Degradation of Bruton's tyrosine kinase (BTK) by conjugating BTK inhibitors to E3 ligase ligands and methods of use thereof

Abstract

Disclosed herein are novel bifunctional compounds formed by conjugating a BTK inhibitor moiety to an E3 ligase ligase moiety, and methods for their preparation and use. These bifunctional compounds function to recruit targeted proteins to E3 ubiquitin ligases for degradation.

Description

[0001] This application is a divisional application of the Chinese patent application with application number 202180031447.3 (application date: April 29, 2021, invention name: Degradation of Bruton's tyrosine kinase (BTK) by conjugating BTK inhibitors with E3 ligase ligands and methods of use thereof). Technical Field

[0002] Disclosed herein are novel bifunctional compounds formed by conjugating a BTK inhibitor moiety to an E3 ligase ligase moiety, and methods for their preparation and use. These bifunctional compounds function to recruit targeted proteins to E3 ubiquitin ligases for degradation. Background Art

[0003] Proteolysis targeting chimeras (PROTACs) are a novel strategy for selectively knocking out target proteins by small molecules (Sakamoto KM et al., Proc Natl Acad Sci [Proceedings of the National Academy of Sciences of the United States of America] 2001, 98:8554-9.; Sakamoto K.M. et al., Methods Enzymol. [Enzymology Methods] 2005; 399:833-847.). PROTACs utilize the ubiquitin-protease system to target specific proteins and induce their degradation in cells (Zhou P. et al., Mol Cell. [Molecular Cell] 2000; 6(3):751-756; Neklesa TK et al., Pharmacol Ther. [Pharmacology and Therapeutics] 2017; 174:138-144; Lu M. et al., Eur J Med Chem. [European Journal of Medicinal Chemistry] 2018; 146:251-259;). The normal physiological function of the ubiquitin-protease system is responsible for clearing 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 under normal and pathological conditions (Ardley H. et al., Essays Biochem. [Biochemical Assay] 2005, 41, 15-30; Komander D. et al., Biochem. [Biochemistry] 2012, 81, 203-229; Grice GL et al., Cell Rep [Cell Reports]. 2015, 12, 545-553; Swatek KN et al., Cell Res. [Cell Research] 2016, 26, 399-422). Ubiquitin (highly conserved in eukaryotic cells) is a modified molecule consisting of 76 amino acids that covalently binds and labels target substrates via a series of enzymatic reactions involving E1, E2 and E3 enzymes. Subsequently, the modified substrate is recognized by the 26S proteasome complex for ubiquitination-mediated degradation. So far, two E1 enzymes have been discovered, namely UBA1 and UBA6. On the other hand, there are about 40 E2 enzymes and more than 600 E3 enzymes, which provide functional diversity for controlling the activity of multiple downstream protein substrates. However, only a limited number of E3 ubiquitin ligases have been successfully hijacked for use in small molecule PROTAC technology: VHL, mouse double minute 2 homolog (MDM2), intracellular inhibitor of apoptosis (cIAP) and cereblon (cereblon) (Philipp O. et al., Chem.Biol. [Chemical Biology] 2017, 12, 2570-2578).

[0004] Bifunctional compounds composed of a target protein-binding portion and an E3 ubiquitin ligase-binding portion have been shown to induce proteasome-mediated degradation of selected proteins. These drug-like molecules offer the potential for temporary control of protein expression and can be used as biochemical agents for the treatment of diseases.In recent years, this newly developed method has been widely used in anti-tumor research (Lu J. et al., Chem Biol. 2015; 22(6):755-763; Ottis P. et al., Chem Biol. 2017; 12(4):892-898.; Crews CM et al., J Med Chem. 2018; 61(2):403-404; Neklesa TK et al., Pharmacol Ther. 2017, 174:138-144.; Cermakova K. et al., Molecules 2018. 23(8).; An S. et al., EBioMedicine 2018.; Lebraud H. et al., Essays Biochem. 2017; 61(5):517-527.; Sun J. et al., J Med Chem. 2018; 61(5):517-527. YH et al., Cell Res. 2018; 28: 779-81; Touré M. et al., Angew Chem Int Ed Engl. 2016; 55(6): 1966-1973; Yonghui Sun et al., Leukemia, Vol. 33, pp. 2105-2110 (2019); Shaodong Liu et al., Medicinal Chemistry Research, Vol. 29, pp. 802-808 (2020); and disclosed or discussed in patent publications, such as US 20160045607, US 20170008904, US 20180050021, US 20180072711, WO2002020740, WO 2014108452, WO 2016146985、WO 2016149668、WO 2016149989、WO2016197032、WO 2016197114、WO 2017011590、WO 2017030814、WO 2017079267、WO2017182418、WO 2017197036, WO 2017197046, WO 2017197051, WO 2017197056, WO2017201449, WO 2017211924, WO 2018033556, and WO 2018071606.

[0005] Bruton's tyrosine kinase (Btk) belongs to the Tec tyrosine kinase family (Vetrie et al., Nature 361:226-233, 1993; Bradshaw, Cell Signal. 22:1175-84, 2010). Btk is mainly expressed in most hematopoietic cells, such as B cells, mast cells and macrophages (Smith et al., J. Immunol. 152:557-565, 1994), and is located 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 in turn phosphorylates PLCγ, which in turn affects B cell function and survival (Humphries et al., J. Biol. Chem. [Journal of Biological Chemistry] 279: 37651, 2004). These signaling pathways must be precisely regulated. Mutations in the gene encoding Btk lead to a human hereditary B cell-specific immunodeficiency disease called X-linked agammaglobulinemia (XLA) (Conley et al., Annu. Rev. Immunol. [Annals of Immunology] 27: 199-227, 2009). Abnormal BCR-mediated signaling may lead to dysregulation of B cell activation, resulting in a variety of autoimmune and inflammatory diseases. Preclinical studies have shown that mice lacking Btk are resistant to developing collagen-induced arthritis. In addition, clinical studies of Rituxan (a CD20 antibody that depletes mature B cells) have shown that B cells play a key role in many inflammatory diseases (such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis) (Gurcan et al., Int. Immunopharmacol. [International Immunopharmacol.] 9: 10-25, 2009). Therefore, Btk inhibitors can be used to treat autoimmune and / or inflammatory diseases.

[0006] It has been shown that inhibition of BTK affects the development of cancer (B cell malignancies) and cell viability, and improves autoimmune diseases such as rheumatoid arthritis and lupus. Inhibition of BTK has also been reported via alternative strategies, such as by degrading BTK (Alexandru D. et al., Biochemistry [Biological Chemistry] 2018, 57, 26, 3564-3575; Adelajda Z. et al., PNAS [Proceedings of the National Academy of Sciences of the United States of America] 2018 115 (31); Dennis D. et al., Blood [Blood], 2019, 133: 952-961; Yonghui S. et al., Cell Research [Cell Research], 2018, 28, 779-781; Yonghui S. et al., Leukemia [Leukemia], 2019, Degradation of Bruton's tyrosine kinase mutants by PROTACs for the potential treatment of ibrutinib-resistant non-Hodgkin lymphomas [PROTAC degradation of Bruton's tyrosine kinase mutants to potentially treat ibrutinib-resistant non-Hodgkin's lymphoma]) and has been disclosed or discussed in patent publications, such as US 20190276459, WO 2019186343, WO 2019186358, WO 2019148150, WO 2019177902, and WO 2019127008.

[0007] WO 2019 / 186343 A1 discloses N-(3-(7H-pyrrolo[2,3-D]pyrimidin-4-yl)phenyl)-benzamide derivatives as BTK depredators having formula (A).

[0008]

[0009] where R 1 、R 1a 、R 2 and R 2a is independently selected at each occurrence from H and F; R 6 Is H or F; R 7 is selected from the group consisting of H, F, Cl, -CH3, -OCH3, and -OCH2CH3; and X 1 It is a set of connectors.

[0010] WO 2019 / 186358 A1 discloses 3-hydroxy-N-(3-(7H-pyrrolo[2,3-D]pyrimidin-4-yl)phenyl)-benzamide derivatives as BTK predatory agents having formula (B),

[0011]

[0012] where R 1 is isobutyl; R 1a It is H; R 2 Is H or F; R 2a Is H or F; R 6 Is H or F; R 7 is selected from the group consisting of H, F, Cl, -CH3, -OCH3, and -OCH2CH3; and X 1 It is a set of connectors.

[0013] There is a need for new BTK inhibitors or degraders that are more potent than known BTK inhibitors and that can inhibit BTK via alternative strategies, such as by degrading BTK. The present application addresses this need. Summary of the Invention

[0014] An object of the present invention is to provide a proteolysis targeting chimera (PROTAC) compound and its preparation and use by conjugating a BTK inhibitor to an E3 ligase ligand, wherein the compound functions to recruit the targeted protein to the E3 ubiquitin ligase for degradation. In particular, the present disclosure provides a PROTAC compound having Formula I.

[0015] Aspect 1: A compound having formula (I):

[0016]

[0017] or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0018] in:

[0019] is a 5- or 6-membered aromatic ring containing 0-3 heteroatoms selected from nitrogen, oxygen and sulfur;

[0020] The moiety is an E3 ubiquitin ligase moiety selected from the group consisting of:

[0021]

[0022] L1, L2, L3, L4 and L5 are each independently a bond, -O-, -CO-, -(CR c R d ) n2 -or-NR c -;

[0023] L6 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-、-(CR a R b ) n1 -NH-(CR e R f ) n3 -;

[0024] Z1, Z2 and Z3 are each independently CR 12 or N;

[0025] X a 、X b 、X c 、X d and X e Each is independently CR 12 or N;

[0026] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 and R 10 are 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, -NO2, -OR a 、-SO2R a 、-COR a 、-CO2R a 、-CONR a R b 、-C(=NR a )NR b R c 、-NR a R b 、-NR a COR b 、-NRa CONR b R c 、-NR a CO2R b 、-NR a SONR b R c 、-NR a SO2NR b R c or -NR a SO2R b , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups is optionally substituted with halogen, hydroxy, -halogen, C 1-8 Alkyl, -C 1-8 Alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl substitution;

[0027] or R at the ortho position of the benzene ring 4 and R 2 forming a 5- or 6-membered carbocyclic ring;

[0028] or X a forms a double bond with any of two adjacent carbon atoms, provided that X a It's CR 12 And R 12 does not exist;

[0029] or Two non-adjacent R on the part 8 Forming a bridge containing one, two or three CH2;

[0030] Each R 12 are independently hydrogen or -C 1-8 alkyl;

[0031] R 9 is a 5- or 6-membered aromatic ring containing 0-3 heteroatoms selected from nitrogen, oxygen and sulfur; each of said aromatic rings is optionally substituted by: halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR a 、-SO2R a 、-COR a 、-CO2R a 、-CONR a R b 、-C(=NR a )NRb R c 、-NR a R b 、-NR a COR b 、-NR a CONR b R c 、-NR a CO2R b 、-NR a SONR b R c 、-NR a SO2NR b R c , or -NR a SO2R b , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with halogen, hydroxy, -halogen, C 1-8 Alkyl, -C 1-8 Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl substitution;

[0032] n1, n2, n3, m1, m2, m3, m4, m5, p1, p2, p3, p4 and p5 are each independently 0, 1, 2, 3 or 4;

[0033] R a 、R b 、R c 、R d 、R e and R f are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0034] Aspect 2: A compound having formula (II):

[0035]

[0036] or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

[0037] in:

[0038] is a 5- or 6-membered aromatic ring containing 0-3 heteroatoms selected from nitrogen, oxygen and sulfur;

[0039] The moiety is an E3 ubiquitin ligase moiety selected from the group consisting of:

[0040]

[0041] L1, L2, L3, L4 and L5 are each independently a bond, -O-, -CO-, -(CR c R d ) n2 -or-NR c -;

[0042] Z1, Z2 and Z3 are each independently CR 12 or N;

[0043] X a 、X b 、X c 、X d and X e Each is independently CR 12 or N;

[0044] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 and R 10 are 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, -NO2, -OR a 、-SO2R a 、-COR a 、-CO2R a 、-CONR a R b 、-C(=NR a )NR b R c 、-NR a R b 、-NR a COR b 、-NR a CONR b R c 、-NR a CO2R b 、-NR a SONR b R c 、-NR a SO2NR b Rc or -NR a SO2R b , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups is optionally substituted with halogen, hydroxy, -halogen, C 1-8 Alkyl, -C 1-8 Alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl substitution;

[0045] Each R 12 are independently hydrogen or -C 1-8 alkyl;

[0046] R 9 is a 5- or 6-membered aromatic ring containing 0-3 heteroatoms selected from nitrogen, oxygen and sulfur; each of said aromatic rings is optionally substituted by: halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR a 、-SO2R a 、-COR a 、-CO2R a 、-CONR a R b 、-C(=NR a )NR b R c 、-NR a R b 、-NR a COR b 、-NR a CONR b R c 、-NR a CO2R b 、-NR a SONR b R c 、-NR a SO2NR b R c , or -NR a SO2R b , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with halogen, hydroxy, -halogen, C 1-8 Alkyl, -C 1-8Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl substitution;

[0047] n1, n2, m1, m2, p1, p2, p3, p4 and p5 are each independently 0, 1, 2, 3 or 4;

[0048] R a 、R b 、R c and R d are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0049] Aspect 3: The compound according to aspect 1 or 2, wherein yes

[0050] wherein Z4, Z5, Z6 and Z7 are each independently selected from CH or N; wherein *1 refers to the part, and **1 refers to the position attached to L1.

[0051] Aspect 4: The compound according to aspect 1, wherein yes wherein Z4, Z5 and Z7 are each independently selected from CH or N.

[0052] Aspect 5: The compound according to aspect 3 or 4, wherein Selected from

[0053] Aspect 6: A compound according to any one of aspects 3-5, wherein p3 is 0, 1 or 2, and each R 7 independently selected from halogen, -C 1-8 Alkyl or -C 1-8 Alkoxy, preferably F, Cl, Br, I, CH3 or -OCH3.

[0054] Aspect 7: The compound according to aspect 1 or 2, wherein Partially selected

[0055]

[0056] Aspect 8: The compound according to Aspect 7, wherein Partially selected

[0057] R 10is selected from hydrogen or halogen; and p5 is 0 or 1.

[0058] Aspect 9: The compound according to aspect 8, wherein Partially selected R 10 is selected from hydrogen, F, Cl, Br and I.

[0059] Aspect 10: The compound according to aspect 1 or 2, wherein Partially selected

[0060] where R 10 It is hydrogen, halogen, -C 1-8 Alkyl, -OR a ; R a is hydrogen or -C 1-8 alkyl; and p5 is 0 or 1.

[0061] Aspect 11: The compound according to Aspect 10, wherein Partially selected where R 10 It is hydrogen, halogen, -C 1-8 Alkyl, or -C 1-8 Alkoxy; preferably fluoro, chloro, methyl or methoxy.

[0062] Aspect 12: The compound according to Aspect 11, wherein Partially selected

[0063]

[0064] Aspect 13: The compound according to aspect 1 or 2, wherein L1 is a bond or -O-, and L2 is a bond.

[0065] Aspect 14: The compound according to aspect 1 or 2, wherein R a and R b are independently selected from hydrogen or CH3; and n1 is 1 or 2.

[0066] Aspect 15: The compound according to Aspect 1 or 2, wherein X a selected from CH or N; X b It is N; X c is CH, and X d It's N.

[0067] Aspect 16: The compound according to aspect 1 or 2, wherein m1, m2, m3, m4 and m5 are each independently selected from 0, 1 or 2, preferably 1.

[0068] Aspect 17: The compound according to aspect 1 or 2, wherein p4 is 0 or 1, R 8 Selected from halogen, OH, or -C 1-8 Alkyl, preferably CH3.

[0069] Aspect 18: The compound according to aspect 1 or 2, wherein for wherein m3 and m4 are each independently 0, 1, 2, 3 or 4, or wherein m3 is 1, 2, 3 or 4, and m4 is 0, 1, 2, 3 or 4.

[0070] Aspect 19: The compound according to aspect 1 or 2, wherein p4 is 2, two non-adjacent R 8 A bridge containing one, two or three CH2 groups is formed.

[0071] Aspect 20: The compound according to aspect 1, wherein Selected from

[0072] Aspect 21: The compound according to Aspect 2, wherein Selected from

[0073] Aspect 22: A compound according to any one of aspects 1-21, wherein Z1 is CH or N; and p2=0.

[0074] Aspect 23: A compound according to any one of aspects 1-22, wherein R 1 is methyl, -CH2OH, -OCH3, -CH2OCH3 or halogen; p1 is 0 or 1, and R 2 It's a halogen.

[0075] Aspect 24: A compound according to any one of aspects 1-23, wherein R 3 is hydrogen; R 4 and R 5 is selected from hydrogen or methyl.

[0076] Aspect 25: A compound according to any one of aspects 1-24, wherein R 9 yes Y1, Y2, Y3 and Y4 are selected from CH, O, S or N; R 11 Selected from hydrogen, halogen, -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR a 、-SO2R a 、-COR a 、-CO2R a 、-CONR a R b 、-C(=NR a )NR b R c 、-NR a R b 、-NR a COR b 、-NR a CONR b R c 、-NR a CO2R b 、-NR a SONR b R c 、-NR a SO2NR b R c , or -NR a SO2R b , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with halogen, hydroxy, halo-C 1-8 Alkyl, -C 1-8 Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl substituted; R a 、R b , and R c are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 p6 is 0, 1, 2, 3, or 4; and p6 is 1, 2, 3, or 4.

[0077] Aspect 26: A compound according to aspect 25, wherein Y1 is CH, S, N or O; Y2 is CH, O or N; Y3 is O, S or N; and Y4 is S, CH or N.

[0078] Aspect 27: The compound according to aspect 25 or 26, wherein Selected from

[0079] Aspect 28: The compound according to Aspect 27, wherein R 11 Selected from

[0080] Aspect 29: The compound according to aspects 1-28, wherein the compound is

[0081]

[0082] The variables are defined as in this article.

[0083] In one embodiment, the compound is

[0084]

[0085] where R 2a and R 2b are 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, -NO2, -OR a 、-SO2R a 、-COR a 、-CO2R a 、-CONR a R b 、-C(=NR a )NR b R c 、-NR a R b 、-NR a COR b 、-NR a CONR b R c 、-NR a CO2R b 、-NR a SONR b R c 、-NR a SO2NR b R c , or -NR a SO2R b , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with halogen, hydroxy, -halogen, C 1-8 Alkyl, -C 1-8 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0086] Aspect 30: The compound according to aspect 1, wherein the compound is selected from compounds 1 to 192.

[0087] In a second aspect, disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0088] In a third aspect, disclosed herein is a method of inhibiting BTK activity, comprising administering to a subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof, including a compound having formula (I) or a specific compound exemplified herein.

[0089] In a fourth aspect, disclosed herein is a method of treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, as a BTK kinase inhibitor, wherein the compound disclosed herein includes a compound having formula (I) or a specific compound exemplified herein. In some embodiments, the disease or disorder is associated with inhibition of BTK inhibition. Preferably, the disease or disorder is cancer.

[0090] In a fifth aspect, disclosed herein is a method of reducing BTK activity by inhibition and / or protein degradation, the method comprising administering to a subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION

[0091] definition

[0092] The following terms have the indicated meanings throughout this specification:

[0093] As used herein, including the appended claims, singular forms of words such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0094] Unless the context clearly indicates otherwise, the term "or" means and is used interchangeably with the term "and / or."

[0095] The term "alkyl" refers to a hydrocarbon group selected from straight-chain and branched saturated hydrocarbon groups containing from 1 to 18 (e.g., from 1 to 12, further such as from 1 to 10, further such as from 1 to 8, or from 1 to 6, or from 1 to 4) carbon atoms. 1-6Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), 1,1-dimethylethyl or tert-butyl ("t-Bu"), 1-pentyl, 2- pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl and 3,3-dimethyl-2-butyl groups.

[0096] The term "propyl" refers to 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr").

[0097] The term "butyl" refers to 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), 1,1-dimethylethyl or tert-butyl ("t-Bu").

[0098] 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.

[0099] 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.

[0100] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0101] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halogen atoms (e.g., fluorine, chlorine, bromine, and iodine). Examples of haloalkyl groups include, but are not limited to, haloC 1-8 Alkyl, halogenated C 1-6 Alkyl or halogenated C 1-4 Alkyl, such as -CF3, -CH2Cl, -CH2CF3, -CHCl2, -CF3, etc.

[0102] The term "alkenyl" refers to a hydrocarbon group selected from straight and branched hydrocarbon groups containing at least one C=C double bond and from 2 to 18 (e.g., from 2 to 8, further e.g., from 2 to 6) carbon atoms. 2-6 Examples of alkenyl groups 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, butane-1,3-dienyl, 2-methylbut-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl groups.

[0103] The term "alkynyl" refers to a hydrocarbon group selected from straight and branched hydrocarbon groups containing at least one C≡C triple bond and from 2 to 18 (e.g., from 2 to 8, further e.g., 2 to 6) carbon atoms. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0104] 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 spiro cycloalkyl groups.

[0105] For example, cycloalkyl group can comprise from 3 to 12, for example from 3 to 10, further for example 3 to 8, further for example 3 to 6, 3 to 5 or 3 to 4 carbon atoms.Even further for example, cycloalkyl group can be selected from and comprise from 3 to 12, for example from 3 to 10, further for example 3 to 8, 3 to 6 carbon atom monocyclic group.The example of monocyclic cycloalkyl group comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl group.Especially, saturated monocyclic cycloalkyl group (for example C 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In preferred embodiments, cycloalkyl groups are monocyclic rings (abbreviated as C 3-6 Examples of bicyclic cycloalkyl groups include those having from 7 to 12 ring atoms, fused bicyclic ring arrangements (selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems), or bridged bicyclic ring arrangements (selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane). Additional examples of bicyclic cycloalkyl groups include those having bicyclic ring arrangements (selected from [5,6] and [6,6] ring systems).

[0106] The term "spirocycloalkyl" refers to a ring structure containing carbon atoms and formed by at least two rings, the at least two rings sharing one atom. The term "7- to 12-membered spirocycloalkyl" refers to a ring structure containing 7 to 12 carbon atoms and formed by at least two rings, the at least two rings sharing one atom.

[0107] The term "fused cycloalkyl" refers to a bicyclic cycloalkyl group as defined herein that is saturated and formed by two or more rings which share two adjacent atoms.

[0108] The term "bridged cycloalkyl" refers to a ring structure containing carbon atoms and formed by at least two rings, the at least two rings sharing two atoms that are not adjacent to each other. The term "7- to 10-membered bridged cycloalkyl" refers to a ring structure containing 7 to 12 carbon atoms and formed by at least two rings, the at least two rings sharing two atoms that are not adjacent to each other.

[0109] The term "cycloalkenyl" refers to a non-aromatic cycloalkyl group of from 3 to 10 carbon atoms having a monocyclic or multiple rings and at least one double bond and preferably from 1 to 2 double bonds. In one embodiment, the cycloalkenyl is a 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.

[0110] The term "fused cycloalkenyl" refers to a bicyclic cycloalkyl group as defined herein containing at least one double bond and formed by two or more rings which share two adjacent atoms.

[0111] The term "cycloalkynyl" refers to a non-aromatic cycloalkyl group of from 5 to 10 carbon atoms having a single ring or multiple rings and having at least one triple bond.

[0112] The term "fused cycloalkynyl" refers to a bicyclic cycloalkyl group as defined herein containing at least one triple bond and formed by two or more rings which share two adjacent atoms.

[0113] The term "benzo-fused cycloalkyl" is a bicyclic fused cycloalkyl group in which a 4- to 8-membered monocyclic cycloalkyl ring is fused to a benzene ring. For example, a benzo-fused cycloalkyl group is The wavy lines indicate the attachment points.

[0114] The term "benzo-fused cycloalkenyl" is a bicyclic fused cycloalkenyl wherein a 4- to 8-membered monocyclic cycloalkenyl ring is fused to a benzene ring.

[0115] The term "benzo-fused cycloalkynyl" is a bicyclic fused cycloalkynyl group wherein a 4- to 8-membered monocyclic cycloalkynyl ring is fused to a benzene ring.

[0116] Examples of fused cycloalkyl, fused cycloalkenyl, or fused cycloalkynyl groups 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, decahydronaphthalene, and benzo[3- to 8-membered cycloalkyl, benzo[C] 4-6 Cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, etc. Preferred embodiments are 8- to 9-membered fused rings, which refer to ring structures containing 8 to 9 ring atoms in the above examples.

[0117] The term "aryl" used alone or in combination with other terms refers to a group selected from:

[0118] a) 5- and 6-membered carbocyclic aromatic rings, such as phenyl;

[0119] b) bicyclic ring systems (e.g. 7- to 12-membered bicyclic ring systems) in which at least one ring is carbocyclic and aromatic, such as naphthyl and indanyl; and,

[0120] c) tricyclic ring systems (eg 10- to 15-membered tricyclic ring systems) in which at least one ring is carbocyclic and aromatic, such as fluorenyl.

[0121] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring carbon atoms (i.e., C 5-10 Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphthalene-1-yl, naphthalene-2-yl, anthracenyl, phenanthrenyl, etc. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphthalene-1-yl or naphthalene-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0122] In particular, the term "bicyclic fused aryl" refers to a bicyclic aryl ring as defined herein. A typical bicyclic fused aryl is naphthalene.

[0123] The term "heteroaryl" refers to a group selected from:

[0124] a) a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom (e.g., from 1 to 4, or in some embodiments, from 1 to 3, in some embodiments, from 1 to 2 heteroatoms) selected from nitrogen (N), sulfur (S), and oxygen (O), wherein the remaining ring atoms are carbon;

[0125] b) a 7- to 12-membered bicyclic ring containing at least one heteroatom (e.g., from 1 to 4, or in some embodiments, from 1 to 3, or in other embodiments, 1 or 2 heteroatoms) selected from N, O, and S, wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0126] c) an 11- to 14-membered tricyclic ring containing at least one heteroatom (e.g., from 1 to 4, or in some embodiments, from 1 to 3, or in other embodiments, 1 or 2 heteroatoms) selected from N, O, and S, wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0127] When the total number of S and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in a heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in an aromatic heterocycle does not exceed 1. When a heteroaryl group contains one or more heteroatom ring members, these heteroatoms may be the same or different. Nitrogen atoms in one or more rings of a heteroaryl group may be oxidized to form N-oxides.

[0128] In particular, the term "bicyclic fused heteroaryl" refers to a 7- to 12-membered, preferably 7- to 10-membered, more preferably 9- or 10-membered fused bicyclic heteroaryl ring as defined herein. Typically, the bicyclic fused heteroaryl is a 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered, or 6-membered / 7-membered bicyclic ring. The group can be attached to the rest of the molecule through either ring.

[0129] Representative examples of bicyclic fused heteroaryl groups include, but are not limited to, the following: benzisoxazolyl, benzodiazolyl, benzofuranyl, benzofurazanyl, benzofuryl, benzimidazolyl, benzisothiazolyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzoxadiazolyl, benzoxazolyl, furopyridinyl, furopyrrolyl, imidazopyridinyl, imidazopyridyl, imidazothiazolyl, indazole pyrazolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridyl, pyrazolotriazinyl, pyridazinopyridinyl, pyrrolopyridinyl, quinazolinyl, quinolinyl, quinoxalinyl, thiazolopyridinyl, thienopyrazinyl, thienopyrazolyl, thienopyridinyl, thienopyrrolyl, thienothiphenyl, or triazolopyridinyl.

[0130] The term "benzo-fused heteroaryl" is a bicyclic fused heteroaryl group wherein a 5- to 7-membered (preferably 5- or 6-membered) monocyclic heteroaryl ring as defined herein is fused to a benzene ring.

[0131] The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably throughout the disclosure herein. In certain embodiments, monocyclic or bicyclic aromatic heterocycles have 5, 6, 7, 8, 9 or 10 ring members, wherein 1, 2, 3 or 4 heteroatom ring members are independently selected from nitrogen (N), sulphur (S) and oxygen (O), and the remaining ring members are carbon. In certain embodiments, monocyclic or bicyclic aromatic heterocycles are monocyclic or bicyclic rings comprising 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulphur (S) and oxygen (O). In certain embodiments, monocyclic or bicyclic aromatic heterocycles are 5 to 6 yuan heteroaryl rings, which are monocyclic and have 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulphur (S) and oxygen (O). In certain embodiments, monocyclic or bicyclic aromatic heterocycles are 8 to 10 yuan heteroaryl rings, which are bicyclic and have 1 or 2 heteroatom ring members independently selected from nitrogen, sulphur and oxygen.

[0132] Examples of heteroaryl groups, or monocyclic or bicyclic aromatic heterocycles, include, but are not limited to, (numbering starting from the attachment position designated as priority 1) 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, or 1,3,4 -thiadiazolyl), tetrazolyl, thienyl (e.g., thien-2-yl, thien-3-yl), triazinyl, benzothienyl, furyl (furyl or furanyl), benzofuranyl, benzimidazolyl, indolyl, isoindolyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl, oxazolyl, or 1,3,4-triazolyl), quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (e.g., benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-oxadiazolyl, 1-oxa-2,4-oxadiazolyl, 1-oxa-2,5-oxadiazolyl, 1-oxa-3, d]thiazolyl, 1-thia-4-oxadiazole, 1-thia-2,3-oxadiazole, 1-thia-2,4-oxadiazole, 1-thia-2,5-oxadiazole, 1-thia-3,4-oxadiazole, 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).

[0133] "Heterocyclyl," "heterocycle," or "heterocyclic" are interchangeable and refer to non-aromatic heterocyclyl groups containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, wherein the remaining ring members are carbon, including monocyclic, fused, bridged, and spiro rings, i.e., containing monocyclic heterocyclyls, bridged heterocyclyls, spiroheterocyclyls, and fused heterocyclic groups.

[0134] As used herein, the term "optionally oxidized sulfur" refers to S, SO or SO2.

[0135] The term "monocyclic heterocyclyl" refers to a monocyclic group in which at least one ring member (e.g., 1-3 heteroatoms, 1 or 2 heteroatoms) is a heteroatom selected from nitrogen, oxygen, or optionally oxidized sulfur. The heterocycle may be saturated or partially saturated.

[0136] Exemplary monocyclic 4- to 9-membered heterocyclyl groups include, but are not limited to, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidinon-2-yl, imidazolidinon-4-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, oxiranyl, aziridine-1-yl, aziridine-2-yl, azetin-1-yl, azetin-2-yl, azetin-3-yl, azetin-4-yl, azetin-5-yl, thiirane, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, azetidin-4-yl, azetidin-5-yl, thiiranyl ... alkyl-3-yl, oxetanyl, thietanyl, 1,2-thiocyclobutane, 1,3-thiocyclobutane, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, oxathianyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxetanyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxetanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,4-thiazepanyl and 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathianyl, oxazepanyl Base, diazepine thiazolinone 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone, 1-Hydroxy-1-pyrrolidone,

[0137] The term " spiro heterocyclic radical " refers to a 5 to 20 yuan polycyclic heterocyclic radical with a ring connected by a shared carbon atom (called spiral atom), which comprises one or more heteroatoms selected from nitrogen, oxygen or the optionally oxidized sulphur as ring members, and remaining ring members are carbon. One or more rings of spiro heterocyclic radical groups can contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, spiro heterocyclic radical is 6 yuan to 14 yuan and more preferably 7 yuan to 12 yuan. According to the shared spiral atom number, spiro heterocyclic radical can be monospiro heterocyclic radical, two-spiro heterocyclic radical or many spiral heterocyclic radicals, and preferably refers to monospiro heterocyclic radical or two-spiro heterocyclic radical, and more preferably 4 yuan / 3 yuan, 4 yuan / 4 yuan, 3 yuan / 5 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospiro heterocyclic radical. Representative examples of spiroheterocyclyl groups include, but are not limited to, the following: 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[2.4]heptane-5-yl). [3.4]octan-6-yl), 2-oxa-6-azaspiro[3.4]octane (e.g., 2-oxa-6-azaspiro[3.4]octane-6-yl), azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]octane-6-yl), azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]octane-6-yl), 1,7-dioxaspiro[4.5]decane, 2-oxa-7-aza-spiro[4.4]nonane (e.g., 2-oxa-7-aza-spiro[4.4]nonan-7-yl), 7-oxa-spiro[3.5]nonyl, and 5-oxa-spiro[2.4]heptyl.

[0138] The term "fused heterocyclic radical" refers to a 5- to 20-membered polycyclic heterocyclic radical group (wherein each ring in the system shares adjacent pairs of atoms (carbon and carbon atoms, or carbon and nitrogen atoms) with another ring), comprising one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulphur as ring members, and the remaining ring members are carbon. One or more rings of the fused heterocyclic radical may contain one or more double bonds, but the fused heterocyclic radical does not have a completely conjugated π electron system. Preferably, the fused heterocyclic radical is 6 to 14 yuan and more preferably 7 to 12 yuan or 7 to 10 yuan. Depending on the number of member rings, the fused heterocyclic radical may be a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic radical. The group may be attached to the remainder of the molecule through any one ring.

[0139] In particular, the term "bicyclic fused heterocyclyl" refers to a 7- to 12-membered, preferably 7- to 10-membered, more preferably 9- or 10-membered fused heterocyclyl as defined herein, comprising two fused rings and comprising 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, isoindolyl, octahydro-benzo[b][1,4]dioxin, dihydroindolyl, isoindolyl, benzopyranyl, dihydrothiazolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl (or tetrahydroisoquinolinyl), dihydrobenzofuranyl, dihydrobenzoxazinyl, dihydrobenzimidazolyl, tetrahydrobenzothiophenyl, tetrahydrobenzofuranyl, benzodioxolanyl (benzodioxolanyl), benzothiophene (benzothiophene ... lyl), benzodioxonyl, chromanyl, chromenyl, octahydrochromenyl, dihydrobenzodioxynyl, dihydrobenzoxezinyl, dihydrobenzodioxepinyl, dihydrothienodioxynyl, dihydrobenzoxazepine Tetrahydrobenzoxazepine Benzazepine, dihydrobenzazepine Tetrahydrobenzazepine 1,5-a]pyrimidin-3-yl.

[0140] The term "benzo-fused heterocyclyl" is a bicyclic fused heterocyclyl wherein a monocyclic 4- to 9-membered heterocyclyl (preferably 5- or 6-membered) as defined herein is fused to a benzene ring.

[0141] The term "bridged heterocyclic group" refers to a 5 to 14-membered polycyclic heterocycloalkyl group (wherein every two rings in the system share two discontinuous atoms), comprising one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulphur as ring members, wherein the remaining ring members are carbon. One or more rings of the bridged heterocyclic group may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, the bridged heterocyclic group is 6 to 14 members and more preferably 7 to 10 members. Depending on the number of member rings, the bridged heterocyclic group can be a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, and preferably refers to a bicyclic, tricyclic or tetracyclic bridged heterocyclic group, and more preferably a bicyclic or tricyclic bridged heterocyclic group. Representative examples of bridged heterocyclic groups include, but are not limited to, the following: 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.2]octyl, and 2-azabicyclo[3.3.2]decyl.

[0142] The term "at least one substituent" disclosed herein includes, for example, from 1 to 4, such as from 1 to 3, further such as 1 or 2 substituents, provided that the valence theory is satisfied. For example, the term "at least one substituent R" disclosed herein includes, for example, from 1 to 4, such as from 1 to 3, further such as 1 or 2 substituents, provided that the valence theory is satisfied. 6d " includes from 1 to 4, such as from 1 to 3, further such as 1 or 2 substituents selected from R as disclosed herein 6d .

[0143] The compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. When the compounds disclosed herein have two or more chiral centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a broader category of stereoisomers. It is intended to include all possible stereoisomers, such as substantially pure resolved enantiomers, their racemic mixtures, and mixtures of diastereomers. It is intended to include stereoisomers of all compounds disclosed herein and / or their pharmaceutically acceptable salts. Unless otherwise specifically stated, a reference to an isomer applies to any possible isomer. Whenever the composition of the isomers is not specified, all possible isomers are included.

[0144] As used herein, the term "substantially pure" means that the target stereoisomer contains no more than 35% by weight, such as no more than 30%, further such as no more than 25%, and even further such as no more than 20% of any one or more other stereoisomers. In some embodiments, the term "substantially pure" means that the target stereoisomer contains no more than 10% by weight, such as no more than 5%, such as no more than 1% of any one or more other stereoisomers.

[0145] When compounds disclosed herein contain olefinic double bonds, unless specified otherwise, such double bonds are intended to include both E and Z geometric isomers.

[0146] When the compounds disclosed herein contain a disubstituted ring system, the substituents found on such ring systems can be in both cis and trans forms. Cis formation means that both substituents are located on the upper side of the carbon 2 substituent positions, while trans formation means that they are located on opposite sides. For example, the disubstituted ring system can be a cyclohexyl ring or a cyclobutyl ring.

[0147] It may be advantageous to separate the reaction products from each other and / or from the starting materials. The desired product of each step or series of steps is separated and / or purified (hereinafter referred to as separation) to the desired uniformity by common techniques in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve many methods, including, for example: reverse phase and normal phase; size exclusion; ion exchange; high, medium, and low pressure liquid chromatography methods and apparatus; small-scale analysis; simulated moving bed ("SMB") and preparative thin or thick layer chromatography, as well as small-scale thin layer and flash chromatography techniques. Those skilled in the art will apply the technology most likely to achieve the desired separation.

[0148] "Diastereoisomers" refer to stereoisomers of compounds that have two or more chiral centers but are not mirror images of each other. Diastereoisomer mixtures can be separated into their individual diastereomers according to 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 as follows: by reacting an enantiomeric mixture with an appropriate optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acid chlorid), converting the enantiomeric mixture into a diastereomeric mixture, separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers into the corresponding pure enantiomers. Enantiomers and diastereomers can also be separated by using a chiral HPLC column.

[0149] Single stereoisomers (e.g., substantially pure enantiomers) can be obtained by resolution of the racemic mixture using an optically active resolving agent to form the diastereomers (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, CH et al. "Chromatographic resolution of enantiomers: Selective review." J. Chromatogr., 113(3) (1975): 283-302). Racemic mixtures of the chiral compounds of the present invention can be separated and isolated by any suitable method, including: (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods; (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of these diastereomers and conversion to pure stereoisomers; and (3) separation of substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., ed., Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0150] "Pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting a free base functional group with a suitable organic acid, or by reacting an acidic group with a suitable base.

[0151] 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 (e.g., a pharmaceutically acceptable addition salt) can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize a variety of synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation.

[0152] As defined herein, "pharmaceutically acceptable salts thereof" include salts of at least one compound of formula (I), and salts of stereoisomers of the compound of formula (I), such as enantiomeric salts and / or diastereomeric salts.

[0153] The terms "administration" and "treating" as used herein, when applied to an animal, a human, a laboratory subject, a cell, a tissue, an organ, or a biological fluid, refer to the contact of an exogenous pharmaceutical, therapeutic, diagnostic agent or composition with an animal, a human, a subject, a cell, a tissue, an organ, or a biological fluid. Treatment of cells encompasses contact of an agent with a cell and contact of an agent with a fluid, wherein the fluid is in contact with the cell. The terms "administration" and "treatment" also refer to in vitro and ex vivo treatment of a cell, such as by a reagent, a diagnostic agent, a binding compound, or another cell. The term "subject" as used herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0154] The term "effective amount" or "therapeutically effective amount" refers to the amount of an active ingredient (e.g., a compound) that, when administered to a subject to treat a disease, or at least one clinical symptom of a disease or disorder, is sufficient to affect the treatment of such disease, disorder, or symptom. A "therapeutically effective amount" may vary with the compound, the disease, disorder, and / or the symptoms of the disease or disorder, the severity of the disease, disorder, and / or the symptoms of the disease or disorder, the age of the subject to be treated, and / or the weight of the subject to be treated. The appropriate amount in any given case will be apparent to those skilled in the art or may be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is the amount of at least one compound disclosed herein and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof, as defined herein, that is effective to treat the disease or disorder of the subject. In the case of combination therapy, a "therapeutically effective amount" refers to the total amount of the combination subject used to effectively treat the disease, disorder, or condition.

[0155] The pharmaceutical compositions comprising the compounds disclosed herein can be administered to subjects in need thereof via oral, inhalation, rectal, parenteral or topical routes. For oral administration, the pharmaceutical composition can be a conventional solid formulation, such as a tablet, powder, granule, capsule, etc.; a liquid formulation, such as an aqueous or oily suspension; or other liquid formulations, such as a syrup, solution, suspension, etc.; for parenteral administration, the pharmaceutical composition can be a solution, an aqueous solution, an oily suspension concentrate, a lyophilized powder, etc. Preferably, the formulation of the pharmaceutical composition is selected from tablets, coated tablets, capsules, suppositories, nasal sprays or injections, more preferably tablets or capsules. The pharmaceutical composition can be a single unit administration with a precise dose. In addition, the pharmaceutical composition may further comprise other active ingredients.

[0156] All formulations of the pharmaceutical composition disclosed herein can be produced by conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients and then made into the desired formulation. "Pharmaceutically acceptable excipient" refers to conventional pharmaceutical carriers suitable for desired pharmaceutical formulations, such as: diluents, vehicles (such as water, various organic solvents, etc.), fillers (such as starch, sucrose, etc.), adhesives (such as cellulose derivatives, alginates, gelatin and polyvinyl pyrrolidone (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 bentonite; Lubricants, such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical composition also includes other pharmaceutically acceptable excipients, such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, aromatic compounds, sweeteners and dyes, etc.

[0157] The term "disease" refers to any illness, ailment, disease, symptom, or indication and is interchangeable with the terms "disorder" or "condition."

[0158] Throughout this specification and the appended claims, unless the context requires otherwise, the term "comprise" and variations such as "comprises and comprising" are intended to specify the presence of the following features, but do not preclude the presence or addition of one or more other features. When used herein, the term "comprise" may be replaced with the terms "contain" or "include", or sometimes "have".

[0159] Throughout this specification and the appended claims, the term “C n-m " indicates a range including endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-8 、C 1-6 wait.

[0160] Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0161] General reaction scheme for compound preparation

[0162] The subject compounds and pharmaceutically acceptable salts thereof can be prepared from (a) commercially available starting materials (b) known starting materials (which can be prepared as described in literature methods) (c) novel intermediates described in the schemes and experimental methods herein. In preparing the compounds of the present invention, the order of the synthetic steps can be changed to increase the yield of the desired product. Some of the compounds of the present invention can be produced by the methods shown in the following reaction schemes and descriptions thereof.

[0163] Plan A

[0164]

[0165] wherein X3 corresponds to Z2 in formula (I), and X4 corresponds to Z3 in formula (I). A-2 can be synthesized from A-1 and piperidin-4-ylmethanol under alkaline conditions. The nitro group in A-2 is then reduced to form A-3, which is then mixed with acrylic acid to produce a mixture of A-4a and A-4b. A-4a and A-4b are then heated in the presence of urea to produce A-5, which is hydrolyzed under acidic conditions to produce A-6. The final intermediate A is obtained by oxidizing A-6 with an oxidizing agent such as IBX.

[0166] Plan B

[0167]

[0168] Wherein n corresponds to n1 in formula (I), X3 corresponds to Z2 in formula (I), and X4 corresponds to Z3 in formula (I). B-3 is synthesized from B-1 and B-2 using Pd as a catalyst, and then B-3 is coupled with B-4 in the presence of a metal catalyst to produce B-5. The ester group in B-5 can be reduced to alcohol B-6 using a reducing agent such as LiAlH4. In the presence of hydrogen, B-6 can be further reduced with Pd / C to produce B-7, which is then oxidized with an oxidizing agent such as IBX to produce intermediate B.

[0169] Plan C

[0170]

[0171] wherein n corresponds to n1 in formula (I), X3 corresponds to Z2 in formula (I), and X4 corresponds to Z3 in formula (I). C-2 can be synthesized from C-1 and (BOC)2O, followed by coupling of C-2 and C-3 in the presence of Pd as a catalyst to yield intermediate C-4. The Boc group is removed under acidic conditions to form C-5, which is then mixed with acrylic acid and heated to yield C-6. C-7 can be synthesized from C-6 and urea under heating, followed by removal of the TBS group in C-7 with TBAF or CsF to yield intermediate C-8, which is then oxidized to intermediate C using an oxidizing agent such as IBX.

[0172] Plan D

[0173]

[0174] Wherein X3 corresponds to Z2 in formula (I), and X4 corresponds to Z3 in formula (I). D-1 and D-2 can be coupled in the presence of a metal catalyst (CuI, Pd, etc.) to produce D-3, which is then coupled with D-4 using Pd as a catalyst to produce D-5. In the presence of Pd / C as a catalyst, the bis(benzyloxy)pyridine group in D-5 is reduced by hydrogen to the piperidine-2,6-dione in D-6, which is then oxidized with an oxidizing agent such as IBX to yield the final intermediate D.

[0175] Plan E

[0176]

[0177] E-3 is synthesized from E-1 and E-2 under alkaline conditions. The hydroxyl group is protected with THP under acidic conditions to yield E-4. The isobenzofuran-1(3H)-one in E-4 can be hydrolyzed with NaOH / H₂O to yield E-5, which is mixed with TBSCl and a base to form intermediate E-6. E-6 is coupled with 3-aminopiperidine-2,6-dione and HATU to yield E-7. The TBS group can be removed with TBAF or CsF to yield E-8. E-9 can be synthesized from E-8 and TsCl under alkaline conditions, followed by removal of the THP group under acidic conditions. The final intermediate, E, is then oxidized with an oxidizing agent.

[0178] Plan F

[0179]

[0180] where R 1 、R 3 、R 4 、R 5 、R 9 、X a 、X c 、X d 、X e, Z2, Z3, Z4 and Z5 are as defined in formula (I), (II) or (III). F-2 is synthesized from F-1 and SEMCl under alkaline conditions, which is further coupled with F-3 using Pd as a catalyst to form F-4. F-4 and F-5 are coupled using Pd as a catalyst to give F-6, which is then removed from the Boc and SEM groups under acidic or alkaline conditions to give F-7, which is then mixed with an aldehyde in the presence of a reducing agent such as NaBH(OAc)3 to form F.

[0181] Plan G

[0182]

[0183] where R 1 、R 3 、R 4 、R 9 、X a 、X c 、X d 、X e , Z2, Z3, Z4 and Z5 are as defined in formula (I). G-1 and G-2 are mixed with CoCl2 as a catalyst to form G-3, and then G-3 is coupled with G-4 using Pd as a catalyst to obtain G-5. The Boc group can be removed in acid to form G-6, which is then mixed with an aldehyde in the presence of a reducing agent such as NaBH(OAc)3 to form G.

[0184] Examples

[0185] The following examples are intended to be purely exemplary and should not be considered as limiting in any way. Although efforts have been made to ensure the accuracy of the numerals (e.g., amount, temperature, etc.) used, some experimental errors and deviations should be considered. Unless otherwise noted, temperatures are degrees Celsius. Reagents are purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, and are used without further purification unless otherwise noted. Unless otherwise noted, reactions described below are carried out under a positive pressure of nitrogen or argon or in anhydrous solvents with a drying tube; Reaction flasks are equipped with rubber septa for introducing substrates and reagents by syringe; and glassware is oven dried and / or heat dried.

[0186] Recorded on an Agilent instrument operating at 400 MHz or a Bruker instrument operating at 500 MHz 1 H NMR spectrum.

[0187] The results were obtained using CDCl3, CD2Cl2, CD3OD, D2O, d6-DMSO, d6-acetone or (CD3)2CO as solvents and tetramethylsilane (0.00 ppm) or residual solvent (CDCl3: 7.25 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; d6-DMSO: 2.50 ppm; d6-acetone: 2.05; (CD3)3CO: 2.05) as reference standards. 1 HNMR spectra. When reporting the number of multiplets, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextet), m (multiplet), br (broad), dd (double of doublet), dt (double of triplet). Coupling constants, if given, are reported in Hertz (Hz).

[0188] LCMS-1: LC-MS spectrometer (Agilent 1260 Infinity) Detector: MWD (190-400 nm), Mass detector: 6120SQ 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 μm Gradient method: Flow rate: 1.8 mL / min Time (min) A (%) B (%)

[0189] Time (min) A(％) B(％) 0.00 95 5 1.5 5 95 2.0 5 95 2.1 95 5 3.0 95 5

[0190] LCMS, LCMS-3: LC-MS spectrometer (Agilent 1260 Infinity II) Detector: MWD (190-400 nm), Mass detector: G6125C SQ Mobile phase: A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid, Column: Poroshell 120 EC-C18, 4.6x50 mm, 2.7 μm Gradient method: Flow rate: 1.8 mL / min Time (min) A (%) B (%)

[0191] Time (min) A(％) B(％) 0.00 95 5 1.5 5 95 2.0 5 95 2.1 95 5 3.0 95 5

[0192] 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, 4.6x50 mm, 2.7 μm Gradient method: Flow rate: 1.2 mL / min Time (min) A (%) B (%)

[0193] Time (min) A(％) B(％) 0.00 90 10 1.5 5 95 2.0 5 95 2.1 90 10 3.0 90 10

[0194] Preparative HPLC was performed on a column (150 x 21.2 mm ID, 5 pm, Gemini NXC 18) at a flow rate of 20 ml / min, an injection volume of 2 ml, at room temperature and UV detection at 214 nm and 254 nm.

[0195] In the following examples, the following abbreviations are used:

[0196]

[0197]

[0198]

[0199] 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

[0200]

[0201]

[0202] Step 1: tert-Butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin- 1-formate

[0203]

[0204] A mixture of tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate (10 g, 29.4 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (9 g, 5.0 mmol), Pd(dppf)Cl2 (2.12 g, 10.6 mmol), and KOAc (4.55 g, 22.75 mmol) in 1,4-dioxane (200 mL) was stirred overnight at 100°C in a round-bottom flask. The mixture was evaporated in vacuo to give a 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.

[0205] Step 2: (1-(4-nitrophenyl)piperidin-4-yl)methanol

[0206]

[0207] To a solution of 1-fluoro-4-nitrobenzene (100.0 g, 710.0 mmol) and 4-piperidinemethanol (98.0 g, 850 mmol) in DMF (1400.0 mL) was added KCO (196.0 g) at 25°C. The mixture was stirred at 80°C for 15 hours. The reaction was monitored by HPLC. The reaction was cooled to room temperature and the mixture was poured into ice water (6000.0 mL) and stirred for 20 minutes. The solid was filtered and washed with water (500.0 mL x 2) and dried to give the product (140.0 g, 83.8%). 1 H NMR (400 MHz, DMSO) δ H 8.03(d,J=9.4Hz,2H),7.01-6.98(m,2H),4.54(t,J=5.3Hz,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.

[0208] Step 3: (1-(4-aminophenyl)piperidin-4-yl)methanol

[0209]

[0210] To 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) under N at 25° C. The mixture was then exchanged with H twice and stirred at 25° C. under an H atmosphere for 15 hours. 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 under vacuum 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=5.3Hz,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.

[0211] Steps 4 and 5: (1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl acetate

[0212]

[0213] At 25 ℃, to a solution of (1-(4-aminophenyl)piperidin-4-yl)methanol (25.0 g, 121.2 mmol) in PhMe (183.0 mL), acrylic acid (13.0 g, 181.8 mmol) was added. The mixture was stirred at 90 ℃ for 15 hours. The reaction was monitored by HPLC. The reaction was cooled to 25 ℃, then HOAc (183.0 mL) and urea (36.4 g, 606.2 mmol) were added. The mixture was stirred at 110 ℃ for 24 hours. The reaction was monitored by HPLC. The reaction was cooled to 25 ℃ and concentrated under vacuum. The residue was dissolved in EtOAc (500.0 mL), then saturated NaHCO 3 was adjusted to pH=7. The resulting solution was extracted with 2x200.0 mL EtOAc, and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and 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=8.9Hz,2H),6.99(d,J=9.0Hz,2H),3.98(d,J=6.2Hz,2H),3.80-3.66(m, [M+H] + =346.2.

[0214] Step 6: 1-(4-(4-(Hydroxymethyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0215]

[0216] (1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl acetate (35.0 g, 121.2 mmol) was added to 2N HCl (260.0 mL) at 25 ° C. The mixture was stirred at 100 ° C for 15 hours. The reaction was monitored by HPLC. The reaction was cooled to 10 ° C and then adjusted to pH = 7 with saturated NaHCO 3. The solid was collected by filtration, washed with water (50.0 mL), and dried to obtain the product (16.9 g, 55%). 1 H NMR (400 MHz, DMSO) δ H10.26(s,1H),7.13(d,J=8.9Hz,2H),6.92(d,J=9.0Hz,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.

[0217] Step 7: 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde

[0218]

[0219] 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) in portions at 25°C (caution: exotherm to 40°C). The mixture was stirred at 25°C for 15 hours. The reaction was monitored by HPLC. Water (300.0 mL) was added to the reaction at 25°C. The solid was filtered and washed with water (100.0 mL) and then EtOAc (100.0 mL). The resulting solution was extracted with 4x200.0 mL EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum 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.

[0220] Step 8: 4-Chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine pyridine

[0221]

[0222] To a mixture of 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (50 g, 179.2 mmol) in DMF (1 L) was added NaH (8.6 g, 215 mmol). The mixture was stirred at 0 ° C for 20 minutes. SEM-Cl (62 g, 232 mmol) was then added. LCMS showed that the reaction was complete. The reaction was concentrated to give a residue, which was separated with DCM and H2O. The combined organic layers were dried over Na2SO4 and MTBE (300 mL) was added to give the product (55 g, 80%). [M+H] + =410.0.

[0223] Step 9: tert-Butyl 4-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[3 ... [2,3-d]pyrimidin-6-yl)phenyl)piperidine-1-carboxylate

[0224]

[0225] A mixture of 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (6.42 g, 11.8 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate (5.18 g, 4.5 mmol), Pd(dppf)Cl2 (0.862 g, 0.75 mmol) and K2CO3 (3.25 g, 23.6 mmol) in 1,4-dioxane (20 mL) and H2O (4 mL) was stirred in a round-bottom flask at 80°C overnight. The mixture was evaporated in vacuo to give the crude product, which was further purified by silica gel column chromatography (PE:EA = 100:0 to 3:1 gradient elution) to give the product (5 g, 70%). [M+H] + =543.4.

[0226] 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)benzene 4-[ ...amino]-piperidine]-1-carboxylate

[0227]

[0228] A mixture of tert-butyl 4-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperidine-1-carboxylate (6.42 g, 11.8 mmol), 3-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (5.18 g, 4.5 mmol), Pd(dppf)Cl2 (0.862 g, 0.75 mmol) and K2CO3 (3.25 g, 23.6 mmol) in 1,4-dioxane (100 mL) and H2O (20 mL) was stirred in a round-bottom flask at 100°C overnight. The mixture was evaporated in vacuo to give a 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.

[0229] Step 11: 3-(tert-Butyl)-N-(4-(7-(hydroxymethyl)-6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[3-(tert-butyl)-N-(4-(7- ... [2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide

[0230]

[0231] 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) and trifluoroacetic acid (20 mL) in dichloromethane (20 mL) was stirred in a round-bottom flask at room temperature overnight. The mixture was evaporated in vacuo to give the crude product (5 g, 81%), which was used in the next step without further purification. [M+H] + =580.4.

[0232] Step 12: 3-(tert-Butyl)-N-(2-methyl-4-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d] (4-pyrimidinyl)benzyl)-1,2,4-oxadiazole-5-carboxamide

[0233]

[0234] To a stirred solution of 3-(tert-butyl)-N-(4-(7-(hydroxymethyl)-6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide (5.0 g, 8.6 mmol) in MeOH (20 mL) was added NH3 / H2O (25%-30%, 10 mL). The mixture was allowed to stir at 0°C for 30 min. LCMS showed that the reaction was complete. The mixture was evaporated in vacuo to give the crude product, which was further purified by silica gel column chromatography (DCM:MeOH=10:1 to 2:1 gradient elution) to give the product (3 g, 60%). [M+H] + =550.4.

[0235] 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

[0236]

[0237] A mixture of 3-(tert-butyl)-N-(2-methyl-4-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (3 g, 5.45 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (1.64 g, 5.45 mmol) in 1,2-dichloromethane (150 mL) and MeOH (30 mL) was stirred in a round-bottom flask at room temperature for 1 hour. NaBH(OAc)3 (2.3 g, 10.84 mmol) was added to the mixture and stirred in a round-bottom flask at room temperature overnight. The mixture was then evaporated in vacuo to give a crude product, which was purified by silica gel column chromatography (gradient elution of DCM:MeOH = 100:0 to 80:20) 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=6.8Hz, 2H),7.55(s,1H),7.45(s,3H),7.21(d,J=7.2Hz,2H),7.01(d,J=7.8Hz,2H),4.64(s,2H ),3.77(d,J=5.6Hz,4H),3.41(s,2H),3.04(s,2H),2.76-2.74(m,4H),2.53-2.42(m,3 H),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.

[0238] 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

[0239]

[0240] The title compound was synthesized using a procedure similar to that of Example 1. 1 H NMR (400 MHz, DMSO) δ H 12.68(s,1H),11.13(s,1H),9.93(s,1H),8.80(s,1H),8.07(s,2H),7.98(d,J=7.7Hz, 2H),7.72(d,J=11.4Hz,1H),7.46(s,2H),7.38(d,J=8.3Hz,3H),5.11(d,J=7.3Hz,1H), 4.56(d,J=5.5Hz,2H),3.62(d,J=12.2Hz,2H),2.98-2.90(m,6H),2.57(t,J=15.0Hz,2 H),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.

[0241] 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

[0242]

[0243] The title compound was synthesized using a procedure similar to that of Example 1. 1 H NMR (400 MHz, DMSO) δ H 12.72(s,1H),10.28(s,1H),9.93(s,1H),8.82(s,1H),8.07(s,2H),8.02(d,J=7.9Hz,2H),7.48(d,J =8.2Hz,1H),7.39(s,3H),7.14(d,J=8.5Hz,2H),6.94(d,J=8.5Hz,2H),4.56(d,J=5.4Hz,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=11.3Hz,2H),1.63(s,2H),1.51(d,J=17.4Hz,1H),1.38(s,9H),1.30-1.28(m,2H);[M+H] + =849.9.

[0244] 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

[0245] Step 1: 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine

[0246]

[0247] To a stirred mixture of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridine (25 g, 59.908 mmol) and 4-bromoiodobenzene (20.3 g, 71.897 mmol) in dioxane (250 mL) and H2O (50 mL) was added K2CO3 (16.6 g, 119.822 mmol) and Pd(dppf)Cl2 (4.4 g, 5.986 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 ° C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (3x500 mL). The combined organic layer was washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EtOAc (10:1) as eluent to afford the product (23 g, 86%). [M+H] + =446.2.

[0248] Step 2: Ethyl 2-(1-[4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl]piperidin-4-yl)acetate

[0249]

[0250] To a stirred solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (15 g, 33.606 mmol) and ethyl 2-(piperidin-4-yl)acetate (8.6 g, 50.410 mmol) in 2-methyl-THF (150 mL) and H2O (15 mL) was added Cs2CO3 (32.9 g, 100.819 mmol), DavePhos (2.7 g, 6.721 mmol) and Pd2(dba)3 (3.1 g, 3.361 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 ° C for 16 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (500 mL), washed with water (3x200 mL) and brine (200 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EtOAc (1:1) as eluent to give the product (14 g, 78%). [M+H] + =537.3.

[0251] Step 3: 2-(1-[4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl]piperidin-4-yl)ethanol

[0252]

[0253] 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 LiAlH4 (1 g, 26.646 mmol) in portions at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding water / ice (50 mL) at 0°C. The resulting mixture was extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EtOAc (1:2) to give the product (11 g, 92%). [M+H] + =495.3.

[0254] Step 4: 3-[4-[4-(2-hydroxyethyl)piperidin-1-yl]phenyl]piperidine-2,6-dione

[0255]

[0256] To a stirred solution of 2-(1-[4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl]piperidin-4-yl)ethanol (10.5 g, 21.228 mmol) in EtOH (100 mL), EtOAc (100 mL) and DCM (20.00 mL) was added Pd / C (wet, 10%) (5 g, 46.984 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. The resulting mixture was filtered and the filter cake was washed with DCM / CH3OH (10:1, 200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EtOAc (1:10) to give the product (5.1 g, 76%). [M+H] + =317.1.

[0257] Step 5: 2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetaldehyde

[0258]

[0259] 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 in a round-bottom flask at room temperature overnight. The reaction was quenched with water, and the mixture was extracted with EtOAc, washed three times with saturated aqueous NaCl solution, and washed twice with saturated aqueous NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to give the product (70 mg, 70%). [M+H] + =315.2.

[0260] Step 6: 3-(tert-Butyl)-N-(4-(6-(4-(1-(2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperid ...4-yl)-1-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperidin-4-yl]piperidin-5-yl]piperidin-6-yl (4-piperidin-4-yl)ethyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxo Heterodiazole-5-carboxamide

[0261]

[0262] 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 in a round-bottom flask for 30 minutes. NaBH(AcO) (15 mg, 0.073 mmol) was then added and stirred at room temperature for 2 hours. The reaction was quenched with water, and the mixture was washed once with saturated NaHCO aqueous solution and then extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to give the crude product, which was further purified by preparative HPLC to afford the product (13.3 mg, 43%). 1 H NMR (400 MHz, DMSO) δ H 12.80(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=5.5Hz,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=11.7Hz,2H),1.81(d,J=11.0Hz,2H),1.69-1.67(m,2H),1.52-1.50(m,1H),1.38(s,9H),1.24-1.22(m,1H); [M+H] + =848.8.

[0263] 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

[0264] Step 1: (1-(4-nitrophenyl)azetidin-3-yl)methanol

[0265]

[0266] A mixture of azetidine-3-ylmethanol HCl salt (8.00 g, 65.041 mmol), 4-fluoronitrobenzene (9.17 g, 65.041 mmol) and Na2CO3 (17.95 g, 130.082 mmol) in DMSO (40 mL) was stirred at 60 ° C for 2 hours. The reaction was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product can be used in the next step without further purification.

[0267] Step 2: (1-(4-aminophenyl)azetidin-3-yl)methanol

[0268]

[0269] 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 at room temperature under a hydrogen atmosphere for 1 hour. 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.

[0270] Step 3: 4-(3-(((tert-Butyldiphenylsilyl)oxy)methyl)azetidin-1-yl)aniline

[0271]

[0272] To a stirred mixture of (1-(4-aminophenyl)azetidin-3-yl)methanol (12.50 g, 70.132 mmol) and imidazole (9.55 g, 140.264 mmol) in DMF (50.00 mL) was added TBDPSCl (45.59 mL, 165.875 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EtOAc (1: 1) to give the product (21.5 g, 73.58%).

[0273] Step 4: Methyl 3-((4-(3-(((tert-butyldiphenylsilyl)oxy)methyl)azetidin-1-yl) phenyl)amino)propionate

[0274]

[0275] 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 H2O (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 dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EtOAc (1: 1) to give the product (2.1 g, 17.40%).

[0276] Step 5: Methyl 3-(1-(4-(3-(((tert-butyldiphenylsilyl)oxy)methyl)azetidine-1- phenyl)ureido)propionate

[0277]

[0278] A mixture of methyl 3-((4-(3-(((tert-butyldiphenylsilyl)oxy)methyl)azetidin-1-yl)phenyl)amino)propanoate (2.10 g, 4.177 mmol) and sodium cyanate (543.09 mg, 8.354 mmol) in AcOH (20.00 mL) and H O (4.00 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. The crude product (2.7 g) was used in the next step without further purification.

[0279] Step 6: 1-(4-(3-(((tert-Butyldiphenylsilyl)oxy)methyl)azetidin-1-yl)phenyl) Dihydropyrimidine-2,4(1H,3H)-dione

[0280]

[0281] A mixture of methyl 3-(1-(4-(3-(((tert-butyldiphenylsilyl)oxy)methyl)azetidin-1-yl)phenyl)ureido)propanoate (2.70 g, 4.947 mmol) and TMSOK (0.76 g, 5.937 mmol) in THF (30.00 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum to give the product (1.1 g, 43.28%). The crude product was used in the next step without further purification.

[0282] Step 7: 1-(4-(3-(Hydroxymethyl)azetidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0283]

[0284] A mixture of 1-(4-(3-(((tert-butyldiphenylsilyl)oxy)methyl)azetidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (3.00 g, 5.840 mmol) and CsF (2.66 g, 17.520 mmol) in DMF (30.00 mL) was stirred at room temperature for 4 hours. The resulting mixture was filtered and the filter cake was washed with DMF. The filtration was concentrated under reduced pressure. The residue was purified by slurry in water. The resulting mixture was filtered and the filter cake was washed with water. The filter cake was dried in vacuo to give the product (1.1 g, 68.42%).

[0285] Step 8: (1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidin-3-yl)methyl 4- Toluenesulfonate

[0286]

[0287] To a stirred mixture of 1-(4-(3-(hydroxymethyl)azetidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (2.2 g, 7.991 mmol), TEA (2.77 mL) and TsCl (4.57 g, 23.973 mmol) in DCM (20.00 mL) was added DMAP (3.9 g, 31.884 mmol). The resulting mixture was stirred at 50 ° C for 4 hours. The reaction was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with citric acid (aqueous solution) and brine, and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH2Cl2 / MeOH (12: 1) to give the product (995.4 mg, 29.00%). 1 H NMR (400 MHz, DMSO) δ H10.23(s,1H),7.94-7.72(m,2H),7.61-7.39(m,2H),7.32-6.94(m,2H),6.50-6.26(m,2H),4.25(d,J=4Hz,2H),3.8 [M+H] + =430.0.

[0288] Step 9: 3-(tert-Butyl)-N-(4-(6-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzene yl)azetidin-3-yl)methyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl 1,2,4-oxadiazole-5-carboxamide

[0289]

[0290] A mixture of (1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidin-3-yl)methyl 4-methylbenzenesulfonate (50.00 mg, 0.116 mmol), 3-(tert-butyl)-N-(2-methyl-4-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (63.99 mg, 0.116 mmol) and DIEA (0.06 mL, 0.471 mmol) in DMSO (1.00 mL) was stirred at 80 ° C for 3 hours. The reaction was quenched with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: mobile phase, water (10 mmol / L NH4HCO3) and ACN (46% phase B to 52% in 8 minutes); detector, UV 254 mm. This gave the product (2.6 mg, 2.77%). 1 HNMR (400 MHz, DMSO) δ H10.22(s,1H),9.89(d,J=4Hz,1H),8.81(s,1H),8.09(d,J=4Hz,2H),7.99(d,J=8.0Hz,2H),7.49(d,J=8H z,1H),7.38-7.36(m,4H),7.11(d,J=8Hz,2H),6.43(d,J=8Hz,2H),4.57(d,J=4Hz,2H),3.96(t,J=8Hz,1H ),3.68(t,J=8Hz,2H),3.63(s,2H),2.97(d,J=12Hz,3H),2.70(t,J=8.0Hz,2H),2.61(d,J=8.0Hz,2H),2 .08-2.05(m,3H),1.77(s,1H),1.71(d,J=16Hz,3H),1.40-1.38(m,12H),1.24(s,1H),0.88(s,4H);[M+H] + =807.0.

[0291] 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

[0292] Step 1: 3-(azetidin-3-yl)propan-1-ol

[0293]

[0294] Tert-butyl 3- (3- hydroxypropyl) azetidine -1- formate (950.00mg, 4.413mmol), DCM (4.0mL) and TFA (2.0mL, 2.693mmol) are put into a 25mL round-bottom flask. The resulting solution is stirred at room temperature for 1 hour. The resulting mixture is concentrated under vacuum to obtain product (1.4g, crude product).

[0295] Step 2: 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-hydroxypropyl)azetidin-1-yl)isoindole 1,3-Phenyline-1,3-dione

[0296]

[0297] 3-(azetidine-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) were placed in a 50 mL round-bottom flask. The resulting solution was stirred at 80 ° C for 1 hour. The reaction mixture was cooled to room temperature. The resulting solution was diluted with EtOAc. The resulting solution was extracted with H2O, 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%).

[0298] Step 3: 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine alkyl-3-yl)propyl 4-methylbenzenesulfonate

[0299]

[0300] 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), TsCl (493.00 mg, 2.586 mmol) were placed in a 25 mL round-bottom flask. The resulting solution was stirred at room temperature overnight. 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%).

[0301] Step 4: 3-(tert-butyl)-N-(4-(6-(4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-diol)- (5-(2-(2-oxoisoindolin-5-yl)azetidin-3-yl)propyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide

[0302]

[0303] 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) were placed in a 25 mL round-bottom flask. The resulting solution was stirred at 70 ° C. in an oil bath overnight. 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 under the following conditions: mobile phase, water (10 mmol / L NH4HCO3) and ACN (40% phase B to 52% in 8 minutes); detector, UV 254 nm. This gave 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=7.8Hz,2H),7. 64(d,J=8.3Hz,1H),7.48(d,J=8.3Hz,1H),7.37(d,J=8.6Hz,4H),6.77(s,1H),6. 63(d,J=5.9Hz,1H),5.07-5-05(m,1H),4.56(s,2H),4.15(t,J=7.8Hz,3H),3.68( d,J=7.5Hz,2H),2.57(d,J=16.3Hz,10H),2.04-1.37(m,18H),1.23(s,2H);[M+H] + =903.42.

[0304] 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

[0305]

[0306] The title compound was synthesized using a procedure similar to that of Example 1.1 H NMR (400 MHz, DMSO) δ H 12.68(s,1H),10.27(s,1H),9.98(d,J=8.0Hz,1H),8.80(s,1H),8.17-7.96(m,4H),7.67( d,J=8.1Hz,1H),7.38(s,3H),7.14(d,J=8.7Hz,2H),6.94(d,J=8.5Hz,2H),5.38(s,1H),3 .74-3.64(m,4H),3.05(s,2H),2.67(dd,J=14.9,8.6Hz,5H),2.54(s,3H),2.32(s,2H),2. 13(s,2H),1.66-1.86(m,7H),1.55(d,J=6.6Hz,3H),1.37(s,9H),1.18-1.28(m,2H);[M+H] + =849.5.

[0307] 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

[0308]

[0309] The title compound was synthesized using a procedure similar to that of Example 1. 1 H NMR (400 MHz, DMSO) δ H 12.68(s,1H),10.27(s,1H),9.97(d,J=7.6Hz,1H),8.80(s,1H),8.10(d,J=8.0Hz,1H),8.04(s,1H) ,7.99(d,J=7.6Hz,2H),7.67(d,J=8.0Hz,1H),7.38(s,3H),7.14(d,J=8.4Hz,2H),6.93(d,J=8.0Hz ,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, [M+H] +=849.8.

[0310] 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

[0311]

[0312] The title compound was synthesized using a procedure similar to that of Example 1. 1 H NMR (400 MHz, DMSO) δ H 12.71(s,1H),10.28(s,1H),8.83(s,1H),8.20(s,1H),7.90(d,J=6.9Hz,2H),7.47(d,J=17.7 Hz,3H),7.36(d,J=6.9Hz,2H),7.13(d,J=7.5Hz,2H),6.93(d,J=7.6Hz,2H),6.78(s,1H),6.5 1(s,1H),4.19(s,3H),3.85(s,1H),3.69(d,J=6.7Hz,4H),2.97(d,J=8.6Hz,3H),2.72-2.62( m,5H),2.17(d,J=19.8Hz,6H),1.87-2.10(m,3H),1.85-1.63(m,8H),1.15-1.25(m,9H);[M+H] + =856.5.

[0313] 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

[0314]

[0315] The title compound was synthesized using a procedure similar to that of 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=9.0Hz,1H),7.46(d,J=18.9Hz,3H), 7.13(d,J=8.5Hz,2H),6.93(d,J=7.9Hz,3H),6.69(s,1H),6.50(s,1H),4.17(d,J=8.7Hz,3H),3.85(s ,1H),3.68(d,J=6.8Hz,4H),3.58(s,4H),2.67(dd,J=13.8,9.1Hz,4H),2.56(s,2H),2.46(s,4H),2.4 1(s,2H),2.22(d,J=6.3Hz,2H),2.14(s,3H),1.82(d,J=12.3Hz,2H),1.73(s,1H),1.21(s,8H);[M+H] + =858.4.

[0316] 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

[0317] Step 1: tert-Butyl 4-(4-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl) Piperazine-1-carboxylate

[0318]

[0319] To a solution of 4-chloro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 14.4 mmol) in dioxane (35 mL) and H₂O (7 mL) was added tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (1.6 g, 4.2 mmol), K₂CO₃ (1.6 g, 12 mmol), and Pd(dppf)Cl₂.CH₂Cl₂ (0.3 g, 0.4 mmol). The mixture was stirred at 80°C for 6 hours. The mixture was concentrated, dissolved in H₂O (30 mL), and extracted with EtOAc (30 mL*2). The organic phase was concentrated and purified by flash chromatography with PE / EA (100:1 to 7:3) to give the product (1.9 g, 86.4%).

[0320] 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]pyrimidine-6- 1-[4-[(1 ...methyl)phenyl)piperazine-1-carboxylate]]

[0321]

[0322] To a solution of tert-butyl 4-(4-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate (1.9 g, 3.4 mmol) in dioxane (30 mL) and H2O (6 mL) was added 7,7-dimethyl-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one (1.4 g, 3.4 mmol), K2CO3 (1.4 g, 10.0 mmol) and Pd(dppf)Cl2.CH2Cl2 (0.3 g, 0.3 mmol). The mixture was stirred at 100° C. under N2 for 18 hours. The solvent was evaporated, H2O (30 mL) was added, and extracted with EtOAc (50 mL*2). The organic phases were combined, concentrated, and purified by flash chromatography using PE / EA (100:1 to 1:100) to give the product (1.1 g, crude).

[0323] 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

[0324]

[0325] 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 (4%, 3 mL) in MeOH. The mixture was stirred at 20-30°C for 1 hour, concentrated and slurried with H2O (30 mL). The solid was filtered and washed with H2O (30 mL). The filter cake was dried under reduced pressure. 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 hours. The solvent was evaporated and 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 directly in the next step. 1 H NMR (400 MHz, DMSO) δ H12.54(s,1H),8.77(s,1H),7.82(d,J=8.4Hz,2H),7.57-7.39(m,3H),6.99(d,J=8.4Hz,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.

[0326] Step 4: 1-(4-(4-(4-(4-(4-(3-(7,7-dimethyl-1-oxo-1,3,4,6,7,8-hexahydro-2H-cyclohexane) (pentyl[4,5]pyrrolo[1,2-a]pyrazin-2-yl)-2-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperidin-2-yl (1H,3H)-dione (methyl)piperidin-1-yl)oxazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0327]

[0328] 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 minutes, NaBH(OAc) 3 (127 mg, 0.6 mmol) was added. The mixture was stirred at 20-30° C. for 3 hours. The solvent was evaporated, H2O (30 mL) was added, and the mixture was extracted with DCM / iPrOH (10:1, 30 mL*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 H12.55(s,1H),10.27(s,1H),8.77(s,1H),7.82(d,J=8.4Hz,2H),7.51-7.36(m,3H),7.13( d,J=8.8Hz,2H),7.01(d,J=8.4Hz,2H),6.93(d,J=8.8Hz,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.

[0329] 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

[0330]

[0331] 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 hour in a round-bottom flask. 3-(tert-butyl)-N-(2-methyl-4-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (62 mg, 0.1 mmol) and DIPEA (39 mg, 0.3 mmol) were then added to the mixture, and 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 H12.69(s,1H),10.36(s,1H),9.92(s,1H),8.81(s,1H),8.10-8.05(m,2H),8 .00(d,J=7.6Hz,2H),7.50-7.35(m,6H),7.18(d,J=8.4Hz,1H),4.56(d,J=4. 8Hz,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.

[0332] 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

[0333] Step 1: 6-(4-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-methyl-3-nitro Pyridine

[0334]

[0335] 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 at 60 ° C for 1 hour under an air atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (5:1) to give the product (5.6 g, 81.74%).

[0336] Step 2: 6-(4-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-methylpyridine- 3-Amine

[0337]

[0338] 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 hours. 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%).

[0339] Step 3: 3-((6-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-methyl (3-pyridinyl)amino)propionic acid

[0340]

[0341] 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 at 90 ° C. for 12 hours under a nitrogen atmosphere. LCMS and TLC showed that most of the starting material was converted to product. After concentration, the mixture (6.1 g, 105.89%) was used directly in the next step.

[0342] Step 4: 1-(6-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-methylpyrrolidone pyrimidine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0343]

[0344] 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 at 105 ° C. for 12 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 1:3) to give the product (3 g, 47.03%).

[0345] Step 5: 1-(6-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methylpyridin-3-yl)dihydropyrimidine-2,4-(1H, 3H)-dione

[0346]

[0347] 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 at 35 ° C. under an air atmosphere overnight. The resulting mixture was extracted with CH2Cl2. The combined organic layers were washed with water and dried over anhydrous Na2SO4. 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=9Hz,1H),6.64(d,J=9Hz,1H),4.26(d,J=15Hz,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=12Hz,2H),1.61(s,1H),1.37(q,J=6Hz,2H),1.23(s,1H),1.17-1.03(m,2H);[M+H] + =333.0.

[0348] Step 6: 3-(tert-butyl)-N-(4-(6-(4-(1-(2-(1-(5-(2,4-dioxotetrahydropyrimidine-1(2H)- yl)-6-methylpyridin-2-yl)piperidin-4-yl)ethyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl (2-Methylbenzyl)-1,2,4-oxadiazole-5-carboxamide

[0349]

[0350] The title compound was synthesized using a procedure similar to that of Example 1. 1 H NMR (400 MHz, DMSO) δ H12.73(s,1H),10.32(s,1H),9.92(s,1H),9.83(s,1H),8.82(s,1H),8.07(s,2H),8.03(d,J=7.2 Hz,2H),7.48(d,J=8.4Hz,1H),7.39(s,4H),6.70(d,J=8.0Hz,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.

[0351] 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

[0352] Step 1: tert-Butyl 4-(5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)piperazine-1-carboxylate acid esters

[0353]

[0354] A mixture of 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (3 g, 10.73 mmol), tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (4.18 g, 10.73 mmol), Na2CO3 (1.25 g, 11.80 mmol) and Pd(dppf)Cl2 (0.39 g, 0.537 mmol) in dioxane (120 mL) and H2O (20 mL) was stirred in a sealed tube at 85°C overnight. After cooling, the reaction mixture was filtered and the solid was washed with 20 mL of MeOH and dried under vacuum to give the product (4.05 g, 91%). [M+H] + =415.0.

[0355] 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

[0356]

[0357] A mixture of tert-butyl 4-(5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)piperazine-1-carboxylate (0.9 g, 2.17 mmol), (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (0.94 g, 2.28 mmol), Na2CO3 (0.46 g, 4.34 mmol) and Pd(dppf)Cl2 (79.3 mg, 0.108 mmol) in dioxane (60 mL) and H2O (10 mL) 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.

[0358] Step 3: (R)-3-(tert-Butyl)-N-(1-(2-methyl-4-(6-(6-(piperazin-1-yl)pyridin-3-yl)-7H-pyridin- (2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide, hydrogen chloride salt

[0359]

[0360] To a solution of tert-butyl (R)-4-(5-(4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)piperazine-1-carboxylate (1.02 g, 1.53 mmol) in DCM (50 mL) in a round-bottom flask was added HCl in dioxane (4 N, 35 mL) at 0°C. The mixture was stirred at 20°C for 2 h. The precipitate was collected by filtration and dried under 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=7.5Hz,1H),9.33(s,2H),9.00(s,1H),8.93(s ,1H),8.35(d,J=8.7Hz,1H),8.05(d,J=8.1Hz,1H),7.99(s,1H),7.75(d, J=8.0Hz,1H),7.55(s,1H),7.12(d,J=8.9Hz,1H),5.50-5.28(m,1H),3. 89(s,4H),3.20(s,4H),2.57(s,3H),1.56(d,J=6.9Hz,3H),1.38(s,9H). [M+H] + =566.3.

[0361] Step 4: (R)-3-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidine-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

[0362]

[0363] 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, hydrogen chloride salt (0.06 g, 0.1 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (0.033 g, 0.11 mmol) and NaOAc (8.2 mg, 0.1 mmol) in DCM / EtOH (30 mL / 10 mL) was stirred in a round-bottom flask at 20° C. for 1 hour. NaBH 3 CN (12.6 mg, 0.2 mmol) was then added. The mixture was stirred at 20° C. overnight. The mixture was concentrated to dryness and purified by silica gel column chromatography (MeOH in DCM, gradient elution from 0% to 12%) to give the product (0.049 g, 57.8%). 1 HNMR (400 MHz, DMSO) δ H 12.60(s,1H),10.27(s,1H),9.97(d,J=6.1Hz,1H),8.79(d,J=18.7Hz,2H),8.18(d,J=7.8Hz,1H),8.09(d,J =7.0Hz,1H),8.04(s,1H),7.67(d,J=7.7Hz,1H),7.30(s,1H),7.13(d,J=6.9Hz,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),2.2 5-2.19(m,2H),1.84-1.81(m,2H),1.75-1.70(m,1H),1.56(t,J=9.1Hz,3H),1.37(s,9H),1.28-1.18(m,2H).

[0364] 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

[0365] Step 1: tert-Butyl (4-bromo-2-fluorophenyl) carbamate

[0366]

[0367] To a 500 mL round-bottom flask at 50° C., 4-bromo-2-fluoroaniline (20.00 g) and (Boc) O (49.80 g) in t-BuOH (250.00 mL) were added. The resulting mixture was stirred at 50° C. overnight under an air atmosphere. The aqueous layer was extracted with EtOAc. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (50:1) to give the product (20 g, 65.7%).

[0368] Step 2: tert-Butyl(4-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-fluoro phenyl) carbamate

[0369]

[0370] To a mixture of tert-butyl (4-bromo-2-fluorophenyl) carbamate (5.00 g) and 4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidine (10.00 g) in a 500 mL round-bottom flask was added Xphos (1.65 g), CsCO (16.90 g), dioxane (300.00 mL) and Pd(dba) (1.80 g) at room temperature. The resulting mixture was stirred at 100 ° C under a nitrogen atmosphere overnight. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5: 1) to give the product (8.0 g, 80.6%).

[0371] Step 3: 4-(4-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-fluoroaniline

[0372]

[0373] 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 at room temperature under an air atmosphere for 2 hours. The resulting mixture was concentrated under vacuum. The crude product was used in the next step without further purification.

[0374] Step 4: 3-((4-(4-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-fluorobenzene (amino)propionic acid

[0375]

[0376] A stirred mixture of 4-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-fluoroaniline (3.80 g) and acrylic acid (2.00 g) in toluene (100.00 mL) was degassed in vacuo and flushed with nitrogen three times, then the mixture was heated to 100° C. in an oil bath for 12 hours. This mixture was used directly in the next step.

[0377] Step 5: 1-(4-(4-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-fluorobenzene 1H,3H)dihydropyrimidine-2,4(1H,3H)-dione

[0378]

[0379] To a mixture of 3-((4-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-fluorophenyl)amino)propanoic acid (1.17 g) was added urea and AcOH (30.00 mL), and the reaction was heated at 105 ° C. under a nitrogen atmosphere for 12 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (20:1) to give the product (3 g, 65.6%).

[0380] Step 6: 1-(2-Fluoro-4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dihydropyrimidine ketone

[0381]

[0382] 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 at 35 ° C overnight. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2 / 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=9Hz,1H),6.76(m,2H),4.36(t,J=5Hz,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.

[0383] Step 7: 2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)piperidin-4-yl)acetaldehyde

[0384]

[0385] 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 completed as determined by LCMS, the mixture was extracted with EA (30 mL*3), dried over anhydrous Na2SO4, and evaporated in vacuo to give a crude product (100 mg, crude product), which was used in the next step without further purification. [M+H] + =334.1.

[0386] Step 8: 3-(tert-butyl)-N-(4-(6-(4-(1-(2-(1-(4-(2,4-dioxotetrahydropyrimidine-1(2H)- 4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methyl (Benzyl)-1,2,4-oxadiazole-5-carboxamide

[0387]

[0388] 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 at room temperature overnight. H2O (30 mL) was added to the mixture and extracted with DCM (30 mL x 2). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was further purified by preparative HPLC to give the product (22 mg, 13.9%). 1 H NMR (400 MHz, DMSO) δ H 12.69(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. 0Hz,2H),7.48(d,J=8.0Hz,1H),7.38-7.36(m,3H),7.20-7.16(m,1H),6.83-6.75(m,2H),4.56(d,J=8 .0Hz,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 [M+H] + =867.5.

[0389] 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

[0390] Step 1: tert-Butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole- 1-aminobenzoic acid ester

[0391]

[0392] A mixture of tert-butyl 4-(4-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate (1 g, 3.03 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (1.54 g, 6.06 mmol), Pd(dppf)Cl2 (0.25 g, 0.303 mmol) and KOAc (0.89 g, 9.09 mmol) in dioxane (20 mL) was stirred overnight at 90° C. in a round-bottom flask under N2. The mixture was evaporated in vacuo to give a 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.

[0393] 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

[0394]

[0395] A mixture of 4-chloro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (0.6 g, 1.43 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.01 g, 1.72 mmol), Pd(dppf)Cl2 (0.12 g, 0.14 mmol), and K2CO3 (0.393 g, 2.86 mmol) in a mixture of dioxane (20 mL) and water (4 mL) was stirred in a round-bottom flask at 80°C overnight. The mixture was evaporated in vacuo to give the crude product, which was further purified by silica gel column chromatography (PE:EA = 100:0 to 1:1 gradient elution) to give the product (0.7 g, 90%). [M+H] + =543.1.

[0396] 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

[0397]

[0398] A mixture of tert-butyl 4-(4-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.7 g, 1.29 mmol), 3-(tert-butyl)-N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (0.521 g, 1.28 mmol), Pd(dppf)Cl2 (0.105 g, 0.13 mmol) and K2CO3 (0.357 g, 2.58 mmol) in a mixture of dioxane (20 mL) and water (7 mL) was stirred in a round-bottom flask at 90°C overnight. The mixture was evaporated in vacuo to give a 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.

[0399] Step 4: 3-(tert-Butyl)-N-(2-fluoro-4-(6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[3-(2-fluoro-4-(6-1- ... [2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide

[0400]

[0401] A mixture of tert-butyl 4-(4-(4-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.12 g, 0.18 mmol) and trifluoroacetic acid (1.25 mL) in dichloromethane (5 mL) was stirred in a round-bottom flask at room temperature for 1 hour. The mixture was evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (0.052 g, 53.1%). [M+H] + =544.0.

[0402] Step 5: 3-(tert-Butyl)-N-(4-(6-(1-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzene 4-yl)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

[0403]

[0404] A mixture of 3-(tert-butyl)-N-(2-fluoro-4-(6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (0.025 g, 0.046 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (0.018 g, 0.060 mmol) in dichloromethane (2.5 mL) and MeOH (0.5 mL) was stirred in a round-bottom flask at room temperature for 1 hour. NaBH(OAc)3 (0.005 g, 0.069 mmol) was added to the mixture and stirred in a round-bottom flask at room temperature overnight. The mixture was then evaporated in vacuo to give the crude product, which was purified by 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=7.5Hz,1H),7.96(d,J=11.4Hz,1H),7.62(s,1H),7.14(d,J=8. 6Hz,3H),6.95(s,2H),4.62(d,J=5.3Hz,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.

[0405] Example 17: 3-(tert-Butyl)-N-(4-(6-(4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxaisoindolin-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

[0406] Step 1: 5-(4-(Hydroxymethyl)piperidin-1-yl)isobenzofuran-1(3H)-one

[0407]

[0408] A solution of 5-fluoroisobenzofuran-1(3H)-one (5.0 g, 33 mmol), piperidin-4-ylmethanol (5.0 g, 43 mmol) and DIPEA (10.0 g, 78 mmol) in DMSO (60 mL) was heated at 130° C. for 3 hours. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to give a crude product, which was further purified by silica gel column chromatography to give the product (7.0 g, 85%). [M+H] + =248.0.

[0409] Step 2: 5-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)piperidin-1-yl)isobenzofuran-1(3H)- ketone

[0410]

[0411] A solution of 5-(4-(hydroxymethyl)piperidin-1-yl)isobenzofuran-1(3H)-one (6.0 g, 24 mmol), pyridinium toluene-4-sulfonate (700 mg, 2.8 mmol) and 3,4-dihydro-2H-pyran (6.5 g, 77 mmol) in DCM (150 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated in vacuo to give a crude product, which was further purified by silica gel column chromatography to give the product (7.1 g, 87%). [M+H] + =332.3.

[0412] Step 3: 2-(Hydroxymethyl)-4-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)piperidin-1-yl)benzene acid

[0413]

[0414] A solution of 5-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)piperidin-1-yl)isobenzofuran-1(3H)-one (7.1 g, 21 mmol) and NaOH (2.5 g, 62.5 mmol) in MeOH (100 mL) / H2O (100 mL) / THF (100 mL) was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the pH value of the residue was adjusted to 6 with 1N HCl. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated in vacuo to give a crude product (6.6 g). [M+H] + =350.4.

[0415] Step 4: 2-(((tert-Butyldimethylsilyl)oxy)methyl)-4-(4-(((tetrahydro-2H-pyran-2-yl) (1-Oxy)methyl)piperidin-1-yl)benzoic acid

[0416]

[0417] A mixture of 2-(hydroxymethyl)-4-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)piperidin-1-yl)benzoic acid (6.6 g, 19 mmol), TBSCl (5.0 g, 33 mmol) and imidazole (5.0 g, 74 mmol) in DCM (200 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated in vacuo to give the crude product, which was further purified by silica gel column chromatography to give the product (8.0 g, 89%). [M+H] + =464.5.

[0418] 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

[0419]

[0420] A solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)piperidin-1-yl)benzoic acid (8.0 g, 17 mmol), HATU (7.6 g, 20 mmol), 3-aminopiperidine-2,6-dione hydrochloride (3.7 g, 22 mmol) and DIPEA (14 mL, 80 mmol) in DMF (100 mL) was stirred at room temperature for 16 hours. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to give the crude product, which was further purified by silica gel column chromatography to give the product (5.6 g, 57%). [M+H] + =574.4.

[0421] Step 6: N-(2,6-dioxopiperidin-3-yl)-2-(hydroxymethyl)-4-(4-((tetrahydro-2H-pyran-2-yl) (2-(2-(2-oxy)methyl)piperidin-1-yl)benzamide

[0422]

[0423] A solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,6-dioxopiperidin-3-yl)-4-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)piperidin-1-yl)benzamide (5.6 g, 9.8 mmol) and TBAF (1 M in THF, 2.5 mmol) in THF (100 mL) was stirred at room temperature for 2 hours. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to give a crude product, which was further purified by silica gel column chromatography to give the product (2.5 g, 55%). [M+H] + =460.4.

[0424] Step 7: 3-(1-oxo-5-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)piperidin-1-yl)isoindole (2-Methyl-1-piperidin-2,6-dione)piperidin-2,6-dione

[0425]

[0426] A solution of N-(2,6-dioxopiperidin-3-yl)-2-(hydroxymethyl)-4-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)piperidin-1-yl)benzamide (2.5 g, 5.4 mmol), TsCl (1.5 g, 7.9 mmol) and Et3N (6 mL, 43 mmol) in DCM (100 mL) was stirred at 40 ° C for 16 hours. The reaction was quenched with water and extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to give the crude product, which was further purified by silica gel column chromatography to give the product (1.9 g, 80%). [M+H] + =442.2.

[0427] Step 8: 3-(5-(4-(Hydroxymethyl)piperidin-1-yl)-1-oxaisoindolin-2-yl)piperidine-2,6-dione

[0428]

[0429] A solution of 3-(1-oxo-5-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (1.8 g, 4.1 mmol) in HCl / dioxane (4N, 5 mL) / DCM (100 mL) / MeOH (100 mL) was stirred at room temperature for 1 hour. The mixture was evaporated in vacuo to give the crude product (1.7 g). [M+H] + =358.3.

[0430] Step 9: 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxaisoindolin-5-yl)piperidine-4-carbaldehyde

[0431]

[0432] 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 hour. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to give a crude product (180 mg). [M+H] + =356.2.

[0433] Step 10: 3-(tert-Butyl)-N-(4-(6-(4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxaiso (indolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methyl (Benzyl)-1,2,4-oxadiazole-5-carboxamide

[0434]

[0435] A mixture of 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxaisoindolin-5-yl)piperidine-4-carbaldehyde (180 mg, 0.51 mmol), 3-(tert-butyl)-N-(2-methyl-4-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (50 mg, 0.091 mmol) and NaBH(OAc) (100 mg, 0.47 mmol) in dichloroethane (10 mL) was stirred at room temperature for 16 hours. The mixture was then evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography to give the product (15 mg, 10%). 1 H NMR (400 MHz, DMSO) δ H 12.69(s,1H),10.71(s,1H),9.92(s,1H),8.81(s,1H),8.07(s,2H),8.00(d, J=7.5Hz,2H),7.55-7.44(m,2H),7.38(s,3H),7.06(d,J=8.5Hz,1H),7.00(s, 1H),5.31(s,2H),4.57(s,3H),3.90(d,J=11.1Hz,2H),2.85(t,J=11.7Hz,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.

[0436] 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

[0437] Step 1: tert-Butyl 4-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate

[0438]

[0439] 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 (4%, 3 mL) in MeOH. The mixture was stirred at 20-30°C for 1 hour. The solvent was evaporated and H2O (20 mL) was added. The mixture was filtered and washed with H2O. The filter cake was dried under reduced pressure and used directly in the next step.

[0440] 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

[0441]

[0442] To a solution of tert-butyl 4-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate (120 mg, 0.3 mmol) in dioxane (15 mL) and H₂O (3 mL) was added 3-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (120 mg, 0.3 mmol), K₂CO₃ (124 mg, 0.9 mmol), and Pd(dppf)Cl₂.CH₂Cl₂ (22 mg, 0.03 mmol). The mixture was stirred at 90° C. under N₂ for 5 h. The solvent was evaporated, H₂O (20 mL) was added, and the mixture was 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).

[0443] Step 3: 3-(tert-Butyl)-N-(2-methyl-4-(6-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d] (4-pyrimidinyl)benzyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride

[0444]

[0445] 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 hours, concentrated to 5 mL, and filtered. The filter cake was washed to give the crude product, which was used directly in the next step. 1 H NMR (400 MHz, DMSO) δ H13.53(s,1H),9.99(s,1H),9.38(s,2H),9.00(s,1H),8.04-8.02(m,4H),7.57(d,J=8.4Hz,1H),7.48(s,1H ),7.14(d,J=8.4Hz,2H),4.59(d,J=5.2Hz,2H),3.54(s,4H),3.22(s,4H),2.50(s,3H),1.38(s,9H);[M+H] + =551.3.

[0446] Step 4: 3-(tert-Butyl)-N-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzene 1-YL)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2, 4-Oxadiazole-5-carboxamide

[0447]

[0448] 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 minutes, NaBH(OAc) 3 (102 mg, 0.48 mmol) was added. The mixture was stirred at 20-30° C. for 5 hours. The solvent was evaporated, H2O (30 mL) was added, and the mixture was extracted with DCM / iPrOH (20:1, 30 mL*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 H12.53(s,1H),10.27(s,1H),9.91(br,1H),8.75(s,1H),8.06(s,2H),7.91(d,J=8.4Hz, 2H),7.47(d,J=8.0Hz,1H),7.22(s,1H),7.13(d,J=8.4Hz,2H),7.04(d,J=8.0Hz,2H),6 .93(d,J=8.4Hz,2H),4.56(d,J=5.6Hz,2H),3.77-3.60(m,4H),3.26(s,4H),2.70-2.64 (m,4H),2.23(d,J=6.0Hz,2H),1.89-1.64(m,3H),1.37(s,9H),1.29-1.17(m,3H);[M+H] + =836.5.

[0449] 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

[0450] Step 1: tert-Butyl 4-(6-(trimethylstannyl)pyridin-3-yl)piperazine-1-carboxylate

[0451]

[0452] A mixture of tert-butyl 4-(6-bromopyridin-3-yl)piperazine-1-carboxylate (1.71 g, 5 mmol), 1,1,1,2,2,2-hexamethyldistannoyl (1.8 g, 5.5 mmol), and Pd(PPh3)4 (0.289 g, 0.25 mmol) in dioxane (50 mL) was stirred at 100 ° C. for 6 hours in a sealed tube. LCMS showed that the starting material was completely converted to the target product. The resulting mixture was used directly in the next step. [M+H] + =428.1.

[0453] Step 2: tert-Butyl 4-(6-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[3-( ... [2,3-d]pyrimidin-6-yl)pyridin-3-yl)piperazine-1-carboxylate

[0454]

[0455] To the mixture of tert-butyl 4-(6-(trimethylstannyl)pyridin-3-yl)piperazine-1-carboxylate in dioxane from the previous step was added a solution of 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (2.05 g, 5 mmol) and Pd(PPh3)2Cl2 (0.178 g, 0.25 mmol) in 30 mL of dioxane. The resulting mixture was stirred at 100 ° C. for 24 hours in a sealed tube. After cooling, the solvent was removed under reduced pressure and the base residue was purified by silica gel chromatography (EtOAc in DCM, gradient elution from 0% to 60%) to give the product (0.31 g, 11.4%). [M+H] + =545.3.

[0456] 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]pyrimidine-6- 1-[4-[(1-[(2-[(2-[(2-( ...

[0457]

[0458] A mixture of 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), Na2CO3 (90 mg, 0.853 mmol) and Pd(dppf)Cl2 (20.8 mg, 0.028 mmol) in dioxane (50 mL) and H2O (10 mL) was stirred in a sealed tube at 100°C overnight. After cooling, the reaction was quenched with water and the mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to give a crude product, which was further purified by silica gel column chromatography (gradient elution of EtOAc in DCM from 0% to 60%) to give the product (0.28 g, 61.9%). [M+H] + =796.0.

[0459] Step 4: (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(5-(piperazin-1-yl)pyridin-2-yl)-7H-pyridin- (2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide, hydrochloride

[0460]

[0461] 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 hours. The solvent was removed in vacuo. 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=7.7Hz,1H),8.80(s,1H),8.44(s,1H),8.09(dd, J=16.1,8.6Hz,2H),8.02(s,1H),7.68(d,J=7.9Hz,1H),7.54(d,J=9.2Hz, 1H),7.45(d,J=9.2Hz,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=6.8Hz,3H),1.37(s,9H);[M+H] + =566.3.

[0462] Step 5: (R)-3-(tert-butyl)-N-(1-(4-(6-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidine-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

[0463]

[0464] A mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(5-(piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide, hydrochloride (0.06 g, 0.094 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (0.033 g, 0.1 mmol) and NaOAc (16.4 mg, 0.2 mmol) in DCM / EtOH (50 mL / 10 mL) was stirred in a round-bottom flask at 20° C. for 1 hour. NaBH 3 CN (12.6 mg, 0.2 mmol) was then added. The mixture was stirred at 20° C. for 8 hours. The mixture was concentrated to dryness and purified by silica gel column chromatography (gradient elution with MeOH in DCM from 0% to 10%) 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=7.3Hz,1H),8.78(s,1H),8.39(s,1H),8.10-8.12(m,3H),7.68(d ,J=8.0Hz,1H),7.46(d,J=9.2Hz,1H),7.40(s,1H),7.13(d,J=8.2Hz,2H),6.93(d,J=8.1Hz,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=5.9Hz [M+H] + =851.5.

[0465] 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

[0466] Step 1: tert-Butyl 4-(4-(4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl) Piperazine-1-carboxylate

[0467]

[0468] To a solution of 4-chloro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 14.4 mmol) in dioxane (35 mL) and H₂O (7 mL) was added tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (1.6 g, 4.2 mmol), K₂CO₃ (1.6 g, 12 mmol), and Pd(dppf)Cl₂.CH₂Cl₂ (0.3 g, 0.4 mmol). The mixture was stirred at 80°C for 6 hours and concentrated to dryness. Water (30 mL) was added to the residue, and the mixture was 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%).

[0469] Step 2: tert-Butyl 4-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate

[0470]

[0471] 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 (4%, 5 mL) in MeOH. After stirring at 20-30°C for 1 hour, the solvent was evaporated and H2O (20 mL) was added. The mixture was filtered and the filter cake was washed with H2O. After drying under reduced pressure, the product (3 g, crude) was isolated and used directly in the next step.

[0472] Step 3: tert-butyl (R)-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

[0473]

[0474] To a solution of tert-butyl 4-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate (413 mg, 1 mmol) in dioxane / HO (5:1, 45 mL) was added (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (413 mg, 1.0 mmol), KCO (414 mg, 3.0 mmol), and Pd(dppf)Cl.CHCl (82 mg, 0.1 mmol). The mixture was stirred at 100° C. under N for 6 hours. After evaporation of the solvent, water (20 mL) was added. The mixture was extracted with DCM (30 mL*2). The organic phases were combined, concentrated, and purified by preparative TLC with DCM / MeOH (100:1 to 20:1) to give the product (600 mg, 90.2%).

[0475] Step 4: (R)-3-(tert-Butyl)-N-(1-(2-methyl-4-(6-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[1-yl]-4- ...piperazin-1-yl]phenyl)-7H-pyrrolo[1-yl]-4-[1-yl]-piperazin-1-yl]phenyl]-7H-pyrrolo [2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride

[0476]

[0477] To a solution of tert-butyl (R)-4-(4-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate (1.1 g, 1.6 mmol) in dioxane (3 mL) was added HCl / dioxane (4N, 30 mL). After stirring at 20-30°C for 3 hours, the mixture was concentrated to 10 mL. The solid was isolated by filtration and washed with dioxane (10 mL). After drying under reduced pressure, the product was isolated (1 g, 100%). 1 H NMR (400 MHz, DMSO) δ H 13.43(s,1H),10.06(d,J=7.2Hz,1H),9.34(s,2H),8.98(s,1H),8.19-7.92(m,4H),7.75(d,J=8.4Hz,1H),7.48(s,1H),7.1 [M+H] + =565.3.

[0478] Step 5: (R)-3-(tert-butyl)-N-(1-(4-(6-(4-(4-(1-(4-(2,4-dioxotetrahydropyrimidine-1 (2H)-(phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methyl (phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0479]

[0480] 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 minutes, NaBH(OAc) 3 (0.85 g, 4.0 mmol) was added. The mixture was stirred at 20-30° C. for another 2 hours. The solvent was evaporated and purified directly by silica gel chromatography with DCM / MeOH (100:1 to 20:1) to give the product (400 mg, 35.4%). 1 H NMR (400 MHz, DMSO) δ H 12.52(s,1H),10.27(s,1H),9.97(d,J=7.6Hz,1H),8.75(s,1H),8.09(d,J=8.4Hz,1H),8.03(s,1H), 7.91(d,J=8.4Hz,2H),7.66(d,J=8.0Hz,1H),7.23(s,1H),7.13(d,J=8.4Hz,2H),7.03(d,J=8.4Hz,2H ),6.93(d,J=8.8Hz,2H),5.38(br,1H),3.69(t,J=6.8Hz,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=7.2Hz,3H),1.37(s,9H),1.24(br,3H);[M+H] + =850.4.

[0481] 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

[0482]

[0483] The title compound was synthesized using a procedure similar to Example 19. 1 H NMR (400 MHz, DMSO) δ H 12.61(s,1H),10.27(s,1H),10.03(d,J=7.2Hz,1H),8.78(s,1H),8.13(d,J=8.0Hz,1H),8.00(d,J=12.0 Hz,1H),7.93(d,J=7.2Hz,2H),7.71(t,J=8.0Hz,1H),7.30(s,1H),7.13(d,J=8.8Hz,2H),7.04(d,J=7.6H z,2H),6.93(d,J=8.0Hz,2H),5.58-5.38(m,1H),3.71-3.66(m,4H),3.26(s,4H),2.72-2.65(m,5H),2.6 0-2.50(m,2H),2.22(br,2H),1.87-1.69(m,3H),1.59(d,J=6.8Hz,3H),1.38(s,9H),1.24(br,3H);[M+H] + =854.4.

[0484] 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

[0485] Step 1: 4-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)piperidine

[0486]

[0487] Into a 1000 mL round-bottom flask was placed 4-piperidineethanol (20.00 g, 154.795 mmol), DMF (300.00 mL), tert-butyl(chloro)diphenylsilane (85.10 g, 309.612 mmol), and imidazole (26.35 g, 386.988 mmol). The resulting solution was stirred at room temperature for 1 hour. The resulting solution was diluted with H2O. The resulting solution was extracted with ethyl acetate, 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 obtain the product (22 g, 38.66%).

[0488] Step 2: 4-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)-1-(3-methyl-4-nitrophenyl)piperidin pyridine

[0489]

[0490] Into a 100 mL round-bottom flask was placed 4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidine (5.00 g, 13.601 mmol), DMSO (50.00 mL), 4-fluoro-2-methyl-1-nitrobenzene (2.11 g, 13.601 mmol), and DIEA (6.80 mL, 39.040 mmol). The resulting solution was stirred at 60 ° C for 1 hour. The reaction mixture was cooled to room temperature. The resulting solution was diluted with H2O. 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%).

[0491] Step 3: 4-(4-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-methylaniline

[0492]

[0493] Into a 100 mL round-bottom flask was placed 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). H2(g) was introduced into the above mixture. 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 product).

[0494] Step 4: 3-((4-(4-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-methyl Phenyl)amino)propionic acid

[0495]

[0496] Into a 100 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 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 at 100° C. overnight. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under vacuum to obtain the product (2.85 g, 74.19%).

[0497] Step 5: 1-(4-(4-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-methylbenzene 1H,3H)dihydropyrimidine-2,4(1H,3H)-dione

[0498]

[0499] In a 100 mL round-bottom flask was placed 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 at 105 ° C overnight. 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%).

[0500] Step 6: 1-(4-(4-(2-hydroxyethyl)piperidin-1-yl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)- diketone

[0501]

[0502] Into a 50 mL round-bottom flask was placed 1-(4-(4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-1-yl)-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione (1.37 g, 2.404 mmol), DMF (10.00 mL), and CsF (1.82 g, 11.981 mmol). The resulting solution was stirred at 40 ° C for 2 hours. The resulting solution was diluted with H2O. 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=8.5Hz,1H),6.83-6.70(m,2H),4.35(t,J=5.0Hz,1H),3.73-3.58(m,3H),3.52-3.38(m,3H),2.80-2. [M+H] + =332.19.

[0503] Step 7: 2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)acetaldehyde

[0504]

[0505] 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 at room temperature overnight in a round-bottom flask. After the reaction was completed as determined by LCMS, the mixture was extracted with EtOAc (30 mL*3), dried over anhydrous Na2SO4, and evaporated in vacuo to give a crude product (100 mg, crude product), which was used in the next step without further purification. [M+H] + =330.1.

[0506] Step 8: 3-(tert-butyl)-N-(4-(6-(4-(1-(2-(1-(4-(2,4-dioxotetrahydropyrimidine-1(2H)- (phenyl)-3-methylphenyl)piperidin-4-yl)ethyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methyl (Benzyl)-1,2,4-oxadiazole-5-carboxamide

[0507]

[0508] 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 at room temperature overnight. H2O (30 mL) was added to the mixture and extracted with DCM (30 mL x 2). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was further purified by preparative HPLC to give the product (32 mg, 20.4%). 1 H NMR (400 MHz, DMSO) δ H12.68(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. 0Hz,2H),7.48(d,J=8.0Hz,1H),7.38-7.37(m,3H),7.40(d,J=8.0Hz,1H),6.81-6.76(m,2H),4.56(d ,J=8.0Hz,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, [M+H] + =863.5.

[0509] 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

[0510]

[0511] The title compound was synthesized using a procedure similar to Example 22. 1 H NMR (400 MHz, DMSO) δ H 12.79(s,1H),10.29(s,1H),10.02(s,1H),8.87-8.16(m,1H),8.25-8.03(m,5H ),7.64(s,1H),7.46-7.41(m,3H),7.18-7.14(m,2H),6.98-6.93(m,2H),4.65(s ,2H),3.73-3.71(m,4H),3.03-3.01(m,2H),2.69-2.60(m,6H),2.25-2.22(m,2 H),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.

[0512] 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

[0513] Step 1: 2-(1-(3-chloro-4-nitrophenyl)piperidin-4-yl)ethan-1-ol

[0514]

[0515] To a solution of 2-chloro-4-fluoro-1-nitrobenzene (141.0 g, 0.8 mol) and K CO (278 g, 2.01 mol) in DMF (300 mL) was added 2-(piperidin-4-yl) ethanol-1-ol (147 g, 0.89 mol). The resulting mixture was then stirred at 25 ° C for 5 hours. TLC (petroleum ether / ethyl acetate = 10 / 1) showed that the starting material was completely consumed. The mixture was poured into H O (300 mL). The aqueous phase was extracted with ethyl acetate (300 mL). The organic layer was dried over anhydrous Na SO , filtered and concentrated in vacuo to give the product (255 g, crude product).

[0516] Step 2: 4-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1-(3-chloro-4-nitrophenyl)piperidine

[0517]

[0518] 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 hours. TLC (petroleum ether / ethyl acetate=10 / 1) showed that the starting material had been completely consumed. The mixture was poured into H2O (765 mL). The aqueous phase was extracted with dichloromethane (765 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the product (320 g, 89.5%).

[0519] Step 3: 4-(4-(2-((tert-Butyldimethylsilyl)oxy)ethyl)piperidin-1-yl)-2-chloroaniline

[0520]

[0521] 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 hours. TLC (petroleum ether / ethyl acetate=2 / 1) showed that the starting material was completely consumed. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO , petroleum ether:ethyl acetate=50:1 to 10:1) to give the product (138.0 g, 46.6%).

[0522] Step 4: 3-((4-(4-(2-((tert-Butyldimethylsilyl)oxy)ethyl)piperidin-1-yl)-2-chlorobenzene (amino)propionic acid

[0523]

[0524] To a solution of 4-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-1-yl)-2-chloroaniline (80.0 g, 0.217 mol) in toluene (400 mL) was added acrylic acid (80 mL), and the mixture was stirred at 110° C. under N 2 for 5 hours. TLC (dichloromethane:methanol=10:1) showed complete consumption of the starting material. The mixture was concentrated under reduced pressure to provide the product (120.0 g, crude).

[0525] Step 5: 2-(1-(3-chloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)ethyl acid esters

[0526]

[0527] To a solution of 3-((4-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-1-yl)-2-chlorophenyl)amino)propanoic acid (120.0 g, 0.272 mol) in HOAc (600 mL) was added urea (32.7 g, 0.544 mol) at 25 ° C. The resulting mixture was then stirred at 120 ° C for 12 hours. TLC (dichloromethane: methanol = 10: 1) showed that the starting material was completely consumed. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO 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=8.80Hz,1H),7.04(d,J=2.80Hz,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=0.80Hz,2H),1.62-1.60(m,3H),1.35-1.33(m,2H);[M+H] + =394.1.

[0528] Step 6: 1-(2-chloro-4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dihydropyrimidine ketone

[0529]

[0530] To a solution of 2-(1-(3-chloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)ethyl acetate (40.0 g, 0.102 mol) in MeOH (120 mL) / THF (120 mL) was added KCO (42.1 g, 0.305 mol) at 25°C. The resulting mixture was then stirred at 25°C for 2 hours. TLC (dichloromethane:methanol=10:1) showed that the starting material was completely consumed. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate=10:1 to 0:1) to give the product (30.0 g, 83.9%). 1 H NMR (400 MHz, DMSO) δ H 10.4(s,1H),7.22(d,J=8.80Hz,1H),7.00(d,J=2.40Hz,1H),6.92(t,J=4.40Hz,1H),4.37(s,1H),3.73(d,J=12.8 [M+H] + =352.1.

[0531] Step 7: 2-(1-(3-chloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)acetaldehyde

[0532]

[0533] 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) and IBX (1.79 g, 6.39 mmol) was added and the reaction was stirred at 25 ° C overnight until LC-MS showed that all the starting material was consumed. EtOAc (30 mL) and water (30 mL) were added to quench the reaction. The mixture was filtered to give the product (1 g, 70%), which was used directly without further purification. [M+H] + =350.2.

[0534] Step 8: 3-(tert-butyl)-N-(4-(6-(4-(1-(2-(1-(3-chloro-4-(2,4-dioxotetrahydropyrimidine-1 (2H)-(2H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)piperidin-4-yl)ethyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methyl (Benzyl)-1,2,4-oxadiazole-5-carboxamide

[0535]

[0536] To a solution of compound 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 PRE-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=7.2Hz,1H),7.40-7.37(m,3H),7.25(d,J=9.2Hz,1H),7.05(s,1H),6.96-6.9 4(m,1H),4.57(s,2H),3.79(d,J=10.7Hz,2H),3.68-3.48(m,4H),3.21-2.81(m,5 H),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.

[0537] 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

[0538] Step 1: tert-Butyl 4-(4-(6-chloro-9H-purin-8-yl)phenyl)piperazine-1-carboxylate

[0539]

[0540] A mixture of 6-chloropyrimidine-4,5-diamine (1 g, 6.9 mmol), tert-butyl 4-(4-formylphenyl)piperazine-1-carboxylate (2 g, 6.9 mmol) and CoCl2 (0.089 g, 0.69 mmol) in DMF (50 mL) was stirred at 85 ° C under an O2 atmosphere overnight. 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.

[0541] 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

[0542]

[0543] A mixture of tert-butyl 4-(4-(6-chloro-9H-purin-8-yl)phenyl)piperazine-1-carboxylate (0.415 g, 1 mmol), (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (0.413 g, 1 mmol), Na2CO3 (0.212 g, 2 mmol) and Pd(dppf)Cl2 (36.5 mg, 0.05 mmol) in dioxane (50 mL) and H2O (8 mL) was stirred in a sealed tube at 100°C for 48 hours. After cooling, the solvent was removed and the residue was purified by silica gel column (EtOAc in DCM, 0% to 100%) to give the product (0.48 g, 72.2%). [M+H] + =666.0.

[0544] Step 3: (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(8-(4-(piperazin-1-yl)phenyl)-9H-purine-6-yl)- (4-(2-(4-(2-methyl-1-phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide) hydrochloride

[0545]

[0546] To a solution of tert-butyl (R)-4-(4-(6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-9H-purin-8-yl)phenyl)piperazine-1-carboxylate (0.2 g, 0.3 mmol) in EtOAc (10 mL) was added HCl in dioxane (4 N, 20 mL) at 0°C. The mixture was stirred at 20°C for 4 hours. The precipitate was collected by filtration and dried under vacuum to give the product (0.14 g, 77.8%).

[0547] Step 4: (R)-3-(tert-butyl)-N-(1-(4-(8-(4-(4-(1-(4-(2,4-dioxotetrahydropyrimidine-1 (2H)-phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-9H-purin-6-yl)-2-methylphenyl)ethyl)-1, 2,4-Oxadiazole-5-carboxamide

[0548]

[0549] A mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(8-(4-(piperazin-1-yl)phenyl)-9H-purin-6-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride (0.14 g, 0.232 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (0.07 g, 0.232 mmol) and NaOAc (38 mg, 0.465 mmol) in DCM / EtOH (100 mL / 50 mL) was stirred in a round-bottom flask at 20° C. for 1 hour. NaBH 3 CN (29 mg, 0.465 mmol) was then added. The mixture was stirred at 20° C. overnight. The mixture was concentrated to dryness and purified by silica gel column chromatography (gradient elution with 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=18.7Hz,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),1.8 4(s,2H),1.75(s,1H),1.57(s,3H),1.39(d,J=5.3Hz,9H),1.26(s,2H);[M+H] + =851.5.

[0550] 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

[0551]

[0552] The title compound was synthesized using a procedure similar 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),3.7 5(d,J=11.5Hz,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.

[0553] 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

[0554] Step 1: tert-Butyl 4-((4-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrole (2,3-d]pyrimidin-6-yl)phenoxy)piperidin-1-yl)methyl)piperidine-1-carboxylate

[0555]

[0556] A mixture of 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (409 mg, 1.0 mmol), tert-butyl 4-((4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidin-1-yl)methyl)piperidine-1-carboxylate (550 mg, 1.1 mmol), Pd(dppf)Cl2 (73 mg, 0.1 mmol) and K2CO3 (276 mg, 2.0 mmol) in dioxane (10 mL) and water (3 mL) was stirred in a round-bottom flask at 80°C overnight. The mixture was used in the next step without further purification. [M+H] + =656.6.

[0557] Step 2: tert-Butyl 4-((4-(4-(4-(4-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)carboxamido) 1-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3-methylphenyl phenoxy)piperidin-1-yl)methyl)piperidine-1-carboxylate

[0558]

[0559] To the solution of the mixture from the last 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)Cl2 (73 mg, 0.1 mmol) and Cs2CO3 (650 mg, 2.0 mmol). The mixture was reacted in a round-bottom flask at 110°C and stirred overnight. The mixture was then evaporated in vacuo to give a 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% over two steps). [M+H] + =893.5.

[0560] Step 3: 3-(tert-Butyl)-N-(4-(7-(hydroxymethyl)-6-(4-((1-(piperidin-4-ylmethyl)piperidin-4-ylmethyl)piperidin-4-yl)- (4-(2-Methylbenzyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide

[0561]

[0562] 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) and trifluoroacetic acid (3 mL) in dichloromethane (3 mL) was stirred in a round-bottom flask at room temperature overnight. The mixture was then evaporated in vacuo to give the crude product (516 mg, crude product) which was used in the next step without further purification. [M+H] + =693.6.

[0563] 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

[0564]

[0565] A mixture of 3-(tert-butyl)-N-(4-(7-(hydroxymethyl)-6-(4-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide (516 mg, 0.55 mmol) and ammonium hydroxide (2 mL) in methanol (10 mL) was stirred at room temperature overnight in a round-bottom flask. The mixture was then evaporated in vacuo to give a 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.

[0566] Step 5: 3-(tert-Butyl)-N-(4-(6-(4-((1-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)- 4-(4-methoxybenzoyl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl (2-Methylbenzyl)-1,2,4-oxadiazole-5-carboxamide

[0567]

[0568] 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 hour in a round-bottom flask. 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 (0.1% FA in water:acetonitrile = 60:40 to 20:80 gradient elution) 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=8.0Hz,2 H),7.48(d,J=8.0Hz,1H),7.38(d,J=7.6Hz,1H),7.31(d,J=13.8Hz,2H),7.16(d,J=8.4Hz,1H),7.10( d,J=8.4Hz,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.

[0569] 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

[0570] Step 1: tert-Butyl 4-(4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropan-2-yl)benzamido)-2-methyl phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperidin- 1-formate

[0571]

[0572] 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)Cl2 (73 mg, 0.1 mmol) and Cs2CO3 (850 mg, 2.6 mmol). The mixture reaction was stirred in a round-bottom flask at 110°C overnight. The mixture was then evaporated in vacuo to give a 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.

[0573] Step 2: 2-Fluoro-N-(5-fluoro-2-methyl-3-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine 4-(2-hydroxypropyl)benzamide and 2-fluoro-N-(5-fluoro-2-methyl-3-(6-(4-piperidin-4- 1-(4-(1-en-2-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-4-(prop-1-en-2-yl)benzamide

[0574]

[0575] A mixture of tert-butyl 4-(4-(4-(5-fluoro-3-(2-fluoro-4-(2-hydroxypropyl-2-yl)benzamido)-2-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperidine-1-carboxylate (570 mg, 0.70 mmol) and trifluoroacetic acid (3 mL) in dichloromethane (6 mL) was stirred in a round-bottom flask at room temperature overnight. The mixture was then evaporated in vacuo to give a crude product. A mixture of the crude product and ammonium hydroxide (2 mL) in methanol (10 mL) was stirred in a round-bottom flask at room temperature overnight. The mixture was then evaporated in vacuo to give a 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.

[0576] Step 3: N-(3-(6-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)- 1-(4-(4-(2-(4-(2-(4-(2-piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4- (2-Hydroxyprop-2-yl)benzamide

[0577]

[0578] A mixture of 2-fluoro-N-(5-fluoro-2-methyl-3-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-4-(2-hydroxypropan-2-yl)benzamide (86 mg, 0.14 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (60 mg, 0.20 mmol) in dichloroethane (20 mL) was stirred in a round-bottom flask at room temperature for 1 hour. NaBH(OAc) (212 mg, 1.0 mmol) was then added to the mixture and stirred in a round-bottom flask at room temperature overnight. The mixture was evaporated in vacuo to give a crude product, which was purified by C18 column chromatography (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 H 12.74(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=8.0Hz,2H),6.93(d,J=8.0Hz,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.

[0579] 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

[0580]

[0581] A mixture of 2-fluoro-N-(5-fluoro-2-methyl-3-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-4-(prop-1-en-2-yl)benzamide (10 mg, 0.17 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (60 mg, 0.20 mmol) in dichloroethane (10 mL) was stirred in a round-bottom flask at room temperature for 1 hour. NaBH(OAc) (212 mg, 1.0 mmol) was then added to the mixture and stirred in a round-bottom flask at room temperature overnight. The mixture was evaporated in vacuo to give a crude product, which was purified by C18 column chromatography (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=7.6Hz,2H),7.84-7.75(m,1H),7.7 1-7.62(m,1H),7.56-7.48(m,2H),7.37(d,J=7.6Hz,2H),7.26(d,J=8.4Hz,1H),7.14(d,J=8.8Hz,2H) ,6.94(d,J=8.4Hz,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.

[0582] 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

[0583]

[0584] The title compound was synthesized using a procedure similar to Example 24. 1H NMR (400 MHz, DMSO) δ H 12.54(s,1H),10.28(s,1H),9.53(s,1H),8.77(s,1H),8.08(s,2H),7.93(d,J=8.4Hz,2H) ,7.46(d,J=8.4Hz,1H),7.24(s,1H),7.15(d,J=8.8Hz,2H),7.06(d,J=8.8Hz,2H),6.95(d ,J=8.4Hz,2H),4.57(d,J=5.2Hz,2H),3.66(t,J=6.4Hz,4H),3.28(s,4H),2.71-2.65(m,5 H),2.55-2.45(m,5H),2.26(br,2H),1.84-1.70(m,3H),1.46(s,9H),1.25(br,3H);[M+H] + =836.5.

[0585] 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

[0586]

[0587] The title compound was synthesized using a procedure similar to Example 24. 1 H NMR (400 MHz, DMSO) δ H 12.62(s,1H),10.28(s,1H),9.64(d,J=8.0Hz,1H),8.78(s,1H),8.14(d,J=8.0Hz,1H),8.00(d,J=12 .0Hz,1H),7.95(d,J=7.6Hz,2H),7.70(t,J=7.6Hz,1H),7.32(s,1H),7.14(d,J=8.8Hz,2H),7.05(d,J =7.6Hz,2H),6.94(d,J=8.8Hz,2H),5.47(t,J=7.6Hz,1H),3.69(t,J=6.8Hz,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=6.4Hz,3H),1.44(s,9H),1.24(br,3H);[M+H] + =854.9.

[0588] 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

[0589]

[0590] The title compound was synthesized using a procedure similar to Example 24. 1 H NMR (400 MHz, DMSO) δ H 12.62(s,1H),10.28(s,1H),10.01-9.98(m,1H),8.79(s,1H),8.14-8.13(m,1H),8.04-8.0 1(m,1H),7.94(d,J=8.0Hz,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=8.0Hz,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.

[0591] 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

[0592]

[0593] The title compound was synthesized using a procedure similar 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),6.95-6.9 1(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.

[0594] 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

[0595]

[0596] The title compound was synthesized using a procedure similar to Example 24. 1 H NMR (400 MHz, DMSO) δ H 12.65(s,1H),10.24(s,1H),9.59(d,J=8.0Hz,1H),8.79-8.76(m,2H),8.18(d,J=8.0Hz,1H),8. 10(d,J=8.0Hz,1H),7.97(d,J=8.0Hz,1H),7.68-7.65(m,1H),7.33(s,1H),7.10(d,J=8.0Hz,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=8.0Hz,3H),1.41(s,9H),1.22-1.19(m,3H);[M+H] + =855.5.

[0597] 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

[0598]

[0599] The title compound was synthesized using a procedure similar to Example 24. 1 H NMR (400 MHz, DMSO) δ H 12.49(s,1H),10.24(s,1H),8.72(s,1H),8.50(br,1H),8.33(s,1H),8.03(s,2H),7.94-7 .85(m,3H),7.41(d,J=7.6Hz,1H),7.19(s,1H),7.11(d,J=8.8Hz,2H),7.01(d,J=7.6Hz,2H ),6.91(d,J=8.8Hz,2H),4.48(br,2H),3.66(t,J=6.8Hz,4H),3.23(s,4H),2.70-2.60(m, 5H),2.60-2.40(m,5H),2.22(br,2H),1.85-1.65(m,3H),1.51(s,9H),1.21(br,3H);[M+H] + =834.5.

[0600] 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

[0601] Step 1: tert-Butyl 4-(4-(4-(5-fluoro-4-((2-fluoro-4-(2-hydroxypropan-2-yl)benzamido)methyl)- 2-(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzene 4-[ ...amino]-piperidine]-1-carboxylate

[0602]

[0603] 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 (542 mg, 1.0 mmol) in dioxane (20 mL) and water (2 mL) was added 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)Cl2 (73 mg, 0.1 mmol) and Cs2CO3 (650 mg, 2.0 mmol). The mixture reaction was stirred in a round-bottom flask at 110°C overnight. The mixture was then evaporated in vacuo to give a 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.

[0604] Step 2: 2-Fluoro-N-(2-fluoro-5-methyl-4-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine (4-(2-hydroxypropyl)benzoic acid)-4-(2-pyridin-4-yl)benzyl)-4-(2-hydroxypropyl)benzamide

[0605]

[0606] A mixture of tert-butyl 4-(4-(4-(5-fluoro-4-((2-fluoro-4-(2-hydroxypropan-2-yl)benzamido)methyl)-2-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperidine-1-carboxylate (340 mg, 0.38 mmol) and trifluoroacetic acid (3 mL) in dichloromethane (12 mL) was stirred in a round-bottom flask at room temperature overnight. The mixture was then evaporated in vacuo to give a crude product. A mixture of the crude product and ammonium hydroxide (2 mL) in methanol (10 mL) was stirred in a round-bottom flask at room temperature overnight. The mixture was evaporated in vacuo to give a 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.

[0607] Step 3: N-(4-(6-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)piperidin- (4-(2-((4-((2-fluoro-5-methylbenzyl)methyl)piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-fluoro-5-methylbenzyl)-2-fluoro-4- (2-Hydroxyprop-2-yl)benzamide

[0608]

[0609] A mixture of 2-fluoro-N-(2-fluoro-5-methyl-4-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-4-(2-hydroxypropan-2-yl)benzamide (90 mg, 0.15 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (60 mg, 0.20 mmol) in dichloroethane (20 mL) was stirred in a round-bottom flask at room temperature for 1 hour. NaBH(OAc)3 (212 mg, 1.0 mmol) was then added to the mixture and stirred overnight at room temperature in a round-bottom flask. The mixture was then evaporated in vacuo to give a 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=7.2Hz,2H),7.72-7.59(m, 1H),7.46-7.28(m,6H),7.14(d,J=8.0Hz,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),2.23-2.0 9(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.

[0610] 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

[0611]

[0612] The title compound was synthesized using a procedure similar 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.

[0613] 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

[0614]

[0615] The title compound was synthesized using a procedure similar to Example 24. 1 H NMR (400 MHz, DMSO) δ H 12.64(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=14.2Hz,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=12.1Hz,2H),1.72(s,1H),1.55(s,3H),1.37(s,9H),1.23(d,J=9.8Hz,2H);[M+H] + =868.8.

[0616] 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

[0617]

[0618] The title compound was synthesized using a procedure similar to Example 24. 1 H NMR (400 MHz, DMSO) δ H 12.68(s,1H),10.37(s,1H),9.91(s,1H),8.80(s,1H),8.22(s,1H),8.07(s,2 H),7.97(s,2H),7.48(s,1H),7.37(s,3H),7.17(d,J=14.2Hz,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=34.4,12.2Hz,7H),1.38(s,9H),1.30(s,3H);[M+H] + =853.8.

[0619] 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

[0620] 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

[0621]

[0622] To a solution of tert-butyl 4-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperidine-1-carboxylate (166 mg, 0.4 mmol) in dioxane / HO (5:1, 50 mL) was added 1-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide (150 mg, 0.4 mmol), KCO (166 mg, 1.2 mmol), and Pd(dppf)Cl.CHCl (33 mg, 0.04 mmol). The reaction mixture was stirred at 90° C. under N for 5 h. The solvent was evaporated, and HO (20 mL) was added. The mixture was extracted with DCM / iPrOH (20:1, 30 mL*3), and the organic phases were combined. The organic phases were washed with brine, concentrated, and purified by preparative TLC using DCM / MeOH to give the product (160 mg, crude).

[0623] Step 2: 1-(tert-Butyl)-N-(2-methyl-4-(6-(4-(piperidin-4-yl)phenyl)-7H-pyrrolo[2,3-d] (4-pyrimidinyl)benzyl)-1H-1,2,3-triazole-4-carboxamide

[0624]

[0625] 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 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (30 mL) and K2CO3 (230 mg) was added. After stirring at 20-30 ° C for 2 hours, the reaction mixture was concentrated. H2O (30 mL) was added and the mixture was extracted with DCM / iPrOH (10:1, 30 mL). The organic phase was separated, concentrated and used directly in the next step.

[0626] Step 3: 1-(tert-Butyl)-N-(4-(6-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzene 4-yl)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

[0627]

[0628] 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 minutes, NaBH(OAc)3 (233 mg, 1.1 mmol) was added. After stirring at 20-30°C for another 5 hours, the mixture was evaporated. To the residue was added H2O (30 mL), and the mixture was extracted with DCM / iPrOH (20:1, 30 mL*3). The organic phases were combined and purified by preparative TLC with DCM / MeOH (10:1) to give the product (32 mg, 10.7%). 1 H NMR (400 MHz, DMSO) δ H 12.66(s,1H),10.27(s,1H),9.07(s,1H),8.80(s,1H),8.74(s,1H),8.19(s,1H),8.06(s, 2H),7.98(d,J=7.6Hz,2H),7.44(d,J=8.4Hz,1H),7.37(d,J=8.0Hz,3H),7.13(d,J=8.4Hz, 2H),6.93(d,J=8.4Hz,2H),4.56(s,2H),3.76-3.66(m,4H),2.98(d,J=8.8Hz,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.

[0629] 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

[0630] Step 1: tert-butyl (R)-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

[0631]

[0632] To a solution of tert-butyl 4-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate (271 mg, 0.5 mmol) in dioxane (25 mL) and H2O (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), K2CO3 (207 mg, 1.5 mmol) and Pd(dppf)Cl2.CH2Cl2 (41 mg, 0.05 mmol). The mixture was stirred at 90°C under N2 for 18 hours. After evaporation of the solvent, water (20 mL) was added. The mixture was extracted with DCM / iPrOH (10:1, 20 mL*2). The organic phases were combined, washed with brine and purified by preparative TLC with DCM / MeOH to give the product (160 mg, crude).

[0633] Step 2: (R)-5-(tert-butyl)-N-(1-(2-methyl-4-(6-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[3-yl]-4-[4-(piperazin-1-yl)phenyl ...7H-pyrrolo[3-yl]-4-[4-(piperazin-1-yl)phenyl]-4 [2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride

[0634]

[0635] To a solution of tert-butyl (R)-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 hours, concentrated to 5 mL, and filtered. The filter cake was washed to give the crude product, which was used directly in the next step. 1 H NMR (400 MHz, DMSO) δ H 13.41(s,1H),9.64(d,J=6.8Hz,1H),9.32(s,2H),8.98(s,1H),8.14-7.97(m,4H),7.74(d,J=7.6Hz,1H),7.48 (s,1H),7.13(d,J=7.6Hz,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.

[0636] Step 3: (R)-5-(tert-butyl)-N-(1-(4-(6-(4-(4-(1-(4-(2,4-dioxotetrahydropyrimidine-1 (2H)-(phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methyl (phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide

[0637]

[0638] To a solution of (R)-5-(tert-butyl)-N-(1-(2-methyl-4-(6-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride (150 mg, 0.25 mmol) in DCM / EtOH (5:1, 30 mL) was added 1-(4-(4-oxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (75 mg, 0.25 mmol) and NaOAc (62 mg, 0.75 mmol). After stirring at 20-30° C. for 60 min, NaBH(OAc) (160 mg, 0.75 mmol) was added. The mixture was stirred at 20-30° C. for 3 h. The solvent was evaporated and H O (30 mL) was added. The mixture was extracted with DCM / iPrOH (20:1, 30 mL*3). The organic phases were combined and concentrated. The residue was purified by preparative TLC using 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=7.2Hz,1H),8.75(s,1H),8.08(d,J=7.2Hz,1H),8. 03(s,1H),7.92(d,J=6.8Hz,2H),7.65(d,J=7.2Hz,1H),7.23(s,1H),7.13(d,J=8.0Hz,2H) ,7.03(d,J=8.0Hz,2H),6.93(d,J=7.2Hz,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.

[0639] 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

[0640]

[0641] The title compound was synthesized using a procedure similar to Example 24. 1 H NMR (400 MHz, DMSO) δ H 12.70(s,1H),10.27(s,1H),9.99(s,1H),8.82-8.79(m,2H),8.31(s,1H),8.20(d,J=8.0Hz,1H ),8.12(d,J=8.0Hz,1H),8.03-8.00(m,1H),7.63-7.60(m,1H),7.35(s,1H),7.13(d,J=8.0Hz, 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.

[0642] 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

[0643] Step 1: (1-(5-Fluoro-2-nitrophenyl)piperidin-4-yl)methanol

[0644]

[0645] To a solution of 2,4-difluoro-1-nitrobenzene (20.0 g, 142.0 mmol) and 4-piperidinemethanol (19.6 g, 170 mmol) in DMF (200.0 mL) was added K2CO3 (39.2 g, 284 mmol) at 25 ° C. The mixture was stirred at 80 ° C for 16 hours. The reaction was monitored by LC-MS. The reaction was cooled to room temperature, poured into ice water (600.0 mL) and stirred for 20 minutes. The solid was filtered, washed with water (500.0 mL x 2), and dried to give the product (28.0 g, 84.0%). [M+H] + =255.1.

[0646] Step 2: (1-(2-amino-5-fluorophenyl)piperidin-4-yl)methanol

[0647]

[0648] 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) under N2 at 25°C. The mixture was then exchanged with H2 twice and stirred at 25°C under an H2 atmosphere for 15 hours. The reaction was monitored by LC-MS. The mixture was filtered through a pad of celite and washed with MeOH (140.0 mL). The filtrate was concentrated under vacuum to give the product (22.6 g, 85.1%). [M+H] + =225.1.

[0649] Step 3: (1-(2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluorophenyl)piperidin-4-yl)methylacetic acid ester

[0650]

[0651] To a solution of (1-(2-amino-5-fluorophenyl)piperidin-4-yl)methanol (22.6 g, 101 mmol) in toluene (200 mL) was added acrylic acid (10.9 g, 151.5 mmol) at 25°C. The mixture was stirred at 90°C for 15 hours. The reaction was monitored by LC-MS. The reaction was cooled to 25°C and HOAc (200 mL) and urea (30.3 g, 505 mmol) were added. The mixture was then stirred at 110°C for 24 hours. The reaction was monitored by LC-MS. The reaction was cooled to 25°C and concentrated under vacuum. The residue was dissolved in EtOAc (500.0 mL) and then adjusted to pH = 7 with saturated NaHCO3. The resulting solution was extracted with 2x200.0 mL 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.

[0652] Step 4: 1-(4-fluoro-2-(4-(hydroxymethyl)piperidin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0653]

[0654] (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 was stirred at 100°C for 1 hour. The reaction was monitored by LC-MS. The reaction was cooled to 10°C and then adjusted to pH = 7 with saturated NaHCO3. The solid was collected by filtration, washed with water (50.0 mL), and dried to obtain the product. [M+H] + =322.1.

[0655] Step 5: 1-(2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluorophenyl)piperidine-4-carbaldehyde

[0656]

[0657] 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 hour. After adding EtOAc (50 mL), the solution was washed three times with brine (50 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography to give the product (350 mg, 54%).

[0658] Step 6: (R)-3-(tert-butyl)-N-(1-(4-(6-(4-(4-((1-(2-(2,4-dioxotetrahydropyrimidine-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

[0659]

[0660] 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 minutes, NaBH(OAc)3 (106 mg, 0.5 mmol) was added. The mixture was stirred at 20-30°C for 2 hours. After evaporation of the solvent under reduced pressure, the residue was purified by preparative TLC with DCM / MeOH to give the product (60 mg, 41.6%). 1 H NMR (400 MHz, DMSO) δ H12.52(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=6.4Hz,2H),7.67(s,1H),7.23(br,2H),7.03(d,J=5.2Hz,2H),6.94(d,J=10.8H z,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.

[0661] 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

[0662]

[0663] The title compound was synthesized using a procedure similar to Example 24. 1 H NMR (400 MHz, DMSO) δ H 12.52(s,1H),10.25(s,1H),9.97(s,1H),8.75(s,1H),8.08(s,1H),8.03(s,1H), 7.92(br,2H),7.67(br,1H),7.23(s,1H),7.03(br,3H),6.86-6.72(m,2H),5.38(s ,1H),3.68(br,3H),3.48(br,1H),3.25(s,4H),2.78-2.55(m,10H),2.23(s,2H),2 .12(s,3H),1.85-1.65(m,3H),1.55(s,3H),1.37(s,9H),1.28-1.15(m,3H);[M+H] + =864.8.

[0664] 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

[0665]

[0666] The title compound was synthesized using a procedure similar to Example 24. 1 H NMR (400 MHz, DMSO) δ H 12.53(s,1H),10.21(s,1H),9.97(d,J=7.6Hz,1H),8.75(s,1H),8.09(d,J=7.6Hz,1H),8.04(s ,1H),7.91(d,J=7.6Hz,2H),7.67(d,J=8.0Hz,1H),7.23(s,1H),7.07-6.98(m,3H),6.59(s,1H) ,6.49(d,J=9.2Hz,1H),5.38(s,1H),3.81-3.72(m,5H),3.50(s,2H),3.26(s,4H),2.84-2.53( m,10H),2.24(s,2H),1.87-1.67(m,3H),1.55(d,J=6.0Hz,3H),1.37(s,9H),1.25(s,3H);[M+H] + =880.8.

[0667] 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

[0668]

[0669] The title compound was synthesized using a procedure similar 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=7.6Hz,2H),7.43(d,J=7.2Hz,1H),7.23(s,1H),7.13(d,J=8.4Hz,2H),7.03(d ,J=7.6Hz,2H),6.93(d,J=8.0Hz,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.

[0670] 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

[0671]

[0672] The title compound was synthesized using a procedure similar to Example 24. 1 H NMR (400 MHz, DMSO) δ H 12.52(s,1H),10.27(s,1H),9.15(s,1H),8.75(s,1H),8.36(s,1H),8.07(s,2H),7.9 1(d,J=8.0Hz,2H),7.45(d,J=7.2Hz,1H),7.22(s,1H),7.13(d,J=8.0Hz,2H),7.03(d ,J=7.2Hz,2H),6.93(d,J=8.0Hz,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.

[0673] 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

[0674]

[0675] 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 AcOH (1 drop) was added to the solution. The resulting mixture was stirred at room temperature for 1 hour, and sodium triacetoxyborohydride (180.2 mg, 0.85 mmol) was added to the mixture in portions. The mixture was stirred for another 1 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),7.6 8-7.64(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=8.0Hz,3H),1.37(s,9H),1.25-1.20(m,2H);[M+H] + =850.6.

[0676] 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

[0677] Step 1: tert-Butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidin Pyridine-1-carboxylate

[0678]

[0679] A mixture of tert-butyl 4-(4-bromophenoxy)piperidine-1-carboxylate (710 mg, 2.0 mmol), bis(pinacolato)diboron (508 mg, 2.0 mmol), Pd(dppf)Cl2 (146 mg, 0.2 mmol) and CH3COOK (300 mg, 3.0 mmol) in dioxane (20 mL) was stirred in a round-bottom flask at 110°C for 4 hours. The mixture was then used in the next step without further purification. [M-99] + =304.2.

[0680] Step 2: tert-Butyl 4-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[3 ... [2,3-d]pyrimidin-6-yl)phenoxy)piperidine-1-carboxylate

[0681]

[0682] To the final step mixture reaction solution, 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (818 mg, 2.0 mmol), Pd(dppf)Cl2 (146 mg, 0.1 mmol) and K2CO3 (400 mg, 3.0 mmol) in dioxane (20 mL) and water (4 mL) were added and stirred at 80°C overnight in a round-bottom flask. The mixture was then evaporated in vacuo to give a 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% over two steps). [M+H] + =559.3.

[0683] 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 4-[ ...amino]-piperidine]-1-carboxylate

[0684]

[0685] A mixture of tert-butyl 4-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenoxy)piperidine-1-carboxylate (538 mg, 0.96 mmol), 3-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (384 mg, 0.96 mmol), Pd(dppf)Cl (70 mg, 0.096 mmol) and KCO (265 mg, 1.92 mmol) in dioxane (16 mL) and water (4 mL) was stirred in a round-bottom flask at 100° C. overnight. The mixture was then evaporated in vacuo to give a 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.

[0686] 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

[0687]

[0688] 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) and trifluoroacetic acid (5 mL) in dichloromethane (5 mL) was stirred in a round-bottom flask at room temperature for 2 hours. The mixture was then evaporated in vacuo to give a crude product which was used in the next step without further purification. To the crude product was added ammonium hydroxide (2 mL) in methanol (10 mL) and stirred in a round-bottom flask at room temperature overnight. The mixture was evaporated in vacuo to give a 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.

[0689] 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

[0690]

[0691] 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 in a round-bottom flask for 1 hour. NaBH(OAc) (212 mg, 1.0 mmol) was then added to the mixture and stirred overnight at room temperature in a round-bottom flask. The mixture was evaporated in vacuo to give a 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=7.6Hz,2H) ,7.48(d,J=7.6Hz,1H),7.29(s,1H),7.17-7.01(m,4H),6.92(d,J=8.4Hz,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.

[0692] 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

[0693] Step 1: Ethyl 2-imino-2-(((3,3,3-trifluoro-2,2-dimethylpropionyl)oxy)amino)acetate

[0694]

[0695] 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 Et3N (30 g, 300 mmol). The mixture was stirred at room temperature for 1 hour, and then ethyl 2-(hydroxyamino)-2-iminoacetate (21 g, 159 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with water (500 mL) and brine (500 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography to give the product (35 g, 82%). [M+H] + =271.1.

[0696] Step 2: Ethyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxylate

[0697]

[0698] 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 hours. After adding EtOAc (300 mL), the reaction mixture was washed with water (300 mL) and brine (300 mL). The organic layer was dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography to give the product (7.5 g, 62%). [M+H] + =253.1.

[0699] Step 3: 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxylic acid

[0700]

[0701] A solution of ethyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxylate (7.0 g, 28 mmol) and LiOH·H2O (1.7 g, 40 mmol) in MeOH / THF / H2O (30 mL / 30 mL / 30 mL) was stirred at room temperature for 16 hours, and the mixture was concentrated and adjusted to pH 6 with 1N aqueous HCl solution to give the product (8.5 g, crude) by filtration. [M+H] + =225.2.

[0702] Step 4: tert-Butyl (4-bromo-2-methylbenzyl) carbamate

[0703]

[0704] To a solution of (4-bromo-2-methylphenyl)methylamine (26 g, 130 mmol) and EtN (20 mL, 145 mmol) in DCM (300 mL) was slowly added BocO (30 g, 138 mmol) at room temperature, and then stirred at room temperature for 1 hour. The reaction mixture was concentrated. EtOAc (200 mL) was added and washed with water (200 mL) and brine (200 mL). The organic phase was dried over NaSO, concentrated and purified by silica gel column chromatography to give the product (42 g, crude product). [M-55] = 244.1.

[0705] Step 5: tert-Butyl (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl) Carbamate

[0706]

[0707] Under N2, a mixture of tert-butyl (4-bromo-2-methylbenzyl) carbamate (42 g, 140 mmol), bis (pinacolato) diboron (33 g, 130 mmol), Pd (PPh3) 2Cl2 (2.0 g, 2.8 mmol) and KOAc (30 g, 306 mmol) in dioxane (300 mL) was stirred at 100 ° C for 16 hours. 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 product). [M+Na] + =370.4.

[0708] Step 6: (2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine

[0709]

[0710] 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 slowly added 4N HCl / dioxane (200 ml). The reaction mixture was stirred at room temperature for 2 hours and then concentrated to remove dioxane. The residue was stirred with MTBE (400 mL), and the solid was collected and dried under vacuum to give the product (31 g, crude). [M-NH2] + =231.3.

[0711] 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

[0712]

[0713] To a mixture of 5-(1,1,1-trifluoro-2-methylprop-2-yl)-1,2,4-oxadiazole-3-carboxylic acid (1.3 g, 5.8 mmol) and DMF (1 drop) in DCM (50 mL) was added oxalyl dichloride (1.5 mL) dropwise. The reaction mixture was stirred at room temperature for 1 hour and then concentrated to give crude 5-(1,1,1-trifluoro-2-methylprop-2-yl)-1,2,4-oxadiazole-3-carbonyl chloride. To a solution of (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine (1.6 g, 5.6 mmol) and Et3N (2 mL, 14.5 mmol) in DCM (40 mL) was added a solution of crude 5-(1,1,1-trifluoro-2-methylprop-2-yl)-1,2,4-oxadiazole-3-carbonyl chloride in DCM (40 mL). The reaction mixture was stirred at room temperature for 1 hour and then quenched with 100 mL of water. The DCM was dried over Na2SO4, concentrated and purified by silica gel column chromatography to give the product (1.7 g, 65%). [M+H] + =454.4.

[0714] Step 8: tert-Butyl 4-(4-(4-(3-methyl-4-((5-(1,1,1-trifluoro-2-methylprop-2-yl)-1,2,4-oxo- heterodiazole-3-carboxamido)methyl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2, 3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate

[0715]

[0716] A mixture of tert-butyl 4-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate (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 (30 mg, 0.041 mmol) and KCO (300 mg, 2.17 mmol) in dioxane (25 mL) and H0 (5 mL) was stirred at 100° C. for 16 h under N2. 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%).

[0717] Step 9: N-(2-methyl-4-(6-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl 1,2,4-oxadiazole-3-carboxamide

[0718]

[0719] A solution of tert-butyl 4-(4-(4-(3-methyl-4-((5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxamido)methyl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate (100 mg, 0.12 mmol) in TFA / DCM (2 mL / 2 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the crude product, which was stirred with NH3 / MeOH (1 M, 10 mL) for 30 minutes. The mixture was then concentrated to give the product (160 mg, crude). [M+H] + =605.6.

[0720] Step 10: N-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)- 1-(4-(4-(2-methyl-1-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

[0721]

[0722] A mixture of N-(2-methyl-4-(6-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzyl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxamide (160 mg, crude), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carboxaldehyde (40 mg, 0.13 mmol) and NaBH(OAc) (100 mg, 0.47 mmol) in dichloroethane (20 mL) was stirred at room temperature for 2 hours. After the addition of EtOAc (100 mL), the solution was washed three times with saturated aqueous NaHCO (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography to give the product (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=7.2Hz,2H),7.45(d,J=8.0Hz,1H),7.27-6.90(m,7H),4.60-4.5 6(m,2H),3.71-3.66(m,4H),3.26(s,3H),2.70-2.66(m,4H),2.26-2.2 2(m,2H),1.82(d,J=11.3Hz,2H),1.72(s,6H),1.32-1.17(m,2H);[M+H] +=890.5.

[0723] 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

[0724]

[0725] 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=7.0Hz,2H),7.44(d,J=8.1Hz,1H),7.26-6.88(m, [M+H] + =888.5.

[0726] 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

[0727]

[0728] The title compound was synthesized using a procedure similar 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.

[0729] 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

[0730]

[0731] The title compound was synthesized using a procedure similar to Example 24. 1 H NMR (400 MHz, DMSO) δ H 12.59(s,1H),10.78(s,1H),9.97(d,J=7.4Hz,1H),8.81(s,1H),8.76(s,1H),8.17(s,2H),8.09(d,J=7. 2Hz,1H),8.04(s,1H),7.66(d,J=8.1Hz,1H),7.30(s,1H),7.03(d,J=8.2Hz,2H),6.96(d,J=8.5Hz,1H),6 .88(d,J=8.2Hz,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=11.7Hz,2H),1.55(d,J=6.3Hz,3H),1.46(s,3H),1.37(s,9H),1.32-1.20(m,2H);[M+H] +=864.8.

[0732] 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

[0733]

[0734] The title compound was synthesized using a procedure similar to Example 24. 1 H NMR (400 MHz, DMSO) δ H 12.60(s,1H),10.78(s,1H),9.97(d,J=7.8Hz,1H),8.79(d,J=18.9Hz,2H),8.10(dd,J=35.4,2 7.5Hz,4H),7.66(d,J=8.0Hz,1H),7.30(s,1H),7.03(d,J=8.3Hz,2H),6.96(d,J=9.1Hz,1H),6. 88(d,J=8.2Hz,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=12.0Hz,2H),1.55(d,J=6.6Hz,3H),1.46(s,3H),1.37(s,9H),1.33-1.21(m,2H);[M+H] + =864.8.

[0735] 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

[0736] Step 1: (1-(4-bromophenyl)piperidin-4-yl)methanol

[0737]

[0738] 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), K3PO4 (3.0 g, 14.2 mmol) were placed in DMSO (20 mL). The resulting mixture was then heated to 80°C overnight until LC-MS showed that all the starting materials were consumed. The mixture was cooled to room temperature, the solid was filtered off, diluted with EtOAc (200 mL), and washed three times with brine. The organic layer was dried over Na2SO4 and concentrated to give a crude product (2.8 g, crude product) which was used directly without further purification. [M+H] + =270.0.

[0739] Step 2: (1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)methanol

[0740]

[0741] (1-(4-bromophenyl)piperidin-4-yl)methanol (2.8 g, crude), Pd(dppf)Cl2 (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 Cs2CO3 (4.6 g, 14.2 mmol) were placed in dioxane / water (300 mL, 10:1). The mixture was stirred at 100°C overnight until LC-MS showed that all the starting material was consumed. The reaction was cooled to room temperature and the solid was filtered off. The filtrate was concentrated and purified on a SiO2 gel column (eluted with EtOAc / hexane = 1:1) to give the title product (3.0 g, 88% over 2 steps). [M+H] + =481.2.

[0742] Step 3: 3-(4-(4-(Hydroxymethyl)piperidin-1-yl)phenyl)piperidine-2,6-dione

[0743]

[0744] (1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)methanol (3.0 g, 6.3 mmol) was dissolved in MeOH (30 mL). Pd / C (10%, w / w, 0.3 g) was added to the solution in one portion. The resulting mixture was stirred overnight under an H2 atmosphere (1 atm) until LC-MS indicated that all the starting material was consumed. The solid was filtered off and the filtrate was concentrated to give the crude product. The crude product was slurried with MTBE to give the desired product (1.2 g, 63.5%). [M+H] + =303.0.

[0745] Step 4: 1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-4-carbaldehyde

[0746]

[0747] 3-(4-(4-(Hydroxymethyl)piperidin-1-yl)phenyl)piperidine-2,6-dione (100.0 mg, 0.33 mmol) was dissolved in DMSO (2 mL). IBX (184.8 mg, 0.66 mmol) was added portionwise to the solution at 0°C, and the mixture was stirred at 0°C for 30 minutes. The mixture was then warmed to room temperature for another hour, until TLC indicated that all the starting material had been consumed. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated to give the desired crude product (100.0 mg, crude), which was used directly without further purification.

[0748] Step 5: (R)-3-(tert-butyl)-N-(1-(4-(6-(4-(4-(1-(4-(2,6-dioxopiperidin-3-yl)benzene 1-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

[0749]

[0750] 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 AcOH (1 drop) was added to the solution. The resulting mixture was stirred at room temperature for 1 hour, and sodium triacetoxyborohydride (180.2 mg, 0.85 mmol) was added to the mixture in portions. The mixture was stirred for another 1 hour until LC-MS indicated that all the starting material was consumed. The solid was filtered and purified by preparative TLC to give the desired product (20.7 mg, 14.3%). 1 HNMR (400 MHz, DMSO) δ H12.52(s,1H),10.78(s,1H),9.97(d,J=8.0Hz,1H),8.75(s,1H),8.09(d,J=8.0Hz,1H),8.03(s,1H),7.91(d,J=8.0H z,2H),7.66(d,J=8.0Hz,1H),7.23(s,1H),7.07-7.01(m,4H),6.89(d,J=8.0Hz,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=8.0Hz,3H),1.37(s,9H),1.28-1.18(m,3H);[M+H] + =849.9.

[0751] 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

[0752]

[0753] 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

[0754]

[0755] 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

[0756]

[0757] A mixture of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(6-(piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (50 mg, 0.083 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidine-4-carbaldehyde (30 mg, 0.095 mmol) and NaBH(OAc) (50 mg, 0.24 mmol) in dichloromethane (20 mL) was stirred at room temperature for 2 hours. After the addition of EtOAc (100 mL), the solution was washed three times with saturated aqueous NaHCO (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography to give the product (15 mg, 21%). 1 H NMR (400 MHz, DMSO) δ H 12.60(s,1H),10.25(s,1H),9.99-9.95(m,1H),8.82-8.77(m,2H),8.23-8.15(m,1H),8.13-7.9 9(m,2H),7.67(d,J=6.6Hz,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.

[0758] 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

[0759]

[0760] 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

[0761] Step 1: tert-Butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate

[0762]

[0763] To a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (2 g, 9.93 mmol) and TEA (1.5 g, 14.89 mmol) in DCM (20 mL) was added methanesulfonyl chloride (1.37 g, 11.92 mmol) at 0° C., and the resulting mixture was stirred at 25° C. for 2 hours. The mixture was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give the product (3 g, 92%), which was used directly in the next step. [M+H] + =280.2.

[0764] Step 2: tert-butyl 4-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)- 1H-pyrazol-1-yl)piperidine-1-carboxylate

[0765]

[0766] 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 dry DMF (10 mL) was added NaH (0.119 g, 3.0 mmol) at 0°C, and the resulting mixture was stirred at 0°C for 1 hour. After adding tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (0.91 g, 3.0 mmol) to the mixture, the reaction was heated to 95°C for 1 hour. The mixture was cooled, quenched with brine (20 mL) at 0°C-10°C, and 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.

[0767] Step 3: tert-Butyl 4-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[3 ... [2,3-d]pyrimidin-6-yl)-3,5-dimethyl-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0768]

[0769] A mixture of 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (0.394 g, 0.96 mmol), tert-butyl 4-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.41 g, 1.01 mmol), Pd(dppf)Cl2 (0.077 g, 0.096 mmol) and K2CO3 (0.265 g, 1.92 mmol) in a mixture of dioxane (10 mL) and water (2.5 mL) was stirred in a round-bottom flask at 90°C overnight. The mixture was evaporated in vacuo to give a 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.

[0770] Step 4: tert-butyl (R)-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]pyrimidine-6- 1H-pyrazol-1-yl)piperidine-1-carboxylate

[0771]

[0772] 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 A mixture of (1,2,4-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (0.284 g, 0.684 mmol), Pd(Ph3P)4 (0.074 g, 0.065 mmol) and K2CO3 (0.18 g, 1.3 mmol) in a mixture of dioxane (16 mL) and water (4 mL) was stirred in a round-bottom flask at 100°C overnight. The mixture was evaporated in vacuo to give a 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.

[0773] Step 5: (R)-3-(tert-butyl)-N-(1-(4-(6-(3,5-dimethyl-1-(piperidin-4-yl)-1H-pyrazole-4-yl)- (4-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole- 5-Formamide

[0774]

[0775] A mixture of tert-butyl (R)-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) and trifluoroacetic acid (5 mL) in dichloromethane (5 mL) was stirred in a round-bottom flask at room temperature for 1 hour. The mixture was evaporated in vacuo to give the crude product, which was used directly in the next step [M+H] + =612.0.

[0776] Step 6: (R)-3-(tert-butyl)-N-(1-(4-(6-(3,5-dimethyl-1-(piperidin-4-yl)-1H-pyrazole-4-yl)- (4-(2-Methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0777]

[0778] A mixture of (R)-3-(tert-butyl)-N-(1-(4-(6-(3,5-dimethyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-7-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (crude from Step 5) and aqueous ammonia (1 mL, 25%) in methanol (5 mL) was stirred in a round-bottom flask at room temperature for 12 hours. The mixture was evaporated in vacuo to give the crude product, which was purified by preparative HPLC to give the product (0.124 g, 59.7% over 2 steps). [M+H] + =582.1.

[0779] Step 7: (R)-3-(tert-butyl)-N-(1-(4-(6-(1-(1-(1-(4-(2,4-dioxotetrahydropyrimidine-1 (2H)-1H-pyrazol-4-yl)-7H-pyrrolo[2, (3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0780]

[0781] A mixture of (R)-3-(tert-butyl)-N-(1-(4-(6-(3,5-dimethyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (0.112 g, 0.192 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (0.087 g, 0.288 mmol) in dichloromethane (10 mL) and MeOH (2 mL) was stirred in a round-bottom flask at room temperature for 0.5 hours. To the mixture was added NaBH(OAc)3 (0.061 g, 0.288 mmol) and stirred in a round-bottom flask at room temperature for 1 hour. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative HPLC to afford the product (0.093 g, 55.7%). 1 HNMR (400 MHz, DMSO) δ H 12.14(s,1H),10.27(s,1H),9.94(d,J=6.4Hz,1H),8.78(s,1H),8.14(s,1H),8.06-7.97(m,2 H),7.66(d,J=8.2Hz,1H),7.14(d,J=7.6Hz,2H),6.94(d,J=6.9Hz,2H),6.75(s,1H),5.42-5.3 3(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,3H),2.39- 2.08(m,12H),1.89-1.67(m,5H),1.54(d,J=5.6Hz,3H),1.36(s,9H),1.32-1.17(m,2H);[M+H] + =867.8.

[0782] 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

[0783]

[0784] A mixture of (R)-3-(tert-butyl)-N-(1-(4-(6-(3,5-dimethyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (0.12 g, 0.206 mmol) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidine-4-carbaldehyde (0.097 g, 0.309 mmol) in dichloromethane (10 mL) and MeOH (2 mL) was stirred in a round-bottom flask at room temperature for 0.5 hours. To the mixture was added NaBH(OAc)3 (0.066 g, 0.309 mmol) and stirred in a round-bottom flask at room temperature for 1 hour. The mixture was then evaporated in vacuo to give the crude product, which was purified by preparative HPLC to afford the product (0.037 g, 20.4%). 1 HNMR (400 MHz, DMSO) δ H 12.13(s,1H),10.25(s,1H),9.94(d,J=7.5Hz,1H),8.78(s,1H),8.18(s,1H),8.06-7.96(m,2H), 7.65(d,J=7.8Hz,1H),7.04(d,J=8.6Hz,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.

[0785] 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

[0786]

[0787] The title compound was synthesized using a procedure similar to that of Example 25. 1H 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=7.8Hz ,1H),7.14(d,J=7.3Hz,2H),6.94(d,J=7.4Hz,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=11.2Hz,4H),1.71(s,1H),1.52(d,J=5.0Hz,3H),1.42(d,J=1.2Hz,9H),1.29-1.16(m,2H);[M+H] + =867.6.

[0788] 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

[0789]

[0790] 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

[0791]

[0792] 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

[0793]

[0794] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H 13.83(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),3.7 7-3.59(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.

[0795] 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

[0796]

[0797] 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

[0798]

[0799] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H13.76(s,1H),10.25(s,1H),9.93(d,J=6.8Hz,1H),8.84(s,1H),8.79(d,J=7.6Hz,1H),8.67( s,1H),8.19(s,2H),7.69(d,J=8.4Hz,1H),7.14(s,2H),7.05(d,J=7.2Hz,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=6.4Hz,3H),1.37(s,9H),1.35-1.16(m,2H);[M+H] + =865.8.

[0800] 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

[0801]

[0802] 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

[0803]

[0804] 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

[0805]

[0806] 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

[0807]

[0808] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H 13.87(s,1H),10.25(s,1H),9.52(d,J=6.4Hz,1H),9.04(s,1H),8.85(s,1H),8.76(d,J=7.6Hz,1H),8.67( s,1H),8.38(d,J=8.4Hz,1H),7.67(d,J=7.6Hz,1H),7.04(d,J=8.4Hz,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=5.2Hz,3H),1.42(s,9H),1.30-1.16(m,3H);[M+H] + =866.5.

[0809] 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

[0810]

[0811] 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

[0812]

[0813] The title compound was synthesized using a procedure similar to that of 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.

[0814] 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

[0815]

[0816] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H12.54(s,1H),10.27(s,1H),9.99(d,J=8.0Hz,1H),8.76(s,1H),8.27(s,1H),8.15(d,J=8.0Hz,1H),7.90( d,J=8.0Hz,2H),7.73(d,J=8.0Hz,1H),7.23(s,1H),7.13(d,J=8.0Hz,2H),7.04(d,J=8.0Hz,2H),6.93(d,J =8.0Hz,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),2.2 3(s,2H),1.82(d,J=12.0Hz,2H),1.73(s,1H),1.57(d,J=8.0Hz,3H),1.37(s,9H),1.27-1.21(m,3H);[M+H] + =866.7.

[0817] 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

[0818]

[0819] 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

[0820]

[0821] 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

[0822]

[0823] 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

[0824]

[0825] The title compound was synthesized using a procedure similar to Example 24. 1 H NMR (400 MHz, DMSO) δ H 12.53(s,1H),10.27(s,1H),10.00(d,J=7.1Hz,1H),8.77(s,1H),8.21(s,1H),7.85(d,J=7.7Hz,2H),7.65(s ,1H),7.49(d,J=8.2Hz,1H),7.13(d,J=8.4Hz,2H),7.01(d,J=7.9Hz,2H),6.93(d,J=8.5Hz,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= [M+H] + =868.8.

[0826] 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

[0827]

[0828] The title compound was synthesized using a procedure similar to Example 24. 1 H NMR (400 MHz, DMSO) δ H12.54(s,1H),10.27(s,1H),9.95(d,J=7.8Hz,1H),8.78(s,1H),8.22(s,1H),7.84(d,J=8.5Hz,2H),7.63(d,J =7.3Hz,1H),7.50(d,J=12.1Hz,1H),7.13(d,J=8.5Hz,2H),7.01(d,J=7.8Hz,2H),6.93(d,J=8.6Hz,2H),6.77( s,1H),5.35(s,1H),3.68(d,J=6.8Hz,4H),3.24(s,4H),2.72-2.61(m,5H),2.52(s,3H),2.46(s,3H),2.22(d,J =6.0Hz,2H),1.81(d,J=12.0Hz,2H),1.72(s,1H),1.55(d,J=6.8Hz,3H),1.38(s,9H),1.28-1.15(m,3H); [M+H] + =868.8.

[0829] 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

[0830] Step 1: tert-Butyl (S)-4-(5-bromopyridin-2-yl)-3-methylpiperazine-1-carboxylate

[0831]

[0832] 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 at 110 ° C for 2 days in a round-bottom flask. The mixture was then cooled, extracted with EtOAc (200 mL * 3), and washed with brine (200 mL). The organic phase was dried over Na2SO4 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.

[0833] Step 2: (S)-(6-(4-(tert-Butoxycarbonyl)-2-methylpiperazin-1-yl)pyridin-3-yl)boronic acid

[0834]

[0835] Under N2 atmosphere, a mixture of tert-butyl (S)-4-(5-bromopyridin-2-yl)-3-methylpiperazine-1-carboxylate (2.71 g, 0.00766 mol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di(1,3,2-dioxaborolane) (3.89 g, 0.0153 mol), Pd(dppf)Cl2 (560 mg, 0.0008 mmol) and KOAc (2.4 g, 0.0245 mol) in dioxane (50 mL) was stirred overnight at 100 ° C in a round-bottom flask. After the reaction was determined to be complete by LCMS, the reaction was cooled. The mixture was extracted with EtOAc (60 mL * 3). The organic layers were combined and washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA=100%:0% to 0%:100%) to afford the product (2.2 g, crude). [M+H] + =322.2.

[0836] Step 3: tert-Butyl (S)-4-(5-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrole (2,3-d)pyrimidin-6-yl)pyridin-2-yl)-3-methylpiperazine-1-carboxylate

[0837]

[0838] A mixture of 4-chloro-6-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.489 mmol), (S)-(6-(4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)pyridin-3-yl)boronic acid (157 mg, 0.489 mmol), Pd(dppf)Cl2 (20 mg, 0.0244 mmol) and K2CO3 (108 mg, 0.782 mmol) in dioxane / water (10 mL / 3 mL) was stirred in a round-bottom flask at 100°C overnight under an N2 atmosphere. The mixture was then allowed to cool. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE:EA = 100%:0% to 50%:50%) to give the product (124 mg, 45%). [M+H] + =559.3.

[0839] Step 4: tert-Butyl (S)-4-(5-(4-(4-((R)-1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide (2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-6-yl)ethyl)-3-fluorophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine 2-Methyl-3-pyridin-2-yl)-3-methylpiperazine-1-carboxylate

[0840]

[0841] Under N2 atmosphere, 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, A mixture of (49 mg, 0.355 mmol) in dioxane / water (10 mL / 3 mL) and (2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (107.1 mg, 0.255 mmol), Pd(dppf)Cl2 (11.4 mg, 0.0155 mmol) and K2CO3 (49 mg, 0.355 mmol) was stirred overnight at 100 ° C in a round-bottom flask. After the reaction was completed as determined by LCMS, the mixture was cooled and then concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA=100%:0% to 70%:30%) to provide the product (155 mg, 86%). [M+H] + =814.5.

[0842] Step 5: 3-(tert-Butyl)-N-((R)-1-(2-fluoro-4-(6-(6-((S)-2-methylpiperazin-1-yl)pyridine-3-yl)- (4-(2-(2-(4-(2-(4-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide))

[0843]

[0844] 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 was adjusted to 8 with NH (7 M in MeOH). The mixture was stirred at room temperature for 30 minutes 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 in the next step without further purification. [M+H] + =584.5.

[0845] Step 6: 3-(tert-Butyl)-N-((R)-1-(4-(6-(6-((S)-4-((1-(4-(2,4-dioxotetrahydropyrimidine- 1-(2H)-1-yl)phenyl)piperidin-4-yl)methyl)-2-methylpiperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (4-pyridin-1,2,4-oxadiazole-5-carboxamide)-2-fluorophenyl

[0846]

[0847] 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-carboxaldehyde (97 mg, 0.322 mmol) in DCM (4 mL) / MeOH (4 mL) was stirred in a round-bottom flask for 5 minutes, and HOAc (3 drops) was added dropwise. The mixture was stirred at room temperature for 2 hours, and then NaBH(OAc) was added. The mixture was stirred at room temperature overnight. After completion of the reaction, as determined 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 H 12.66(s,1H),10.27(s,1H),10.02(d,J=8.0Hz,1H),8.80(d,J=12.0Hz,2H),8.19(d,J=8.0Hz,1H),8.13(d,J=8.0Hz,1H),7.99(d,J=12.0 Hz,1H),7.71(t,J=8.0Hz,1H),7.34(s,1H),7.13(d,J=8.0Hz,2H),6.98-6.86(m,3H),5.46(t,J=8.0Hz,1H),4.58(s,1H),4.13(d,J=12.0 Hz,1H),3.75-3.65(m,4H),3.08(t,J=12.0Hz,1H),2.93(d,J=8.0Hz,1H),2.82(d,J=8.0Hz,1H),2.70-2.66(m,4H),2.28-2.20(m,1H),2. [M+H] + =869.8.

[0848] 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

[0849]

[0850] The title compound was synthesized using a procedure similar to Example 80. 1 H NMR (400 MHz, DMSO) δ H 12.67(s,1H),10.27(s,1H),10.02(d,J=8.0Hz,1H),8.80(d,J=12.0Hz,2H),8.19(d,J=8.0Hz,1H),8.13(d,J=8.0Hz,1H),8.00(d,J=12 .0Hz,1H),7.71(t,J=8.0Hz,1H),7.35(s,1H),7.14(d,J=8.0Hz,2H),6.92(dd,J=14.9,8.2Hz,3H),5.46(t,J=8.0Hz,1H),4.58(s,1H), 4.13(d,J=12.0Hz,1H),3.70(s,4H),3.15-3.02(m,1H),2.93(d,J=8.0Hz,1H),2.82(d,J=8.0Hz,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=12.0Hz,3H),1.74(s,1H),1.59(d,J=8.0Hz,3H),1.38(s,9H),1.26-1.18(m,5H);[M+H] + =869.8.

[0851] 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

[0852]

[0853] 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

[0854]

[0855] 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

[0856]

[0857] 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

[0858]

[0859] 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

[0860]

[0861] 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

[0862]

[0863] 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

[0864]

[0865] 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

[0866]

[0867] 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

[0868]

[0869] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H12.53(s,1H),10.27(s,1H),9.49(d,J=7.2Hz,1H),8.75(s,1H),8.11-7.99(m,2H),7.91(d,J=7.6Hz,2H),7.64 (d,J=7.6Hz,1H),7.23(s,1H),7.13(d,J=7.6Hz,2H),7.03(d,J=7.6Hz,2H),6.93(d,J=7.6Hz,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.

[0870] 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

[0871]

[0872] 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

[0873]

[0874] 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

[0875]

[0876] 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

[0877]

[0878] 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

[0879]

[0880] 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

[0881]

[0882] 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

[0883]

[0884] 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

[0885]

[0886] 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

[0887]

[0888] 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

[0889]

[0890] 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

[0891]

[0892] 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

[0893]

[0894] 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

[0895]

[0896] 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

[0897]

[0898] The title compound was synthesized using a procedure similar to Example 14. 1 H NMR (400 MHz, DMSO) δ H 12.60(s,1H),10.27(s,1H),9.55(d,J=7.2Hz,1H),8.82(s,1H),8.76(s,1H),8.19(d,J=8.0Hz, 1H),8.08(d,J=7.2Hz,1H),8.04(s,1H),7.65(d,J=7.6Hz,1H),7.30(s,1H),7.13(d,J=8.0Hz,2 H),7.00-6.93(m,3H),5.39(s,1H),3.70(brs,4H),3.60(brs,4H),2.68(brs,4H),2.53-2.41(m ,7H),2.22(s,2H),1.83-1.65(m,3H),1.52(d,J=5.2Hz,3H),1.43(s,9H),1.23(brs,2H);[M+H] + =851.6.

[0899] 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

[0900]

[0901] The title compound was synthesized using a procedure similar to Example 14. 1 H NMR (400 MHz, DMSO) δ H 12.58(s,1H),10.26(s,1H),9.96(d,J=8.0Hz,1H),8.81(s,1H),8.76(s,1H),8.17(d,J=8.0Hz,1H),8.09(d,J=8.0Hz,1H),8. 04(s,1H),7.66(d,J=8.0Hz,1H),7.28(s,1H),7.13(d,J=4.0Hz,2H),6.97-6.85(m,3H),5.37(t,J=8.0Hz,1H),4.58(s,1H),4. 12(d,J=12.0Hz,1H),3.69(s,4H),3.07(t,J=16.0Hz,2H),2.93(d,J=8.0Hz,2H),2.82(d,J=12.0Hz,2H),2.68(s,5H),2.52(s, [M+H] + =865.5.

[0902] 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

[0903]

[0904] The title compound was synthesized using a procedure similar to Example 14. 1 H NMR (400 MHz, DMSO) δ H12.58(s,1H),10.29(s,1H),9.96(d,J=8.0Hz,1H),8.81(s,1H),8.76(s,1H),8.17(d,J=8.0Hz,1H),8.09(d,J=8.0Hz ,1H),8.04(s,1H),7.66(d,J=8.0Hz,1H),7.28(s,1H),7.14(d,J=8.0Hz,2H),6.97-6.83(m,3H),5.42-5.31(m,1H),4. 58(s,1H),4.12(d,J=8.0Hz,1H),3.70(s,4H),3.12-3.03(m,2H),2.93(d,J=8.0Hz,2H),2.82(d,J=8.0Hz,2H),2.68(s [M+H] + =865.6.

[0905] 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

[0906]

[0907] The title compound was synthesized using a procedure similar 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=7.8Hz,2H),7.63(d,J=6. 7Hz,1H),7.48(d,J=12.2Hz,1H),7.13(d,J=8.1Hz,2H),7.01(d,J=7.6Hz,2H),6.93(d,J=7.7Hz,2H),6.7 7(s,1H),5.36(s,1H),3.69(d,J=6.3Hz,4H),3.28(d,J=30.9Hz,9H),2.73-2.62(m,4H),2.46(s,3H),2. 23(d,J=5.6Hz,2H),1.87-1.66(m,3H),1.53(d,J=5.9Hz,3H),1.44(s,9H),1.23(q,J=14.1Hz,2H);[M+H] + =868.8.

[0908] 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

[0909]

[0910] The title compound was synthesized using a procedure similar to Example 19. 1 H NMR (400 MHz, DMSO) δ H 12.70(s,1H),10.27(s,1H),9.26(d,J=8.0Hz,1H),8.81(s,1H),8.39(m,1H),8.12-8.07(m,2 H),7.99-7.96(m,1H),7.72-7.70(m,1H),7.47-7.46(m,2H),7.13(d,J=8.0Hz,2H),6.93(d,J= 8.0Hz,2H),5.48-5.46(m,1H),3.69-3.68(m,4H),2.69-2.66(m,4H),2.52-2.51(m,7H),2.25 -2.24(m,2H),1.82-1.75(m,4H),1.57(d,J=8.0Hz,3H),1.44(s,9H),1.25-1.22(m,2H);[M+H] + =855.5.

[0911] 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

[0912] Step 1: (2-(Aminomethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) Methanol hydrochloride

[0913]

[0914] To a solution of tert-butyl (2- (hydroxymethyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-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 h. After completion of the reaction as determined 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 to collect the filter cake to give the product (1.6 g, crude product), which was used directly without further purification. [M+H] + =264.3.

[0915] Step 2: 3-(tert-butyl)-N-(2-(hydroxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (2-Alkyl)benzyl)-1,2,4-oxadiazole-5-carboxamide

[0916]

[0917] A mixture of 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylic acid sodium (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 at room temperature for 5 minutes in a round-bottom flask. (2-(aminomethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol hydrochloride (500 mg, 1.67 mmol) was then added. The mixture was stirred at room temperature for 2.5 h. After completion of the reaction as determined by LCMS, the mixture was extracted with EtOAc (50 mL*3), washed with brine (40 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA=100%:0% to 50%:50%) to provide the desired product (242 mg, 30%). [M+H-H2O] + =398.3.

[0918] 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]pyrimidine-6- 1-[4-[(1 ...methyl)phenyl)piperazine-1-carboxylate]]

[0919]

[0920] A mixture of tert-butyl 4-(4-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl)piperazine-1-carboxylate (100 mg, 0.184 mmol), 3-(tert-butyl)-N-(2-(hydroxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (160 mg, 0.386 mmol), KCO (81.2 mg, 0.588 mmol), and Pd(dppf)Cl (13.4 mg, 0.0184 mmol) in dioxane:water (10 mL:3 mL) was stirred 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% to 0%:100%) to give the desired product (57 mg, 39%). [M+H] + =797.5.

[0921] Step 4: 3-(tert-Butyl)-N-(2-(hydroxymethyl)-4-(6-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[3-(4-(piperazin-1-yl)phenyl)-1-[4-(4-(piperazin-1-yl)phenyl)-2-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[3-(4-(4-(pi [2,3-d]pyrimidin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide

[0922]

[0923] 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 was adjusted to 8 with NH3 (7 M in MeOH). The mixture was stirred at room temperature for 30 minutes and concentrated in vacuo to give the desired product (50 mg, crude) which was used in the next step without further purification. [M+H] + =567.5.

[0924] Step 5: 3-(tert-Butyl)-N-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzene 1-yl)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

[0925]

[0926] 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-carboxaldehyde (32 mg, 0.106 mmol) in DCM (5 mL):MeOH (5 mL) was stirred in a round-bottom flask. The mixture was stirred at room temperature for 5 minutes, and HOAc (3 drops) was added dropwise. The mixture was stirred at room temperature for 2 h. NaBH(OAc) (93.3 mg, 0.44 mmol) was then added. The mixture was stirred at room temperature overnight. After completion of the reaction, as determined 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=8.0Hz,1H),7.90(d,J=4.0 Hz,2H),7.51(d,J=8.0Hz,1H),7.22(s,1H),7.14(d,J=8.0Hz,2H),7.05(d,J=4.0Hz,2H),6.94(d,J=8.0H z,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 [M+H] + =852.8.

[0927] 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

[0928] Step 1: 1-(4-(3-methyl-2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde

[0929]

[0930] 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (100 mg, 0.3 mmol), K2CO3 (229 mg, 1.7 mmol) and MeI (236 mg, 1.7 mmol) were placed in DMF (5 mL). The mixture was stirred at room temperature overnight until LC-MS showed that all the starting materials were consumed. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were washed with brine (100 mL*3), dried over Na2SO4, and concentrated to give the desired product (100 mg, 96%). [M+H] + =315.2.

[0931] Step 2: (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(5-(4-((1-(4-(3-methyl-2,4-dioxo- (2H-pyrrolo[2,3-d]pyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl) (4-pyrimidinyl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0932]

[0933] (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(5-(piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide (100 mg, 0.2 mmol), 1-(4-(3-methyl-2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (100 mg, 0.3 mmol) and AcOH (1 drop) were placed 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 in one portion to the mixture, and the mixture was stirred at room temperature for another 1 hour until LC-MS indicated that all the 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 H12.61(s,1H),9.96(d,J=7.1Hz,1H),8.78(s,1H),8.39(s,1H),8.06-8.02(m,3H),7.68(d,J=8.0Hz,1H), 7.51-7.47(m,1H),7.40(s,1H),7.14(d,J=8.1Hz,2H),6.94(d,J=8.3Hz,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=12.2Hz,2H),1.55(d,J=6.2Hz,3H),1.37(s,9H),1.26-1.22(m,3H);[M+H] + =865.5.

[0934] 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

[0935]

[0936] The title compound was synthesized using a procedure similar to Example 20. 1 H NMR (400 MHz, DMSO) δ H12.52(s,1H),10.38(s,1H),9.95(s,J=8.0Hz,1H),8.75(s,1H),8.08(s,J=8.4Hz,1H),8.04(s,1H) ,7.91(d,J=8.0Hz,2H),7.66(d,J=8.4Hz,1H),7.23-7.06(m,2H),7.04(d,J=7.2Hz,2H),6.83-6.75( m,2H),5.38(brs,1H),3.76(d,J=11.2Hz,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=6.4Hz,3H),1.37(s,9H),1.21(brs,2H);[M+H] + =868.5.

[0937] 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

[0938]

[0939] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H13.85(s,1H),10.26(s,1H),9.94(d,J=6.4Hz,1H),8.88(s,1H),8.83-8.73(m,1H),8.64(s,1H),8.22-8.05(m,2 H),7.70(d,J=8.4Hz,1H),7.20(d,J=8.0Hz,1H),7.04(d,J=8.4Hz,1H),6.87-6.72(m,2H),5.51-5.23(m,1H),3.7 6-3.61(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, [M+H] + =879.8.

[0940] 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

[0941]

[0942] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H10.26(s,1H),9.93(d,J=6.4Hz,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=8.0Hz,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=6.0Hz,3H),1.37(s,9H),1.30-1.17(m,2H); [M+H] + =895.8.

[0943] 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

[0944]

[0945] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H 13.56(s,1H),10.26(s,1H),9.91(d,J=7.2Hz,1H),8.87(s,1H),8.76(s,2H),7.86(s,1H) ,7.69(d,J=8.0Hz,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=4.8Hz,3H),1.36(s,9H),130-1.15(m,2H);[M+H] + =879.6.

[0946] 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

[0947]

[0948] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.53(s,1H),10.27(s,1H),9.60(d,J=6.7Hz,1H),8.77(s,1H),7.85(d,J=8.1Hz,2H),7.64(s,1H),7.47 (d,J=6.9Hz,1H),7.13(d,J=8.2Hz,2H),7.01(d,J=7.8Hz,2H),6.93(d,J=6.8Hz,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=31.5Hz,4 [M+H] + =868.8.

[0949] Example 116: (R)-3-(tert-butyl)-N-(1-(4-(6-(3-(4-((1-(4-(2,4-dioxotetrahydropyrimidine-1 (2H)-(phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methyl (phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[0950]

[0951] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H12.67(s,1H),10.27(s,1H),9.98(d,J=6.8Hz,1H),8.81(s,1H),8.10(d,J=8.4Hz,1H),8.04(s,1H),7.68(d,J=7. 2Hz,1H),7.60(s,1H),7.49(d,J=7.4Hz,1H),7.41(s,1H),7.33(t,J=8.0Hz,1H),7.14(d,J=8.0Hz,2H),7.00-6.8 5(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=5.6Hz,2H),1.91(d, J=1.2Hz,1H),1.83(d,J=12.0Hz,2H),1.74(brs,1H),1.55(d,J=6.0Hz,3H),1.37(s,9H),1.32-1.15(m,2H);[M+H] + =850.8.

[0952] 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

[0953]

[0954] The title compound was synthesized using a procedure similar to that of 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=8.8Hz,1H),8.06(d,J= 8.0Hz,1H),8.02(s,1H),7.64(d,J=8.0Hz,1H),7.29(s,1H),7.14(d,J=8.4Hz,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.

[0955] 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

[0956]

[0957] The title compound was synthesized in a similar manner to Example 1. 1H NMR(400MHz,dmso)δ12.53(s,1H),10.26(s,1H),9.57(d,J=8.0Hz,1H),8.76(s,1H),8.27(s,1H),8.14(d,J=8.0Hz,1H),7. 90(d,J=8.0Hz,2H),7.71(d,J=8.0Hz,1H),7.23(s,1H),7.14(d,J=8.0Hz,2H),7.04(d,J=8.0Hz,2H),6.93(d,J=8.0Hz,2H), 5.46-5.30(m,2H),4.93-4.70(m,2H),3.75-3.63(m,4H),3.26(s,4H),3.02-2.89(m,2H),2.72-2.65(m,4H),2.57-2.53(m, 2H), 2.23 (d, J = 4.0Hz, 2H), 1.81 (d, J = 8.0Hz, 2H), 1.78-1.66 (m, 1H), 1.55 (d, J = 8.0Hz, 3H), 1.42 (s, 9H), 1.29-1.24 (m, 2H). [M+H] + =866.8.

[0958] 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

[0959]

[0960] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H12.60(s,1H),10.30(s,1H),9.95(d,J=8.0Hz,1H),8.78(s,1H),8.39(s,1H),8.10-8.00(m,3H),7.68(d,J =8.0Hz,1H),7.46(d,J=8.0Hz,1H),7.40(s,1H),7.19(t,J=8.0Hz,1H),6.88(s,1H),6.82(d,J=8.0Hz,1H), 6.68(d,J=8.0Hz,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. [M+H] + =851.8.

[0961] 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

[0962]

[0963] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H12.13(s,1H),10.26(s,1H),9.55(d,J=8.0Hz,1H),8.77(s,1H),8.23(s,1H),8.08(d,J=8.0Hz,1H),7.6 8(d,J=8.0Hz,1H),7.12(d,J=8.0Hz,2H),6.92(d,J=8.0Hz,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, [M+H] + =883.9.

[0964] 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

[0965]

[0966] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.11(s,1H),10.26(s,1H),8.95(d,J=8.0Hz,1H),8.75(s,1H),8.64(s,1H),7.98-7.95(m ,2H),7.65(d,J=8.0Hz,1H),7.12(d,J=8.0Hz,2H),6.92(d,J=8.0Hz,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=8.0Hz,3H),1.24-1.19(m,3H);[M+H] +=866.7.

[0967] 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

[0968]

[0969] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.12(s,1H),10.26(s,1H),9.03(d,J=8.0Hz,1H),8.76(s,1H),8.62(s,1H),8.21(s,1H),8.05(d,J= 8.0Hz,1H),7.72(d,J=8.0Hz,1H),7.12(d,J=8.0Hz,2H),6.92(d,J=8.0Hz,2H),6.72(s,1H),5.40-5.3 3(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,3 [M+H] + =882.9.

[0970] 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

[0971]

[0972] The title compound was synthesized using a procedure similar to that of 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=8.0Hz,1H),9.00(s,1H),8.48(s,1H),8.22(d,J=8.8Hz,1H),8.00(d, J=8.0Hz,1H),7.95(s,1H),7.72(d,J=8.0Hz,1H),7.67(s,1H),7.62(d,J=6.4Hz,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 [M+H] + =879.6.

[0973] 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

[0974]

[0975] The title compound was synthesized using a procedure similar to that of 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.

[0976] 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

[0977]

[0978] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.60(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),2.1 2(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.

[0979] 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

[0980]

[0981] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.61(s,1H),10.25(s,1H),9.49(d,J=7.2Hz,1H),8.39(s,1H),8.16-7.90(m,3H),7.65(d,J= 8.0Hz,1H),7.53-7.31(m,2H),7.04(d,J=8.4Hz,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.

[0982] 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

[0983]

[0984] The title compound was synthesized using a procedure similar to that of 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 [M+H] + =869.7.

[0985] 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

[0986]

[0987] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.62(s,1H),10.25(s,1H),9.60(d,J=7.7Hz,1H),8.38(s,1H),7.99(d,J=9.0Hz,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),3.60-3.7 5(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=6.5Hz,3H),1.43(s,9H),1.15-1.29(m,3H); [M+H] + =883.8.

[0988] 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

[0989]

[0990] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.61(s,1H),10.25(s,1H),9.54(d,J=7.6Hz,1H),8.39(s,1H),8.11-7.98(m,3H),7.6 6(d,J=8.0Hz,1H),7.46(d,J=7.6Hz,1H),7.40(s,1H),7.04(d,J=8.8Hz,1H),6.85-6.7 4(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=6.0Hz,3H),1.43(s,9H),1.31-1.16(m,2H);[M+H] + =865.8.

[0991] 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

[0992]

[0993] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H12.63(s,1H),10.25(s,1H),9.57(d,J=7.6Hz,1H),8.37(s,1H),7.98(d,J=8.4Hz,1H),7.64(d,J=7.2 Hz,1H),7.49(d,J=11.8Hz,1H),7.42(d,J=8.4Hz,1H),7.04(d,J=8.4Hz,1H),6.98(s,1H),6.82(s,1H ),6.77(d,J=8.6Hz,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=6.2Hz,3H),1.44(s,9H),1.25-1.19(m,2H);[M+H] + =883.7.

[0994] 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

[0995]

[0996] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.62(s,1H),10.27(s,1H),9.59(d,J=7.6Hz,1H),8.77(s,1H),8.12(d,J=8.4Hz,1H),7.63(d ,J=7.6Hz,1H),7.49(d,J=11.2Hz,1H),7.13(d,J=8.4Hz,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.

[0997] 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

[0998]

[0999] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.62(s,1H),10.25(s,1H),9.58(d,J=8.0Hz,1H),8.77(s,1H),8.12(d,J=8.4Hz,1H),7.63(d,J=7.6Hz,1 H),7.48(d,J=12.0Hz,1H),7.04(d,J=8.4Hz,1H),6.92(d,J=8.8Hz,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.

[1000] 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

[1001]

[1002] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H12.61(s,1H),10.25(s,1H),9.54(d,J=7.6Hz,1H),8.39(s,1H),8.11-7.98(m,3H ),7.66(d,J=8.0Hz,1H),7.46(d,J=8.0Hz,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=6.0Hz,3H),1.43(s,9H),1.31-1.16(m,2H);[M+H] + =851.6.

[1003] 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

[1004]

[1005] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.62(s,1H),10.26(s,1H),9.56(d,J=7.6Hz,1H),8.37(s,1H),7.98(d,J=8.4Hz,1H),7.64( d,J=7.2Hz,1H),7.49(d,J=11.8Hz,1H),7.42(d,J=7.0Hz,1H),7.13(d,J=8.2Hz,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 =4.6Hz,2H),1.88-1.66(m,3H),1.53(d,J=6.4Hz,3H),1.44(s,9H),1.26-1.21(m,2H);[M+H] + =869.6.

[1006] 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

[1007]

[1008] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (500 MHz, DMSO) δ H 12.06(s,1H),10.25(s,1H),9.22(d,J=8.0Hz,1H),8.66(s,1H),8.12(s,1H),8.03(d,J=8.0H z,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=24.0,12.0Hz,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.

[1009] 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

[1010]

[1011] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H12.62(s,1H),10.26(s,1H),9.57(d,J=8.0Hz,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=8.0Hz,1H),7.72(d,J=8.0Hz,1H),7.47(d,J=8.0Hz,1H),7.41(s,1H),7.13(d,J=8.0H z,2H),6.93(d,J=8.0Hz,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=12.0Hz,2H),1.73(s,1H),1.55(d,J=8.0Hz,3H),1.42(s,9H);[M+H] + =867.7.

[1012] 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

[1013]

[1014] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H12.62(s,1H),10.24(s,1H),9.56(d,J=8.0Hz,1H),8.79(s,1H),8.40(s,1H),8.27(s,1H),8.13(d,J=8.0Hz,1H),8.02(d ,J=8.0Hz,1H),7.72(d,J=8.0Hz,1H),7.46(d,J=8.0Hz,1H),7.41(s,1H),7.04(d,J=8.0Hz,1H),6.82(s,1H),6.78(d,J=8 .0Hz,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. [M+H] + =881.9.

[1015] 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

[1016]

[1017] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H12.15(s,1H),10.27(s,1H),9.97(d,J=8.0Hz,1H),8.79(s,1H),8.25(s,1H),8.11(d,J=8.0Hz,1H),7 .72(d,J=8.0Hz,1H),7.14(d,J=8.0Hz,2H),6.94(d,J=8.0Hz,2H),6.76(s,1H),5.41-5.36(m,2H),4.8 7-4.73(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),2.27-2.0 9(m,8H),1.81-1.77(m,4H),1.69(s,1H),1.56(d,J=8.0Hz,3H),1.36(s,9H),1.24-1.19(m,3H);[M+H] + =883.7.

[1018] 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

[1019]

[1020] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H12.15(s,1H),10.26(s,1H),9.93(d,J=8.0Hz,1H),8.82(s,1H),7.88(d,J=8.0Hz,1H),7.56(d,J=8.0Hz ,1H),7.13(d,J=8.0Hz,2H),6.93(d,J=8.0Hz,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=8.0Hz,3H),1.37(s,9H),1.24-1.19(m,3H);[M+H] + =901.7.

[1021] 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

[1022] Step 1: tert-Butyl 4-(5-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[3-(4 ... [2,3-d]pyrimidin-6-yl)pyridin-2-yl)piperazine-1-carboxylate

[1023]

[1024] To a mixture of tert-butyl 4-(5-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)piperazine-1-carboxylate (2.05 g, 5.0 mmol) in DMF (25 mL) was added NaH (0.24 g of a 60% dispersion in mineral oil, 6.0 mmol). The mixture was stirred at 0 ° C. for 60 minutes. SEM-Cl (1.02 g, 6.0 mmol) was then added. LCMS showed that the reaction was complete. The reaction was quenched with 10% NaCl aqueous solution (10 mL). The resulting suspension was sonicated for 5 minutes, filtered and concentrated in vacuo to give the product (2.97 g, crude product) which was used in the next step without further purification. [M+H] + =545.8.

[1025] 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]pyrimidine (6-pyridinyl)pyridin-2-yl)piperazine-1-carboxylate

[1026]

[1027] A mixture of 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)Cl2 (20 mg, 0.027 mmol) and Cs2CO3 (270 mg, 0.81 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) was stirred in a round-bottom flask at 100°C overnight. The mixture was evaporated in vacuo to give a 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.

[1028] 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

[1029]

[1030] A mixture of tert-butyl (R)-4-(5-(4-(4-(1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)ethyl)-2-fluoro-3-methylphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)pyridin-2-yl)piperazine-1-carboxylate (138 mg, 0.17 mmol) and trifluoroacetic acid (16 mL) in dichloromethane (5 mL) was stirred in a round-bottom flask at room temperature for 3 hours. The mixture was evaporated in vacuo. The residue was dissolved in MeOH (10 mL) and NH3 / H2O (2 mL) was added. The mixture was stirred at room temperature for 30 min. LCMS showed that the reaction was complete. The mixture was evaporated in vacuo to give the product (415 mg, crude product) which was used in the next step without further purification. [M+H] + =584.4.

[1031] Step 4: (R)-5-(tert-butyl)-N-(1-(4-(6-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidine-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

[1032]

[1033] A mixture of (R)-5-(tert-butyl)-N-(1-(3-fluoro-2-methyl-4-(6-(6-(piperazin-1-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide (207 mg, crude) and 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbaldehyde (40 mg, 0.14 mmol) in DCM (10 mL) and MeOH (2 mL) was stirred in a round-bottom flask at room temperature for 2 hours. NaBH(OAc)3 (212 mg, 1.0 mmol) was added to the mixture and stirred at room temperature in a round-bottom flask overnight. The mixture was then purified by preparative TLC (DCM:MeOH=7:1) to give the product (40 mg, 57%). 1 H NMR (400 MHz, DMSO) δ H 12.64(s,1H),10.27(s,1H),9.62(d,J=7.6Hz,1H),8.76(s,1H),8.14(d,J=8.4Hz,1H),7.74-7.5 7(m,1H),7.48(d,J=8.0Hz,1H),7.13(d,J=8.8Hz,2H),7.03-6.88(m,3H),6.84(s,1H),5.48-5.3 2(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.

[1034] 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

[1035]

[1036] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H12.61(s,1H),10.24(s,1H),9.60(d,J=7.6Hz,1H),8.75(s,1H),8.13(d,J=7.2Hz,1H),7.64(t,J=7.2Hz,1 H),7.47(d,J=8.0Hz,1H),7.04(d,J=8.4Hz,1H),6.92(d,J=9.2Hz,1H),6.87-6.80(m,2H),6.77(d,J=8.0Hz ,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=6.4Hz,3H),1.43(s,9H),1.27-1.17(m,2H);[M+H] + =883.8.

[1037] 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

[1038]

[1039] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H12.60(s,1H),10.26(s,1H),9.92(d,J=7.9Hz,1H),8.82(s,1H),8.67(s,1H),8.03(d,J=8.7Hz,1H),7.83( s,2H),7.66(d,J=8.0Hz,1H),7.13(d,J=8.8Hz,2H),7.00(d,J=9.0Hz,1H),6.93(d,J=8.9Hz,2H),5.43-5.3 1(m,1H),3.70(t,J=7.7Hz,4H),3.60(s,4H),2.67(t,J=11.0Hz,4H),2.50(s,3H),2.46(s,4H),2.22(d,J=5 .7Hz,2H),1.82(d,J=12.2Hz,2H),1.72(s,1H),1.55(d,J=6.8Hz,3H),1.37(s,9H),1.23(d,J=11.3Hz,2H); 19 F NMR (376.42 MHz, DMSO) δ F -160.30; [M+H] + =869.7.

[1040] 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

[1041]

[1042] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H12.52(s,1H),10.74(s,1H),9.95(d,J=7.7Hz,1H),8.09(d,J=8.1Hz,1H),8.04(s,1H),7.92(d,J=8.3Hz,2H) ,7.66(d,J=8.3Hz,1H),7.23(s,1H),7.04-7.01(m,4H),6.49(d,J=8.5Hz,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. [M+H] + =835.7.

[1043] 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

[1044]

[1045] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H12.61(s,1H),10.26(s,1H),9.58(d,J=8.0Hz,1H),8.79(d,J=8.0Hz,1H),8.27(s,1H),8.15(t,J= 8.0Hz,2H),7.71(d,J=8.0Hz,1H),7.28(s,1H),7.13(d,J=8.0Hz,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),2.2 2(d,J=4.0Hz,2H),1.82(d,J=12.0Hz,2H),1.73(s,1H),1.55(d,J=8.0Hz,3H),1.42(s,9H);[M+H] + =867.8.

[1046] 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

[1047]

[1048] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H12.60(s,1H),10.24(s,1H),9.58(d,J=8.0Hz,1H),8.79(d,J=8.0Hz,1H),8.27(s,1H),8.15(t,J=8.0Hz,2H),7.71 (d,J=8.0Hz,1H),7.28(s,1H),7.04(d,J=8.0Hz,1H),6.96(d,J=8.0Hz,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=12.0,6.0Hz,3H),2.74-2.60(m,5H),2.48(s,3H),2.2 [M+H] + =881.8.

[1049] 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

[1050]

[1051] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H12.60(s,1H),9.96(d,J=8.0Hz,1H),8.81(s,1H),8.77(s,1H),8.11-8.09(m,1H),8.05-8.02(m,1H),7.6 6-7.64(m,1H),7.25(s,1H),7.14(d,J=8.0Hz,2H),6.96-6.92(m,3H),5.40-5.36(m,1H),3.69-3.66(m,4 H),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=6.6Hz,3H),1.37(s,9H);[M+H] + =865.8.

[1052] 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

[1053]

[1054] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H12.60(s,1H),10.25(s,1H),9.94(d,J=8.0Hz,1H),8.79(s,1H),8.39(s,1H),8.13-7.96(m,3H),7. 68(d,J=8.0Hz,1H),7.54-7.34(m,2H),7.13(d,J=8.0Hz,2H),6.93(d,J=8.0Hz,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=4.0Hz,3H),2.24(d,J=4.0Hz,2H ),1.81(d,J=12.0Hz,2H),1.72(s,1H),1.56(d,J=4.0Hz,3H),1.37(s,9H),1.29-1.17(m,3H);[M+H] + =851.7.

[1055] 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

[1056]

[1057] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.58(s,1H),10.25(s,1H),9.98-9.90(m,1H),8.93-8.65(m,2H),8.22-8.13(m,1H),8.12 -8.00(m,2H),7.71-7.61(m,1H),7.29(s,1H),7.17-7.09(m,2H),7.00-6.88(m,3H),5.38(s ,1H),3.75-3.50(m,9H),2.67(s,5H),2.55-2.52(m,3H),2.47-2.42(m,2H),2.22(s,2H),1. 82(d,J=12.0Hz,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.

[1058] 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

[1059]

[1060] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.14(s,1H),10.25(s,1H),9.55(d,J=8.0Hz,1H),8.82(s,1H),7.89(d,J=8.0Hz,1H),7.53(d,J=8.0Hz ,1H),7.13(d,J=8.0Hz,2H),6.93(d,J=8.0Hz,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=8.0Hz,3H),1.43(s,9H),1.27-1.21(m,3H);[M+H] + =901.7.

[1061] 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

[1062]

[1063] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H12.61(s,1H),10.25(s,1H),9.82(d,J=8.0Hz,1H),8.79(s,1H),8.39(s,1H),8.13-8.0 2(m,3H),7.48-7.39(m,3H),7.13(d,J=8.0Hz,2H),6.93(d,J=8.0Hz,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); [M+H] + =849.7.

[1064] 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

[1065]

[1066] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.60(s,1H),10.25(s,1H),9.82(d,J=8.0Hz,1H),8.81(s,1H),8.77(s,1H),8.14-8.10(m ,3H),7.47(d,J=8.0Hz,1H),7.28(s,1H),7.13(d,J=8.0Hz,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),2.4 7-2.44(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.

[1067] 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

[1068]

[1069] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.68(s,1H),10.26(s,1H),9.86(d,J=7.6Hz,1H),8.61(s,1H),7.86-7.72(m,2H) ,7.57(d,J=8.0Hz,1H),7.36(d,J=2.0Hz,1H),7.15(d,J=8.8Hz,2H),6.96(d,J=8. 4Hz,2H),5.42-5.21(m,1H),3.86-3.54(m,6H),3.18-2.87(m,5H),2.80-2.64(m,7 H),2.48-2.25(m,8H),2.11-1.80(m,5H),1.51(d,J=6.8Hz,3H),1.36(s,9H);[M+H] + =867.9.

[1070] 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

[1071]

[1072] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H12.53(s,1H),10.81(s,1H),9.95(d,J=7.2Hz,1H),8.75(s,1H),8.09(d,J=7.6Hz,1H),8.03(s,1H),7.9 2(d,J=8.4Hz,2H),7.67(d,J=7.8Hz,1H),7.22-7.14(m,5H),7.03(d,J=8.4Hz,2H),5.38(t,J=7.6Hz,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=6.4Hz,3H),1.37(s,9H);[M+H] + =806.8.

[1073] 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

[1074]

[1075] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.68(s,1H),10.25(s,1H),10.00(d,J=8.0Hz,1H),8.81(s,1H),8.39(s,1H),8.15-8.04(m,2H),7. 98(d,J=12.0Hz,1H),7.73(t,J=8.0Hz,1H),7.51-7.42(m,2H),7.13(d,J=8.0Hz,2H),6.93(d,J=8.0H z,2H),5.62-5.42(m,1H),3.81-3.58(m,4H),3.10-2.82(m,1H),2.75-2.62(m,4H),2.54(s,6H),2.2 4(s,2H),1.82(d,J=12.0Hz,2H),1.74(s,1H),1.60(d,J=8.0Hz,3H),1.38(s,9H),1.23(s,3H);[M+H]+ =855.8.

[1076] Example 155: (R)-3-(tert-Butyl)-N-(1-(4-(6-(1-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-3,5-dimethyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-N-methyl-1,2,4-oxadiazole-5-carboxamide

[1077]

[1078] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.19(s,1H),10.23(s,1H),8.80(s,1H),8.15-8.01(m,2H),7.73-7.55(m,1H),7.15(d,J=8.4Hz,2H),6 .95(d,J=8.4Hz,2H),6.83-6.71(m,1H),6.02-5.87(m,1H),3.71(d,J=6.8Hz,4H),3.21-3.11(m,1H),3. 10-2.91(m,2H),2.82-2.78(m,1H),2.76-2.73(m,2H),2.72-2.65(m,4H),2.44-2.32(m,6H),2.32-2.20 (m,5H),2.05(s,2H),1.93-1.88(m,2H),1.75-1.68(m,1H),1.66-1.59(m,2H),1.37-1.31(m,11H);[M+H] + =881.7.

[1079] Example 156: (R)-5-(tert-Butyl)-N-(5-(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)-2,3-dihydro-1H-inden-1-yl)-1,2,4-oxadiazole-3-carboxamide

[1080]

[1081] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H12.51(s,1H),10.24(s,1H),9.39(d,J=8.0Hz,1H),8.75(s,1H),8.13-8.10(m,2H),7.90(d,J=8.0Hz ,2H),7.43(d,J=8.0Hz,1H),7.21(s,1H),7.13(d,J=8.0Hz,2H),7.04(d,J=8.0Hz,2H),6.93(d,J=8. 0Hz,2H),5.63-5.61(m,1H),3.71-3.68(m,4H),3.26-3.15(m,5H),3.01-2.97(m,1H),2.69-2.64(m, [M+H] + =848.8.

[1082] Example 157: (R)-3-(tert-Butyl)-N-(1-(4-(6-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)azetidin-3-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[1083]

[1084] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.70(s,1H),10.26(s,1H),9.97(d,J=7.6Hz,1H),8.81(s,1H),8.13-7.99(m,4H),7. 68(d,J=8.2Hz,1H),7.48(d,J=7.2Hz,2H),7.40(s,1H),7.13(d,J=8.8Hz,2H),6.93(d ,J=8.8Hz,2H),5.44-5.33(m,1H),3.74-3.59(m,6H),2.72-2.53(m,11H),2.38(s,2H) ,1.79(d,J=12.0Hz,2H),1.55(d,J=6.8Hz,3H),1.38(s,9H),1.31-1.22(m,2H);[M+H] + =821.8.

[1085] Example 158: 3-(tert-Butyl)-N-((1R)-1-(4-(6-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-3-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[1086]

[1087] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.67(s,1H),10.26(s,1H),9.97(d,J=7.6Hz,1H),8.81(s,1H),8.14-7.94(m,4H),7. 67(d,J=8.2Hz,1H),7.43(d,J=6.4Hz,2H),7.39(s,1H),7.13(d,J=8.6Hz,2H),6.94(d ,J=8.0Hz,2H),5.44-5.34(m,1H),3.77-3.63(m,4H),2.79-2.53(m,12H),2.45-2.22( m,3H),1.92-1.60(m,4H),1.55(d,J=6.8Hz,3H),1.37(s,9H),1.31-1.24(m,2H);[M+H] + =835.7.

[1088] Example 159: (R)-3-(tert-Butyl)-N-(1-(4-(6-(6-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2,5-dihydro-1H-pyrrol-3-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[1089]

[1090] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H12.93(s,1H),10.27(s,1H),9.99(d,J=7.6Hz,1H),9.27(s,1H),8.85(s,1H),8.49(d,J=6.8Hz,1H ),8.18-8.08(m,2H),8.06(s,1H),7.92-7.81(m,1H),7.72-7.59(m,2H),7.15(d,J=8.4Hz,2H),6. 96(d,J=8.4Hz,2H),6.80(s,1H),5.46-5.33(m,1H),4.53-3.88(m,4H),3.78-3.64(m,4H),3.00(s [M+H] + =834.8.

[1091] Example 160: (R)-3-(tert-Butyl)-N-(1-(4-(6-(2-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[1092]

[1093] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.67(s,1H),10.26(s,1H),9.96(d,J=7.8Hz,1H),9.03(s,2H),8.79(s,1H),8.08(d,J=7.4Hz,1 H),8.04(s,1H),7.67(d,J=8.2Hz,1H),7.37(s,1H),7.13(d,J=8.9Hz,2H),6.93(d,J=9.0Hz,2H), 5.38(s,1H),3.83(s,4H),3.64-3.75(m,4H),2.61-2.71(m,4H),2.43-2.58(m,7H),2.23(s,2H), 1.83(d,J=12.7Hz,2H),1.73(s,1H),1.55(d,J=6.9Hz,3H),1.37(s,9H),1.15-1.30(m,2H);[M+H] + =852.8.

[1094] Example 161: (R)-3-(tert-Butyl)-N-(1-(4-(6-(1-(1-(((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)glycyl)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

[1095]

[1096] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.15(s,1H),10.27(s,1H),9.94(d,J=7.6Hz,1H),8.79(s,2H),8.07-7.90(m,2H),7.65(d,J=8.4Hz,1H),7.1 5(d,J=8.8Hz,2H),6.95(d,J=8.8Hz,2H),6.75(s,1H),5.43-5.29(m,1H),4.60-4.43(m,2H),4.14(dd,J=44.8 ,16.0Hz,2H),3.82(d,J=12.8Hz,1H),3.76-3.64(m,4H),3.44-3.37(m,1H),3.28-3.20(m,1H),2.95-2.81(m, [M+H] + =924.8.

[1097] Example 162: 3-(tert-Butyl)-N-((1R)-1-(4-(6-(6-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-3-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[1098]

[1099] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H12.87(s,1H),10.26(s,1H),10.00(d,J=7.6Hz,1H),9.19(s,1H),8.84(s,1H),8.38(d,J=8.0Hz,1H),8.16-8.03(m, 2H),7.68(d,J=7.6Hz,1H),7.57-7.44(m,2H),7.13(d,J=8.8Hz,2H),6.93(d,J=8.0Hz,2H),5.44-5.31(m,1H),3.74- 3.62(m,4H),3.60-3.50(m,1H),3.06-2.96(m,1H),2.72-2.58(m,6H),2.54(s,3H),2.42-2.30(m,2H),2.27-2.17(m, [M+H] + =836.8.

[1100] Example 163: 3-(tert-Butyl)-N-((1R)-1-(4-(6-(1-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-3-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

[1101]

[1102] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H12.16(s,1H),10.26(s,1H),9.93(d,J=8.0Hz,1H),8.79(s,1H),8.09-7.90(m,2H),7.65(d, J=8.0Hz,1H),7.14(d,J=8.0Hz,2H),6.94(d,J=8.0Hz,2H),6.75(s,1H),5.47-5.17(m,1H),4 .93(s,1H),3.78-3.62(m,4H),3.21-2.76(m,4H),2.74-2.55(m,6H),2.45-2.10(m,9H),1.85 (d,J=12.0Hz,2H),1.64(s,1H),1.54(d,J=8.0Hz,3H),1.36(s,9H),1.30-1.18(m,3H); [M+H] + =853.8.

[1103] Example 164: (R)-3-(tert-Butyl)-N-(1-(4-(6-(4-(6-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide

[1104]

[1105] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.48(s,1H),10.26(s,1H),9.96(d,J=8.0Hz,1H),8.74(s,1H),8.10-7.97(m,2H),7.89(d,J=8.0Hz,2H ),7.66(d,J=8.0Hz,1H),7.24-7.05(m,3H),6.94(d,J=8.0Hz,2H),6.54(d,J=8.0Hz,2H),5.45-5.21(m,1 H),4.55-4.15(m,2H),4.04(s,4H),3.76-3.61(m,4H),3.20-2.80(m,2H),2.75-2.60(m,4H),2.53(s,4H) ,1.76(d,J=12.0Hz,2H),1.68-1.60(m,1H),1.55(d,J=8.0Hz,2H),1.37(s,9H),1.33-1.22(m,3H);[M+H] +=862.9.

[1106] Example 165: (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)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide

[1107]

[1108] The title compound was synthesized using a procedure similar to that of Example 25. 1 H NMR (400 MHz, DMSO) δ H 12.62(s,1H),10.26(s,1H),9.89(d,J=7.6Hz,1H),8.78(s,1H),8.39(s,1H),8.11-7.98(m,3H ),7.66(d,J=8.0Hz,1H),7.51-7.35(m,2H),7.14(d,J=8.4Hz,2H),6.93(d,J=8.0Hz,2H),5.41 -5.28(m,1H),3.84-3.53(m,5H),2.75-2.58(m,5H),2.57-2.51(m,7H),2.32-2.14(m,2H),2.0 0-1.62(m,4H),1.54(d,J=6.8Hz,3H),1.49(s,3H),1.39-1.10(m,5H),1.03-0.95(m,2H);[M+H] + =849.8.

[1109] Example 166: (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)-3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxamide

[1110] Step 1: Lithium 3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxylate

[1111]

[1112] To a mixture of ethyl 3-(1-methylcyclopropyl)-1,2,4-oxadiazole-5-carboxylate (1.0 g, 5.0 mmol) in THF / MeOH / water (5 mL / 5 mL / 1 mL) was added LiOH HO (0.23 g, 5.5 mmol). The mixture was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The reaction was concentrated in vacuo to give the product (1.48 g, crude), which was used in the next step without further purification. [M+H] + =168.8.

[1113] Step 2: (R)-N-(1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene (1-Methylcyclopro...

Claims

1. A compound, which is:

2. A compound having the following structure: or a pharmaceutically acceptable salt thereof.

3. A compound, which is:

4. A compound having the following structure: or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising the compound according to claim 1, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising the compound according to claim 3, or a pharmaceutically acceptable salt thereof.

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