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

Abstract

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, and methods for their preparation and use.

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, and methods for their preparation and use. [Background technology]

[0002] Proteolysis-inducing chimeric molecules (PROTACs) are a novel strategy for selectively knocking down target proteins with 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 TKet 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 KNet al., Cell Res. 2016, 26, 399-422). Ubiquitin, which is highly conserved in eukaryotic cells, is a modified molecule consisting of 76 amino acids that covalently attaches to and labels 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 about 40 E2 enzymes and more than 600 E3 enzymes that provide functional diversity and govern 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 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 consisting 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 antitumor research (Lu J.et al.,Chem Biol.2015;22(6):755-763;Ottis P.et al.,Chem Biol.2017;12(4):892-898.;Crews CMet al.,J Med Chem.2018;61(2):403-404;Neklesa TKet al.,Pharmacol Ther.2017,174:138-144.;Cermakova K.et al.,Molecules,2018.23(8).;An S.et al.,EBioMedicine,2018.;Lebraud H.et al.,Essays Biochem.2017;61(5):517-527.;Sun YHet 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 mainly 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. Once activated, 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 an inherited 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 dysregulation of 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 a critical role for 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). Thus, 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 by 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 lymphomas), and are disclosed or discussed in patent publications, such as 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 H, F, Cl, -CH 3 , -OCH 3 , and -OCH 2 CH 3 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 H, F, Cl, -CH 3 , -OCH 3 , and -OCH 2 CH 3 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 via 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 molecule (PROTAC) 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 a PROTAC compound having formula I: [Means for solving the problem]

[0010] Aspect 1: A compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof. [In formula: [ka] is a 5- or 6-membered aromatic ring containing 0-3 heteroatoms selected from nitrogen, oxygen and sulfur; [ka] teeth, [ka] 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 , Xb , 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, -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 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; or R 4 and R at the ortho position of the phenyl ring. 2 or forms a 5- or 6-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 R 12 conditional on the absence of; or [ka] Two non-adjacent R on 8 1, 2 or 3 CH 2 It forms 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 , -NRa 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 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: Compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof. [In formula: [ka] is a 5- or 6-membered aromatic ring containing 0-3 heteroatoms selected from nitrogen, oxygen and sulfur; [ka] teeth, [ka] 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, -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 , -CO2 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 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 1~8 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 Ra , -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 may be 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.

[0012] Aspect 3: [ka] but, [ka] and; Here, Z 4 , Z 5 , Z 6 and Z 7 are each independently selected from CH or N; * 1, [ka] and ** 1, L 1 3. The compound according to embodiment 1 or 2, wherein

[0013] Aspect 4: [ka] but, [ka] where Z 4 , Z 5 and Z 7 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 Alkoxy, preferably F, Cl, Br, I, CH 3 , or -OCH 3 A compound according to any one of aspects 3 to 5, selected from:

[0016] Aspect 7: [ka] but, [ka] 3. The 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 10 is selected from hydrogen, F, Cl, Br, and I.

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

[0020] Aspect 11: [ka] but, [ka] where R 10 But hydrogen, halogen, -C 1~8 Alkyl, or -C 1~8 Alkoxy; preferably, fluoro, chloro, methyl or methoxy.

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

[0022] Aspect 13: L 1 is a bond or -O-, and L 2 The compound according to embodiment 1 or 2, wherein is a bond.

[0023] Aspect 14: R a and R b are independently hydrogen or CH 3 and n1 is 1 or 2.

[0024] Aspect 15: X a is selected from CH or N; X b But N;X c is CH and X d is N.

[0025] Embodiment 16: A compound according to embodiment 1 or 2, wherein ml, 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 is halogen, OH, or -C 1~8 Alkyl, preferably CH 3 3. The compound according to embodiment 1 or 2, selected from:

[0027] Aspect 18: [ka] but, [ka] (wherein m3 and m4 are each independently 0, 1, 2, 3, or 4), or [ka] (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 But 1, 2 or 3 CH 2 The compound according to embodiment 1 or 2, forming a bridge comprising:

[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] Aspect 22: Z 1 A compound according to any of the preceding embodiments, wherein: is CH or N; and p2=0.

[0032] Aspect 23: R 1 Methyl, -CH 2 OH, -OCH 3 , -CH 2 OCH 3 or halogen; p1 is 0 or 1, and R 2 A compound according to any of the preceding aspects, wherein is halogen.

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

[0034] Aspect 25: R 9 but, [ka] 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 aR b , -C(=NR a )NR b R c , -NR a R b , -NR a COR b , -NR a CONR b R c , -NR a CO 2 R b , -NR a SONR b R c , -NR a SO 2 NR b R c , or -NR a SO 2 R b -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 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 0, 1, 2, 3 or 4;

[0035] Aspect 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.

[0036] Aspect 27: [ka] but, [ka] 27. The 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] The compound according to any one of the preceding claims, wherein the variables are as defined herein.

[0039] In one embodiment, the compound is [ka] [Wherein, R 2a and R 2b are each independently hydrogen, halogen, -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 aCOR 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 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 1~8 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 pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically 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 pharma- ceutically 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 said patient a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically 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, said disease or disorder is associated with inhibition of BTK. Preferably, said disease or disorder is cancer.

[0044] In a fifth aspect, disclosed herein is a method of reducing BTK activity by inhibition and / or proteolysis comprising administering to an individual a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[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, such as 1 to 12, further such as 1 to 10, and even further such as 1 to 8, or 1 to 6, or 1 to 4 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms (i.e., C 1~6Examples 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"), and 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 are 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, e.g., -CF 3 , -CH 2 Cl, -CH 2 CF 3 , -CHCl 2 , -CF 3 etc.

[0055] The term "alkenyl" refers to a hydrocarbon group selected from linear and branched hydrocarbon groups containing at least one C=C double bond and 2 to 18, such as 2 to 8, further such as 2 to 6 carbon atoms. Alkenyl groups, such as 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 hex-1,3-dienyl groups.

[0056] The term "alkynyl" refers to a hydrocarbon group selected from linear 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 sharing 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 1 to 2 double bonds. In one embodiment, cycloalkenyl is cyclopentenyl or cyclohexenyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, preferably cyclohexenyl.

[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 having 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 which 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 attachment points.

[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 cycloalkyls, fused cycloalkenyls, or fused cycloalkynyls 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 benzocycloalkyls, benzoC 4~6 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 refers 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, means 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, e.g., 10-15 membered tricyclic ring systems (wherein at least one ring is carbocyclic and aromatic, e.g., 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) 7-12 membered bicyclic rings containing at least one heteroatom selected from N, O, and S, e.g., 1-4, or in some embodiments 1-3, or in other embodiments 1 or 2 heteroatoms, with the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is in the aromatic ring; and c) 11-14 membered tricyclic rings containing at least one heteroatom selected from N, O, and S, for example 1-4, or in some embodiments 1-3, 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. It refers to a group selected from:

[0074] When the total number of S and O atoms in a heteroaryl group exceeds 1, the heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in a heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in an aromatic heterocycle is 1 or less. When a heteroaryl 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 7-12 membered, preferably 7-10 membered, more preferably 9 or 10 membered fused bicyclic heteroaryl ring as defined herein. Typically, a bicyclic fused heteroaryl is a 5-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 phenyl. canyl, 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, the monocyclic or bicyclic aromatic heterocyclic ring has 5, 6, 7, 8, 9 or 10 ring members, where 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, the 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, the 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 8-10 membered heteroaryl ring that is bicyclic and has 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-thiadiazolyl, 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, These include 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 non-aromatic heterocyclyl groups that contain one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, 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 2 Refers to...

[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 may 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, homopipera aziridinyl, homopiperidinyl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxepanyl, thiepanyl, 1,4-oxathienyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl and 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathienyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydro These include 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 5-20 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, linked through one common carbon atom (referred to as a spiro atom). One or more rings of a spiroheterocyclyl group may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably, the spiroheterocyclyl is 6 to 14 membered, more preferably 7 to 12 membered. 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]heptane-5-yl), 2-oxa-6-azaspiro[3.3]heptane (e.g., 2-oxa-6-azaspiro[3.3]heptane-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 5-20 membered polycyclic heterocyclyl group, where 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, 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 fully 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 7-12 membered, preferably 7-10 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]dioxine, indolinyl, isoindolinyl, benzopyranyl, dihydrothiazolopyrimidinyl, tetrahydroquinolyl, tetrahydroisoquinolyl (or tetrahydroisoquinolinyl), dihydrobenzofuranyl, dihydrobenzoxazinyl, dihydrobenzimidazolyl, tetrahydrobenzothienyl, and the like. aryl, 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 5-14 membered polycyclic heterocyclic alkyl group in which every two rings in the system share two discontinuous 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 of the bridged heterocyclyl group may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably, the bridged heterocyclyl has 6-14 members, more preferably 7-10 members. Depending on the number of membered rings, the bridged heterocyclyl can be a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, preferably a bicyclic, tricyclic or tetracyclic bridged heterocyclyl, more preferably a bicyclic or tricyclic bridged heterocyclyl. Representative examples of bridged heterocyclyls 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 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 the 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, as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and / or their pharma-ceutically acceptable salts are intended to be included. Unless specifically stated otherwise, a 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, such as 1% by weight or less of any other stereoisomer(s).

[0092] When compounds disclosed herein contain olefinic double bonds, unless otherwise specified, such double bonds are 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 system may adopt cis and trans configurations.Cis configuration means that both substituents are found on the top of the two substituents arrangement on carbon, while trans means that they are on opposite sides.For example, disubstituted cyclic ring system can be a cyclohexyl or cyclobutyl ring.

[0094] It may be advantageous to separate reaction products from each other 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: reversed and normal phase; size exclusion; ion exchange; high-pressure, medium-pressure and low-pressure liquid chromatography methods and equipment; 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. The skilled artisan will apply the technique most likely to achieve the desired separation.

[0095] "Diastereomer" refers to stereoisomers of a compound that have two or more chiral centers, but are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers based on their physical 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 by using chiral HPLC columns.

[0096] Single stereoisomers, e.g., substantially pure enantiomers, can be obtained by resolving the racemic mixture using methods such as forming diastereomers using optically active resolving agents (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C.H., et al. "Chromatographic resolution of enantiomers: Selective review." J. Chromatogr., 113(3) (1975): pp. 283-302). Racemic mixtures of chiral compounds of the present invention can be separated and isolated by any suitable method, including (1) 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 salts that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, and the like, and 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 functional group with a suitable organic acid, or by reacting an acidic group with a suitable base.

[0098] In addition, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, such as a pharma- ceutically 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 to prepare non-toxic pharma-ceutically acceptable addition salts without undue experimentation.

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

[0100] The terms "administration", "administering", "treating" and "treatment" as used herein when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid refer to the contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent to the cell as well as contact of a reagent to a liquid, where the liquid contacts the cell. The terms "administration" and "treatment" also refer to in vitro and ex vivo treatment of a cell, for example, with a reagent, diagnostic agent, binding compound, or with another cell. The term "subject" as used herein 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 of the clinical symptoms 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 in any given situation may be apparent to one of ordinary skill in the art or may be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound disclosed herein and / or at least one stereoisomer thereof, and / or at least one pharma- ceutically acceptable salt thereof, effective to "treat" a disease or disorder in a subject as defined herein. In the example of a combination therapy, a "therapeutically effective amount" refers to the total amount of the combined objects 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, the pharmaceutical composition can be a conventional solid formulation, such as tablet, powder, granule, capsule, etc., liquid formulation, such as aqueous or oily suspension or other liquid formulation, such as syrup, solution, suspension or the like;For parenteral administration, the pharmaceutical composition can be a liquid, aqueous solution, oily suspension concentrate, freeze-dried powder or the like.Preferably, the formulation of the pharmaceutical composition is selected from tablet, coated tablet, capsule, suppository, nasal spray or injection, more preferably tablet or capsule.The pharmaceutical composition can be a single unit dose with a precise dosage.In addition, the pharmaceutical composition can further comprise additional active ingredients.

[0103] All the 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, and then the desired formulation can be produced. "Pharmaceutically acceptable additives" refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, such as: diluents, vehicles, such as water, various organic solvents, etc., fillers, such as starch, sucrose, etc., binders, such as cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone (PVP); wetting agents, such as glycerol; disintegrants, 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 pharma- ceutically acceptable excipients, such as decentralized agents, stabilizers, thickeners, complexing agents, buffers, permeation 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 which follow, unless the context otherwise requires, the term "comprise", as well as 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 substituted with the terms "containing", "including" or sometimes "having".

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

[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 pharma- ceutically 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 as described in the schemes and experimental procedures herein. In preparing the compounds of the present invention, the order of synthetic steps can be altered to increase the yield of the desired product. Some of the compounds of the present invention can be produced by the methods as shown in the following reaction schemes and their descriptions.

[0109] Scheme A [ka] In the formula, X 3 is Z in formula (I). 2 Corresponding to and X 4 is Z in formula (I). 3 A-2 can be synthesized from A-1 and piperidin-4-ylmethanol under basic conditions, then the nitro group in A-2 is reduced 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 by using an oxidation reagent such as IBX.

[0110] Scheme B [ka] In the formula, n corresponds to n1 in formula (I), and X 3 is Z in formula (I). 2 Corresponding to and X 4 is Z in formula (I). 3 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 converted to B-5 by LiAlH 4 B-6 can be further reduced with Pd / C in the presence of hydrogen to give B-7, which is then oxidized to intermediate B using an oxidizing reagent such as IBX.

[0111] Scheme C [ka] In the formula, n corresponds to n1 in formula (I), and X 3 is Z in formula (I). 2 Corresponding to and X 4 is Z in formula (I). 3 C-2 corresponds to C-1 and (BOC) 2 O, then C-2 and C-3 are coupled using Pd as a catalyst to give intermediate C-4. The Boc group can be removed in 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, then the TBS group in C-7 can be removed by 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] In the formula, X 3 is Z in formula (I). 2 Corresponding to and X 4 is Z in formula (I). 3D-1 and D-2 can be coupled in a metal catalyst (CuI, Pd, etc.) 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. 2 Hydrolysis with 0 can give E-5, which is 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 then the THP group can 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 , Z 2 , Z 3 , Z 4 and Z 5is 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 Pd as catalyst to form F-4. F-4 is coupled with F-5 in Pd as catalyst to give F-6, and the Boc and SEM groups are removed under acidic or basic conditions to give F-7, which is cleaved by cleavage with NaBH(OAc) 3 It is mixed with an aldehyde in the presence of a reducing reagent such as 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 , Z 2 , Z 3 , Z 4 and Z 5 is defined as in formula (I). G-1 and G-2 are treated with CoCl as a catalyst. 2 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 can be reacted with NaBH(OAc) 3 It is mixed with an aldehyde in the presence of a reducing reagent such as to form G. EXAMPLES

[0116] The examples below are intended to be purely illustrative and should not be considered 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 introducing 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 analyzed using CDCl 3 , CD 2 Cl 2 , CD 3 O.D., D. 2 O, d 6 -DMSO, d 6 -Acetone or (CD 3 ) 2 CO as the solvent and tetramethylsilane (0.00 ppm) or residual solvent (CDCl 3 :7.25ppm;CD 3 OD: 3.31 ppm; 2 O: 4.79 ppm; 6 -DMSO: 2.50 ppm; 6 -Acetone: 2.05; (CD 3 ) 3CO:2.05) was obtained as the reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sexlet), m (multiplet), br (broadened), dd (double doublet), dt (double triplet). When 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 with 0.1% formic acid, B: acetonitrile with 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 with 0.1% formic acid, B: acetonitrile with 0.1% formic acid, Column: Poroshell 120 EC-C18, 4.6×50 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) with 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] 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)Cl in 1,4-dioxane (200 mL). 2A mixture of (2.12 g, 10.6 mmol) and KOAc (4.55 g, 22.75 mmol) was stirred in a round-bottom flask at 100 °C overnight. The mixture was evaporated in vacuum to give the crude product, which was further purified by silica gel column chromatography (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), 2 CO 3 (196.0 g) was added at 25° C. The mixture reaction 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] N 2To a solution of (1-(4-nitrophenyl)piperidin-4-yl)methanol (140.0 g, 592.7 mmol) in MeOH (1680.0 mL) was added 10% Pd / C (28.0 g) at 25° C., and the mixture was then heated under H 2 Exchange twice with H 2 The mixture was stirred under 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) δ H 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 h. 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 h. The reaction was monitored by HPLC. The reaction was cooled to 25° C. and concentrated under vacuum. The residue was dissolved in EtOAc (500.0 mL) and then saturated NaHCO 3The pH was adjusted to 7 with 2×200.0 mL of EtOAc. The resulting solution was extracted with 2×200.0 mL of EtOAc and the organic layers were combined. The organic layers were 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 H 10.32 (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 h. The reaction was monitored by HPLC. The reaction was cooled to 10° C. and then washed with saturated NaHCO 3 The pH was adjusted to pH = 7 with 50.0 mL of water. 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 H10.26 (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 h. 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 washed with Na 2 SO 4 It was dried over and concentrated in vacuo to give a 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

Chem.

[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

Chem.

[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] 1,4-dioxane (100 mL) and H 2 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 in O (20 mL). 2 (0.862 g, 0.75 mmol) and K 2 CO 3 A mixture of (3.25 g, 23.6 mmol) was stirred in a round-bottom flask at 100 °C overnight. The mixture was evaporated in vacuum to give the crude product, which was further purified by silica gel column chromatography (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 at room temperature overnight in a round-bottom flask. 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 NH 3 / H 2O (25%-30%, 10 mL) was added. The mixture was stirred at 0° C. for 30 min. LCMS showed the reaction was complete. The mixture was evaporated in vacuum 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 at room temperature for 1 h in a round-bottom flask. The mixture was cooled to room temperature and cooled to room temperature. 3 (2.3 g, 10.84 mmol) and stirred at room temperature overnight in a round-bottom flask. The mixture was then evaporated in vacuum 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] Dioxane (250 mL) and H 2 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 20O (50 mL) was added K 2 CO 3 (16.6 g, 119.822 mmol) and Pd(dppf)Cl 2(4.4 g, 5.986 mmol) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 16 h. 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 extracted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 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] 2-Methyl-THF (150 mL) and H 2 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 2O (15 mL) was added Cs 2 CO 3 (32.9g, 100.819mmol), DavePhos (2.7g, 6.721mmol) and Pd 2 (dba) 3 (3.1 g, 3.361 mmol) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100° C. for 16 h under 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 washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography 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 4 (1 g, 26.646 mmol) was added 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 washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography 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 nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was diluted with DCM / CH 3OH (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 at room temperature in a round-bottom flask overnight. The reaction was quenched with water, and the mixture was extracted with EtOAc, washed three times with saturated aqueous NaCl and with saturated aqueous NaHCO. 3 The organic layer was washed twice with anhydrous Na 2 SO 4 It was dried over 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 min in a round-bottom flask. Then, NaBH(AcO) 3 (15 mg, 0.073 mmol) was added and stirred at room temperature for 2 h. The reaction was quenched with water and the mixture was diluted with saturated NaHCO 3 The organic layer was washed once with aqueous solution of 1,000 ml of DCM and then extracted with anhydrous Na 2 SO 4 Drying over and evaporation in vacuo gave 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] Azetidin-3-ylmethanol HCl salt (8.00 g, 65.041 mmol), 4-fluoronitrobenzene (9.17 g, 65.041 mmol) and Na in DMSO (40 mL) 2 CO 3(17.95 g, 130.082 mmol) 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 washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give the crude product, which 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 h 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 h. The reaction was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and washed with anhydrous Na 2 SO 4After 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] H 2 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 2H2O (50.00 mL) and THF (50.00 mL) was stirred at 50° C. overnight. The reaction was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography 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] AcOH (20.00 mL) and H 2A 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 O (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 h. 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 h. 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 vacuum 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 h. 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 anhydrous Na 2 SO 4 The mixture was dried over ice. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified with CH 2 Cl 2 Elution with 12:1 MeOH / MeOH gave 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 h. The reaction was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and extracted with anhydrous Na 2 SO 4 The mixture was dried over ice. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions: mobile phase, water (10 mmol / L NH 4 HCO 3) and ACN (phase B 46% to 52% in 8 min); detector, UV 254 mm. This yielded 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 h. 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 h. The reaction mixture was cooled to room temperature. The resulting solution was diluted with EtOAc. The resulting solution was diluted with H 2 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 under vacuum. 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 applied to a silica gel column with dichloromethane / methanol (10:1). The crude product (35 mg) was purified by preparative HPLC with the following conditions: mobile phase, water (10 mmol / L NH 4 HCO3 ) and ACN (40% to 52% phase B in 8 min); detector, UV 254 nm. This yielded 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 H12.68 (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 H12.68 (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] Dioxane (35 mL) and H 2To a solution of 4-chloro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 14.4 mmol) in 2H2O (7 mL), 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), K 2 CO 3 (1.6 g, 12 mmol) and Pd(dppf)Cl 2 .CH 2 Cl 2 (0.3 g, 0.4 mmol) was added. The mixture was stirred at 80° C. for 6 h. The mixture was concentrated and 2 The residue was dissolved in 2H2O (30 mL) and extracted with EtOAc (30 mL x 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] Dioxane (30 mL) and H 2 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 20O (6 mL), 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), K 2 CO 3(1.4 g, 10.0 mmol) and Pd(dppf)Cl 2 .CH 2 Cl 2 (0.3 g, 0.3 mmol) was added. The mixture was heated at 100 °C and heated with N 2 The mixture was stirred at room temperature for 18 h. The solvent was evaporated and 2 0 (30 mL) and extracted with EtOAc (50 mL x 2). The organic phases were combined, concentrated and purified by flash chromatography with 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 purified with H 2 The solid was filtered and diluted with H2O (30 mL). 2 The solid was transferred to a flask and HCl / MeOH (4N, 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. 1H 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 and H2 0 (30 mL) was added and extracted with DCM / iPrOH (10:1, 30 mL x 3). The organic phases were combined, concentrated and purified by preparative TLC with DCM / MeOH (10:1) to give the product (53 mg, 31%). 1 H NMR (400 MHz, DMSO) δ H 12.55 (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 at room temperature for 1 h in a round-bottom flask. After the mixture was added to 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), the mixture was stirred at room temperature overnight. The reaction 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 air atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (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 at room temperature under a hydrogen atmosphere for 5 h. 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 h at 90° C. under 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 h at 105° C. under 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 stirred in CH 2 Cl 2 The combined organic layer was washed with water and extracted with anhydrous Na 2 SO 4 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. 1H NMR (400 MHz, DMSO) δ H 12.73 (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] Dioxane (120 mL) and H 24-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), Na in O (20 mL). 2 CO 3 (1.25 g, 11.80 mmol) and Pd(dppf)Cl 2 A mixture of (0.39 g, 0.537 mmol) 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] Dioxane (60 mL) and H 2 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), Na in O (10 mL). 2 CO 3 (0.46 g, 4.34 mmol) and Pd(dppf)Cl 2(79.3 mg, 0.108 mmol) was stirred in a sealed tube at 100° C. overnight. 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 (4N, 35 mL) at 0° C. The mixture was stirred at 20° C. for 2 h. The precipitate was collected by filtration and dried in vacuum 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 at 20° C. for 1 h in a round-bottom flask. Then, NaBH 3 CN (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 (gradient elution of MeOH in DCM from 0% to 12%) 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] In a 500 mL round bottom flask, 4-bromo-2-fluoroaniline (20.00 g) and (Boc) in t-BuOH (250.00 mL) were added. 2 O (49.80 g) was added at 50° C. overnight. The resulting mixture was stirred overnight at 50° C. under 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] A mixture of tert-butyl (4-bromo-2-fluorophenyl)carbamate (5.00 g) and 4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidine (10.00 g) was added to a 500 mL round-bottom flask containing Xphos (1.65 g), Cs 2 CO 3 (16.90 g), dioxane (300.00 mL) and Pd 2 (dba) 3 (1.80 g) was added at room temperature. The resulting mixture was stirred overnight at 100° C. under nitrogen atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 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 h at room temperature under air atmosphere. The resulting mixture was concentrated under vacuum. 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 vacuum and flushed with nitrogen three times, then the mixture was heated at 100° C. in an oil bath for 12 hours. The mixture was used as is 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 nitrogen atmosphere for 12 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1.25 ml of 1:1 hexanediaminetetraacetate (CH 3 ). 2 Cl 2 Purification by elution with 20:1 MeOH / MeOH gave 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 extracted with anhydrous Na 2 SO 4 The mixture was dried over ice. After filtration, the filtrate was concentrated under reduced pressure. The residue was analyzed by preparative TLC (CH 2 Cl 2 / 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 at room temperature overnight in a round bottom flask. After the reaction was determined to be complete by LCMS, the mixture was extracted with EA (30 mL x 3) and diluted with anhydrous Na 2 SO4 It was dried over 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. The mixture was diluted with H 2 O (30 mL) was added and extracted with DCM (30 mL x 2). 2 SO 4 It was dried over, 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] 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)Cl in dioxane (20 mL). 2A mixture of (0.25 g, 0.303 mmol) and KOAc (0.89 g, 9.09 mmol) was added to a round-bottom flask and cooled to 200° C. 2 The mixture was stirred at 90° C. under reduced pressure overnight. The mixture was evaporated in vacuum to give the crude product, which was further purified by silica gel column chromatography (PE:EA=100:0 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] 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 in a mixture of dioxane (20 mL) and water (4 mL). 2 (0.12 g, 0.14 mmol) and K 2 CO 3 (0.393 g, 2.86 mmol) was stirred in a round-bottom flask at 80 °C overnight. The mixture was evaporated in vacuum to give the crude product, which was further purified by silica gel column chromatography (PE:EA = 100:0 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] 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 in a mixture of dioxane (20 mL) and water (7 mL). 2 (0.105g, 0.13mmol) and K 2 CO 3 A mixture of (0.357 g, 2.58 mmol) was stirred in a round-bottom flask at 90 °C overnight. The mixture was evaporated in vacuum to give the crude product, which was further purified by silica gel column chromatography (PE:EA = 100:0 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) in dichloromethane (5 mL) and trifluoroacetic acid (1.25 mL) was stirred in a round-bottom flask at room temperature for 1 h. 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 at room temperature for 1 h in a round-bottom flask. The mixture was treated with NaBH(OAc) 3 (0.005 g, 0.069 mmol) was added and stirred at room temperature overnight in a round-bottom flask. The mixture was then evaporated in vacuum 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%).1 H 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 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with anhydrous Na 2 SO 4 It was dried over and evaporated in vacuum 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 h. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with brine and diluted with anhydrous Na 2 SO 4 It was dried over and evaporated in vacuum 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] MeOH (100 mL) / H 2 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 2H2O (100 mL) / THF (100 mL) was stirred at room temperature for 16 h. 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 and extracted with anhydrous Na 2 SO 4 It was dried over water 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 h. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with brine and extracted with anhydrous Na 2 SO 4 It was dried over and evaporated in vacuum 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 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with anhydrous Na 2 SO 4It was dried over and evaporated in vacuum 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 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with anhydrous Na 2 SO 4 It was dried over and evaporated in vacuum 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] 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 Et 3A solution of N (6 mL, 43 mmol) was stirred at 40° C. for 16 h. The reaction was quenched with water and extracted with DCM. The organic layer was washed with anhydrous Na 2 SO 4 It was dried over and evaporated in vacuum 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 h. 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 washed with anhydrous Na 2 SO 4 It was dried over 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] 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) in dichloroethane (10 mL). 3 (100 mg, 0.47 mmol) was stirred at room temperature for 16 h. 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 H 2 O (20 mL) was added. The mixture was filtered and 2 The filter cake was dried under vacuum 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] Dioxane (15 mL) and H 2To 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 20O (3 mL), 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), K 2 CO 3 (124 mg, 0.9 mmol) and Pd(dppf)Cl 2 .CH 2 Cl 2 (22 mg, 0.03 mmol) was added. The mixture was heated at 90 °C with N 2 The mixture was stirred at room temperature for 5 h. The solvent was evaporated and H 2 O (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 as is for the next step. 1H NMR (400 MHz, DMSO) δ H 13.53 (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) 3 (102 mg, 0.48 mmol) was added. The mixture was stirred at 20-30 °C for 5 h. The solvent was evaporated and H 2O (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%). 1 H 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] 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), Pd(PPh 3 ) 4 A mixture of (0.289 g, 0.25 mmol) 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 the mixture of tert-butyl 4-(6-(trimethylstannyl)pyridin-3-yl)piperazine-1-carboxylate in dioxane from the previous step was added 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (2.05 g, 5 mmol) and Pd(PPh) in 30 mL of dioxane. 3 ) 2 Cl 2 A solution of (0.178 g, 0.25 mmol) was added. 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] Dioxane (50 mL) and H 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 (0.31 g, 0.569 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 (0.235 g, 0.569 mmol) in O (10 mL), Na 2 CO 3 (90 mg, 0.853 mmol) and Pd(dppf)Cl 2 (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 washed with anhydrous Na 2 SO 4 The mixture was dried over water 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 (4N, 20 mL) at 0° C. The mixture was stirred at 20° C. for 48 h. 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 at 20° C. for 1 h in a round-bottom flask. Then, NaBH 3 CN (12.6 mg, 0.2 mmol) was added. The mixture was stirred for 8 h 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] Dioxane (35 mL) and H 2 To a solution of 4-chloro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 14.4 mmol) in 2H2O (7 mL), 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), K 2 CO 3 (1.6 g, 12 mmol) and Pd(dppf)Cl 2 .CH 2 Cl 2 (0.3 g, 0.4 mmol) was added. 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 the mixture was stirred for 1 h at 20-30 °C for 1 h. 2 O (20 mL) was added. The mixture was filtered and the filter cake was diluted with H 2 The mixture was washed with O. 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] Dioxane / H 2 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 2H2O (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), K 2 CO 3 (414 mg, 3.0 mmol) and Pd(dppf)Cl 2 .CH 2 Cl 2 (82 mg, 0.1 mmol) was added. The mixture was heated at 100 °C and heated with N 2It was stirred for 6 hours below. After evaporating the solvent, water (20 mL) was added. The mixture was extracted with DCM (30 mL × 2). The combined organic phases were concentrated and purified by preparative TLC with DCM / MeOH (100:1 - 20:1) to obtain 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

Chemical Structure

[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) 3 (0.85 g, 4.0 mmol) was added. The mixture was stirred at 20-30° C. for another 2 h. The solvent was evaporated and directly purified by chromatography on silica gel with DCM / MeOH (100:1-20:1) 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 in a similar manner to 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 h. The resulting solution was diluted with H 2The mixture was diluted with 200 mL of ethyl acetate. 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 h. The reaction mixture was cooled to room temperature. The resulting solution was diluted with H 2 The mixture was diluted with 0.25 mL of ethyl acetate and 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). 2(g) was introduced. 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 maintained under an inert purged 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 give 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 under vacuum. 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 h. The resulting solution was diluted with H 2 The mixture was diluted with O. 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 H 10.22 (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 overnight at room temperature in a round bottom flask. After the reaction was determined to be complete by LCMS, the mixture was extracted with EtOAc (30 mL x 3) and purified by elution with anhydrous Na 2 SO 4 It was dried over 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. The mixture was diluted with H 2 O (30 mL) was added and extracted with DCM (30 mL x 2). 2 SO 4 It was dried over, 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 in a similar manner to Example 22. 1 H NMR (400 MHz, DMSO) δ H12.79 (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] 2-Chloro-4-fluoro-1-nitrobenzene (141.0 g, 0.8 mol) in DMF (300 mL) and K 2 CO 3 To a solution of (278 g, 2.01 mol) 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 diluted with H 2 The aqueous phase was poured into 200 mL of ethyl acetate (300 mL). The aqueous phase was extracted with ethyl acetate (300 mL). The organic layer was washed with anhydrous Na 2 SO 4Drying at 40° C., filtering and concentrating in vacuo gave 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 diluted with H 2 The aqueous phase was poured into 200 mL of dichloromethane (765 mL). The aqueous phase was extracted with dichloromethane (765 mL). The organic layer was washed with anhydrous Na 2 SO 4 Drying at rt, filtering and concentrating in vacuo gave 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 2, 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), acrylic acid (80 mL) was added and the mixture was heated at 110 °C with N 2 The mixture was stirred under reduced pressure 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 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 (SiO 2 , 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 H7.23 (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), 2 CO 3 (42.1 g, 0.305 mol) was added 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 (SiO 2 , 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 H10.4 (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) 3 (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 H 12.72 (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] 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 in DMF (50 mL). 2 A mixture of (0.089 g, 0.69 mmol) was incubated at 85 °C overnight with O 2 The mixture was stirred under atmospheric pressure. 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] Dioxane (50 mL) and H 2 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), Na in O (8 mL). 2 CO 3 (0.212 g, 2 mmol) and Pd(dppf)Cl 2(36.5 mg, 0.05 mmol) 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 (4N, 20 mL) at 0° C. The mixture was stirred at 20° C. for 4 h. The precipitate was collected by filtration and dried in vacuum 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 at 20° C. for 1 h in a round-bottom flask. Then, NaBH 3 CN (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 (gradient elution of MeOH in DCM from 0% to 10%) to give the product (92.6 mg, 46.7%). 1 H NMR (400 MHz, DMSO) δ H 13.76 (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 in a similar manner to Example 24. 1 H NMR (400 MHz, DMSO) δ H 12.61 (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] 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 in dioxane (10 mL) and water (3 mL). 2 (73 mg, 0.1 mmol) and K 2 CO 3 (276 mg, 2.0 mmol) 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 2 (73 mg, 0.1 mmol) and Cs 2CO 3 (650 mg, 2.0 mmol) was added. The mixture reaction was stirred in a round bottom flask at 110 °C overnight. The mixture was then evaporated in vacuum 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 at room temperature overnight in a round-bottom flask. 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) in methanol (10 mL) and ammonium hydroxide (2 mL) was stirred at room temperature overnight in a round-bottom flask. The mixture was then evaporated in vacuum to give the crude product, which was purified by C18 column chromatography (0.1% FA in water:acetonitrile=90:10 to 60:40 gradient elution) 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 at room temperature for 1 h in a round-bottom flask. 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 was purified by C18 column chromatography (gradient elution with 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 2 (73 mg, 0.1 mmol) and Cs 2 CO 3 (850 mg, 2.6 mmol) was added. The mixture reaction was stirred at 110 °C overnight in a round bottom flask. The mixture was then evaporated in vacuum 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) in dichloromethane (6 mL) and trifluoroacetic acid (3 mL) was stirred at room temperature overnight in a round-bottom flask. 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 at room temperature overnight in a round-bottom flask. 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 at room temperature for 1 h in a round-bottom flask. The mixture was then added with NaBH(OAc) 3 (212 mg, 1.0 mmol) was added and stirred at room temperature overnight in a round-bottom flask. The mixture was evaporated in vacuum to give the crude product, which was purified by C18 column chromatography (0.1% FA in water:acetonitrile = 80:20 to 40:60 gradient elution) 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 at room temperature for 1 h in a round-bottom flask. The mixture was then added with NaBH(OAc) 3(212 mg, 1.0 mmol) was added and stirred at room temperature overnight in a round-bottom flask. The mixture was evaporated in vacuum to give the crude product, which was purified by C18 column chromatography (0.1% FA in water:acetonitrile=75:25 to 30:70 gradient elution) 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 in a similar manner to Example 24. 1 H NMR (400 MHz, DMSO) δ H12.54 (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 in a similar manner to Example 24. 1 H NMR (400 MHz, DMSO) δ H12.62 (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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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

Chemical Structure

[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 diluted with 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 2 (73 mg, 0.1 mmol) and Cs 2 CO 3 (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 vacuum 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) in dichloromethane (12 mL) and trifluoroacetic acid (3 mL) was stirred at room temperature overnight in a round-bottom flask. 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 at room temperature overnight in a round-bottom flask. The mixture was evaporated in vacuo to give the crude product, which was purified by C18 column chromatography (0.1% HCl in water:acetonitrile = 85:15 to 40:60 gradient elution) 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 at room temperature for 1 h in a round-bottom flask. The mixture was then added with NaBH(OAc) 3(212 mg, 1.0 mmol) was added and stirred at room temperature overnight in a round-bottom flask. The mixture was evaporated in vacuum to give the crude product, which was purified by 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 in a similar manner to Example 24. 1 H NMR (400 MHz, DMSO) δ H12.49 (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 in a similar manner to 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 in a similar manner to 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] Dioxane / H 2To 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 2H2O (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), K 2 CO 3 (166 mg, 1.2 mmol) and Pd(dppf)Cl 2 .CH 2 Cl 2 (33 mg, 0.04 mmol) was added. The reaction mixture was heated at 90° C. with N 2 The mixture was stirred under reduced pressure for 5 h. The solvent was evaporated and 2 O (20 mL) was added. The mixture was extracted with DCM / iPrOH (20:1, 30 mL×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 purified by HPLC.2 CO 3 (230 mg) was added. After stirring at 20-30° C. for 2 h, the reaction mixture was concentrated. 2 O (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 such 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) 3 (233 mg, 1.1 mmol) was added. After stirring at 20-30° C. for an additional 5 h, the mixture was evaporated. The residue was treated with H 2 O (30 mL) was added and the mixture was extracted with DCM / iPrOH (20:1, 30 mL x 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 H12.66 (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] Dioxane (25 mL) and H 2To 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 2HO (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), K 2 CO 3 (207 mg, 1.5 mmol) and Pd(dppf)Cl 2 .CH 2 Cl 2 (41 mg, 0.05 mmol) was added. The mixture was heated at 90 °C with N 2 The mixture was stirred under reduced pressure for 18 hours. 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 as is for the next step. 1H 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) 3 (160 mg, 0.75 mmol) was added. The mixture was stirred at 20-30 °C for 3 h. The solvent was evaporated and H 2O (30 mL) was added. The mixture was extracted with DCM / iPrOH (20:1, 30 mL x 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 in a similar manner to Example 24. 1 H NMR (400 MHz, DMSO) δ H12.70 (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] 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 with K 2 CO 3(39.2 g, 284 mmol) was added at 25° C. The mixture reaction was stirred at 80° C. for 16 h. 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 min. The solid was filtered, washed with water (500.0 mL×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] N 2 To a solution of (1-(5-fluoro-2-nitrophenyl)piperidin-4-yl)methanol (28.0 g, 118.5 mmol) in MeOH (300.0 mL) was added 10% Pd / C (2.80 g) at 25° C., and the mixture was then heated under H 2 Exchange twice and H 2 The mixture was stirred under 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 in vacuo 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 reaction was stirred at 90° C. for 15 h. 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 h. The reaction was monitored by LC-MS. The reaction was cooled to 25° C. and concentrated under vacuum. The residue was dissolved in EtOAc (500.0 mL) and then saturated NaHCO 3 The pH was adjusted to pH=7 with 50.0 mL of EtOAc. The resulting solution was extracted with 2×200.0 mL of EtOAc and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. 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 h. The reaction was monitored by LC-MS. The reaction was cooled to 10° C. and then washed with saturated NaHCO 3 The pH was adjusted to 7 with 50.0 mL of water. 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 extracted with Na 2 SO 4 It was dried over, 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) 3(106 mg, 0.5 mmol) was added. The mixture was stirred at 20 - 30 °C for 2 hours. After the solvent was evaporated under reduced pressure, the residue was purified by preparative TLC with DCM / MeOH to obtain the product (60 mg, 41.6%). 1 H 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

Chemical Structure

[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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 h and sodium triacetoxyborohydride (180.2 mg, 0.85 mmol) was added to the mixture in one portion. The mixture was stirred for an additional 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] tert-Butyl 4-(4-bromophenoxy)piperidine-1-carboxylate (710 mg, 2.0 mmol), bis(pinacolato)diboron (508 mg, 2.0 mmol), Pd(dppf)Cl in dioxane (20 mL). 2 (146 mg, 0.2 mmol) and CH 3 A mixture of COOK (300 mg, 3.0 mmol) was stirred in a round-bottom flask at 110° C. for 4 h. 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 dissolved in 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (818 mg, 2.0 mmol), Pd(dppf)Cl in dioxane (20 mL) and water (4 mL). 2 (146 mg, 0.1 mmol) and K 2 CO 3(400 mg, 3.0 mmol) and stirred at 80 °C overnight in a round-bottom flask. The mixture was then evaporated in vacuum 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] 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 in dioxane (16 mL) and water (4 mL). 2 (70 mg, 0.096 mmol) and K 2 CO 3 (265 mg, 1.92 mmol) was stirred in a round-bottom flask at 100° C. overnight. The mixture was then evaporated in vacuum 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 at room temperature in a round-bottom flask for 2 h. 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 at room temperature in a round-bottom flask overnight. The mixture was evaporated in vacuum to give the crude product, which was purified by C18 column chromatography (0.1% HCl in water:acetonitrile = 80:20 to 40:60 gradient elution) 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 at room temperature for 1 h in a round-bottom flask. The mixture was then treated with NaBH(OAc) 3 (212 mg, 1.0 mmol) was added and stirred at room temperature overnight in a round-bottom flask. The mixture was evaporated in vacuum to give the crude product, which was purified by C18 column chromatography (0.1% FA in water:acetonitrile = 80:20 to 30:70 gradient elution) 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 Et 3 N (30 g, 300 mmol) was added. The mixture was stirred at room temperature for 1 h, then ethyl 2-(hydroxyamino)-2-iminoacetate (21 g, 159 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was washed with water (500 mL) and brine (500 mL). The organic layer was extracted with Na 2 SO 4 The mixture was dried over ice, 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 addition of EtOAc (300 mL), the reaction mixture was washed with water (300 mL) and brine (300 mL). The organic layer was extracted with Na 2 SO 4 The mixture was dried over ice, 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] MeOH / THF / H 2 Ethyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxylate (7.0 g, 28 mmol) and LiOH H in 2O (30 mL / 30 mL / 30 mL). 2 A solution of 2H2O (1.7 g, 40 mmol) was stirred at room temperature for 16 h, the mixture was concentrated, adjusted to pH=6 with 1N aqueous HCl, and the product (8.5 g, crude) was obtained by filtration. [M+H] + = 225.2.

[0283] Step 4: tert-Butyl (4-bromo-2-methylbenzyl)carbamate [ka] (4-Bromo-2-methylphenyl)methanamine (26 g, 130 mmol) and Et 3 In a solution of N (20 mL, 145 mmol), 22H2O (30 g, 138 mmol) was added slowly at room temperature and then stirred 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 washed with Na 2 SO 4 It was dried over, 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] N 2 A mixture of tert-butyl (4-bromo-2-methylbenzyl)carbamate (42 g, 140 mmol), bis(pinacolato)diboron (33 g, 130 mmol), Pd(PPh 3 ) 2 Cl 2 A mixture of (2.0 g, 2.8 mmol) and KOAc (30 g, 306 mmol) was stirred at 100° C. for 16 h. 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 h and then concentrated to remove dioxane. The residue was stirred with MTBE (400 mL) and the solid was collected and dried in vacuum to give the product (31 g, crude). [M-NH 2 ] + = 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 dropwise oxalyl dichloride (1.5 mL). The reaction mixture was stirred at room temperature for 1 h and then concentrated to give crude 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carbonyl chloride. (2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine (1.6 g, 5.6 mmol) and Et 3 To a solution of N (2 mL, 14.5 mmol) 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 washed with Na 2 SO 4It was dried over, 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] N 2 Dioxane (25 mL) and H 2 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-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 in O (5 mL). 2 (30 mg, 0.041 mmol) and K 2 CO 3 A mixture of (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 h. The reaction mixture was concentrated to give the crude product which was purified by NH 3 / MeOH (1M, 10 mL) for 30 min. 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] 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) in dichloroethane (20 mL). 3 (100 mg, 0.47 mmol) was stirred at room temperature for 2 h. After adding EtOAc (100 mL), the solution was diluted with saturated NaHCO 3 The organic layer was washed three times with 50 mL of aqueous solution (50 mL) and 50 mL of brine. 2 SO 4 It was dried over, 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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), K 3 PO 4(3.0 g, 14.2 mmol) was taken up 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 extracted with Na 2 SO 4 Drying on and concentration gave 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 2 (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 Cs 2 CO 3 (4.6 g, 14.2 mmol) was taken up 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 solids were filtered off. The filtrate was concentrated and purified by SiO 2 Purification by gel column elution with EtOAc / hexanes 1:1 gave 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 heated to 100° C. for 2 h until LC-MS showed that all starting material had been consumed. 2 The mixture was stirred under atmosphere (1 atm) overnight. 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 min. The mixture was then warmed to room temperature for an additional 1 h until TLC showed that all starting material had been consumed. The mixture was diluted with water, extracted with EtOAc, washed with brine, and washed with Na 2 SO 4 Drying over and concentration gave 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 h and sodium triacetoxyborohydride (180.2 mg, 0.85 mmol) was added to the mixture in one portion. The mixture was stirred for an additional 1 h until LC-MS showed that all starting material was 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] (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) in dichloroethane (20 mL). 3 (50 mg, 0.24 mmol) was stirred at room temperature for 2 h. After adding EtOAc (100 mL), the solution was diluted with saturated NaHCO 3 The organic layer was washed three times with aqueous solution (50 mL) and brine (50 mL). 2 SO 4 It was dried over, 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 h. The mixture was washed with brine and diluted with Na 2 SO 4 It was dried over, filtered and evaporated in vacuo to give the product (3 g, 92%) which was used as such 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 h. 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 h. 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] 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 in a mixture of dioxane (10 mL) and water (2.5 mL). 2 (0.077g, 0.096mmol) and K 2 CO 3 A mixture of (0.265 g, 1.92 mmol) was stirred in a round-bottom flask at 90 °C overnight. The mixture was evaporated in vacuum to give the crude product, which was further purified by silica gel column chromatography (PE:EA = 100:0 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-(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(Ph) in a mixture of dioxane (16 mL) and water (4 mL).3 P) 4 (0.074g, 0.065mmol) and K 2 CO 3 A mixture of (0.18 g, 1.3 mmol) was stirred in a round-bottom flask at 100 °C overnight. The mixture was evaporated in vacuum to give the crude product, which was further purified by silica gel column chromatography (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 h. The mixture was evaporated in vacuum 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 h. 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 at room temperature for 0.5 h in a round-bottom flask. The mixture was treated with NaBH(OAc) 3(0.061 g, 0.288 mmol) was added and stirred at room temperature in a round bottom flask 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 H 12.14 (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 at room temperature for 0.5 h in a round-bottom flask. The mixture was treated with NaBH(OAc) 3 (0.066 g, 0.309 mmol) was added 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), 2.38-2.18 (m, 10H), 2.14-2.03 (m, 8H), 1.85-1.63 (m, 6H), 1.54 (d, J = 6.3Hz, 3H), 1.36 (s, 9H), 1.27-1.13 (m, 2H);[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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 and extracted with EtOAc (200 mL×3) and washed with brine (200 mL). The organic phase was purified by HCl distillation. 2 SO 4 The mixture was dried over 100° C. 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] 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 in dioxane (50 mL). 2 A mixture of (560 mg, 0.0008 mmol) and KOAc (2.4 g, 0.0245 mol) was heated in a round-bottom flask overnight at 100 °C under N 2 The mixture was stirred under an atmosphere of 0.5%. After the reaction was determined to be complete by LCMS, the reaction was cooled. The mixture was extracted with EtOAc (60 mL x 3). The organic layers were combined, washed with brine (100 mL) and washed with anhydrous Na 2 SO 4 The mixture was dried over 100 ml 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] 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 in dioxane / water (10 mL / 3 mL). 2 (20 mg, 0.0244 mmol) and K 2 CO 3 A mixture of (108 mg, 0.782 mmol) was heated in a round-bottom flask overnight at 100 °C with N 2 The mixture was stirred under an atmosphere of 0.5%. The mixture was then cooled. The mixture was concentrated in vacuum, and the residue was purified by silica gel column chromatography (PE:EA=100%:0%-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-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (107.1 mg, 0.255 mmol), Pd(dppf)Cl in dioxane / water (10 mL / 3 mL). 2 (11.4 mg, 0.0155 mmol) and K 2 CO 3 A mixture of (49 mg, 0.355 mmol) was heated in a round-bottom flask overnight at 100 °C with N 2 The mixture was stirred under an atmosphere of 0.05%. 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%-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. The mixture was then concentrated in vacuo. The residue was dissolved in MeOH (10 mL) and the pH value was adjusted to NH 3 (7M in MeOH) to adjust to 8. The mixture was stirred at room temperature for 30 min 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 for 5 min in a round bottom flask and HOAc was added dropwise (3 drops). The mixture was stirred at room temperature for 2 h and then NaBH(OAc) 3 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. 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 in a similar manner to 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

Chemical formula

[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

Chemical formula

[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

Chemical formula

[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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 4M 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 as is 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 min. 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 h. After the reaction was determined to be complete by LCMS, the mixture was extracted with EtOAc (50 mL x 3), washed with brine (40 mL) and diluted with Na 2 SO 4 The mixture was dried over 100° C. 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+HH 2 O] + = 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] Dioxane: 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), K 2 CO 3 (81.2 mg, 0.588 mmol) and Pd(dppf)Cl 2 A mixture of (13.4 mg, 0.0184 mmol) was stirred in a round-bottom flask at 90° C. overnight. The mixture was then cooled and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA=100%:0%-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. The mixture was then concentrated in vacuo. The residue was dissolved in MeOH (10 mL) and the pH value was adjusted to 30° C. with NH 3 (7M in MeOH) to give 8. 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 min and HOAc was added dropwise (3 drops). The mixture was stirred at room temperature for 2 h. Then NaBH(OAc) 3(93.3 mg, 0.44 mmol) 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. 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), K 2 CO 3 (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) and extracted with Na 2 SO 4 After drying and concentration, the desired product was obtained (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) in DCM / MeOH (5 mL, 10:1). The mixture was stirred at room temperature for 30 min. 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 hour 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 in a similar manner to Example 20. 1H 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 in a similar manner to Example 25. 1 H NMR (400 MHz, DMSO) δ H13.85 (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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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

Chemical Structure

[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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 60% dispersion in mineral oil, 6.0 mmol). The mixture was stirred at 0° C. for 60 min. Then SEM-Cl (1.02 g, 6.0 mmol) was added. LCMS showed the reaction was complete. The reaction was quenched with 10% aqueous NaCl (10 mL). The resulting suspension was sonicated for 5 min, 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] 1,4-Dioxane (10 mL) and H 2 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-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 in O (2 mL). 2 (20 mg, 0.027 mmol) and Cs 2 CO 3(270 mg, 0.81 mmol) was stirred in a round-bottom flask at 100° C. overnight. The mixture was evaporated in vacuum to give the crude product, which was further purified by silica gel column chromatography (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) in dichloromethane (5 mL) and trifluoroacetic acid (16 mL) was stirred in a round-bottom flask at room temperature for 3 h. The mixture was evaporated in vacuo. The residue was dissolved in MeOH (10 mL) and NH 3 / H 2 O (2 mL) was added. The mixture was stirred at room temperature for 30 min. LCMS showed 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 at room temperature for 2 h in a round-bottom flask. The mixture was added with NaBH(OAc) 3 (212 mg, 1.0 mmol) was added and stirred at room temperature overnight in a round-bottom flask. 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 H12.64 (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 in a similar manner to Example 25. 1 H NMR (400 MHz, DMSO) δ H12.61 (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 in a similar manner to Example 25. 1 H NMR (400 MHz, DMSO) δ H12.60 (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 in a similar manner to Example 25. 1 H NMR (400 MHz, DMSO) δ H12.52 (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 in a similar manner to Example 25. 1 H NMR (400 MHz, DMSO) δ H12.61 (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 in a similar manner to Example 25. 1 H NMR (400 MHz, DMSO) δ H12.60 (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 in a similar manner to Example 25. 1 H NMR (400 MHz, DMSO) δ H12.60 (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 in a similar manner to Example 25. 1 H NMR (400 MHz, DMSO) δ H12.60 (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 in a similar manner to Example 25. 1 H NMR (400 MHz, DMSO) δ H12.58 (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 in a similar manner to 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 in a similar manner to 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, (8H), 2.24-2.20 (m, 3H), 1.84-1.69 (m, 3H), 1.37 (s, 9H), 1.28-1.19 (m, 3H) + = 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to 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 in a similar manner to Example 25. 1 H NMR (400 MHz, DMSO) δ H12...

Claims

1. A compound of formula (III) 【Chemistry 1】 [In the formula, p1 and p5 each independently represent 0 or 1; Z 1 , Z 4 and Z 5 are each independently CH or N; Xa, Xb, Xc and Xd are each independently CH or N; Y 1 , Y 2 , Y 3 and Y 4 are each independently CR 11 , O or N; R 1 is hydrogen, halogen or -C 1-8 alkyl; R 2 is halogen or -C 1-8 alkyl, said -C 1-8 alkyl being optionally substituted with halogen or hydroxy; R 4 is hydrogen or —C 1-8 alkyl; R 10 is —C 1-8 alkyl; and R 11 is hydrogen or —C 1-8 alkyl. or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof, wherein p1 and p5 are each independently 1.

3. The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein Z 1 is CH.

4. The compound according to claim 1, wherein X a , X b and X d are each independently N, or a pharma- ceutically acceptable salt thereof.

5. The compound according to claim 1, wherein X c is CH, or a pharma- ceutically acceptable salt thereof.

6. The compound according to claim 1, wherein R 1 is hydrogen, -F or -CH 3 , or a pharma- ceutically acceptable salt thereof.

7. The compound according to claim 1, wherein R 2 is —CH 3 or —CH 2 OH, or a pharma- ceutically acceptable salt thereof.

8. The compound according to claim 1, wherein R 4 is —CH 3 , or a pharma- ceutically acceptable salt thereof.

9. The compound according to any one of claims 1 to 8, wherein R 10 is -CH 3 , or a pharma- ceutically acceptable salt thereof.

10. R 11 is 【Chemistry 2】 10. The compound according to any one of claims 1 to 9, wherein:

11. 【Chemical 3】 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof, selected from:

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable carrier or excipient.

13. The pharmaceutical composition of claim 12 for inhibiting BTK activity.

14. 13. The pharmaceutical composition of claim 12 for treating a disease or disorder in a patient, wherein the disease or disorder is associated with inhibition of BTK.

15. The pharmaceutical composition of claim 14, wherein the disease or disorder is cancer.

16. The pharmaceutical composition of claim 12 for reducing BTK activity by inhibition and / or proteolysis.

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