOH (5 mL) was stirred in a round-bottom flask. The mixture was stirred at room temperature for 5 minutes, and HOAc was added dropwise (3 drops). The mixture was stirred at room temperature for 2 hours. NaBH(OAc) (93.3 mg, 0.44 mmol) was then added. The mixture was stirred at room temperature overnight. After the reaction was determined to be complete by LCMS, the reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM:MeOH=95%:5%) to give the target product (18.11 mg, 24.1%). 1 H NMR (400 MHz, DMSO) δ H 12.54 (s, 1H), 10.27 (s, 1H), 9.87 (s, 1H), 8.77 (s, 1H), 8.31 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 4.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.22 (s, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 4.0 Hz, 2H), 6.94 (d, J = 8.0 Hz, 2H), 5.40 (s, 1H), 4.76 (s, 2H), 4.62 (s, 2H), 3.73-3.67 (m, 4H), 3.29-3.23 (m, 4H), 3.05-2.84 (m, 2H), 2.70-2.65 (m, 5H), 2.23 (s, 2H), 1.83 (d, J = 12.0 Hz, 2H), 1.77-1.67 (m, 1H), 1.37 (s, 9H), 1.25 (s, 3H);[M+H] + = 852.8.

[0368] Example 110: (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(5-(4-((1-(4-(3-methyl-2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide Step 1: 1-(4-(3-methyl-2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde [ka] 1-(4-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (100 mg, 0.3 mmol), K2CO3 (229 mg, 1.7 mmol), and MeI (236 mg, 1.7 mmol) were taken in DMF (5 mL). The mixture was stirred at room temperature overnight until LC-MS showed that all starting material was consumed. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2SO4, and concentrated to give the desired product (100 mg, 96%). [M+H] + =315.2.

[0369] Step 2: (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(5-(4-((1-(4-(3-methyl-2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(5-(piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (100 mg, 0.2 mmol), 1-(4-(3-methyl-2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (100 mg, 0.3 mmol), and AcOH (1 drop) were added to DCM / MeOH (5 mL, 10:1). The mixture was stirred at room temperature for 30 minutes. NaBH(OAc)3 (84.8 mg, 0.4 mmol) was added to the mixture in one portion, and the mixture was stirred at room temperature for an additional 1 h until LC-MS showed that all starting material was consumed. The mixture was concentrated and purified by preparative TLC (eluted with MeOH / DCM = 1:10) to give the desired product (33 mg, 38.2%). 1 H NMR (400 MHz, DMSO) δ H 12.61 (s, 1H), 9.96 (d, J = 7.1 Hz, 1H), 8.78 (s, 1H), 8.39 (s, 1H), 8.06-8.02 (m, 3H), 7.68 (d, J = 8.0 Hz, 1H), 7.51-7.47 (m, 1H), 7.40 (s, 1H), 7.14 (d, J = 8.1 Hz, 2H), 6.94 (d, J = 8.3 Hz, 2H), 5.42-5.38 (m, 1H), 3.75-3.64 (m, 5H), 3.41-3.38 (m, 4H), 3.03 (s, 3H), 2.84-2.78 (m, 2H), 2.74-2.66 (m, 3H), 2.54 (s, 3H), 2.50-2.45 (m, 3H), 2.24 (s, 1H), 1.82 (d, J = 12.2 Hz, 2H), 1.55 (d, J = 6.2 Hz, 3H), 1.37 (s, 9H), 1.26-1.22 (m, 3H);[M+H] + = 865.5.

[0370] Example 111: (R)-3-(tert-butyl)-N-(1-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 20. 1 H NMR (400 MHz, DMSO) δ H 12.52 (s, 1H), 10.38 (s, 1H), 9.95 (s, J = 8.0 Hz, 1H), 8.75 (s, 1H), 8.08 (s, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.4 Hz, 1H), 7.23-7.06 (m, 2H), 7.04 (d, J = 7.2 Hz, 2H), 6.83-6.75 (m, 2H), 5.38 (brs, 1H), 3.76 (d, J = 11.2 Hz, 2H), 3.62 (s, 2H), 3.26 (s, 4H), 2.80-2.64 (m, 4H), 2.55-2.45 (m, 7H), 2.22 (s, 2H), 1.83-1.65 (m, 3H), 1.55 (d, J = 6.4 Hz, 3H), 1.37 (s, 9H), 1.21 (brs, 2H);[M+H] + = 868.5.

[0371] Example 112: (R)-3-(tert-butyl)-N-(1-(4-(8-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-methylphenyl)-9H-purin-6-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H 13.85 (s, 1H), 10.26 (s, 1H), 9.94 (d, J = 6.4 Hz, 1H), 8.88 (s, 1H), 8.83-8.73 (m, 1H), 8.64 (s, 1H), 8.22-8.05 (m, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.87-6.72 (m, 2H), 5.51-5.23 (m, 1H), 3.76-3.61 (m, 3H), 3.51-3.40 (m, 1H), 2.97 (s, 4H), 2.75-2.62 (m, 4H), 2.58-2.53 (m, 7H), 2.37 (s, 3H), 2.30-2.21 (m, 2H), 2.12 (s, 3H), 1.87-1.78 (m, 2H), 1.76-1.66 (m, 1H), 1.59-1.50 (m, 3H), 1.37 (s, 9H), 1.28-1.15 (m, 2H);[M+H] + = 879.8.

[0372] Example 113: (R)-3-(tert-butyl)-N-(1-(4-(8-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-methoxyphenyl)-9H-purin-6-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H10.26 (s, 1H), 9.93 (d, J = 6.4 Hz, 1H), 8.88 (s, 1H), 8.85-8.75 (m, 1H), 8.70 (s, 1H), 8.01-7.85 (m, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.20-7.70 (m, 2H), 6.87-6.73 (m, 2H), 5.38 (s, 1H), 3.95 (s, 3H), 3.80-3.55 (m, 5H), 3.50-3.40 (m, 2H), 3.25-3.15 (m, 5H), 2.80-2.60 (m, 5H), 2.35-2.15 (m, 2H), 2.12 (s, 3H), 1.91-1.81 (m, 3H), 1.55 (d, J = 6.0 Hz, 3H), 1.37 (s, 9H), 1.30-1.17 (m, 2H);[M+H] + = 895.8.

[0373] Example 114: (R)-3-(tert-butyl)-N-(1-(4-(8-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-methylphenyl)-9H-purin-6-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H13.56 (s, 1H), 10.26 (s, 1H), 9.91 (d, J = 7.2 Hz, 1H), 8.87 (s, 1H), 8.76 (s, 2H), 7.86 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.09-6.90 (m, 3H), 6.85-6.75 (m, 2H), 5.38 (s, 1H), 3.76-3.60 (m, 3H), 3.50-3.40 (m, 1H), 3.34 (s, 4H), 2.79 (s, 3H), 2.75-2.60 (m, 4H), 2.27-2.18 (m, 2H), 2.12 (s, 3H), 1.91-1.65 (m, 3H), 1.55 (d, J = 4.8 Hz, 3H), 1.36 (s, 9H), 130-1.15 (m, 2H);[M+H] + = 879.6.

[0374] Example 115: (R)-5-(tert-butyl)-N-(1-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.53 (s, 1H), 10.27 (s, 1H), 9.60 (d, J = 6.7 Hz, 1H), 8.77 (s, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.64 (s, 1H), 7.47 (d, J = 6.9 Hz, 1H), 7.13 (d, J = 8.2 Hz, 2H), 7.01 (d, J = 7.8 Hz, 2H), 6.93 (d, J = 6.8 Hz, 2H), 6.78 (s, 1H), 5.41 (s, 1H), 3.70 (s, 4H), 3.25 (s, 4H), 3.10-2.86 (m, 1H), 2.68 (s, 4H), 2.51-2.57 (m, 2H), 2.37 (d, J = 31.5 Hz, 4H), 2.22 (s, 2H), 1.79 (t, J = 21.4 Hz, 3H), 1.53 (d, J = 4.6 Hz, 3H), 1.43 (s, 9H), 1.23 (d, J = 11.7 Hz, 2H);[M+H] + = 868.8.

[0375] Example 116: (R)-3-(tert-butyl)-N-(1-(4-(6-(3-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.67 (s, 1H), 10.27 (s, 1H), 9.98 (d, J = 6.8 Hz, 1H), 8.81 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.60 (s, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.41 (s, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.00-6.85 (m, 3H), 5.38 (s, 1H), 3.69 (brs, 4H), 3.27 (brs, 4H), 2.68 (brs, 4H), 2.54 (s, 6H), 2.24 (d, J = 5.6 Hz, 2H), 1.91 (d, J = 1.2 Hz, 1H), 1.83 (d, J = 12.0 Hz, 2H), 1.74 (brs, 1H), 1.55 (d, J = 6.0 Hz, 3H), 1.37 (s, 9H), 1.32-1.15 (m, 2H);[M+H] + = 850.8.

[0376] Example 117: (R)-5-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)isoxazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.59 (s, 1H), 10.27 (s, 1H), 9.35-9.24 (m, 1H), 8.81 (s, 1H), 8.76 (s, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 8.02 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.29 (s, 1H), 7.14 (d, J = 8.4 Hz, 2H), 6.99-6.91 (m, 3H), 6.56 (s, 1H), 5.41-5.32 (m, 1H), 3.73-3.66 (m, 4H), 3.65-3.56 (m, 4H), 2.73-2.65 (m, 5H), 2.55-2.52 (m, 5H), 2.26-2.19 (m, 2H), 1.94-1.89 (m, 2H), 1.87-1.78 (m, 2H), 1.54-1.46 (m, 3H), 1.32 (s, 9H), 1.27-1.21 (m, 2H);[M+H] + = 850.5.

[0377] Example 118: (R)-5-(tert-butyl)-N-(1-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized in a similar manner to Example 1. 1H NMR (400 MHz, dmso) δ 12.53 (s, 1H), 10.26 (s, 1H), 9.57 (d, J = 8.0 Hz, 1H), 8.76 (s, 1H), 8.27 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.23 (s, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 5.46 - 5.30 (m, 2H), 4.93 - 4.70 (m, 2H), 3.75 - 3.63 (m, 4H), 3.26 (s, 4H), 3.02 - 2.89 (m, 2H), 2.72 - 2.65 (m, 4H), 2.57 - 2.53 (m, 2H), 2.23 (d, J = 4.0 Hz, 2H), 1.81 (d, J = 8.0 Hz, 2H), 1.78 - 1.66 (m, 1H), 1.55 (d, J = 8.0 Hz, 3H), 1.42 (s, 9H), 1.29 - 1.24 (m, 2H). [M+H] + = 866.8.

[0378] Example 119: (R)-3-(tert-butyl)-N-(1-(4-(6-(5-(4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.60 (s, 1H), 10.30 (s, 1H), 9.95 (d, J = 8.0 Hz, 1H), 8.78 (s, 1H), 8.39 (s, 1H), 8.10-8.00 (m, 3H), 7.68 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.19 (t, J = 8.0 Hz, 1H), 6.88 (s, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 5.38 (s, 1H), 3.80-3.61 (m, 4H), 3.09-2.89 (m, 1H), 2.75-2.63 (m, 5H), 2.24 (d, J = 6.0 Hz, 2H), 1.82 (d, J = 12.0 Hz, 2H), 1.74 (s, 1H), 1.55 (d, J = 8.0 Hz, 3H), 1.37 (s, 9H), 1.27-1.17 (m, 2H);[M+H] + = 851.8.

[0379] Example 120: (R)-5-(tert-butyl)-N-(1-(4-(6-(1-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.13 (s, 1H), 10.26 (s, 1H), 9.55 (d, J = 8.0 Hz, 1H), 8.77 (s, 1H), 8.23 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.0 Hz, 2H), 6.73 (s, 1H), 5.37-5.35 (m, 2H), 4.83-4.71 (m, 2H), 4.12 (s, 1H), 3.67-3.66 (m, 4H), 2.94 (s, 2H), 2.68-2.61 (m, 4H), 2.35 (s, 3H), 2.25-2.20 (m, 5H), 2.09-2.03 (m, 4H), 1.81-1.77 (m, 4H), 1.51 (d, J = 8.0 Hz, 3H), 1.39 (s, 9H), 1.23-1.19 (m, 3H);[M+H] + = 883.9.

[0380] Example 121: (R)-1-(tert-butyl)-N-(1-(4-(6-(1-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1H-1,2,3-triazole-4-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.11 (s, 1H), 10.26 (s, 1H), 8.95 (d, J = 8.0 Hz, 1H), 8.75 (s, 1H), 8.64 (s, 1H), 7.98-7.95 (m, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.0 Hz, 2H), 5.39-5.36 (m, 1H), 4.14 (s, 1H), 3.69-3.66 (m, 4H), 2.96 (s, 2H), 2.68-2.61 (m, 5H), 2.34-2.32 (m, 4H), 2.25-2.06 (m, 9H), 1.81-1.65 (m, 5H), 1.60 (s, 9H), 1.49 (d, J = 8.0 Hz, 3H), 1.24-1.19 (m, 3H);[M+H] + = 866.7.

[0381] Example 122: (R)-1-(tert-butyl)-N-(1-(4-(6-(1-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)phenyl)ethyl)-1H-1,2,3-triazole-4-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.12 (s, 1H), 10.26 (s, 1H), 9.03 (d, J = 8.0 Hz, 1H), 8.76 (s, 1H), 8.62 (s, 1H), 8.21 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.0 Hz, 2H), 6.72 (s, 1H), 5.40-5.33 (m, 2H), 4.85-4.74 (m, 2H), 4.12 (s, 1H), 3.69-3.66 (m, 4H), 2.94 (s, 2H), 2.68-2.61 (m, 4H), 2.34 (s, 3H), 2.25-2.08 (m, 9H), 1.81-1.78 (m, 4H), 1.59 (s, 9H), 1.50 (d, J = 8.0 Hz, 3H), 1.24-1.19 (m, 3H);[M+H] + = 882.9.

[0382] Example 123: (R)—N-(1-(4-(6-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-5-(1-(hydroxymethyl)cyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H13.63 (s, 1H), 10.91 (s, 1H), 10.38 (s, 1H), 9.60 (d, J = 8.0 Hz, 1H), 9.00 (s, 1H), 8.48 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.95 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.67 (s, 1H), 7.62 (d, J = 6.4 Hz, 1H), 7.42-7.23 (m, 2H), 5.42-5.33 (m, 1H), 4.14-4.00 (m, 3H), 3.79-3.76 (m, 5H), 3.68-3.65 (m, 5H), 3.24-3.09 (m, 7H), 2.77-2.72 (m, 1H), 2.68-2.63 (m, 1H), 2.55 (s, 3H), 2.19 (s, 3H), 2.15-2.07 (m, 2H), 1.85-1.67 (m, 2H), 1.51 (d, J = 7.2 Hz, 3H), 1.34-1.28 (m, 2H), 1.26-1.20 (m, 2H);[M+H] + = 879.6.

[0383] Example 124: (R)—N-(1-(4-(6-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.62 (s, 1H), 10.27 (s, 1H), 9.50 (s, 1H), 8.98-8.55 (m, 2H), 8.19 (s, 1H), 8.11-7.90 (m, 2H), 7.63 (s, 1H), 7.29 (s, 1H), 7.20-7.07 (m, 2H), 7.04-6.84 (m, 3H), 5.44-5.26 (m, 1H), 3.77-3.51 (m, 9H), 3.47-3.42 (m, 3H), 2.74-2.61 (m, 4H), 2.45-2.39 (m, 2H), 2.30-2.09 (m, 2H), 1.93-1.62 (m, 3H), 1.61-1.43 (m, 6H), 1.41-1.30 (m, 2H), 1.29-1.08 (m, 5H);[M+H] + = 849.6.

[0384] Example 125: (R)—N-(1-(4-(6-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.60 (s, 1H), 10.25 (s, 1H), 9.49 (s, 1H), 9.01-8.62 (m, 2H), 8.18 (s, 1H), 8.11-7.94 (m, 2H), 7.64 (s, 1H), 7.29 (s, 1H), 7.08-6.89 (m, 2H), 6.86-6.67 (m, 2H), 5.46-5.28 (m, 1H), 3.79-3.54 (m, 7H), 3.53-3.39 (m, 3H), 3.38-3.36 (m, 3H), 2.83-2.61 (m, 5H), 2.26-2.17 (m, 2H), 2.12 (s, 3H), 1.89-1.70 (m, 3H), 1.60-1.47 (m, 6H), 1.41-1.32 (m, 2H), 1.30-1.11 (m, 5H);[M+H] + = 863.6.

[0385] Example 126: (R)—N-(1-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.61 (s, 1H), 10.25 (s, 1H), 9.49 (d, J = 7.2 Hz, 1H), 8.39 (s, 1H), 8.16-7.90 (m, 3H), 7.65 (d, J = 8.0 Hz, 1H), 7.53-7.31 (m, 2H), 7.04 (d, J = 8.4 Hz, 1H), 6.87-6.71 (m, 2H), 5.45-5.24 (m, 1H), 3.75-3.63 (m, 3H), 3.53-3.36 (m, 4H), 2.74-2.62 (m, 4H), 2.56-2.53 (m, 4H), 2.29-2.20 (m, 2H), 2.12 (s, 3H), 1.90-1.61 (m, 7H), 1.57-1.47 (m, 6H), 1.42-1.35 (m, 2H), 1.31-1.11 (m, 5H);[M+H] + = 863.6.

[0386] Example 127: (R)-5-(tert-butyl)-N-(1-(4-(6-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.62 (s, 1H), 10.26 (s, 1H), 9.59 (s, 1H), 8.80 (s, 1H), 8.37 (s, 1H), 7.97 (s, 1H), 7.65 (s, 1H), 7.48 (s, 2H), 7.12 (s, 2H), 6.92 (s, 3H), 5.40 (s, 1H), 3.69 (s, 4H), 2.67 (s, 5H), 2.36-2.51 (m, 7H), 2.23 (s, 2H), 1.65-1.84 (m, 3H), 1.53 (s, 3H), 1.43 (s, 9H), 1.23 (s, 2H);[M+H] + = 869.7.

[0387] Example 128: (R)-5-(tert-butyl)-N-(1-(4-(6-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.62 (s, 1H), 10.25 (s, 1H), 9.60 (d, J = 7.7 Hz, 1H), 8.38 (s, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.65 (s, 1H), 7.50-7.39 (m, 2H), 7.09-6.96 (m, 2H), 6.87-6.75 (m, 2H), 5.41 (s, 1H), 3.60-3.75 (m, 3H), 3.48 (s, 1H), 2.60-2.77 (m, 5H), 2.45-2.51 (m, 3H), 2.42 (s, 3H), 2.23 (s, 2H), 2.12 (s, 3H), 1.65-1.84 (m, 3H), 1.53 (d, J = 6.5 Hz, 3H), 1.43 (s, 9H), 1.15-1.29 (m, 3H);[M+H] + = 883.8.

[0388] Example 129: (R)-5-(tert-butyl)-N-(1-(4-(6-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.61 (s, 1H), 10.25 (s, 1H), 9.54 (d, J = 7.6 Hz, 1H), 8.39 (s, 1H), 8.11-7.98 (m, 3H), 7.66 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.40 (s, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.85-6.74 (m, 2H), 5.46-5.33 (m, 1H), 3.81-3.42 (m, 6H), 3.08-2.53 (m, 14H), 2.24 (s, 2H), 2.12 (s, 3H), 1.89-1.68 (m, 3H), 1.53 (d, J = 6.0 Hz, 3H), 1.43 (s, 9H), 1.31-1.16 (m, 2H);[M+H] + = 865.8.

[0389] Example 130: (R)-5-(tert-butyl)-N-(1-(4-(6-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.63 (s, 1H), 10.25 (s, 1H), 9.57 (d, J = 7.6 Hz, 1H), 8.37 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.49 (d, J = 11.8 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.98 (s, 1H), 6.82 (s, 1H), 6.77 (d, J = 8.6 Hz, 1H), 5.42-5.31 (m, 1H), 3.76-3.41 (m, 6H), 3.08-2.53 (m, 11H), 2.46 (s, 3H), 2.23 (s, 2H), 2.12 (s, 3H), 1.88-1.65 (m, 3H), 1.53 (d, J = 6.2 Hz, 3H), 1.44 (s, 9H), 1.25-1.19 (m, 2H);[M+H] + = 883.7.

[0390] Example 131: (R)-5-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.62 (s, 1H), 10.27 (s, 1H), 9.59 (d, J = 7.6 Hz, 1H), 8.77 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 11.2 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.99-6.88 (m, 3H), 6.84 (s, 1H), 5.43-5.26 (m, 1H), 3.72-3.64 (m, 4H), 3.63-3.47 (m, 4H), 2.73-2.62 (m, 4H), 2.47-2.41 (m, 6H), 2.26-2.14 (m, 2H), 1.86-1.67 (m, 5H), 1.57-1.48 (m, 3H), 1.44 (s, 9H), 1.28-1.15 (m, 2H);[M+H] + = 869.7.

[0391] Example 132: (R)-5-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.62 (s, 1H), 10.25 (s, 1H), 9.58 (d, J = 8.0 Hz, 1H), 8.77 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 12.0 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 6.86-6.80 (m, 2H), 6.78 (d, J = 8.4 Hz, 1H), 5.50-5.31 (m, 1H), 3.80-3.62 (m, 4H), 3.61-3.55 (m, 4H), 2.74-2.62 (m, 4H), 2.47-2.43 (m, 6H), 2.25-2.16 (m, 2H), 2.12 (s, 3H), 1.84-1.71 (m, 5H), 1.55-1.50 (m, 3H), 1.44 (s, 9H), 1.27-1.17 (m, 2H);[M+H] + = 883.8.

[0392] Example 133: (R)-5-(tert-butyl)-N-(1-(4-(6-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.61 (s, 1H), 10.25 (s, 1H), 9.54 (d, J = 7.6 Hz, 1H), 8.39 (s, 1H), 8.11-7.98 (m, 3H), 7.66 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.18-7.10 (m, 1H), 6.89-6.96 (m, 1H), 5.46-5.33 (m, 1H), 3.69 (s, 6H), 2.76-2.53 (m, 14H), 2.24 (s, 2H), 1.89-1.68 (m, 5H), 1.53 (d, J = 6.0 Hz, 3H), 1.43 (s, 9H), 1.31-1.16 (m, 2H);[M+H] + = 851.6.

[0393] Example 134: (R)-5-(tert-butyl)-N-(1-(4-(6-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.62 (s, 1H), 10.26 (s, 1H), 9.56 (d, J = 7.6 Hz, 1H), 8.37 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.49 (d, J = 11.8 Hz, 1H), 7.42 (d, J = 7.0 Hz, 1H), 7.13 (d, J = 8.2 Hz, 2H), 7.01-6.89 (m, 3H), 5.41-5.31 (m, 1H), 3.77-3.63 (m, 5H), 2.74-2.53 (m, 12H), 2.46 (s, 3H), 2.23 (d, J = 4.6 Hz, 2H), 1.88-1.66 (m, 3H), 1.53 (d, J = 6.4 Hz, 3H), 1.44 (s, 9H), 1.26-1.21 (m, 2H);[M+H] + = 869.6.

[0394] Example 135: (R)-3-(tert-butyl)-N-(1-(1-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (500 MHz, DMSO) δ H12.06 (s, 1H), 10.25 (s, 1H), 9.22 (d, J = 8.0 Hz, 1H), 8.66 (s, 1H), 8.12 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.20-6.78 (m, 6H), 4.86-4.65 (m, 2H), 3.90-3.77 (m, 1H), 3.75-3.64 (m, 4H), 3.54 (s, 3H), 3.29-3.23 (m, 1H), 3.11 (s, 1H), 3.00 (dd, J = 24.0, 12.0 Hz, 2H), 2.75-2.61 (m, 4H), 2.46 (s, 4H), 2.21 (s, 1H), 1.90-1.62 (m, 6H), 1.36 (s, 9H), 1.27-1.22 (m, 2H), 1.22-1.16 (m, 4H);[M+H] + = 844.6.

[0395] Example 136: (R)-5-(tert-butyl)-N-(1-(4-(6-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.62 (s, 1H), 10.26 (s, 1H), 9.57 (d, J = 8.0 Hz, 1H), 8.79 (s, 1H), 8.40 (s, 1H), 8.27 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.41 (s, 1H), 7.13 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 5.45-5.33 (m, 2H), 4.95-4.65 (m, 2H), 3.76-3.64 (m, 6H), 2.75-2.61 (m, 6H), 2.54 (s, 4H), 2.24 (s, 3H), 1.82 (d, J = 12.0 Hz, 2H), 1.73 (s, 1H), 1.55 (d, J = 8.0 Hz, 3H), 1.42 (s, 9H);[M+H] + = 867.7.

[0396] Example 137: (R)-5-(tert-butyl)-N-(1-(4-(6-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.62 (s, 1H), 10.24 (s, 1H), 9.56 (d, J = 8.0 Hz, 1H), 8.79 (s, 1H), 8.40 (s, 1H), 8.27 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.41 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.82 (s, 1H), 6.78 (d, J = 8.0 Hz, 1H), 5.46-5.36 (m, 2H), 4.95-4.75 (m, 2H), 3.75-3.62 (m, 3H), 3.52-3.42 (m, 2H), 2.80-2.61 (m, 5H), 2.54 (s, 4H), 2.24 (s, 2H), 2.12 (s, 3H), 1.81 (d, J = 12.0 Hz, 2H), 1.73 (s, 1H), 1.55 (d, J = 8.0 Hz, 3H), 1.42 (s, 9H), 1.30-1.18 (m, 5H);[M+H] + = 881.9.

[0397] Example 138: (R)-3-(tert-butyl)-N-(1-(4-(6-(1-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.15 (s, 1H), 10.27 (s, 1H), 9.97 (d, J = 8.0 Hz, 1H), 8.79 (s, 1H), 8.25 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.0 Hz, 2H), 6.76 (s, 1H), 5.41-5.36 (m, 2H), 4.87-4.73 (m, 2H), 4.15 (s, 1H), 3.71-3.68 (m, 4H), 2.96 (s, 2H), 2.70-2.64 (m, 4H), 2.37 (s, 3H), 2.27-2.09 (m, 8H), 1.81-1.77 (m, 4H), 1.69 (s, 1H), 1.56 (d, J = 8.0 Hz, 3H), 1.36 (s, 9H), 1.24-1.19 (m, 3H);[M+H] + = 883.7.

[0398] Example 139: (R)-3-(tert-butyl)-N-(1-(4-(6-(1-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-(hydroxymethyl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.15 (s, 1H), 10.26 (s, 1H), 9.93 (d, J = 8.0 Hz, 1H), 8.82 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 6.35 (s, 1H), 5.41-5.37 (m, 2H), 4.79-4.67 (m, 2H), 4.14 (s, 1H), 3.70-3.68 (m, 4H), 2.97 (s, 2H), 2.68-2.64 (m, 4H), 2.34 (s, 3H), 2.25-2.20 (m, 4H), 2.09-2.03 (m, 4H), 1.81-1.77 (m, 4H), 1.69 (s, 1H), 1.57 (d, J = 8.0 Hz, 3H), 1.37 (s, 9H), 1.24-1.19 (m, 3H);[M+H] + = 901.7.

[0399] Example 140: (R)-5-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide Step 1: tert-butyl 4-(5-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)piperazine-1-carboxylate [ka] To a mixture of tert-butyl 4-(5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)piperazine-1-carboxylate (2.05 g, 5.0 mmol) in DMF (25 mL) was added NaH (0.24 g of a 60% dispersion in mineral oil, 6.0 mmol). The mixture was stirred at 0° C. for 60 minutes. SEM-Cl (1.02 g, 6.0 mmol) was then added. LCMS showed the reaction was complete. The reaction was quenched with 10% aqueous NaCl (10 mL). The resulting suspension was sonicated for 5 minutes, filtered, and concentrated in vacuo to give the product (2.97 g, crude), which was used for the next step without further purification. [M+H] + = 545.8.

[0400] Step 2: tert-butyl (R)-4-(5-(4-(4-(1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)ethyl)-2-fluoro-3-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)piperazine-1-carboxylate [ka] tert-Butyl 4-(5-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)piperazine-1-carboxylate (147 mg, 0.27 mmol), (R)-5-(tert-butyl)-N-(1-(3-fluoro-2-methyl-2-pyridin-2-yl)piperazine-1-carboxylate) in 1,4-dioxane (10 mL) and HO (2 mL). A mixture of 4-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl-1,2,4-oxadiazole-3-carboxamide (120 mg, 0.27 mmol), Pd(dppf)Cl (20 mg, 0.027 mmol), and CsCO (270 mg, 0.81 mmol) was stirred in a round-bottom flask at 100 °C overnight. The mixture was evaporated in vacuo to give the crude product, which was further purified by silica gel column chromatography (PE: EtOAc = 100:1 to 1:2 gradient elution) to give the product (138 mg, 62%). [M+H] + = 814.7.

[0401] Step 3: (R)-5-(tert-butyl)-N-(1-(3-fluoro-2-methyl-4-(6-(6-(piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] A mixture of tert-butyl (R)-4-(5-(4-(4-(1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)ethyl)-2-fluoro-3-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)piperazine-1-carboxylate (138 mg, 0.17 mmol) and trifluoroacetic acid (16 mL) in dichloromethane (5 mL) was stirred in a round-bottom flask at room temperature for 3 hours. The mixture was evaporated in vacuo. The residue was dissolved in MeOH (10 mL) and NH3 / H2O (2 mL) was added. The mixture was stirred at room temperature for 30 minutes. LCMS showed that the reaction was complete. The mixture was evaporated in vacuo to give the product (415 mg, crude), which was used for the next step without further purification. [M+H] + = 584.4.

[0402] Step 4: (R)-5-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] A mixture of (R)-5-(tert-butyl)-N-(1-(3-fluoro-2-methyl-4-(6-(6-(piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide (207 mg, crude) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (40 mg, 0.14 mmol) in DCM (10 mL) and MeOH (2 mL) was stirred in a round-bottom flask at room temperature for 2 hours. To the mixture was added NaBH(OAc) (212 mg, 1.0 mmol), and the mixture was stirred in a round-bottom flask at room temperature overnight. The mixture was then purified by preparative TLC (DCM:MeOH=7:1) to give the product (40 mg, 57%). 1 H NMR (400 MHz, DMSO) δ H 12.64 (s, 1H), 10.27 (s, 1H), 9.62 (d, J = 7.6 Hz, 1H), 8.76 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.74-7.57 (m, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.8 Hz, 2H), 7.03-6.88 (m, 3H), 6.84 (s, 1H), 5.48-5.32 (m, 1H), 3.73-3.65 (m, 4H), 3.62-3.54 (m, 4H), 2.71-2.61 (m, 4H), 2.48-2.43 (m, 4H), 2.41 (s, 3H), 2.26-2.16 (m, 2H), 1.89-1.67 (m, 4H), 1.56-1.50 (m, 3H), 1.43 (s, 9H), 1.28-1.18 (m, 2H);[M+H] + = 869.8.

[0403] Example 141: (R)-5-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.61 (s, 1H), 10.24 (s, 1H), 9.60 (d, J = 7.6 Hz, 1H), 8.75 (s, 1H), 8.13 (d, J = 7.2 Hz, 1H), 7.64 (t, J = 7.2 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 9.2 Hz, 1H), 6.87-6.80 (m, 2H), 6.77 (d, J = 8.0 Hz, 1H), 5.53-5.29 (m, 1H), 3.74-3.64 (m, 3H), 3.62-3.53 (m, 4H), 2.75-2.63 (m, 4H), 2.47-2.39 (m, 6H), 2.25-2.17 (m, 2H), 2.12 (s, 3H), 1.90-1.64 (m, 7H), 1.53 (d, J = 6.4 Hz, 3H), 1.43 (s, 9H), 1.27-1.17 (m, 2H);[M+H] + = 883.8.

[0404] Example 142: (R)-3-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.60 (s, 1H), 10.26 (s, 1H), 9.92 (d, J = 7.9 Hz, 1H), 8.82 (s, 1H), 8.67 (s, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.83 (s, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 9.0 Hz, 1H), 6.93 (d, J = 8.9 Hz, 2H), 5.43-5.31 (m, 1H), 3.70 (t, J = 7.7 Hz, 4H), 3.60 (s, 4H), 2.67 (t, J = 11.0 Hz, 4H), 2.50 (s, 3H), 2.46 (s, 4H), 2.22 (d, J = 5.7 Hz, 2H), 1.82 (d, J = 12.2 Hz, 2H), 1.72 (s, 1H), 1.55 (d, J = 6.8 Hz, 3H), 1.37 (s, 9H), 1.23 (d, J = 11.3 Hz, 2H); 19 F NMR (376.42 MHz, DMSO) δ F -160.30;[M+H] + = 869.7.

[0405] Example 143: 3-(tert-butyl)-N-((1R)-1-(4-(6-(4-(4-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)pyrrolidin-3-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.52 (s, 1H), 10.74 (s, 1H), 9.95 (d, J = 7.7 Hz, 1H), 8.09 (d, J = 8.1 Hz, 1H), 8.04 (s, 1H), 7.92 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 8.3 Hz, 1H), 7.23 (s, 1H), 7.04-7.01 (m, 4H), 6.49 (d, J = 8.5 Hz, 2H), 5.41-5.37 (m, 1H), 3.69-3.65 (m, 1H), 3.3-3.23 (m, 5H), 3.05-2.98 (m, 2H), 2.65-2.58 (m, 4H), 2.53-2.49 (m, 3H), 2.50-2.47 (m, 5H), 2.45-2.40 (m, 2H), 2.15-2.10 (m, 2H), 2.05-1.98 (m, 1H), 1.78-1.72 (m, 1H), 1.55 (d, J = 6.6 Hz, 3H), 1.37 (s, 9H);[M+H] + = 835.7.

[0406] Example 144: (R)-5-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.61 (s, 1H), 10.26 (s, 1H), 9.58 (d, J = 8.0 Hz, 1H), 8.79 (d, J = 8.0 Hz, 1H), 8.27 (s, 1H), 8.15 (t, J = 8.0 Hz, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.13 (d, J = 8.0 Hz, 2H), 6.99-6.88 (m, 3H), 5.50-5.27 (m, 2H), 4.91-4.74 (m, 2H), 3.74-3.55 (m, 9H), 3.42 (s, 1H), 2.74-2.61 (m, 5H), 2.47 (s, 4H), 2.22 (d, J = 4.0 Hz, 2H), 1.82 (d, J = 12.0 Hz, 2H), 1.73 (s, 1H), 1.55 (d, J = 8.0 Hz, 3H), 1.42 (s, 9H);[M+H] + = 867.8.

[0407] Example 145: (R)-5-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.60 (s, 1H), 10.24 (s, 1H), 9.58 (d, J = 8.0 Hz, 1H), 8.79 (d, J = 8.0 Hz, 1H), 8.27 (s, 1H), 8.15 (t, J = 8.0 Hz, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.86-6.72 (m, 2H), 5.46-5.23 (m, 2H), 4.95-4.69 (m, 3H), 3.74-3.64 (m, 4H), 3.60 (s, 4H), 3.46 (dd, J = 12.0, 6.0 Hz, 3H), 2.74-2.60 (m, 5H), 2.48 (s, 3H), 2.22 (d, J = 4.0 Hz, 2H), 2.12 (s, 3H), 1.81 (d, J = 8.0 Hz, 2H), 1.75-1.71 (m, 1H), 1.54 (d, J = 8.0 Hz, 3H), 1.42 (s, 9H);[M+H] + = 881.8.

[0408] Example 146: (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(6-(4-((1-(4-(3-methyl-2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.60 (s, 1H), 9.96 (d, J = 8.0 Hz, 1H), 8.81 (s, 1H), 8.77 (s, 1H), 8.11-8.09 (m, 1H), 8.05-8.02 (m, 1H), 7.66-7.64 (m, 1H), 7.25 (s, 1H), 7.14 (d, J = 8.0 Hz, 2H), 6.96-6.92 (m, 3H), 5.40-5.36 (m, 1H), 3.69-3.66 (m, 4H), 3.62-3.58 (m, 4H), 3.02 (s, 3H), 3.10-3.00 (m, 2H), 2.75-2.70 (m, 4H), 2.52-2.50 (m, 4H), 2.25-2.20 (m, 4H), 2.03-1.97 (m, 1H), 1.86-1.84 (m, 2H), 1.84-1.82 (m, 2H), 1.55 (d, J = 6.6 Hz, 3H), 1.37 (s, 9H);[M+H] + = 865.8.

[0409] Example 147: (S)-3-(tert-butyl)-N-(1-(4-(6-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.60 (s, 1H), 10.25 (s, 1H), 9.94 (d, J = 8.0 Hz, 1H), 8.79 (s, 1H), 8.39 (s, 1H), 8.13-7.96 (m, 3H), 7.68 (d, J = 8.0 Hz, 1H), 7.54-7.34 (m, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 5.45-5.33 (m, 1H), 3.75-3.63 (m, 4H), 2.73-2.60 (m, 5H), 2.53 (s, 6H), 2.51 (d, J = 4.0 Hz, 3H), 2.24 (d, J = 4.0 Hz, 2H), 1.81 (d, J = 12.0 Hz, 2H), 1.72 (s, 1H), 1.56 (d, J = 4.0 Hz, 3H), 1.37 (s, 9H), 1.29-1.17 (m, 3H);[M+H] + = 851.7.

[0410] Example 148: (S)-3-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.58 (s, 1H), 10.25 (s, 1H), 9.98-9.90 (m, 1H), 8.93-8.65 (m, 2H), 8.22-8.13 (m, 1H), 8.12-8.00 (m, 2H), 7.71-7.61 (m, 1H), 7.29 (s, 1H), 7.17-7.09 (m, 2H), 7.00-6.88 (m, 3H), 5.38 (s, 1H), 3.75-3.50 (m, 9H), 2.67 (s, 5H), 2.55-2.52 (m, 3H), 2.47-2.42 (m, 2H), 2.22 (s, 2H), 1.82 (d, J = 12.0 Hz, 2H), 1.73 (s, 1H), 1.58-1.51 (m, 3H), 1.37 (s, 9H), 1.29-1.17 (m, 3H);[M+H] + = 851.8.

[0411] Example 149: (R)-5-(tert-butyl)-N-(1-(4-(6-(1-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-(hydroxymethyl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.14 (s, 1H), 10.25 (s, 1H), 9.55 (d, J = 8.0 Hz, 1H), 8.82 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 6.34 (s, 1H), 5.42-5.34 (m, 2H), 4.81-4.67 (m, 2H), 4.14 (s, 1H), 3.70-3.68 (m, 4H), 2.99 (s, 2H), 2.68-2.64 (m, 4H), 2.34 (s, 3H), 2.25-2.20 (m, 4H), 2.09-2.03 (m, 4H), 1.83-1.80 (m, 4H), 1.69 (s, 1H), 1.54 (d, J = 8.0 Hz, 3H), 1.43 (s, 9H), 1.27-1.21 (m, 3H);[M+H] + = 901.7.

[0412] Example 150: (R)-3-(tert-butyl)-N-(5-(6-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.61 (s, 1H), 10.25 (s, 1H), 9.82 (d, J = 8.0 Hz, 1H), 8.79 (s, 1H), 8.39 (s, 1H), 8.13-8.02 (m, 3H), 7.48-7.39 (m, 3H), 7.13 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 5.63-5.61 (m, 1H), 3.69-3.68 (m, 4H), 3.23-3.17 (m, 1H), 3.05-2.95 (m, 1H), 2.70-2.64 (m, 4H), 2.55-2.53 (m, [M+H] + = 849.7.

[0413] Example 151: (R)-3-(tert-butyl)-N-(5-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.60 (s, 1H), 10.25 (s, 1H), 9.82 (d, J = 8.0 Hz, 1H), 8.81 (s, 1H), 8.77 (s, 1H), 8.14-8.10 (m, 3H), 7.47 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.13 (d, J = 8.0 Hz, 2H), 6.97-6.91 (m, 3H), 5.62-5.60 (m, 1H), 3.69-3.60 (m, 8H), 3.20-3.17 (m, 1H), 3.00-2.95 (m, 1H), 2.67-2.63 (m, 4H), 2.47-2.44 (m, 4H), 2.23-2.21 (m, 3H), 1.84-1.69 (m, 3H), 1.36 (s, 9H), 1.28-1.19 (m, 3H);[M+H] + = 849.7.

[0414] Example 152: (R)-3-(tert-butyl)-N-(1-(4-(6-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-3,5-dimethyl-1H-pyrazol-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.68 (s, 1H), 10.26 (s, 1H), 9.86 (d, J = 7.6 Hz, 1H), 8.61 (s, 1H), 7.86-7.72 (m, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.15 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 5.42-5.21 (m, 1H), 3.86-3.54 (m, 6H), 3.18-2.87 (m, 5H), 2.80-2.64 (m, 7H), 2.48-2.25 (m, 8H), 2.11-1.80 (m, 5H), 1.51 (d, J = 6.8 Hz, 3H), 1.36 (s, 9H);[M+H] + = 867.9.

[0415] Example 153: 3-(tert-butyl)-N-((1R)-1-(4-(6-(4-(4-(3-(4-(2,6-dioxopiperidin-3-yl)phenyl)cyclobutyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.53 (s, 1H), 10.81 (s, 1H), 9.95 (d, J = 7.2 Hz, 1H), 8.75 (s, 1H), 8.09 (d, J = 7.6 Hz, 1H), 8.03 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 7.8 Hz, 1H), 7.22-7.14 (m, 5H), 7.03 (d, J = 8.4 Hz, 2H), 5.38 (t, J = 7.6 Hz, 1H), 3.86-3.78 (m, 1H), 3.26 (s, 4H), 3.20-3.10 (m, 1H), 3.00 (brs, 1H), 2.81-2.59 (m, 3H), 2.53 (s, 3H), 2.46 (s, 4H), 2.25-2.10 (m, 1H), 2.03 (s, 1H), 1.95-1.82 (m, 3H), 1.55 (d, J = 6.4 Hz, 3H), 1.37 (s, 9H);[M+H] + = 806.8.

[0416] Example 154: (R)-3-(tert-butyl)-N-(1-(4-(6-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-fluorophenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.68 (s, 1H), 10.25 (s, 1H), 10.00 (d, J = 8.0 Hz, 1H), 8.81 (s, 1H), 8.39 (s, 1H), 8.15-8.04 (m, 2H), 7.98 (d, J = 12.0 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.51-7.42 (m, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 5.62-5.42 (m, 1H), 3.81-3.58 (m, 4H), 3.10-2.82 (m, 1H), 2.75-2.62 (m, 4H), 2.54 (s, 6H), 2.24 (s, 2H), 1.82 (d, J = 12.0 Hz, 2H), 1.74 (s, 1H), 1.60 (d, J = 8.0 Hz, 3H), 1.38 (s, 9H), 1.23 (s, 3H);[M+H] + = 855.8.

[0417] Example 155: (R)-3-(tert-butyl)-N-(1-(4-(6-(1-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-N-methyl-1,2,4-oxadiazole-5-carboxamide [ka] The title compound was synthesized using a procedure similar to that described in Example 25. 1 H NMR (400 MHz, DMSO) δ H12.19 (s, 1H), 10.23 (s, 1H), 8.80 (s, 1H), 8.15-8.01 (m, 2H), 7.73-7.55 (m, 1H), 7.15 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.83-6.71 (m, 1H), 6.02-5.87 (m, 1H), 3.71 (d, J = 6.8 ...

Claims

1. Compounds of formula (I) 【Chemical 1】 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof [In the formula: 【Chemistry 2】 is a 5- or 6-membered aromatic ring containing 0-3 heteroatoms selected from nitrogen, oxygen and sulfur; 【Chemistry 3】 teeth, 【Chemistry 4】 an E3 ubiquitin ligase moiety selected from: L 1 , L 2 , L 3 , L 4 and L 5 are each independently a bond, —O—, —CO—, —(CR c R d ) n2 -or-NR c - and; L 6 are each independently -(CR a R b ) n1 -, -CO-(CR a R b ) n1 -NH-(CR e R f ) n3 -, -CO-(CR a R b ) n1 -NH-, or -(CR a R b ) n1 -NH-(CR e R f ) n3 - and; Z 1 , Z 2 and Z 3 are each independently, CR 12 or N; X a , X b , X c , X d and X e are each independently, CR 12 or N; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 10 are each independently hydrogen, halogen, or —C 1～8 Alkyl, —C 1～8 Alkoxy, -C 2～8 Alkenyl, -C 2～8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —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 and -C 1～8 Alkyl, -C 2～8 Alkenyl, -C 2～8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from halogen, hydroxy, -haloC 1～8 Alkyl, -C 1～8 optionally substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or R 4 and R at the ortho position of the phenyl ring 2 forms a 5- or 6-membered carbocyclic ring; or X a and either one of two adjacent carbon atoms forms a double bond, provided that Xa is CR 12 and R 12 Is it conditional on the absence of or 【Chemistry 5】 Two non-adjacent R 8 is 1, 2 or 3 CH 2 forming a bridge including; Each R 12 are independently hydrogen or —C 1～8 is alkyl; R 9 is a 5- or 6-membered aromatic ring containing 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur; each of said aromatic rings is 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 ) 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 said -C 1～8 Alkyl, -C 2～8 Alkenyl, -C 2～8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from halogen, hydroxy, -haloC 1～8 Alkyl, -C 1～8 optionally substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; n1, n2, n3, m1, m2, m3, m4, m5, p1, p2, p3, p4, and p5 are each independently 0, 1, 2, 3, or 4; R a , R b , R c , R d , R e and R f are each independently hydrogen, —C 1～8 Alkyl, -C 2～8 Alkenyl, -C 2～8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

2. Compound of formula (II): 【Chemistry 6】 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof [In the formula: 【Chemistry 7】 is a 5- or 6-membered aromatic ring containing 0-3 heteroatoms selected from nitrogen, oxygen and sulfur; 【Chemistry 8】 teeth, 【Chemistry 9】 an E3 ubiquitin ligase moiety selected from: L 1 , L 2 , L 3 , L 4 and L 5 are each independently a bond, —O—, —CO—, —(CR c R d ) n2 -or-NR c - and; Z 1 , Z 2 and Z 3 are each independently, CR 12 or N; X a , X b , X c , X d and X e are each independently, CR 12 or N; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 10 are each independently hydrogen, halogen, or —C 1～8 Alkyl, -C 1～8 Alkoxy, -C 2～8 Alkenyl, -C 2～8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —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 and -C 1～8 Alkyl, -C 2～8 Alkenyl, -C 2～8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from halogen, hydroxy, -haloC 1～8 Alkyl, -C 1～8 optionally substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; Each R 12 are independently hydrogen or —C 1～8 is alkyl; R 9 is a 5- or 6-membered aromatic ring containing 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur; each of said aromatic rings is 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 ) 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 said -C 1～8 Alkyl, -C 2～8 Alkenyl, -C 2～8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from halogen, hydroxy, -haloC 1～8 Alkyl, -C 1～8 optionally substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; n1, n2, m1, m2, p1, p2, p3, p4, and p5 are each independently 0, 1, 2, 3, or 4; R a , R b , 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. 【Request 3】 【Chemical 10】 but, 【Chemistry 11】 and Here, Z 4 , Z 5 , Z 6 and Z 7 are each independently selected from CH or N; * 1 is, 【Chemistry 12】 and ** 1 is L 1 3. The compound of claim 1 or 2, wherein the compound is attached to 【Request 4】 【Chemical 13】 but, 【Chemistry 14】 where Z 4 , Z 5 and Z 7 are each independently selected from CH or N.

5. 【Chemical 15】 but, 【Chemistry 16】 5. The compound according to claim 3 or 4, selected from:

6. p3 is 0, 1, or 2, and each R 7 are independently halogen, —C 1～8 Alkyl, or -C 1～8 Alkoxy, preferably F, Cl, Br, I, CH 3 , or -OCH 3 The compound according to any one of claims 3 to 5, selected from: 【Request 7】 【Chemical 17】 but, 【Chemistry 18】 3. The compound of claim 1 or 2, selected from:

8.

19. but, 【Chemistry 20】 and R 10 8. The compound of claim 7, wherein is selected from hydrogen or halogen; and p5 is 0 or 1.

9. 【Catalog 21】 but, 【Chemical 22】 and R 10 The compound of claim 8 , wherein is selected from hydrogen, F, Cl, Br and I.

10.

23. but, 【Chemistry 24】 where R 10 But hydrogen, halogen, -C 1～8 Alkyl, -OR a and R a is hydrogen or -C 1～8 3. The compound of claim 1 or 2, wherein p5 is 0 or 1;

11. 【Catalog 25】 but, 【Chemical 26】 wherein R 10 But hydrogen, halogen, -C 1～8 Alkyl, or -C 1～8 11. A compound according to claim 10, wherein the alkoxy is fluoro, chloro, methyl or methoxy.

12.

27. but, 【Chemical 28】 12. The compound of claim 11 selected from:

13. L 1 is a bond or —O—, and L 2 The compound of claim 1 or 2, wherein is a bond.

14. R a and R b are independently hydrogen or CH 3 and n1 is 1 or 2. The compound of claim 1 or 2, wherein n1 is selected from the group consisting of:

15. X a is selected from CH or N; X b is N; X c is CH and X d The compound according to claim 1 or 2, wherein is N.

16. 3. The compound of claim 1 or 2, wherein m1, m2, m3, m4 and m5 are each independently selected from 0, 1 or 2, preferably 1.

17. p4 is 0 or 1, and R 8 is halogen, OH, or -C 1～8 Alkyl, preferably CH 3 3. The compound of claim 1 or 2, selected from:

18.

29. but, 【Chemistry 30】 (wherein m3 and m4 are each independently 0, 1, 2, 3, or 4), or 【Chemical 31】 3. The compound according to claim 1, wherein m3 is 1, 2, 3 or 4, and m4 is 0, 1, 2, 3 or 4.

19. p4 is 2 and two non-adjacent R 8 But 1, 2 or 3 CH 2 3. The compound of claim 1 or 2, forming a bridge comprising:

20. 【Catalog 32】 but, 【Chemical 33】 2. The compound of claim 1 selected from:

21.

34. but, 【Chemistry 35】 3. The compound of claim 2, selected from:

22. Z 1 The compound of any one of claims 1 to 21, wherein is CH or N; and p2=0.

23. R 1 is methyl, -CH 2 OH, -OCH 3 , -CH 2 OCH 3 or halogen; p1 is 0 or 1, and R 2 The compound according to any one of claims 1 to 22, wherein is halogen.

24. R 3 is hydrogen; R 4 and R 5 A compound according to any one of claims 1 to 23, wherein is selected from hydrogen or methyl.

25. R 9 but, 【Chemical 36】 and Y 1 , Y 2 , Y 3 and Y 4 is selected from CH, O, S or N; R 11 But 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 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 selected from halogen, hydroxy, -haloC 1～8 Alkyl, -C 1～8 optionally substituted with alkyloxy, 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 25. The compound of any one of claims 1 to 24, wherein p6 is alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and p6 is 0, 1, 2, 3, or 4.

26. Y 1 is CH, S, N or O; Y 2 is CH, O or N; Y 3 is O, S, or N; and Y 4 is S, CH or N. 【Request 27】 【Chemical 37】 but, 【Chemical 38】 27. The compound of claim 25 or 26, selected from:

28. R 11 but, 【Chemical 39】 28. The compound of claim 27, selected from:

29.

40. 29. The compound of claims 1-28, wherein the variables are defined as in the claims. 【Request 30】 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 【Table 1-17】 【Table 1-18】 【Table 1-19】 【Table 1-20】 【Table 1-21】 【Table 1-22】 【Table 1-23】 【Table 1-24】 【Table 1-25】 2. The compound of claim 1 selected from:

31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

32. 31. A method of inhibiting BTK activity comprising administering to an individual a compound of any one of claims 1 to 30, including a compound of formula (I) or the specific compounds exemplified in the claims, or a pharmaceutically acceptable salt thereof.

33. 31. 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 claims 1 to 30, or a pharmaceutically acceptable salt thereof, as a BTK kinase inhibitor, wherein the disease or disorder is associated with inhibition of BTK, and preferably the disease or disorder is cancer.

34. 31. A method of decreasing BTK activity by inhibition and / or proteolysis, comprising administering to an individual a compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof.

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