Pyrimidines for the degradation of Bruton's tyrosine kinases

Abstract

To provide a compound that induces Btk proteolysis via the ubiquitin proteolysis pathway. [Solution] The present invention relates to a compound of formula (I) that is useful as a drug in the treatment of CLL. JPEG2026063166000023.jpg70150 And provides pharmaceutically acceptable salts thereof.

Description

[Background Technology]

[0001] Bruton's tyrosine kinase (Btk) is the most important signaling enzyme expressed in hematopoietic cells. Btk plays an essential role in the B cell signaling pathway, linking stimulation of the cell surface B cell receptor (BCR) to downstream intracellular responses. Btk is a critical regulator of B cell development, activation, signaling, and survival (Kurosaki, Curr Op Imm, 2000, pp. 276-281; ​​Schaeffer and Schwartzberg, Curr Op Imm, 2000, pp. 282-288). Furthermore, Btk plays a role in other hematopoietic cell signaling pathways, such as TNF-α production mediated by Toll-like receptors (TLRs) and cytokine receptors in macrophages, IgE receptor (FcepsilonRI) signaling in mast cells, inhibition of Fas / APO-1 apoptotic signaling in B-lineage lymphoid cells, and collagen-stimulated platelet aggregation. For example, see CAJeffries et al., (2003), Journal of Biological Chemistry, Vol. 278, pp. 26258-26264; NJHorwood et al., (2003), The Journal of Experimental Medicine, Vol. 197, pp. 1603-1611; Iwaki et al., (2005), Journal of Biological Chemistry, Vol. 280 (No. 48), pp. 40261-40270; Vassilev et al., (1999), Journal of Biological Chemistry, Vol. 274 (No. 3), pp. 1646-1656; and Quek et al., (1998), Current Biology, Vol. 8 (No. 20), pp. 1137-1140. Currently, Btk inhibitors are under research. As an alternative to inhibition, Btk proteolysis may affect B cell function not only by blocking BCR signaling but also by reducing the presence of Btk protein from the cell itself. Reducing Btk protein should lead to decreased Btk kinase activity and impaired Btk's protein interactions or scaffolding function.Therefore, there is a medical need to develop Btk degrading agents. [Prior art documents] [Non-patent literature]

[0002] [Non-Patent Document 1] Kurosaki, Curr Op Imm, 2000, pp. 276-281. [Non-Patent Document 2] Schaeffer and Schwartzberg, *Curr Op Imm*, 2000, pp. 282-288. [Non-Patent Document 3] CAJeffries et al. (2003), Journal of Biological Chemistry, Vol. 278: pp. 26258-26264. [Non-Patent Document 4] NJHorwood et al., (2003), The Journal of Experimental Medicine, Vol. 197: pp. 1603-1611. [Non-Patent Document 5] Iwaki et al., (2005), Journal of Biological Chemistry, Vol. 280 (No. 48): pp. 40261-40270. [Non-Patent Document 6] Vassilev et al., (1999), Journal of Biological Chemistry, Vol. 274 (No. 3): pp. 1646-1656. [Non-Patent Document 7] Quek et al., (1998), Current Biology, Vol. 8 (No. 20): pp. 1137-1140. [Overview of the Initiative] [Means for solving the problem]

[0003] (Summary of the invention) In some embodiments, compounds that induce proteolysis of Btk via the ubiquitin proteolysis pathway are provided herein.

[0004] In some embodiments, the compound of formula (I),

[0005] [Chemical Formula] [wherein, R 1 is selected from the group consisting of hydrogen, C1-C3 alkyl, CN, C1-C3 haloalkyl, halo, CH2OCH3, CH2OH, and CH2CN; R 2 and R 3 are each independently selected from the group consisting of hydrogen and halo; R 4a and R 4b are each independently selected from the group consisting of hydrogen, C1-C3 alkyl, and CH2OCH3; R 5 is selected from the group consisting of hydrogen, halo, and C1-C3 alkyl]; or a pharmaceutically acceptable salt thereof is provided.

[0006] In some embodiments, R 1 is selected from the group consisting of hydrogen, C1-C3 alkyl, CN (cyano), C1-C3 haloalkyl, halo, CH2OCH3, CH2OH, and CH2CN, or a pharmaceutically acceptable salt thereof. In some embodiments, R 1 is C1-C3 alkyl or a pharmaceutically acceptable salt thereof. In some embodiments, R 1 is methyl or a pharmaceutically acceptable salt thereof. In some embodiments, R 1 is hydrogen or a pharmaceutically acceptable salt thereof. In some embodiments, R 1 is CN or a pharmaceutically acceptable salt thereof. In some embodiments, R 1 is C1-C3 haloalkyl or a pharmaceutically acceptable salt thereof. In some embodiments, R 1 is CF3 or a pharmaceutically acceptable salt thereof. In some embodiments, R 1is a halo or a pharmaceutically acceptable salt thereof. In some embodiments, R 1 is Cl or a pharmaceutically acceptable salt thereof. In some embodiments, R 1 is F or a pharmaceutically acceptable salt thereof. In some embodiments, R 1 is CH2OCH3 or a pharmaceutically acceptable salt thereof. In some embodiments, R 1 is CH2OH or a pharmaceutically acceptable salt thereof. In some embodiments, R 1 This refers to CH2CN or a pharmaceutically acceptable salt thereof.

[0007] In some embodiments, R 2 R is selected from the group consisting of hydrogen and halos, or pharmaceutically acceptable salts thereof. In some embodiments, R 2 is hydrogen or a pharmaceutically acceptable salt thereof. In some embodiments, R 2 is a halo or a pharmaceutically acceptable salt thereof. In some embodiments, R 2 This is F or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, R 3 R is selected from the group consisting of hydrogen and halos, or pharmaceutically acceptable salts thereof. In some embodiments, R 3 is hydrogen or a pharmaceutically acceptable salt thereof. In some embodiments, R 3 is a halo or a pharmaceutically acceptable salt thereof. In some embodiments, R 3 This is F or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, R 4a and R 4b R is independently selected from the group consisting of hydrogen, C1-C3 alkyl and CH2OCH3, or pharmaceutically acceptable salts thereof. In some embodiments, R 4a is hydrogen, and R 4b is hydrogen or a pharmaceutically acceptable salt thereof. In some embodiments, R 4ais hydrogen, and R 4b is methyl or a pharmaceutically acceptable salt thereof. In some embodiments, R 4a It is methyl, and R 4b is hydrogen or a pharmaceutically acceptable salt thereof. In some embodiments, R 4a is hydrogen, and R 4b is ethyl or a pharmaceutically acceptable salt thereof. In some embodiments, R 4a It is ethyl, and R 4b is hydrogen or a pharmaceutically acceptable salt thereof. In some embodiments, R 4a It is methyl, and R 4b is methyl or a pharmaceutically acceptable salt thereof. In some embodiments, R 4a is hydrogen, and R 4b is isopropyl or a pharmaceutically acceptable salt thereof. In some embodiments, R 4a It is isopropyl, and R 4b is hydrogen or a pharmaceutically acceptable salt thereof. In some embodiments, R 4a is hydrogen, and R 4b is CH2OCH3 or a pharmaceutically acceptable salt thereof. In some embodiments, R 4a It is CH2OCH3, and R 4b This is hydrogen or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, R 5 R is selected from the group consisting of hydrogen, halos and C1-C3 alkyl groups, or pharmaceutically acceptable salts thereof. In some embodiments, R 5 is hydrogen or a pharmaceutically acceptable salt thereof. In some embodiments, R 5 is a halo or a pharmaceutically acceptable salt thereof. In some embodiments, R 5 is F or a pharmaceutically acceptable salt thereof. In some embodiments, R 5 is Cl or a pharmaceutically acceptable salt thereof. In some embodiments, R 5 This is methyl or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, R 1 It is methyl, and R 2 is hydrogen or a pharmaceutically acceptable salt thereof. In some embodiments, R 1 It is methyl, and R 2 is hydrogen, and R 3 is hydrogen or a pharmaceutically acceptable salt thereof. In some embodiments, R 1 It is methyl, and R 2 is hydrogen, and R 3 is hydrogen, and R 4a is hydrogen, and R 4b is methyl or a pharmaceutically acceptable salt thereof. In some embodiments, R 1 It is methyl, and R 2 is hydrogen, and R 3 is hydrogen, and R 5 is hydrogen or a pharmaceutically acceptable salt thereof. In some embodiments, R 1 It is methyl, and R 4a is hydrogen, and R 4b is methyl or a pharmaceutically acceptable salt thereof. In some embodiments, R 2 is hydrogen, and R 4a is hydrogen, and R 4b is methyl or a pharmaceutically acceptable salt thereof. In some embodiments, R 3 is hydrogen, and R 4a is hydrogen, and R 4b This is methyl or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, R 5 is hydrogen, and R 4a is hydrogen, and R 4b is methyl or a pharmaceutically acceptable salt thereof. In some embodiments, R 5 is hydrogen, and R 4a is hydrogen, and R 4b It is methyl, and R 3 is hydrogen or a pharmaceutically acceptable salt thereof. In some embodiments, R 5is hydrogen, and R 4a is hydrogen, and R 4b is methyl, and R 3 is hydrogen, and R 2 is hydrogen or a pharmaceutically acceptable salt thereof. In some embodiments, R 5 is hydrogen, and R 4a is hydrogen, and R 4b is methyl, and R 3 is hydrogen, and R 1 is methyl or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, R 1 is methyl, and R 3 is halo or a pharmaceutically acceptable salt thereof. In some embodiments, R 1 is methyl, and R 3 is F or a pharmaceutically acceptable salt thereof. In some embodiments, R 1 is methyl, and R 2 is halo or a pharmaceutically acceptable salt thereof. In some embodiments, R 1 is methyl, and R 2 is F or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, R 5 is halo, and R 4a is hydrogen, and R 4b is methyl or a pharmaceutically acceptable salt thereof. In some embodiments, R 5 is F, and R 4a is hydrogen, and R 4b is methyl or a pharmaceutically acceptable salt thereof. In some embodiments, R 5 is halo, and R 4a is methyl, and R 4b is hydrogen or a pharmaceutically acceptable salt thereof. In some embodiments, R 5 is F, and R 4a is methyl, and R 4b is hydrogen or a pharmaceutically acceptable salt thereof. In some embodiments, R5 It is a halo, and R 4a is hydrogen, and R 4b is ethyl or a pharmaceutically acceptable salt thereof. In some embodiments, R 5 F is R 4a is hydrogen, and R 4b is ethyl or a pharmaceutically acceptable salt thereof. In some embodiments, R 5 It is a halo, and R 4a It is ethyl, and R 4b is hydrogen or a pharmaceutically acceptable salt thereof. In some embodiments, R 5 F is R 4a It is ethyl, and R 4b This is hydrogen or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, pharmaceutical compositions are provided that, in combination with a pharmaceutically acceptable carrier, comprise a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, a therapeutically effective amount is used in combination with a pharmaceutically acceptable carrier.

[0017] [ka] A pharmaceutical composition is provided containing, or a pharmaceutically acceptable salt thereof.

[0018] In some embodiments, the compound is

[0019] [ka] or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the compound is

[0021] [ka] That is the case.

[0022] In some embodiments, the compound is

[0023] [ka] It is a pharmaceutically acceptable salt.

[0024] In some embodiments, the compound is 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the compound is 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide.

[0026] In some embodiments, the compound is 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide.

[0027] In some embodiments, the compound is 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2R)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-{(1R)-1-[4-(6-{[5-(4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}piperazine-1-yl)pyridine-2-yl]amino}pyrimidine-4-yl)-2-methylphenyl]ethyl}-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)-3-fluorophenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2R)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)-3-fluorophenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-ethylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)-3-fluorophenyl]ethyl}-2-ethylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2R)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-ethylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-{(1R)-1-[4-(6-{[5-(4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2,2-dimethylpiperazine-1-yl)pyridine-2-yl]amino}pyrimidine-4-yl)-2-methylphenyl]ethyl}-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-3-fluoro-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-{(1R)-1-[4-(6-{[5-(4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}piperazine-1-yl)pyridine-2-yl]amino}pyrimidine-4-yl)-3-fluoro-2-methylphenyl]ethyl}-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-{(1R)-1-[4-(6-{[5-(4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}piperazine-1-yl)pyridine-2-yl]amino}pyrimidine-4-yl)-5-fluoro-2-methylphenyl]ethyl}-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-(propan-2-yl)piperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-[(1R)-1-{2-chloro-4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]phenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2R)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-(methoxymethyl)piperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-(trifluoromethyl)phenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; and Selected from the group consisting of 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-fluorophenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; or pharmaceutically acceptable salts thereof.

[0028] Definition of Terms As used in this specification and the appended claims, unless otherwise specified, the following terms have the meanings set forth below.

[0029] When used herein and in the claims thereof, it should be noted that, unless otherwise explicitly indicated in the context, the singular forms ("a," "an," and "the") include multiple subjects. Therefore, for example, a reference to "compound" includes a single compound as well as one or more of the same or different compounds.

[0030] In some cases, the number of carbon atoms in a certain part is determined by the prefix "C". x ~C y」 This is shown by x = y = x, where x is the minimum value and y is the maximum number of carbon atoms in the substituent. Therefore, for example, "C1-C3 alkyl" means an alkyl substituent containing 1 to 3 carbon atoms.

[0031] As used herein, the term "alkyl" refers to a saturated, linear or branched hydrocarbon chain group having 1, 2, 3, 4, 5, or 6 carbon atoms, unless otherwise specified. The term "C1-C3 alkyl" refers to an alkyl group having 1, 2, or 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, and isopropyl. In some embodiments, the alkyl group is methyl. In some embodiments, the alkyl group is ethyl. In some embodiments, the alkyl group is propyl. In some embodiments, the alkyl group is isopropyl.

[0032] As used herein, the term "halo" means Cl (chloro), Br (bromo), I (iodine), and F (fluoro). In some embodiments, the halo is selected from the group consisting of Cl or F. In some embodiments, the halo is Cl. In some embodiments, the halo is F.

[0033] As used herein, the term “haloalkyl” refers to an alkyl group in which one or more hydrogen atoms are replaced by a halo group, as defined herein. For example, the term “C 1~ A "C3 haloalkyl" refers to a haloalkyl group having one, two, or three carbon atoms. In some embodiments, one, two, or three hydrogen atoms can be replaced by fluoro groups, respectively. Examples of haloalkyl groups include trifluoromethyl or CF3. [Brief explanation of the drawing]

[0034] [Figure 1] This figure shows the in vivo activity of compound 1 (Example 1) in TCL1-driven CLL with the BtkC481S mutation in C57BL / 6 mice. [Modes for carrying out the invention]

[0035] In some embodiments, the compounds disclosed herein include two ligands linked via a linker. The first ligand is capable of binding to Btk. The second ligand is capable of recruiting a ubiquitin ligase. In some embodiments, the ubiquitin ligase is an E3 ligase. In some embodiments, the E3 ubiquitin ligase is cereblon (CRBN) and / or contains cereblon (CRBN). In some embodiments, the second ligand is capable of recruiting CRBN. In some embodiments, the second ligand is capable of binding to CRBN. In some embodiments, the compounds described herein are capable of binding to Btk and recruiting a ubiquitin ligase containing cereblon. In some embodiments, the compounds disclosed herein recruit an E3 ligase to Btk, causing proximity-induced ubiquitination and degradation of Btk by the ubiquitin-proteasome system (UPS). In some embodiments, the compounds disclosed herein can bind to Btk and reduce the amount of Btk in cells by degradation.

[0036] In some embodiments, the compounds disclosed herein are useful in the treatment of chronic lymphocytic leukemia (CLL). For example, the compounds described herein are useful in treating CLL by degrading Btk in patients via the ubiquitin proteolytic pathway.

[0037] In some embodiments, the compounds disclosed herein are Btk C481S In cell lines expressing Btk C481S It degrades the protein (Btk protein with the C481 mutation).

[0038] In some embodiments, a method is provided for treating a patient with CLL, comprising the step of administering a compound of formula (I) to the patient.

[0039] In some embodiments, a method for treating CLL is provided, comprising the step of administering a therapeutically effective amount of a compound of formula (I) to a subject in need thereof.

[0040] The term "pharmaceutically acceptable salt" refers to a salt that is free from excessive toxicity, irritation, and allergic reactions, and is suitable for use in contact with human and lower animal tissues within the bounds of sound medical judgment, with a reasonable benefit-to-risk ratio.

[0041] As used herein, the term "subject" refers to a human being. The terms "human being," "patient," and "subject" are used synonymously herein.

[0042] As used herein, the terms “to treat,” “treating,” and “treatment” refer to a method of alleviating or suppressing a disease and / or its associated symptoms.

[0043] The term "therapeutic dose" refers to the amount of a compound, or a pharmaceutically acceptable salt thereof, that, when administered therapeutically to a particular subject or population, is sufficient to prevent the occurrence of one or more symptoms of the condition or disorder being treated, or to alleviate to some extent one or more symptoms of the condition or disorder being treated. In some embodiments, the amount is effective in breaking down Btk in a patient.

[0044] General synthesis The compounds of this disclosure can be better understood in relation to the following synthetic schemes and methods illustrating means by which the compounds can be prepared. Typical procedures, but not limited to them, are shown in Schemes 1 to 5. In Schemes 1 to 5, the variable group R 1 , R 2 , R 3 , R 4 and R 5This may be as described herein. The final compound of the present invention was named using the ACD / Name 2021.1.3 (file version N15E41, Build 123232, July 7, 2021) software program and / or by using the Struct=Name naming algorithm as part of CHEMDRAW® Professional v.20.1.1.125. The intermediate was named using CHEMDRAW® Professional v.20.1.1.125.

[0045] The compounds of the present invention can be prepared according to the scheme described below.

[0046] [ka]

[0047] A method for preparing substituted 1-phenyldihydropyrimidine-2,4(1H,3H)-dione base units 1-6 is illustrated in Scheme 1. Substituent R in compound 1-1 5 This can be a halo, hydrogen, or C1-C3 alkyl, as described herein. The reaction of compound 1-1 with tert-butyldimethylsilyl chloride in the presence of imidazole can yield compound 1-2. The reaction of compound 1-2 with acrylic acid using heat can form compound 1-3. Compound 1-3 can be reacted with urea in heated acetic acid to produce compound 1-4. Compound 1-4 can be treated with an aqueous solution of HCl to produce intermediate 1-5. Intermediate 1-5 can be treated with iodine and then with Ph3P in the presence of imidazole to produce iodine compound 1-6, or intermediate 1-5 can be treated with CBr4 and then with Ph3P to produce bromo compound 1-6.

[0048] [ka]

[0049] A method for preparing substituent units 2-7 is illustrated in Scheme 2. Substituting benzaldehyde 2-1 [wherein R 1 , R 2 and R 3 The reaction of (S)-2-methylpropane-2-sulfinamide 2-2 with [which may be as described herein] can produce compound 2-3. Reaction of compound 2-3 with CH3MgBr under Grignard reaction conditions can produce intermediate 2-4. Intermediate 2-5 can be synthesized from intermediate 2-4 using bis(pinacolate)diborone and a palladium catalyst. Amine 2-6 can be prepared from intermediate 2-5 by removing the t-butylsulfinyl group with a strong acid or iodine. Heteroarylcarboxamide base unit 2-7 can be synthesized directly from amine 2-6 by methyl 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate.

[0050] [ka]

[0051] As shown in Scheme 3, the basic unit 3-4 [in the formula, R 4a and R 4b [As described herein] can be prepared from compound 3-3 by hydrogenation or nitro reduction reaction. Intermediate compound 3-3 is S N These compounds can be prepared from 2-nitro-5-halopyridine compound 3-1 and substituted piperazine compound 3-2 by an Ar reaction or a Buchwald-Hartwing cross-coupling reaction.

[0052] [ka]

[0053] A general synthesis for the intermediates of Equations 4-5 is shown in Scheme 4, R 1 , R2 , R 3 , R 4a and R 4b This may be as described herein. Intermediate 4-2 can be prepared by the Suzuki reaction of base unit 2-7 with 4,6-dichloropyrimidine 4-1. Intermediate 4-4 can be prepared from compound 4-2 by the Buchwald-Hartwig cross-coupling reaction with substituted 2-aminopyridine compound 3-4. The tert-butyloxycarbonyl protecting group can be cleaved with hydrochloric acid or trifluoroacetic acid to produce base unit 4-5.

[0054] [ka]

[0055] A general synthesis for the target compound of formula 5-4 is shown in scheme 5, R 1 , R 2 , R 3 , R 4a , R 4b and R 5 This may be as described herein. Iodine or bromo base units 1-6 can be reacted with intermediates 4-5 by an alkylation reaction using sodium iodide and a base, such as N,N-diisopropylethylamine, to produce target compounds 5-4.

[0056] Since the scope of this disclosure is defined in the attached claims, it should be understood that the synthesis schemes and certain examples illustrated in the Examples section are illustrative and should not be interpreted as limiting the scope of this disclosure. All substitutes, modifications, and equivalents of the synthesis methods and certain examples are included within the scope of the claims.

[0057] The following embodiments can be used for illustrative purposes and should not be considered to limit the scope of the present disclosure.

[0058] Exemplary compounds of formula (I) include, but are not limited to, the compounds listed in Table 1 below, and pharmaceutically acceptable salts thereof.

[0059] [Table 1] JPEG2026063166000013.jpg192151 JPEG2026063166000014.jpg194150 JPEG2026063166000015.jpg180150 [Examples]

[0060] [Table 2] JPEG2026063166000017.jpg79150

[0061] The final compound obtained via preparative HPLC may be concentrated after lyophilization. The final example was determined at 254 nm by HPLC and LC-MS and purified to a purity of typically ≥95%. 1 ¹H NMR spectra were recorded using a Bruker Avance® III 400 MHz NMR spectrometer or a Bruker Ascend® 500 MHz NMR spectrometer. Chemical shifts (δ) were reported as parts per million (ppm) relative to the non-deuterated solvent remaining as an internal reference.

[0062] [Example 1] 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide

[0063] [Example 1A] (S,E)-N-(4-bromo-2-methylbenzylidene)-2-methylpropane-2-sulfinamide A 5 L reactor was packed at ambient temperature with triisopropyl borate (1.50 L, 6.53 mol), 4-bromo-2-methylbenzaldehyde (1.00 kg, 5.02 mol), and (S)-2-methylpropane-2-sulfinamide (669 g, 5.53 mol). The mixture was stirred at 80°C for 12 hours. The reaction was repeated twice on the same scale. Water (10.0 L) was added to the three combined reaction mixtures, the mixture was extracted with ethyl acetate (4.0 L x 2), washed with brine (5.0 L), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was ground in petroleum ether (5.0 L) for 2 hours and filtered. The filtered cake was washed with petroleum ether, and the cake was dried under reduced pressure to produce the title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 8.79 (s, 1H), 7.77 (d, J =6.4 Hz, 1H), 7.44 (s, 1H), 7.43 (d, J =6.4 Hz, 1H), 2.59 (s, 3H), 1.27 (s, 9H) ppm.

[0064] [Example 1B] (S)-N-((R)-1-(4-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide A 50 L reactor was packed with dichloromethane (20.0 L) and Example 1A (1.00 kg, 3.31 mol). The mixture was cooled to -20°C. CH3MgBr (3.0 M in tetrahydrofuran, 1.65 L, 4.96 mol) was added dropwise at -20°C. The mixture was then stirred at ambient temperature for 16 hours. The reaction mixture was cooled in an ice bath and saturated NH4Cl aqueous solution (5.0 L) was added. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (3.0 L × 2). The combined organic phase was washed with brine (5.0 L), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was ground in petroleum ether. The crude material was isolated by filtration, washed with petroleum ether, and dried under reduced pressure. The same reaction was repeated five times to produce the title compound.1 ¹H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 7.38-7.31 (m, 3H), 5.33 (d, J = 5.2 Hz, 1H), 4.55 (m, 1H), 2.30 (s, 3H), 1.40 (d, J = 5.2 Hz, 1H), 1.08 (s, 9H) ppm. MS (ESI) m / z 318.0, 320.0 (M+H) + .

[0065] [Example 1C] (S)-2-methyl-N-((R)-1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)propan-2-sulfinamide A 5 L reactor was packed at ambient temperature with Example 1B (600 g, 1.89 mol), dioxane (3.6 L), bis(pinacolate)diboron (600 g, 2.36 mol), potassium acetate (370 g, 3.77 mol), and Pd(dppf)Cl2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 23.0 g, 0.07 mol). The mixture was degassed with nitrogen and stirred at 85°C under nitrogen for 8 hours. The same reaction was repeated four times on the same scale. Five batches of the combined reaction mixture were filtered through diatomaceous earth, and the filter cakes were washed with ethyl acetate (0.5 L x 3). The filtrate was concentrated under reduced pressure, and the residue was subjected to silica flash column chromatography using petroleum ether and ethyl acetate to produce the title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 7.58-7.38 (m, 3H), 5.31 (d, J =4.8 Hz, 1H), 4.60 (m, 1H), 2.31 (s, 3H), 1.40 (d, J =6.8 Hz, 1H), 1.27 (s, 12H), 1.08 (s, 9H) ppm.MS(ESI)m / z366.2(M+H) + .

[0066] [Example 1D] (R)-1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethaneamine A 3 L reactor was packed with Example 1C (250 g, 680 mmol) and ethyl acetate (750 mL) at 20°C. The mixture was cooled to 0°C. Hydrogen chloride in ethyl acetate (4 M, 750 mL) was added to the mixture at 0°C. The reaction mixture was stirred at 20°C for 2 hours. The mixture was filtered, and the solid product was ground in ethyl acetate, filtered, and dried under reduced pressure to obtain the crude title compound as a hydrochloride salt. 1 ¹H NMR (400 MHz, dimethyl sulfoxide-d6): 8.62 (br s, 3 H), 7.52-7.60 (m, 3 H), 4.51-4.54 (br d, J = 5.2 Hz, 1 H), 2.35 (s, 3 H), 1.46 (d, J = 6.8 Hz, 3 H), 1.28 (s, 12 H) ppm. MS (ESI) m / z 262.1 (M+H) + .

[0067] [Example 1E] (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 To a solution of Example 1D (20 g, 77 mmol) and methyl 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate (31.0 g, 168 mmol) in ethanol (200 mL), triethylamine (64.0 mL, 459 mmol) was added at 20 °C. The mixture was stirred at 65 °C for 16 hours, and then concentrated under reduced pressure to remove the ethanol. Water was added to the mixture, and the mixture was extracted with ethyl acetate (three times). The combined organic layers were washed with saturated aqueous ammonium chloride (once) and brine (once), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to produce the crude substance. The crude substance was purified by silica gel column chromatography and eluted with petroleum ether and ethyl acetate to produce the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 9.83 (d, J =7.7 Hz, 1H), 7.53 - 7.43 (m, 3H), 5.28 (quintet, J =7.1 Hz, 1H), 2.37 (s, 3H), 1.45 (d, J =7.0 Hz, 3H), 1.35 (s, 9H), 1.27 (s, 12H) ppm.MS(ESI)m / z414.3(M+H) + .

[0068] [Example 1F] 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)aniline A 3 L reactor was packed at ambient temperature with 2-(4-aminophenyl)ethane-1-ol (176 g, 1.28 mol), N,N-dimethylformamide (1.8 L), imidazole (91.7 g, 1.35 mol), and tert-butyldimethylsilyl chloride (222 g, 1.48 mol). The mixture was stirred at ambient temperature for 6 hours. Ethyl acetate (500 mL) and water (300 mL) were added to the mixture. The organic phase was separated, washed with brine (300 mL), dried over sodium sulfate, concentrated under reduced pressure, and the residue was subjected to flash column chromatography (eluted with petroleum ether and ethyl acetate) to produce the title compound. MS(ESI) m / z 252.2(M+H) + .

[0069] [Example 1G] 3-((4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)amino)propanoic acid Example 1F (196 g, 0.78 mol) was packed into a 3 L reactor. Toluene (1.4 L) and acrylic acid (67.4 g, 0.94 mol) were added to the mixture. The reaction mixture was stirred at 110°C for 12 hours under nitrogen. The mixture was concentrated under reduced pressure until dry to produce the crude title compound. MS(ESI)m / z324.2(M+H) + .

[0070] [Example 1H] 4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)phenethylacetate Crude Example 1G (252g, 0.78mol) was mixed with acetic acid (1.8L) and urea (46.8g, 0.78mol). The reaction mixture was stirred under nitrogen at 110°C for 12 hours and then cooled to ambient temperature. Water (600mL) and ethyl acetate (600mL) were added to the mixture. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (600mL). The combined organic phase was washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure until dry to produce the crude title compound. MS(ESI)m / z 277.1(M+H) + .

[0071] [Example 1I] 1-(4-(2-hydroxyethyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Crude Example 1H (176 g, 0.63 mol) was mixed with 6N HCl aqueous solution (1.23 L, 7.39 mol), and the mixture was stirred at ambient temperature for 6 hours. The reaction mixture was concentrated under reduced pressure until dry, and the residue was ground with ethanol / ethyl acetate (250 mL / 250 mL) for 30 minutes. The substance was isolated by filtration and dried under vacuum to produce the crude title compound. MS(ESI)m / z235.1(M+H) + .

[0072] [Example 1J] 1-(4-(2-iodoethyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione A 250 mL flask was filled with Example 1I (10.0 g, 0.04 mol) and dichloromethane (100 mL). In an ice bath, iodine (16.3 g, 0.06 mol) was added in small amounts, followed by Ph3P (16.8 g, 0.06 mol), and then imidazole (4.36 g, 0.06 mol). The reaction mixture was then stirred at ambient temperature for 3 hours. The same reaction was repeated seven times in parallel on the same scale. The eight batches of reaction mixtures were combined and poured into a mixture of water (800 mL) and ethyl acetate (800 mL). After vigorous stirring, the organic phase was separated, filtered, dried over sodium sulfate, and filtered again. The filtrate was concentrated under reduced pressure to produce the title compound. 1 ¹H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 10.34 (s, 1H), 7.32-7.24 (m, 4H), 3.75 (m, 2H), 3.49 (m, 2H), 3.13 (m, 2H), 2.72 (m, 2H) ppm. MS(ESI) m / z 345.0(M+H) + .

[0073] [Example 1K] tert-butyl(S)-3-methyl-4-(6-nitropyridine-3-yl)piperazine-1-carboxylate To a solution of 5-chloro-2-nitropyridine (30 g, 189 mmol) in toluene (600 mL), (S)-tert-butyl 3-methylpiperazine-1-carboxylate (37.9 g, 189 mmol), potassium phosphate (60.2 g, 284 mmol), and (R)-(+)-2,2'-bis(diphenylphosphin)-1,1'-binaphthyl (5.89 g, 9.46 mmol) were added at 20°C. The reaction vessel was evacuated, refilled with argon three times (backfilled), and palladium(II) acetate (2.124 g, 9.46 mmol) was added in one step at 20°C. Then, the vessel was evacuated and refilled with argon three more times. The reaction mixture was heated to 90°C and stirred at 90°C under an argon atmosphere for 24 hours. The reaction mixture was cooled, filtered through a diatomaceous earth pad, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by a silica flash column (eluted with tetrahydrofuran in petroleum ether from 0% to 50%) to produce the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 8.11-8.26 (m, 2 H), 7.42 (dd, J=9.38, 3.00 Hz, 1 H), 4.32 (br s, 1 H), 3.93 (br s, 1 H), 3.79 (br d, J=12.76 Hz, 2 H), 3.14-3.29 (m, 2 H), 3.06 (br s, 1 H), 1.42 (s, 9 H), 1.08 (d, J=6.63 Hz, 3 H) ppm.MS(ESI)m / z323.2(M+H) + .

[0074] [Example 1L] tert-butyl(S)-4-(6-aminopyridine-3-yl)-3-methylpiperazine-1-carboxylate To a suspension of Pd / C (10 wt%, 46.2 g, 43.4 mmol) in tetrahydrofuran (700 mL), Example 1K (70 g, 217 mmol) was added, and the reaction mixture was stirred at ambient temperature for 24 hours under hydrogen (15 psi). The same reaction was repeated on the same scale. The combined reaction mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure to obtain the crude product. This substance was ground with petroleum ether and ethyl acetate, the resulting solid was filtered, and the filtration cake was dried under vacuum to produce the title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 7.62 (d, J=2.63 Hz, 1 H), 7.20 (dd, J=8.76, 2.63 Hz, 1 H), 6.40 (d, J=8.76 Hz, 1 H), 5.56 (s, 2 H), 3.55 (br d, J=11.38 Hz, 1 H), 3.39 (br d, J=5.13 Hz, 2 H), 3.17 (br s, 2 H), 2.71 - 2.90 (m, 2 H), 1.41 (s, 9 H), 0.75 (d, J=6.25 Hz, 3 H) ppm.MS(ESI)m / z293.2(M+H) + .

[0075] [Example 1M] (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidine-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide A mixture of Example 1E (10 g, 24.19 mmol) and 4,6-dichloropyrimidine (7.21 g, 48.4 mmol) in tetrahydrofuran (400 mL) was added at 20°C with a solution of potassium phosphate (10.27 g, 48.4 mmol) in water (100 mL). The mixture was degassed at ambient temperature using a nitrogen stream, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.885 g, 1.210 mmol) was added to the mixture under N2. The reaction mixture was heated to 80°C and stirred for 2 hours. The mixture was cooled, poured into water, and extracted with ethyl acetate (three times). The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica column chromatography eluting with tetrahydrofuran in petroleum ether to obtain the crude title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 9.93 (d, J=7.8 Hz, 1H), 9.07 (s, 1H), 8.30 (s, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 5.33 (quintet, J=7.2 Hz, 1H), 2.48 - 2.47 (m, 1H), 2.47 (s, 2H), 1.50 (d, J=7.0 Hz, 3H), 1.36 (s, 9H) ppm.MS(ESI)m / z400.1(M+H) + .

[0076] [Example 1N] tert-butyl(S)-4-(6-((6-(4-((R)-1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide)ethyl)-3-methylphenyl)pyrimidine-4-yl)amino)pyridine-3-yl)-3-methylpiperazine-1-carboxylate In Example 1, 1 L (25 g, 86 mmol) of 1,4-dioxane (500 mL) was mixed with 1 M of Example 1 (34.2 g, 86 mmol), Cs2CO3 (55.7 g, 171 mmol), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4.95 g, 8.55 mmol) at 20°C. The reaction vessel was evacuated, refilled with argon, and the process was repeated three times. Then, (tris(dibenzylidene-acetone)dipalladium(0)) (3.91 g, 4.28 mmol) was added under argon. The reaction vessel was evacuated, refilled with argon, and the process was repeated three times. The reaction mixture was heated to 100°C and stirred at 100°C for 16 hours. The reaction mixture was cooled, filtered through a diatomaceous earth pad, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica column chromatography using tetrahydrofuran elution in petroleum ether to obtain the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 10.02 (s, 1 H), 9.89 (d, J=7.88 Hz, 1 H), 8.71 (d, J=0.75 Hz, 1 H), 7.97 - 8.10 (m, 2 H), 7.79 - 7.88 (m, 2 H), 7.71 (br d, J=8.50 Hz, 1 H), 7.61 (d, J=8.63 Hz, 1 H), 7.44 (dd, J=9.13, 2.88 Hz, 1 H), 5.33 (quintet, J=7.13 Hz, 1 H), 3.73 - 3.92 (m, 2 H), 3.60 (br d, J=11.51 Hz, 1 H), 3.31 (br s, 1 H), 3.16 (br d, J=11.88 Hz, 2 H), 2.88 - 3.01 (m, 1 H), 2.47 (s, 3 H), 1.51 (d, J=6.88 Hz, 3 H), 1.42 (s, 9 H), 1.36 (s, 9 H), 0.88 (d, J=6.38 Hz, 3 H) ppm.MS(ESI)m / z656.2(M+H) + .

[0077] [Example 10] 3-(tert-butyl)-N-((R)-1-(2-methyl-4-(6-((5-((S)-2-methylpiperazine-1-yl)pyridine-2-yl)amino)pyrimidine-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide In Example 1, a solution of N (32 g, 48.8 mmol) dioxane in 300 mL was mixed with hydrochloride (4 N in dioxane, 300 mL). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was filtered to isolate the crude substance, which was dried under vacuum. The crude substance was diluted with water (300 mL), and saturated sodium bicarbonate aqueous solution was added to the mixture to adjust the pH to 8. The mixture was extracted (twice) with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to produce the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 10.00 (s, 1 H), 9.88 (d, J=7.78 Hz, 1 H), 8.70 (d, J=0.88 Hz, 1 H), 8.04 (br s, 1 H), 8.00 (d, J=2.89 Hz, 1 H), 7.79-7.89 (m, 2 H), 7.71 (br d, J=8.66 Hz, 1 H), 7.61 (d, J=8.66 Hz, 1 H) 7.43 (dd, J=9.16, 2.89 Hz, 1 H) 5.33 (quintet, J=7.12 Hz, 1 H) 3.67-3.81 (m, 2H), 3.67-3.81 (m, 1 H), 3.67-3.81 (m, 1 H), 3.08-3.17 (m, 1 H), 2.89-3.06 (m, 3 H), 2.74-2.89 (m, 2 H), 2.47 (s, 3 H), 1.51 (d, J=7.03 Hz, 3 H), 1.36 (s, 9 H), 0.96 (d, J=6.53 Hz, 3 H) ppm.MS(ESI)m / z556.2(M+H) + .

[0078] [Example 1P] 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide To a solution of Example 1O (24.7 g, 44.5 mmol) in acetonitrile (500 mL), Example 1J (18.36 g, 53.3 mmol), N,N-diisopropylethylamine (46.6 mL, 267 mmol), and sodium iodide (19.99 g, 133 mmol) were added at 20°C. The reaction mixture was then stirred at 90°C for 16 hours. The reaction mixture was cooled, poured into ice water, and filtered. The filtered cake was ground twice with ethyl acetate / tetrahydrofuran. The substance was dried under reduced pressure to produce the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 10.33 (s, 1 H), 9.99 (s, 1 H), 9.89 (d, J=7.78 Hz, 1 H), 8.70 (s, 1 H), 7.96 - 8.09 (m, 2 H), 7.80 - 7.87 (m, 2 H), 7.70 (br d, J=7.65 Hz, 1 H), 7.61 (d, J=8.66 Hz, 1 H), 7.44 (dd, J=9.10, 2.82 Hz, 1 H), 7.19 - 7.32 (m, 4 H), 5.33 (br t, J=7.28 Hz, 1 H), 3.86 (br d, J=6.65 Hz, 1 H), 3.76 (t, J=6.65 Hz, 2 H), 3.21 (br d, J=11.92 Hz, 1 H), 2.99 (br t, J=9.35 Hz, 1 H), 2.84 (br d, J=10.79 Hz, 1 H), 2.77 (br t, J=7.47 Hz, 2 H), 2.69 (br t, J=6.65 Hz, 3 H), 2.56 (br s, 2 H), 2.47 (s, 3 H), 2.44 (br s, 1 H), 2.26 - 2.37 (m, 1 H), 1.51 (d, J=6.90 Hz, 3 H), 1.36 (s, 9 H), 0.99 (d, J=6.27 Hz, 3 H) ppm.MS(ESI)m / z772.2(M+H) + .

[0079] [Example 2] 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2R)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide

[0080] [Example 2A] tert-butyl(R)-3-methyl-4-(6-nitropyridine-3-yl)piperazine-1-carboxylate The title compound was prepared by replacing (S)-tert-butyl 3-methylpiperazine-1-carboxylate with (R)-tert-butyl 3-methylpiperazine-1-carboxylate, following the procedure used in Example 1K. 1 ¹H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 8.13-8.24 (m, 2 H), 7.43 (dd, J=9.32, 3.06 Hz, 1 H), 4.32 (br s, 1 H), 3.85-4.03 (br s, 1 H), 3.79 (br d, J=12.88 Hz, 2 H), 2.97-3.30 (m, 3 H), 1.43 (s, 9 H), 1.08 (d, J=6.50 Hz, 3 H) ppm.MS(ESI)m / z323.2(M+H) + .

[0081] [Example 2B] tert-butyl(R)-4-(6-aminopyridine-3-yl)-3-methylpiperazine-1-carboxylate The title compound was prepared by replacing Example 1K with Example 2A and following the procedure used in Example 1L. 1 H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 7.62 (d, J=2.63 Hz, 1 H), 7.20 (dd, J=8.76, 2.75 Hz, 1 H), 6.40 (d, J=8.76 Hz, 1 H), 5.54 (s, 2 H), 3.56 (br d, J=10.76 Hz, 1 H), 3.40 (br s, 2 H) 3.17 (br s, 2 H), 2.71 - 2.88 (m, 2 H), 1.41 (s, 9 H), 0.76 (d, J=6.13 Hz, 3 H) ppm.MS(ESI)m / z293.1(M+H) + .

[0082] [Example 2C] tert-butyl(R)-4-(6-((6-(4-((R)-1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide)ethyl)-3-methylphenyl)pyrimidine-4-yl)amino)pyridine-3-yl)-3-methylpiperazine-1-carboxylate The title compound was prepared by replacing Example 1L with Example 2B and following the procedure used in Example 1N. 1 H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 9.99 (s, 1 H), 9.87 (d, J=7.78 Hz, 1 H), 8.70 (d, J=1.00 Hz, 1 H), 7.98 - 8.07 (m, 2 H), 7.79 - 7.88 (m, 2 H), 7.71 (br d, J=9.16 Hz, 1 H), 7.60 (d, J=8.66 Hz, 1 H), 7.45 (dd, J=9.10, 2.82 Hz, 1 H), 5.33 (quintet, J=7.25 Hz, 1 H), 3.75 - 3.88 (m, 2 H), 3.56 - 3.65 (m, 1 H), 3.11 - 3.22 (m, 2 H), 2.90 (s, 1 H), 2.52 (br s, 1 H), 2.47 (s, 3 H), 1.51 (d, J=7.03 Hz, 3 H), 1.42 (s, 9 H), 1.36 (s, 9 H), 0.89 (d, J=6.40 Hz, 3 H) ppm.MS(ESI)m / z656.3(M+H) + .

[0083] [Example 2D] 3-(tert-butyl)-N-((R)-1-(2-methyl-4-(6-((5-((R)-2-methylpiperazine-1-yl)pyridine-2-yl)amino)pyrimidine-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound was prepared by replacing Example 1N with Example 2C and following the procedure used in Example 1O. 1H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 9.97 (s, 1 H), 9.87 (d, J=7.78 Hz, 1 H), 8.70 (d, J=1.00 Hz, 1 H), 8.03 (br s, 1 H), 7.98 (d, J=2.76 Hz, 1 H), 7.80 - 7.87 (m, 2 H), 7.69 (br d, J=8.66 Hz, 1 H), 7.60 (d, J=8.66 Hz, 1 H), 7.41 (dd, J=9.16, 2.89 Hz, 1 H), 5.26 - 5.40 (m, 1 H), 3.65 - 3.77 (m, 1 H), 3.01 - 3.15 (m, 1 H), 2.90 - 2.98 (m, 2 H), 2.84 - 2.90 (m, 1 H), 2.69 - 2.79 (m, 2 H), 2.52 (br d, J=1.88 Hz, 1 H), 2.47 (s, 3 H), 1.51 (d, J=6.90 Hz, 3 H), 1.36 (s, 9 H), 0.96 (d, J=6.53 Hz, 3 H) ppm.MS(ESI)m / z556.4(M+H) + .

[0084] [Example 2E] 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2R)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide The title compound was prepared by replacing Example 1O with Example 2D and following the procedure used in Example 1P. 1H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 10.31 (br s, 1 H), 9.97 (s, 1 H), 9.87 (br d, J=6.02 Hz, 1 H), 8.70 (d, J=0.88 Hz, 1 H), 7.94 - 8.10 (m, 2 H), 7.78 - 7.89 (m, 2 H), 7.70 (br d, J=8.03 Hz, 1 H), 7.60 (d, J=8.66 Hz, 1 H), 7.43 (dd, J=9.16, 2.89 Hz, 1 H), 7.18 - 7.32 (m, 4 H), 5.24 - 5.42 (m, 1 H), 3.81 - 3.90 (m, 1 H), 3.76 (t, J=6.65 Hz, 2 H), 3.16 - 3.26 (m, 1 H), 2.93 - 3.05 (m, 1 H), 2.84 (br d, J=10.67 Hz, 1 H), 2.73 - 2.81 (m, 2 H), 2.67 - 2.73 (m, 3 H), 2.53 - 2.62 (m, 2 H), 2.47 (s, 3 H), 2.44 (br s, 1 H), 2.27 - 2.36 (m, 1 H), 1.51 (d, J=7.03 Hz, 3 H), 1.36 (s, 9 H), 0.99 (d, J=6.40 Hz, 3 H) ppm.MS(ESI)m / z772.2(M+H) + .

[0085] [Example 3] 3-tert-butyl-N-{(1R)-1-[4-(6-{[5-(4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}piperazine-1-yl)pyridine-2-yl]amino}pyrimidine-4-yl)-2-methylphenyl]ethyl}-1,2,4-oxadiazole-5-carboxamide

[0086] [Example 3A] tert-butyl 4-(6-nitropyridine-3-yl)piperazine-1-carboxylate The title compound was prepared by replacing (S)-tert-butyl3-methylpiperazine-1-carboxylate with tert-butylpiperazine-1-carboxylate, following the procedure used in Example 1K. MS(ESI)m / z309.2(M+H) + .

[0087] [Example 3B] tert-butyl 4-(6-aminopyridine-3-yl)piperazine-1-carboxylate The title compound was prepared by replacing Example 1K with Example 3A and following the procedure used in Example 1L. MS(ESI)m / z 279.3(M+H) + .

[0088] [Example 3C] tert-butyl(R)-4-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide)ethyl)-3-methylphenyl)pyrimidine-4-yl)amino)pyridine-3-yl)piperazine-1-carboxylate The title compound was prepared by replacing Example 1L with Example 3B and following the procedure used in Example 1N. 1 H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 10.03 (s, 1H), 9.90 (d, J = 7.8 Hz, 1H), 8.71 (s, 1H), 8.06 (br d, J = 2.9 Hz, 2H), 7.85 - 7.80 (m, 2H), 7.71 (br d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.47 (dd, J = 2.9, 9.1 Hz, 1H), 5.38 - 5.28 (m, 1H), 3.46 (br d, J = 4.8 Hz, 4H), 3.12 - 3.02 (m, 4H), 2.47 (s, 3H), 1.51 (d, J = 6.9 Hz, 3H), 1.42 (s, 9H), 1.37 - 1.34 (m, 9H) ppm.MS(ESI)m / z642.4(M+H) + .

[0089] [Example 3D] (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-((5-(piperazin-1-yl)pyridine-2-yl)amino)pyrimidine-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound was prepared by replacing Example 1N with Example 3C and following the procedure used in Example 10. 1 H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 10.01 (s, 1H), 9.89 (d, J=7.8 Hz, 1H), 8.71 (s, 1H), 8.14-7.95 (m, 2H), 7.89-7.77 (m, 2H), 7.71 (br d, J=8.4 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.46 (dd, J=2.9, 9.1 Hz, 1H), 5.33 (quintet, J=7.1 Hz, 1H), 3.19-3.11 (m, 4H), 3.05-2.96 (m, 4H), 2.47 (s, 3H), 1.51 (d, J=7.0 Hz, 3H), 1.36 (s, 9H) ppm.MS(ESI)m / z542.3(M+H) + .

[0090] [Example 3E] 3-tert-butyl-N-{(1R)-1-[4-(6-{[5-(4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}piperazine-1-yl)pyridine-2-yl]amino}pyrimidine-4-yl)-2-methylphenyl]ethyl}-1,2,4-oxadiazole-5-carboxamide The title compound was prepared by replacing Example 1O with Example 3D and following the procedure used in Example 1P. 1H NMR (500 MHz, dimethyl sulfoxide-d6): δ ppm 10.34 (s, 1H), 9.99 (s, 1H), 9.88 (d, J = 7.8 Hz, 1H), 8.70 (s, 1H), 8.08-8.00 (m, 2H) 7.85-7.80 (m, 2H), 7.69 (brs, 1H), 7.63-7.58 (m, 1H), 7.47 (dd, J = 9.1, 3.0 Hz, 1H), 7.30-7.21 (m, J = 8.3 Hz, 4H), 5.33 (p, J = 7.1 Hz, 1H), 3.76 (t, J = 6.7 Hz, 2H), 3.14 (brs, 4H), 2.79 (brs, 2H), 2.70 (t, J = 6.7 Hz, 2H), 2.61 (brs, 5H), 2.47 (s, 3H), 1.51 (d, J = 7.0 Hz, 3H), 1.36 (s, 9H) ppm.MS(ESI)m / z758.3(M+H) + .

[0091] [Example 4] 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)-3-fluorophenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide

[0092] [Example 4A] (E)-2-(3-fluoro-4-nitrophenyl)-N,N-dimethylethene-1-amine A mixture of 2-fluoro-4-methyl-1-nitrobenzene (1.50 kg, 9.63 mol) and N,N-dimethylformamide-dimethylacetal (1.72 kg, 14.5 mol, 1.92 L) in N,N-dimethylformamide (2.4 L) was degassed, purged three times with nitrogen, and the mixture was stirred under nitrogen at 120°C (internal reading) for 2 hours. The reaction mixture was concentrated under reduced pressure. The crude product was ground with petroleum ether / tert-butylmethyl ether (1:1, 10.0 L) and filtered. The filtered cake was washed with petroleum ether / tert-butylmethyl ether (1:1, 2.0 L) and dried under vacuum to produce the title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 7.92 (t, J = 8.4 Hz, 1 H), 7.03 (d, J = 13.6 Hz, 1H), 6.89-6.84 (m, 2H), 5.05 (d, J = 13.2 Hz, 1H), 2.95 (s, 6H) ppm.

[0093] [Example 4B] 2-(3-fluoro-4-nitrophenyl)ethane-1-ol To aqueous hydrochloric acid (4M, 7.50 L), Example 4A (1.00 kg, 4.76 mol) was added in small increments at ambient temperature. The mixture was stirred at ambient temperature for 12 hours and extracted with 2-methyltetrahydrofuran (3.0 L x 7). The combined organic phase was washed with brine (5.0 L) and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to a volume of 10 L and cooled in an ice bath. Sodium borohydride (214 g, 5.68 mol) was added in small increments in an ice bath, and the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was cooled in an ice bath and quenched with 0.5 N aqueous hydrochloric acid (5.0 L). The organic phase was separated, washed with brine (3.0 L), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to produce the crude title compound.

[0094] [Example 4C] tert-butyl(3-fluoro-4-nitrophenethoxy)dimethylsilane To a mixture of crude Example 4B (660 g, 3.56 mol) and imidazole (364 g, 5.34 mol) in tetrahydrofuran (4.4 L), tert-butyldimethylsilyl chloride (804 g, 5.34 mol, 654 mL) was added in portions at ambient temperature. The mixture was stirred at ambient temperature for 12 hours, quenched by adding water (3.0 L), and diluted with ethyl acetate (3.0 L). The organic layer was separated, washed with brine (5.0 L), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica flash column chromatography (petroleum ether and ethyl acetate) to produce the title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 7.92-8.05 (m, 1H), 7.11-7.20 (m, 2H), 3.79-3.92 (m, 2H), 2.80-2.93 (m, 2H), 0.80 (s, 9H), -0.09 (s, 6H) ppm.

[0095] [Example 4D] 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-fluoroaniline To a suspension of Pd / C (2.346 g, 2.204 mmol) in tetrahydrofuran (100 mL), Example 4C (5.5 g, 18.37 mmol) was added at 25°C. The resulting mixture was stirred at 25°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure at 40°C to produce the title compound. MS(ESI)m / z 270.1(M+H) + .

[0096] [Example 4E] 3-((4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-fluorophenyl)amino)propanoic acid To a solution of Example 4D (2.5 g, 9.28 mmol) in toluene (25 mL), acrylic acid (0.802 g, 11.13 mmol) was added. The reaction mixture was heated to 120 °C and stirred for 16 hours. The reaction mixture was cooled to 20 °C and concentrated under reduced pressure to produce the crude title compound. MS(ESI)m / z 342.1(M+H)+ .

[0097] [Example 4F] 4-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-3-fluorophenethyl acetate To a solution of Example 4E (3 g, 8.78 mmol) in acetic acid (30 mL), urea (1.583 g, 26.4 mmol) was added. The reaction mixture was heated to 120 °C and stirred for 16 hours. The reaction mixture was cooled to 20 °C and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Phenomenex Luna® C18 column, 50*250 mm, 10 μm, using water and 0.1% formic acid in acetonitrile as mobile phase) to obtain the title compound. MS(ESI) m / z 295.1 (M+H) + .

[0098] [Example 4G] 1-(2-fluoro-4-(2-hydroxyethyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione To a solution of Example 4F (1.1 g, 3.74 mmol) in water (1 mL), concentrated hydrochloric acid (37%, 1 mL) was added at 20°C. The reaction mixture was stirred at 20°C for 12 hours. The reaction mixture was concentrated under reduced pressure to produce the title compound. MS(ESI)m / z253.1(M+H) + .

[0099] [Example 4H] 1-(4-(2-bromoethyl)-2-fluorophenyl)dihydropyrimidine-2,4(1H,3H)-dione In Example 4, CBr4 (0.789 g, 2.379 mmol) was added to a solution of 4G (0.3 g, 1.189 mmol) in dichloromethane (20 mL), and then Ph3P (0.624 g, 2.379 mmol) was added at 0°C. The reaction mixture was stirred at 20°C for 12 hours. The reaction mixture was concentrated under reduced pressure at 40°C. The residue was purified by silica flash column chromatography (ethyl acetate in petroleum ether, 0-100%) to produce the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 10.47 (s, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.27 (br d, J = 11.2 Hz, 1H), 7.16 (br d, J = 7.6 Hz, 1H), 3.77 (t, J = 7.2 Hz, 2H), 3.70 (t, J = 6.8 Hz, 2H), 3.16 (t, J = 7.2 Hz, 2H), 2.71 (t, J = 6.8 Hz, 2H) ppm.MS(ESI)m / z315.0, 317.0(M+H) + .

[0100] [Example 4I] 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)-3-fluorophenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide To a solution of Example 1O (80 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL), Example 4H (54 mg, 0.17 mmol), sodium iodide (65 mg, 0.43 mmol), and N,N-diisopropylethylamine (56 mg, 0.43 mmol) were added. The mixture was stirred at 80°C for 16 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was subjected directly to reverse-phase preparative HPLC to produce the title compound (Gilson GX-281 system, Waters® Xbridge C18 column, 30 × 100 mm × 10 μm, mobile phase: water and 10 mM ammonium bicarbonate in acetonitrile). 1¹H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 10.46 (s, 1 H), 9.99 (s, 1 H), 9.89 (d, J=7.89 Hz, 1 H), 8.70 (d, J=0.66 Hz, 1 H), 7.96 - 8.08 (m, 2 H), 7.80 - 7.86 (m, 2 H), 7.66 - 7.75 (m, 1 H), 7.60 (d, J=8.77 Hz, 1 H), 7.44 (dd, J=9.21, 2.85 Hz, 1 H), 7.33 (t, J=8.11 Hz, 1 H), 7.24 (dd, J=11.62, 1.53 Hz, 1 H), 7.15 (dd, J=8.11, 1.53 Hz, 1 H), 5.33 (t, J=7.34 Hz, 1 H), 3.82 - 3.91 (m, 1 H), 3.69 (t, J=6.69 Hz, 2 H), 3.21 (br d, J=11.84 Hz, 1 H), 2.98 (br t, J=9.32 Hz, 1 H), 2.77 - 2.83 (m, 2 H), 2.69 - 2.72 (m, 2 H), 2.53 - 2.64 (m, 2 H), 2.52 (d, J=1.75 Hz, 2 H), 2.47 (s, 3 H), 2.41 - 2.46 (m, 1H), 2.26 - 2.32 (m, 1 H), 1.51 (d, J=7.02 Hz, 3 H), 1.36 (s, 9 H), 0.98 (d, J=6.36 Hz, 3 H) ppm.LC / MS(ESI+)m / z790.3(M+H) + .

[0101] [Example 5] 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2R)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)-3-fluorophenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide To a solution of Example 2D (100 mg, 0.18 mmol) in N,N-dimethylformamide (2 mL), Example 4H (68 mg, 0.22 mmol), sodium iodide (81 mg, 0.54 mmol), and N,N-diisopropylethylamine (70 mg, 0.54 mmol) were added. The mixture was stirred at 80°C for 16 hours. The mixture was cooled to ambient temperature and filtered. The title compound was isolated from the filtrate by direct reverse-phase preparative HPLC (Gilson GX-281 system, Phenomenex Luna® C18 column, 30 × 75 mm × 3 μm, mobile phase: water and 0.1% formic acid in acetonitrile). 1 ¹H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 10.45 (s, 1 H), 9.99 (s, 1 H), 9.88 (d, J=7.82 Hz, 1 H), 8.70 (s, 1 H), 7.98 - 8.07 (m, 2 H), 7.79 - 7.87 (m, 2 H), 7.66 - 7.74 (m, 1 H), 7.60 (d, J=8.68 Hz, 1 H), 7.40 - 7.48 (m, 1 H), 7.33 (t, J=8.19 Hz, 1 H), 7.21 - 7.28 (m, 1 H), 7.15 (d, J=8.31 ​​Hz, 1 H), 5.24 - 5.44 (m, 1 H), 3.76 - 3.97 (m, 1 H), 3.69 (t, J=6.66 Hz, 2 H), 3.13 - 3.26 (m, 2 H), 2.94 - 3.06 (m, 1 H), 2.77 - 2.92 (m, 3 H), 2.71 (t, J=6.66 Hz, 3 H), 2.56 - 2.65 (m, 1 H), 2.47 (s, 3 H), 2.33 - 2.46 (m, 2 H), 1.51 (d, J=6.85 Hz, 3 H), 1.36 (s, 9 H), 0.98 (d, J=6.24 Hz, 3H) ppm.LC / MS(ESI + ):m / z790.2(M+H) + .

[0102] [Example 6] 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-ethylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide

[0103] [Example 6A] (S)-tert-butyl3-ethyl-4-(6-nitropyridine-3-yl)piperazine-1-carboxylate 5-Fluoro-2-nitropyridine (1.00 g, 7.04 mmol) and (S)-tert-butyl 3-ethylpiperazine-1-carboxylate (1.96 g, 9.15 mmol) were dissolved in N,N-dimethylformamide, and potassium carbonate (2.92 g, 21.11 mmol) was added. The reaction mixture was stirred at 70°C for 15 hours and concentrated under reduced pressure to remove most of the solvent. The residue was diluted with dichloromethane, washed with water, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to produce the crude title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 8.21 (d, J=2.88 Hz, 1 H), 8.15 (d, J=9.26 Hz, 1 H), 7.42 (dd, J=9.32, 2.94 Hz, 1 H), 3.89 - 4.17 (m, 3 H), 3.82 (br d, J=12.88 Hz, 1 H), 2.90 - 3.27 (m, 3 H), 1.47 - 1.69 (m, 2 H), 1.42 (s, 9 H), 0.90 (br s, 3 H) ppm.LC / MS(ESI + ):m / z337.0(M+H) + .

[0104] [Example 6B] (S)-tert-butyl4-(6-aminopyridine-3-yl)-3-ethylpiperazine-1-carboxylate Example 6A (2.0 g, 5.95 mmol) was dissolved in methanol (200 mL). Pd / C (10 wt%, 0.32 g, 3.0 mmol) was added to the mixture. The reaction mixture was hydrogenated using a hydrogen balloon at ambient temperature for 2 days. The mixture was filtered through diatomaceous earth, and the solid cake was washed with methanol and ethyl acetate. The filtrate was concentrated under reduced pressure to produce the crude title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 7.59 (br d, J=2.01 Hz, 1 H), 7.12 - 7.21 (m, 1 H), 6.40 (d, J=8.78 Hz, 1 H), 5.46 (br s, 2 H), 3.47 - 3.76 (m, 2 H), 2.98 - 3.23 (m, 2 H), 2.85 (br d, J=4.64 Hz, 2 H), 2.52 (br d, J=1.88 Hz, 1 H), 1.41 (s, 9 H), 1.35 (s, 1 H), 1.25 (br s, 1 H), 0.77 (br t, J=7.22Hz, 3H) ppm.LC / MS(ESI + ):m / z307.2(M+H) + .

[0105] [Example 6C] tert-butyl(S)-4-(6-((6-(4-((R)-1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide)ethyl)-3-methylphenyl)pyrimidine-4-yl)amino)pyridine-3-yl)-3-ethylpiperazine-1-carboxylate To a solution of Example 1E (300 mg, 0.75 mmol) in 1,4-dioxane (6 mL), Example 6B (253 mg, 0.83 mmol), Pd2(dba)3 (CAS 52409-22-0, 34 mg, 0.038 mmol), XantPhos (CAS 161265-03-8, 43 mg, 0.075 mmol), and cesium carbonate (489 mg, 1.50 mmol) were added. The mixture was degassed using an argon stream and stirred at 100°C for 16 hours. The reaction mixture was cooled, diluted with ethyl acetate, and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and purified by silica chromatography using ethyl acetate and petroleum ether to produce the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 9.98 (s, 1 H), 9.89 (d, J=7.78 Hz, 1 H), 8.70 (s, 1 H), 7.96 - 8.07 (m, 2 H), 7.80 - 7.86 (m, 2 H), 7.66 - 7.74 (m, 1 H), 7.60 (d, J=8.66 Hz, 1 H), 7.38 - 7.48 (m, 1 H), 5.33 (quintet, J=7.09 Hz, 1 H), 3.90 (br d, J=11.04 Hz, 2 H), 3.60 (br dd, J=6.53, 3.01 Hz, 1 H), 3.12 - 3.29 (m, 2 H), 2.89 - 3.05 (m, 2 H), 2.47 (s, 3 H), 1.61 (s, 1 H), 1.51 (br d, J=6.90 Hz, 3 H), 1.42 (s, 9 H), 1.36 (s, 9 H), 1.21 - 1.31 (m, 1 H), 0.86 (br s, 3 H) ppm.LC / MS(ESI+):m / z670.4(M+H) + .

[0106] [Example 6D] 3-(tert-butyl)-N-((R)-1-(4-(6-((5-((S)-2-ethylpiperazine-1-yl)pyridine-2-yl)amino)pyrimidine-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide To a solution of Example 6C (150 mg, 0.22 mmol) in 1,4-dioxane (3 mL), hydrochloride (4N in dioxane, 3 mL) was added dropwise at ambient temperature. The mixture was stirred for 2 hours, concentrated under reduced pressure, diluted with water (5 mL), and treated with saturated sodium carbonate aqueous solution to adjust the pH to 8. The mixture was extracted with ethyl acetate (15 mL, 3 times), the organic phase was dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to produce the crude title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 9.94 (s, 1 H), 9.89 (d, J=7.78 Hz, 1 H), 8.69 (s, 1 H), 7.92 - 8.05 (m, 2 H), 7.80 - 7.87 (m, 2 H), 7.63 - 7.72 (m, 1 H), 7.60 (d, J=8.66 Hz, 1 H), 7.37 (dd, J=9.03, 2.89 Hz, 1 H), 5.33 (quintet, J=7.09 Hz, 1 H), 3.45 (br dd, J=6.71, 2.45 Hz, 1 H), 3.09 - 3.17 (m, 1H), 2.80 - 2.94 (m, 4 H), 2.66 - 2.74 (m, 1 H), 2.47 (s, 3 H), 1.75 (ddd, J=13.61, 9.47, 7.40 Hz, 1 H), 1.51 (d, J=6.90 Hz, 3 H), 1.36 (s, 9 H), 1.22 - 1.30 (m, 1 H), 0.79 (t, J=7.47 Hz, 3 H) ppm.LC / MS(ESI+):m / z570.4(M+H) + .

[0107] [Example 6E] 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-ethylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide Example 6D (480 mg, 0.79 mmol), Example 1J (327 mg, 0.95 mmol), N,N-diisopropylethylamine (277 μL, 1.58 mmol), and potassium iodide (657 mg, 3.96 mmol) were mixed in N,N-dimethylformamide (8 mL). The mixture was stirred at 80°C for 4 hours. The mixture was cooled, quenched with a few drops of formic acid, and the title compound was isolated by direct reverse-phase preparative HPLC (Phenomenex Gemini® AXA C18 column, 30 × 250 mm × 5 μm, with water and 0.1% formic acid in acetonitrile as mobile phases). 1 H NMR (500 MHz, dimethyl sulfoxide-d6): δ ppm 9.89 (s, 1H), 9.53 (s, 1H), 9.38 (d, J = 7.6 Hz, 1H), 8.64 (d, J = 1.1 Hz, 1H), 7.94 (dd, J = 11.8, 2.1 Hz, 2H), 7.84 - 7.78 (m, 2H), 7.64 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.33 (dd, J = 9.1, 3.1 Hz, 1H), 7.28 - 7.18 (m, 4H), 5.34 (p, J = 7.1 Hz, 1H), 3.73 (t, J = 6.7 Hz, 2H), 3.53 (s, 1H), 3.24 (d, J = 12.2 Hz, 1H), 3.10 - 3.02 (m, 1H), 2.79 (ddt, J = 14.1, 7.8, 3.6 Hz, 4H), 2.68 (t, J = 6.7 Hz, 2H), 2.60 (s, 2H), 2.45 (s, 3H), 2.41 - 2.27 (m, 3H), 1.73 - 1.59 (m, 1H), 1.52 (d, J = 7.0 Hz, 3H), 1.35 (s, 9H), 0.79 (t, J = 7.4 Hz, 3H) ppm.LC / MS(ESI+):m / z 786.7(M+H) + .

[0108] [Example 7] 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)-3-fluorophenyl]ethyl}-2-ethylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide Example 6D (120 mg, 0.21 mmol), Example 4H (100 mg, 0.32 mmol), N,N-diisopropylethylamine (184 μL, 1.05 mmol), and sodium iodide (95 mg, 0.63 mmol) were mixed in acetonitrile (2.4 mL). The mixture was stirred at 80°C for 16 hours. The mixture was cooled, quenched with a few drops of formic acid, and the title compound was isolated by direct reverse-phase preparative HPLC (Phenomenex Luna® C18 column, 30 × 75 mm × 3 μm, mobile phase: water and 0.1% formic acid in acetonitrile). 1H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 10.46 (s, 1 H), 9.96 (s, 1 H), 9.89 (d, J=7.75 Hz, 1 H), 8.69 (s, 1 H), 7.94 - 8.05 (m, 2 H), 7.80 - 7.86 (m, 2 H), 7.64 - 7.73 (m, 1 H), 7.60 (d, J=8.63 Hz, 1 H), 7.37 - 7.44 (m, 1 H), 7.33 (t, J=8.19 Hz, 1 H), 7.21 - 7.28 (m, 1 H), 7.08 - 7.17 (m, 1 H), 5.25 - 5.41 (m, 1 H), 3.68 (t, J=6.63 Hz, 2 H), 3.57 - 3.65 (m, 1 H), 3.00 (br t, J=10.57 Hz, 1 H), 2.86 - 2.95 (m, 2 H), 2.81 (br d, J=6.38 Hz, 2 H), 2.71 (br t, J=6.63 Hz, 2 H), 2.60 - 2.65 (m, 1 H), 2.47 (br s, 5 H), 2.21 - 2.31 (m, 2 H), 1.62 - 1.76 (m, 1 H), 1.51 (d, J=7.00 Hz, 3 H), 1.36 (s, 9 H), 1.22 - 1.31 (m, 1 H), 0.81 (br t, J=7.38 Hz, 3 H) ppm.LC / MS(ESI+):m / z804.3(M+H) + .

[0109] [Example 8] 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2R)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-ethylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide

[0110] [Example 8A] (R)-tert-Butyl 3-ethyl-4-(6-nitropyridin-3-yl)piperazine-1-carboxylate The title compound was prepared according to the procedure used in Example 6A, replacing (S)-tert-butyl 3-ethylpiperazine-1-carboxylate with (R)-tert-butyl 3-ethylpiperazine-1-carboxylate. LC / MS(ESI + ): m / z 337.0 (M+H) + .

[0111] [Example 8B] (R)-tert-Butyl 4-(6-aminopyridin-3-yl)-3-ethylpiperazine-1-carboxylate The title compound was prepared according to the procedure used in Example 6B, replacing Example 6A with Example 8A. LC / MS(ESI + ): m / z 307.2 (M+H) + .

[0112] [Example 8C] tert-Butyl (R)-4-(6-((6-(4-((R)-1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)-3-ethylpiperazine-1-carboxylate The title compound was prepared according to the procedure used in Example 6C, replacing Example 6B with Example 8B. LC / MS(ESI+): m / z 670.1 (M+H) + .

[0113] [Example 8D] 3-(tert-Butyl)-N-((R)-1-(4-(6-((5-((R)-2-ethylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound was prepared according to the procedure used in Example 6D, replacing Example 6C with Example 8C. LC / MS(ESI+): m / z 570.7 (M+H) + .

[0114] [Example 8E] 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2R)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-ethylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide The title compound was prepared by replacing Example 6D with Example 8D and following the procedure used in Example 6E. 1 ¹H NMR (400 MHz, dimethyl sulfoxide-d6): δ 9.95 (s, 1H), 9.79 (s, 1H), 9.40 (d, J = 7.5 Hz, 1H), 8.70 (s, 1H), 8.09 (s, 1H), 7.99 (s, 1H), 7.82 (d, J = 7.8 Hz, 2H), 7.74 (d, J = 8.7 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.51 (s, 1H), 7.33-7.28 (m, 4H), 5.34 (p, J = 7.1 Hz, 1H), 3.75 (t, J = 6.7 Hz, 2H), 3.40-3.32 (m, 4H), 3.28 (s, 2H), 3.20 (s, 1H), 3.10-3.03 (m, 1H), 3.00-2.90 (m, 3H), 2.69 (t, J = 6.7 Hz, 2H), 2.46-2.45 (m, 5H), 1.52 (d, J = 6.9 Hz, 3H), 1.35 (s, 9H), 0.83 (t, J = 7.1 Hz, 3H) ppm.LC / MS(ESI+):m / z786.9(M+H) + .

[0115] [Example 9] 3-tert-butyl-N-{(1R)-1-[4-(6-{[5-(4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2,2-dimethylpiperazine-1-yl)pyridine-2-yl]amino}pyrimidine-4-yl)-2-methylphenyl]ethyl}-1,2,4-oxadiazole-5-carboxamide

[0116] [Example 9A] tert-butyl 3,3-dimethyl-4-(6-nitropyridine-3-yl)piperazine-1-carboxylate 5-Bromo-2-nitropyridine (5.68 g, 28.0 mmol) and tert-butyl 3,3-dimethylpiperazine-1-carboxylate (3.0 g, 14.00 mmol) were dissolved in dioxane (150 mL). To the mixture, cesium carbonate (9.12 g, 28.0 mmol), BINAP((R / S)-2,2'-bis(diphenylphosphin)-1,1'-binaphthyl, 0.872 g, 1.40 mmol), and tris(dibenzylideneacetone)dipalladium(0) (1.282 g, 1.40 mmol) were added. The reaction mixture was stirred at 120 °C for 15 hours under a nitrogen atmosphere. The mixture was cooled and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica chromatography (ethyl acetate and hexane) to produce the title compound. LC / MS(ESI+)m / z336.9(M+H) + .

[0117] [Example 9B] tert-butyl 4-(6-aminopyridine-3-yl)-3,3-dimethylpiperazine-1-carboxylate Example 9A (1.1 g, 3.27 mmol) was dissolved in methanol (100 mL). Pd / C (10 wt%, 0.17 g, 1.64 mmol) was added to the mixture. The reaction mixture was hydrogenated using a hydrogen balloon at ambient temperature for 2 days. The mixture was filtered through diatomaceous earth, and the filter cake was washed with methanol and ethyl acetate. The filtrate was concentrated under reduced pressure to produce the crude title compound. LC / MS (ESI+) m / z 307.2 (M+H) + .

[0118] [Example 9C] tert-butyl(R)-4-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide)ethyl)-3-methylphenyl)pyrimidine-4-yl)amino)pyridine-3-yl)-3,3-dimethylpiperazine-1-carboxylate A stirred mixture of 1,4-dioxane (6.5 mL), Example 9B (400 mg, 1.30 mmol), Example 1E (522 mg, 1.30 mmol), racemic BINAP-Pd-G3 (CAS2151915-22-7, 130 mg, 0.13 mmol), and cesium carbonate (1276 mg, 3.92 mmol) was heated at 105°C for 2 hours in a Biotage® Initiator + microwave synthesizer. The mixture was cooled and filtered. The filtrate was concentrated under reduced pressure and purified by silica chromatography using ethyl acetate and hexane to produce the title compound. LC / MS (ESI+): m / z 670.6 (M+H) + .

[0119] [Example 9D] (R)-3-(tert-butyl)-N-(1-(4-(6-((5-(2,2-dimethylpiperazine-1-yl)pyridine-2-yl)amino)pyrimidine-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide Example 9C (845 mg, 1.26 mmol) was dissolved in 1,4-dioxane (3 mL), and the hydrochloride salt (4N in 1,4-dioxane, 1.6 mL) was added to the mixture. The mixture was stirred at ambient temperature for 2 hours and concentrated under reduced pressure to produce the crude title compound as the hydrochloride salt. LC / MS (ESI+): m / z 570.7 (M+H) + .

[0120] [Example 9E] 3-tert-butyl-N-{(1R)-1-[4-(6-{[5-(4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2,2-dimethylpiperazine-1-yl)pyridine-2-yl]amino}pyrimidine-4-yl)-2-methylphenyl]ethyl}-1,2,4-oxadiazole-5-carboxamide Example 9D (200 mg, 0.35 mmol), Example 1J (145 mg, 0.42 mmol), N,N-diisopropylethylamine (123 μL, 0.70 mmol), and potassium iodide (291 mg, 1.76 mmol) were mixed in N,N-dimethylformamide (3.5 mL). The mixture was stirred at 80°C for 4 hours. The mixture was cooled, quenched with a few drops of formic acid, and the title compound was isolated by direct reverse-phase preparative HPLC (Phenomenex Gemini® AXA C18 column, 30 × 250 mm × 5 μm, mobile phase: water and 0.1% formic acid in acetonitrile). 1H NMR (500 MHz, dimethyl sulfoxide-d6): δ ppm 10.25 (s, 1H), 10.07 (s, 1H), 9.81 (d, J = 7.8 Hz, 1H), 8.68 (d, J = 1.1 Hz, 1H), 8.04 (d, J = 3.0 Hz, 2H), 7.80-7.76 (m, 2H), 7.67 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.50 (dd, J = 8.9, 2.7 Hz, 1H), 7.21 (d, J = 8.6 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H), 5.27 (p, J = 7.1 Hz, 1H), 3.70 (t, J = 6.7 Hz, 2H), 3.01 (s, 2H), 2.70 (t, J = 7.6 Hz, 2H), 2.64 (td, J = 6.7, 2.6 Hz, 2H), 2.50 - 2.43 (m, 4H), 2.41 (s, 3H), 2.37-2.27 (m, 2H), 1.45 (d, J = 7.0 Hz, 3H), 1.29 (s, 9H), 0.94 (s, 6H).LC / MS(ESI+)m / z786.9(M+H) + .

[0121] [Example 10] 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-3-fluoro-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide

[0122] [Example 10A] 1-Bromo-2-fluoro-4-iodo-3-methylbenzene A 5 L reactor was packed with 1-bromo-2-fluoro-4-iodobenzene (288 g, 0.96 mol) in anhydrous tetrahydrofuran (2 L). The mixture was cooled to -60°C, lithium diisopropylamide (2 M, 526 mL, 1.05 mol) in tetrahydrofuran was added, and the mixture was stirred at -60°C for 1 hour. Iodomethane (163 g, 1.15 mol) was added, and the mixture was stirred at -60°C for 12 hours. The reaction mixture was diluted with water (1 L) and extracted with methyl tert-butyl ether (1 L x 3). The same reaction was repeated three times on the same scale. The combined organic layers from four batches were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to produce the crude title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 7.46 (d, J =8.4 Hz, 1H), 7.10 (t, J =7.6 Hz, 1H), 2.41 (s, 3H) ppm.

[0123] [Example 10B] 4-Bromo-3-fluoro-2-methylbenzaldehyde A 5 L reactor was packed with Example 10A (360 g, 1.14 mol) and anhydrous tetrahydrofuran (1.8 L) and cooled to -60°C. iPrMgCl (isopropyl magnesium chloride, 2 M in tetrahydrofuran, 572 mL, 1.14 mol) was added, and the mixture was stirred at -60°C for 1 hour. Morpholine-4-carbaldehyde (158 g, 1.37 mol) was added to the mixture at -60°C. The mixture was stirred at 0-5°C for 4 hours. The reaction mixture was diluted with saturated NH4Cl aqueous solution (0.8 L) and extracted with methyl tert-butyl ether (1.7 L x 3). The same reaction was repeated twice on the same scale. The combined organic layers of the three batches were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to produce the crude title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 10.18 (s, 1H), 7.54 (d, J =8.4 Hz, 1H), 7.45 (d, J =8.4 Hz, 1H), 2.60 (s, 3H) ppm.

[0124] [Example 10C] (S,E)-N-(4-Bromo-3-fluoro-2-methylbenzylidene)-2-methylpropan-2-sulfinamide A 3 L reactor was charged with triisopropyl borate (840 g, 4.47 mol), crude Example 10B (746 g, 3.44 mol), and (S)-2-methylpropan-2-sulfinamide (542 g, 4.47 mol) at ambient temperature. The mixture was stirred at 70 °C for 12 hours. The mixture was cooled to ambient temperature, diluted with water (3.0 L), extracted with dichloromethane (2.0 L × 2), washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was triturated with methyl tert-butyl ether to give the title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 8.78 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 2.55 (s, 3H), 1.28 (s, 9H) ppm. MS(ESI) m / z 320.0, 322.0 (M+H) + .

[0125] [Example 10D] (S)-N-((R)-1-(4-Bromo-3-fluoro-2-methylphenyl)ethyl)-2-methylpropan-2-sulfinamide A 10 L reactor was charged with anhydrous dichloromethane (4.4 L) and Example 10C (220 g, 0.69 mol). The mixture was cooled to 0 °C. CH3MgBr (3.0 M in tetrahydrofuran, 573 mL, 1.72 mol) was added dropwise at 0 °C. The mixture was then stirred at ambient temperature for 12 hours. The reaction mixture was cooled in an ice bath, and saturated aqueous NH4Cl solution (2.2 L) was added to the mixture. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (2.2 L × 2). The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was triturated in hexane, filtered, and dried under reduced pressure to give the title compound. 1¹H NMR (400 MHz, dimethyl sulfoxide): δ ppm 7.52 (t, J = 8.0 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 5.43 (d, J = 5.6 Hz, 1H), 4.59 (m, 1H), 2.26 (s, 3H), 1.42 (d, J = 6.8 Hz, 3H), 1.09 (s, 9H) ppm. MS (ESI) m / z 336.0, 338.0 (M+H) + .

[0126] [Example 10E] (S)-N-((R)-1-(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide To a solution of Example 10D (10.5 g, 30.0 mmol) in 1,4-dioxane (200 mL), bis(pinacolate)diborone (9.13 g, 36.0 mmol) and potassium acetate (5.88 g, 60.0 mmol) were added at 20°C. The reaction vessel was evacuated, refilled with nitrogen three times, and then 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (2.45 g, 3.00 mmol) was added. The reaction vessel was evacuated and again refilled with nitrogen three times. The reaction mixture was heated to 100°C and stirred for 16 hours. The reaction mixture was cooled and filtered through a diatomaceous earth pad. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography by elution with petroleum ether and ethyl acetate to produce the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 7.38 - 7.48 (m, 1H), 7.24 (d, J =7.75 Hz, 1H), 5.35 - 5.43 (m, 1H), 4.53 - 4.69 (m, 1H), 2.19 (d, J =2.00 Hz, 3H), 1.42 (d, J =6.63 Hz, 3H), 1.28 (s, 12H), 1.08 (s, 9H) ppm.

[0127] [Example 10F] (R)-1-(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethane-1-amine To a solution of Example 10E (20.0 g, 52.2 mmol) in methyl tert-butyl ether (400 mL), hydrochloride (4N in methyl tert-butyl ether, 400 mL) was added dropwise at ambient temperature. The mixture was stirred for 3 hours, concentrated under reduced pressure, and ground in methyl tert-butyl ether (50 mL). The solid was isolated by filtration and dried under vacuum to produce the crude title compound. 1 ¹H NMR (400 MHz, dimethyl sulfoxide-d6): δ 8.63 (br s, 3H), 7.56 - 7.49 (m, 1H), 7.43 (d, J = 7.9 Hz, 1H), 4.57 (q, J = 6.7 Hz, 1H), 2.22 (d, J = 1.8 Hz, 3H), 1.46 (d, J = 6.6 Hz, 3H), 1.29 (s, 12H) ppm.MS(ESI)m / z280.0(M+H) + .

[0128] [Example 10G] (R)-3-(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-5-carboxamide To a solution of Example 10F (7.00 g, 21.1 mmol) and methyl 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate (9.70 g, 52.7 mmol) in ethanol (140 mL), triethylamine (23.5 mL, 169 mmol) was added at 20 °C. The mixture was stirred at 60 °C for 12 hours, and then concentrated under reduced pressure to remove the ethanol. The crude substance was purified by column chromatography of silica gel eluted with petroleum ether and ethyl acetate to produce the title compound. 1¹H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 9.90 (br d, J = 7.6 Hz, 1H), 7.47 (t, J = 6.9 Hz, 1H), 7.38 - 7.22 (m, 1H), 5.28 (br t, J = 7.2 Hz, 1H), 2.33 - 2.18 (m, 3H), 1.46 (br d, J = 6.9 Hz, 3H), 1.42 - 1.19 (m, 2¹H) ppm.MS(ESI)m / z432.2(M+H) + .

[0129] [Example 10H] (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidine-4-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide A mixture of Example 10G (2.80 g, 6.49 mmol) and 4,6-dichloropyrimidine (1.93 g, 12.98 mmol) in tetrahydrofuran (120 mL) was added at 20°C to a solution of potassium phosphate (2.76 g, 12.98 mmol) in water (30 mL). The mixture was degassed at ambient temperature using a nitrogen stream, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (265 mg, 0.33 mmol) was added to the mixture under N2. The reaction mixture was heated to 80°C and stirred for 2 hours. The mixture was cooled, poured into water, and extracted with ethyl acetate (three times). The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica column chromatography eluting with tetrahydrofuran in petroleum ether to obtain the crude title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 9.93 (d, J=7.8 Hz, 1H), 9.07 (s, 1H), 8.30 (s, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 5.33 (quintet, J=7.2 Hz, 1H), 2.48 - 2.47 (m, 1H), 2.47 (s, 2H), 1.50 (d, J=7.0 Hz, 3H), 1.36 (s, 9H) ppm.MS(ESI)m / z418.2(M+H) + .

[0130] [Example 10I] tert-butyl(S)-4-(6-((6-(4-((R)-1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide)ethyl)-2-fluoro-3-methylphenyl)pyrimidine-4-yl)amino)pyridine-3-yl)-3-methylpiperazine-1-carboxylate To a solution of Example 10H (500 mg, 1.20 mmol) in 1,4-dioxane (10 mL), Example 1 L (385 mg, 1.32 mmol), Pd2(dba)3 (CAS 52409-22-0, 55 mg, 0.06 mmol), XantPhos (CAS 161265-03-8, 69 mg, 0.12 mmol), and cesium carbonate (780 mg, 2.39 mmol) were added. The mixture was degassed using a nitrogen stream and stirred at 100°C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled, diluted with ethyl acetate, filtered through diatomaceous earth, concentrated under reduced pressure, and purified by silica chromatography using ethyl acetate and petroleum ether to produce the title compound. LC / MS (ESI+): m / z 674.4 (M+H) + .

[0131] [Example 10J] 3-(tert-butyl)-N-((R)-1-(3-fluoro-2-methyl-4-(6-((5-((S)-2-methylpiperazine-1-yl)pyridine-2-yl)amino)pyrimidine-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide To a solution of Example 10I (150 mg, 0.223 mmol) in methyl tert-butyl ether (2 mL), the hydrochloride salt (4N, 2 mL in methyl tert-butyl ether) was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to produce the title compound as the hydrochloride salt. LC / MS (ESI+): m / z 574.4 (M+H) + .

[0132] [Example 10K] 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-3-fluoro-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide To a solution of Example 10J (100 mg, 0.17 mmol) in N,N-dimethylformamide (2 mL), Example 1J (54 mg, 0.17 mmol), potassium iodide (145 mg, 0.87 mmol), and potassium carbonate (48 mg, 0.35 mmol) were added. The mixture was stirred at 80°C for 2 hours. The mixture was cooled to ambient temperature, filtered, and the title compound was isolated by direct reverse-phase preparative HPLC (Gilson GX-281 system, Phenomenex Gemini® NX C18 column, 30 × 75 mm × 3 μm, mobile phase: water and 10 mM ammonium bicarbonate in acetonitrile). 1H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 10.33 (s, 1H), 10.08 (s, 1H), 9.93 (br d, J = 7.5 Hz, 1H), 8.72 (s, 1H), 7.96 (br d, J = 2.4 Hz, 2H), 7.81 (t, J = 8.0 Hz, 1H), 7.72 (br d, J = 2.0 Hz, 1H), 7.43 (br d, J = 8.3 Hz, 2H), 7.32-7.17 (m, 4H), 5.33 (quintet, J = 6.9 Hz, 1H), 3.92-3.83 (m, 1H), 3.76 (t, J = 6.7 Hz, 2H), 3.26-3.16 (m, 1H), 2.98 (br t, J = 9.5 Hz, 1H), 2.85 (br d, J = 10.6 Hz, 1H), 2.81-2.74 (m, 2H), 2.69 (br t, J = 6.7 Hz, 3H), 2.61 - 2.54 (m, 2H), 2.46-2.42 (m, 1H), 2.35 (d, J = 1.8 Hz, 3H), 2.31-2.25 (m, 1H), 1.52 (d, J = 7.0 Hz, 3H), 1.36 (s, 9H), 0.98 (d, J = 6.3 Hz, 3H) ppm.MS(ESI)m / z790.3(M+H) + .

[0133] [Example 11] 3-tert-butyl-N-{(1R)-1-[4-(6-{[5-(4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}piperazine-1-yl)pyridine-2-yl]amino}pyrimidine-4-yl)-3-fluoro-2-methylphenyl]ethyl}-1,2,4-oxadiazole-5-carboxamide

[0134] [Example 11A] tert-butyl(R)-4-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide)ethyl)-2-fluoro-3-methylphenyl)pyrimidine-4-yl)amino)pyridine-3-yl)piperazine-1-carboxylate To a solution of Example 10H (2.40 g, 5.46 mmol) in 1,4-dioxane (80 mL), Example 3B (1.67 g, 6.00 mmol), Pd2(dba)3 (CAS 52409-22-0, 250 mg, 0.27 mmol), XantPhos (CAS 161265-03-8, 316 mg, 0.32 mmol), and cesium carbonate (3.56 g, 10.91 mmol) were added. The mixture was degassed using a nitrogen stream and stirred at 100°C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled, diluted with ethyl acetate, filtered through diatomaceous earth, concentrated under reduced pressure, and purified by silica chromatography using ethyl acetate and petroleum ether to produce the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 10.15 (s, 1H), 9.96 (d, J = 7.8 Hz, 1H), 8.75 (s, 1H), 8.08 - 7.94 (m, 2H), 7.87 - 7.68 (m, 2H), 7.52 - 7.40 (m, 2H), 5.41 - 5.29 (m, 1H), 3.48 (br d, J = 4.8 Hz, 4H), 3.14 - 3.03 (m, 4H), 2.37 (d, J = 1.9 Hz, 3H), 1.53 (d, J = 7.0 Hz, 3H), 1.43 (s, 9H), 1.38 (s, 9H) ppm.LC / MS(ESI+):m / z660.4(M+H) + .

[0135] [Example 11B] (R)-3-(tert-butyl)-N-(1-(3-fluoro-2-methyl-4-(6-((5-(piperazin-1-yl)pyridine-2-yl)amino)pyrimidine-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide To a solution of Example 11A (3.15 g, 4.30 mmol) in 1,4-dioxane (40 mL), hydrochloride (4N in 1,4-dioxane, 40 mL) was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to produce the title compound as hydrochloride. 1 H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 10.11 (s, 1H), 10.06 - 9.88 (m, 1H), 8.74 (s, 1H), 8.00 (br s, 2H), 7.87 - 7.64 (m, 2H), 7.45 (br d, J = 7.1 Hz, 2H), 5.35 (br t, J = 6.9 Hz, 1H), 3.04 (br s, 4H), 2.86 (br s, 4H), 2.37 (br s, 3H), 1.53 (br d, J = 6.6 Hz, 3H), 1.37 (s, 9H) ppm.LC / MS(ESI+):m / z560.3(M+H) + .

[0136] [Example 11C] 3-tert-butyl-N-{(1R)-1-[4-(6-{[5-(4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}piperazine-1-yl)pyridine-2-yl]amino}pyrimidine-4-yl)-3-fluoro-2-methylphenyl]ethyl}-1,2,4-oxadiazole-5-carboxamide To a solution of Example 11B (130 mg, 0.21 mmol) in N,N-dimethylformamide (1 mL), Example 1J (86 mg, 0.25 mmol), sodium bromide (129 mg, 1.25 mmol), and sodium bicarbonate (70 mg, 0.84 mmol) were added. The mixture was stirred at 80°C for 12 hours. The mixture was cooled to ambient temperature, filtered, and the title compound was isolated by direct reverse-phase preparative HPLC (Phenomenex Gemini® NX C18 column, 40 × 80 mm × 3 μm, mobile phase: water and 10 mM ammonium bicarbonate in acetonitrile). 1H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 10.34 (s, 1 H), 10.09 (s, 1 H), 9.94 (br d, J=7.63 Hz, 1 H), 8.72 (s, 1 H), 8.01 (br s, 1 H), 7.81 (br t, J=8.07 Hz, 1 H), 7.39-7.49 (m, 2 H), 7.21-7.30 (m, 3 H), 5.33 (br t, J=6.94 Hz, 1 H), 3.76 (t, J=6.63 Hz, 2 H), 3.14 (br s, 5 H), 2.74-2.82 (m, 2 H), 2.69 (br t, J=6.69 Hz, 2 H), 2.52-2.64 (m, 6 H), 2.35 (d, J=1.50 Hz, 3 H), 1.51 (br d, J=6.88 Hz, 3 H), 1.36 (s, 9 H) ppm.MS(ESI)m / z776.3(M+H) + .

[0137] [Example 12] 3-tert-butyl-N-{(1R)-1-[4-(6-{[5-(4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}piperazine-1-yl)pyridine-2-yl]amino}pyrimidine-4-yl)-5-fluoro-2-methylphenyl]ethyl}-1,2,4-oxadiazole-5-carboxamide

[0138] [Example 12A] 4-Bromo-5-fluoro-2-methylbenzaldehyde A 2 L flask was filled with 1-bromo-2-fluoro-4-iodo-5-methylbenzene (25 g, 79 mmol) and anhydrous tetrahydrofuran (400 mL) and cooled to -25°C. iPrMgCl (isopropyl magnesium chloride, 1.3 M in tetrahydrofuran, 67.2 mL, 87 mmol) was added, and the mixture was stirred at -25°C for 30 minutes. Anhydrous N,N-dimethylformamide (7.38 mL, 96 mmol) was added to the mixture at -25°C. The mixture was left to stand, then warmed to 0-5°C and stirred for 1.5 hours. The reaction mixture was carefully quenched with 1 N hydrochloric acid (200 mL), and the mixture was extracted with ethyl acetate (three times). The combined organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to produce the crude title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 10.21 (d, J =1.7 Hz, 1H), 7.58-7.54 (m, 2H), 2.64 (s, 3H) ppm.

[0139] [Example 12B] (S,E)-N-(4-bromo-5-fluoro-2-methylbenzylidene)-2-methylpropane-2-sulfinamide A 1 L flask was filled with Example 12A (17.00 g, 78.0 mmol) and dichloromethane (340 mL). To this stirred solution, (S)-2-methylpropane-2-sulfinamide (10.44 g, 86.0 mmol) and titanium(IV) ethoxide (35.7 g, 157 mmol) were added at ambient temperature. The mixture was stirred for 16 hours and then quenched at 0°C with water (36 mL). The mixture was filtered, and the filtrate was washed with dichloromethane (three times using 300 mL). The filtrate was concentrated under reduced pressure, and the crude substance was ground in hexane (50 mL) for 30 minutes. The solid was isolated by filtration, washed with hexane, and dried under high vacuum to produce the title compound.

[0140] [Example 12C] (S)-N-((R)-1-(4-bromo-5-fluoro-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide A 2 L flask was packed with anhydrous dichloromethane (400 mL) and Example 12B (21.6 g, 67.5 mmol). The mixture was cooled to 0°C. CH3MgBr (3.0 M in tetrahydrofuran, 56.2 mL, 169 mmol) was added dropwise at 0°C. The mixture was then stirred at 0°C for 5 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution (500 mL). The organic phase was separated, and the aqueous phase was extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica column chromatography using ethyl acetate and petroleum ether to isolate the title compound. MS(ESI)m / z 335.9, 337.9(M+H) + .

[0141] [Example 12D] (S)-N-((R)-1-(5-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide To a solution of Example 12C (15.0 g, 43.3 mmol) in 1,4-dioxane (300 mL), bis(pinacolate)diborone (13.19 g, 51.9 mmol) and potassium acetate (8.49 g, 87.0 mmol) were added at 20°C. The reaction vessel was evacuated, refilled with nitrogen three times, and then 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (3.53 g, 4.33 mmol) was added. The reaction vessel was evacuated and again refilled with nitrogen three times. The reaction mixture was heated to 100°C and stirred for 16 hours. The reaction mixture was cooled and filtered through a diatomaceous earth pad. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography by elution with petroleum ether and ethyl acetate to produce the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 7.51 (d, J=6.0 Hz, 1H), 7.05 (d, J=10.5 Hz, 1H), 4.80 (br d, J=3.4 Hz, 1H), 3.49 (br d, J=2.6 Hz, 1H), 2.34 (s, 3H), 1.50 - 1.44 (m, 3H), 1.36 (s, 12H), 1.23 - 1.19 (m, 9H) ppm.

[0142] [Example 12E] (R)-1-(5-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethane-1-amine To a solution of Example 12D (3.00 g, 7.83 mmol) in dichloromethane (10 mL), hydrochloride (4N in 1,4-dioxane, 30 mL) was added dropwise at ambient temperature. The mixture was stirred for 24 hours and concentrated under reduced pressure to produce the crude title compound. MS(ESI)m / z 280.0(M+H) + .

[0143] [Example 12F] (R)-3-(tert-butyl)-N-(1-(5-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide To a solution of Example 12E (3.80 g, 13.61 mmol) and methyl 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate (3.76 g, 20.42 mmol) in tetrahydrofuran (60 mL), 2,3,4,6,7,8,9,10-octahydropyrimide[1,2-a]azepine (6.16 mL, 40.80 mmol) was added at ambient temperature. The reaction mixture was stirred at 85 °C for 16 hours, cooled, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted with hexane and ethyl acetate to produce the title compound. MS(ESI)m / z432.2(M+H) + .

[0144] [Example 12G] (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidine-4-yl)-5-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound was prepared by replacing Example 10G with Example 12F and following the procedure used in Example 10H. MS(ESI)m / z 418.2(M+H) + .

[0145] [Example 12H] tert-butyl(R)-4-(6-((6-(4-(1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide)ethyl)-2-fluoro-5-methylphenyl)pyrimidine-4-yl)amino)pyridine-3-yl)piperazine-1-carboxylate A stirred mixture of 1,4-dioxane (6.5 mL), Example 3B (406 mg, 1.46 mmol), Example 12G (435 mg, 1.04 mmol), racemic BINAP-Pd-G3 (CAS2151915-22-7, 99 mg, 0.1 mmol), and cesium carbonate (746 mg, 2.29 mmol) was heated at 110°C for 4 hours under a nitrogen atmosphere. The mixture was cooled, filtered, concentrated under reduced pressure, and the residue was purified by silica chromatography using ethyl acetate and hexane to isolate the title compound. LC / MS (ESI+): m / z 660.4 (M+H) + .

[0146] [Example 12I] (R)-3-(tert-butyl)-N-(1-(5-fluoro-2-methyl-4-(6-((5-(piperazin-1-yl)pyridine-2-yl)amino)pyrimidine-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide The title compound was prepared by replacing Example 11A with Example 12H and following the procedure used in Example 11B. MS(ESI)m / z 560.4(M+H) + .

[0147] [Example 12J] 3-tert-butyl-N-{(1R)-1-[4-(6-{[5-(4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}piperazine-1-yl)pyridine-2-yl]amino}pyrimidine-4-yl)-5-fluoro-2-methylphenyl]ethyl}-1,2,4-oxadiazole-5-carboxamide To a solution of Example 12I (100 mg, 0.17 mmol) in N,N-dimethylformamide (1.7 mL), Example 1J (81 mg, 0.24 mmol), potassium iodide (139 mg, 0.84 mmol), and N,N-diisopropylethylamine (205 μL, 1.17 mmol) were added. The mixture was stirred at 80°C for 2 hours. The mixture was cooled to ambient temperature, filtered, and the title compound was isolated by direct reverse-phase preparative HPLC (Phenomenex Gemini® AXA C18 column, 30 × 250 mm × 5 μm, mobile phase: water and 0.1% formic acid in acetonitrile). 1 H NMR (500 MHz, dimethyl sulfoxide-d6): δ ppm 10.34 (s, 1H), 10.11 (s, 1H), 9.87 (d, J = 7.9 Hz, 1H), 8.73 (s, 1H), 8.04-7.95 (m, 2H) 7.83 (d, J = 8.0 Hz, 1H), 7.72 (brs, 1H), 7.50-7.45 (m, 1H), 7.43 (d, J = 12.5 Hz, 1H), 7.30-7.20 (m, 4H), 5.29 (p, J = 7.2 Hz, 1H), 3.76 (t, J = 6.7Hz, 2H), 3.14 (brs, 4H), 2.81 (brs, 2H), 2.70 (t, J = 6.8 Hz, 2H), 2.67-2.55 (m, 3H), 2.42 (s, 3H), 1.51 (d, J = 7.0 Hz, 3H), 1.37 (s, 9H) ppm.MS(ESI)m / z776.8(M+H) + .

[0148] [Example 13] 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-(propan-2-yl)piperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide

[0149] [Example 13A] tert-butyl(S)-3-isopropyl-4-(6-nitropyridine-3-yl)piperazine-1-carboxylate To a mixture of dimethyl sulfoxide (10 mL) and 5-fluoro-2-nitropyridine (467 mg, 3.28 mmol), (S)-tert-butyl 3-isopropylpiperazine-1-carboxylate (500 mg, 2.190 mmol) and N,N-diisopropylethylamine (1.147 mL, 6.57 mmol) were added under N2 conditions at 20°C. The reaction mixture was stirred at 120°C for 16 hours. The mixture was cooled and poured into ice water (30 mL). The substance in the mixture was collected by filtration. This substance was ground in a mixture of ethyl acetate and petroleum ether to form a slurry. The slurry was filtered, and the filtered cake was dried under vacuum to produce the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 8.25 (d, J=3.00 Hz, 1 H), 8.11 (d, J=9.26 Hz, 1 H), 7.46 (dd, J=9.38, 3.00 Hz, 1 H), 4.02-4.13 (m, 1 H), 3.92 (br d, J=12.26 Hz, 3 H), 3.18 (br s, 1 H), 2.84-3.10 (m, 2 H), 2.01-2.15 (m, 1 H), 1.41 (s, 9 H), 1.05 (br d, J=4.38 Hz, 3 H), 0.73 (d, J=6.75 Hz, 3 H) ppm.

[0150] [Example 13B] tert-butyl(S)-4-(6-aminopyridine-3-yl)-3-isopropylpiperazine-1-carboxylate To a mixture of Pd / C (10 wt%, 121 mg, 0.114 mmol) in ethyl acetate (12 mL), Example 13A (400 mg, 1.142 mmol) was added at ambient temperature. The mixture was hydrogenated for 2 hours using a hydrogen balloon. The mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure to produce the crude title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 7.66 (br s, 1 H), 7.21 (br d, J=7.75 Hz, 1 H), 6.39 (d, J=8.75 Hz, 1 H), 5.49 (br s, 2 H), 3.35-3.65 (m, 2 H), 2.90 (br s, 3 H), 2.51-2.54 (m, 2 H), 1.77 (br s, 1 H), 1.41 (s, 9 H), 0.70 - 0.91 (m, 6 H) ppm.

[0151] [Example 13C] tert-butyl(S)-4-(6-((6-(4-((R)-1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide)ethyl)-3-methylphenyl)pyrimidine-4-yl)amino)pyridine-3-yl)-3-isopropylpiperazine-1-carboxylate To a solution of Example 1M (200 mg, 0.49 mmol) in 1,4-dioxane (5 mL), Example 13B (233 mg, 0.73 mmol), Pd2(dba)3 (CAS 52409-22-0, 44 mg, 0.049 mmol), XantPhos (CAS 161265-03-8, 28 mg, 0.049 mmol), and cesium carbonate (316 mg, 0.97 mmol) were added. The mixture was degassed using a nitrogen stream and stirred at 100°C for 12 hours. The reaction mixture was cooled, diluted with ethyl acetate, and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by silica chromatography using tetrahydrofuran and petroleum ether to produce the title compound. LC / MS (ESI+): m / z 684.5 (M+H) + .

[0152] [Example 13D] 3-(tert-butyl)-N-((R)-1-(4-(6-((5-((S)-2-isopropylpiperazine-1-yl)pyridine-2-yl)amino)pyrimidine-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide To a solution of Example 13C (280 mg, 0.372 mmol) in 1,4-dioxane (3 mL), the hydrochloride salt (4N in dioxane, 3 mL) was added dropwise at ambient temperature. The mixture was stirred for 1 hour and concentrated under reduced pressure to produce the crude title compound as the hydrochloride salt. 1H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 9.89 (s, 1 H), 8.67 (s, 1 H), 7.97 (br d, J=2.64 Hz, 2 H), 7.77 - 7.88 (m, 1 H), 7.74 - 7.89 (m, 1 H), 7.55 - 7.69 (m, 2 H), 7.21 - 7.43 (m, 2 H), 5.33 (quintet, J=7.12 Hz, 1 H), 3.21 - 3.31 (m, 3 H), 3.00 - 3.11 (m, 1 H), 2.83 - 2.92 (m, 1 H), 2.62 - 2.82 (m, 3 H), 2.47 (s, 3 LC / MS(ESI+):m / z584.5(M+H) + .

[0153] [Example 13E] 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-(propan-2-yl)piperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide To a solution of Example 13D (220 mg, 0.34 mmol) in acetonitrile (5 mL), Example 1J (175 mg, 0.51 mmol), sodium iodide (153 mg, 1.02 mmol), and N,N-diisopropylethylamine (296 μL, 1.70 mmol) were added. The mixture was stirred at 80°C for 16 hours. The mixture was cooled to ambient temperature, filtered, and the title compound was isolated by direct reverse-phase preparative HPLC (Waters® Xbridge C18 column, 30 × 100 mm × 10 μm, mobile phase: water and 10 mM ammonium bicarbonate in acetonitrile). 1H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 10.35 (s, 1 H), 9.86-10.00 (m, 2 H), 8.68 (s, 1 H), 8.00 (br d, J=2.63 Hz, 2 H), 7.82 (br s, 2 H), 7.60 (br d, J=8.55 Hz, 2 H), 7.36-7.47 (m, 1 H), 7.25 (q, J=8.70 Hz, 4 H), 5.27-5.39 (m, 1 H), 3.69-3.80 (m, 2 H), 3.38-3.43 (m, 2 H), 3.09-3.20 (m, 1 H), 2.88 (br s, 1 H), 2.73-2.79 (m, 2 H), 2.67-2.71 (m, 2 H), 2.52 (d, J=1.75 Hz, 2 H), 2.47 (s, 3 H), 2.28-2.35 (m, 2 H), 2.17-2.26 (m, 2 H), 1.51 (d, J=7.02 Hz, 3 H), 1.36 (s, 9 H), 0.89 (d, J=6.58 Hz, 3 H), 0.76 (d, J=6.80 Hz, 3 H) ppm.MS(ESI)m / z800.5(M+H) + .

[0154] [Example 14] 3-tert-butyl-N-[(1R)-1-{2-chloro-4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]phenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide

[0155] [Example 14A] (S,E)-N-(4-bromo-2-chlorobenzylidene)-2-methylpropane-2-sulfinamide A 1 L flask was packed at ambient temperature with triisopropyl borate (139 g, 0.74 mol), 4-bromo-2-chlorobenzaldehyde (125 g, 0.57 mol), and (S)-2-methylpropane-2-sulfinamide (90 g, 0.74 mol). The mixture was stirred at 70°C for 12 hours. Water (0.5 L) was added, and the mixture was extracted with dichloromethane (0.5 L x 3), washed with brine (1.0 L), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The reaction was repeated three times on the same scale. The crude products obtained from all four batches were combined to produce the title compound. MS(ESI) m / z 322.0, 324.0 (M+H) + .

[0156] [Example 14B] (S)-N-((R)-1-(4-bromo-2-chlorophenyl)ethyl)-2-methylpropane-2-sulfinamide A 5 L reactor was packed with dichloromethane (3.5 L) and Example 14A (173 g, 0.53 mol). The mixture was cooled to 0°C. CH3MgBr (3.0 M in tetrahydrofuran, 268 mL, 0.80 mol) was added dropwise at 0°C. The mixture was stirred at ambient temperature for 12 hours. The reaction mixture was cooled in an ice bath, and saturated NH4Cl aqueous solution (1.6 L) was added to the mixture. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (0.5 L x 3). The reaction was repeated four times on the same scale. The combined organic layers were washed with brine (5.5 L), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was ground in hexane to produce the crude title compound. MS(ESI) m / z 338.0, 340.0 (M+H) + .

[0157] [Example 14C] (S)-N-((R)-1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide To a solution of Example 14B (15.0 g, 40.0 mmol) in 1,4-dioxane (150 mL), bis(pinacolate)diborone (10.1 g, 40.0 mmol) and potassium acetate (7.82 g, 80.0 mmol) were added at 20°C. The reaction vessel was evacuated, refilled with nitrogen three times, and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (3.26 g, 4.0 mmol) was added. The reaction vessel was evacuated and again refilled with nitrogen three times. The reaction mixture was heated to 110°C and stirred for 16 hours. The reaction mixture was cooled and filtered through a diatomaceous earth pad. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography by elution with petroleum ether and ethyl acetate to produce the title compound. MS(ESI)m / z386.2(M+H) + .

[0158] [Example 14D] (R)-1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethane-1-amine To a solution of Example 14C (8.00 g, 20.7 mmol) in 1,4-dioxane (100 mL), the hydrochloride salt (4N in 1,4-dioxane, 100 mL) was added dropwise at ambient temperature. The mixture was stirred for 2 hours and concentrated under reduced pressure to produce the crude title compound as the hydrochloride salt. MS(ESI)m / z 282.3(M+H) + .

[0159] [Example 14E] (R)-3-(tert-butyl)-N-(1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide To a solution of Example 14D (6.60 g, 20.8 mmol) and methyl 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate (7.64 g, 41.5 mmol) in ethanol (180 mL), triethylamine (17.4 mL, 125 mmol) was added at 20 °C. The mixture was stirred at 80 °C for 12 hours, and then concentrated under reduced pressure to remove the ethanol. The crude substance was purified by column chromatography of silica gel eluted with petroleum ether and ethyl acetate to produce the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 9.95 (d, J=7.5 Hz, 1H), 7.65 - 7.56 (m, 3H), 5.42 (quintet, J=7.2 Hz, 1H), 1.48 (d, J=7.1 Hz, 3H), 1.36 (s, 9H), 1.28 (s, 12H) ppm.MS(ESI)m / z434.4(M+H) + .

[0160] [Example 14F] (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidine-4-yl)-2-chlorophenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide To a mixture of Example 14E (6.00 g, 13.83 mmol) and 4,6-dichloropyrimidine (2.47 g, 16.60 mmol) in 1,4-dioxane (111 mL) and water (28 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.13 g, 1.38 mmol) and potassium phosphate (5.87 g, 27.7 mmol) were added. The mixture was degassed at ambient temperature using a nitrogen stream and stirred at 80°C for 1 hour under a nitrogen atmosphere. The mixture was cooled, poured into water, and extracted with ethyl acetate (three times). The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica column chromatography eluting with ethyl acetate in hexane to obtain the crude title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 10.02 (br d, J=7.63 Hz, 1H), 9.11 (d, J=0.63 Hz, 1H), 8.39 (d, J=0.75Hz, 1H), 8.31 (d, J=1.63 Hz, 1H), 8.23 (dd, J=8.25, 1.63 Hz, 1H), 7.74 (d, J=8.25 Hz, 1H), 5.47 (br t, J=7.19 Hz, 1H), 1.53 (d, J=7.00 Hz, 3H), 1.37 (s, 9H) ppm.MS(ESI)m / z420.1, 422.1(M+H) + .

[0161] [Example 14G] tert-butyl(S)-4-(6-((6-(4-((R)-1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide)ethyl)-3-chlorophenyl)pyrimidine-4-yl)amino)pyridine-3-yl)-3-methylpiperazine-1-carboxylate To a solution of 1,4-dioxane (6.4 mL) containing 14H (288 mg, 0.69 mmol), 1 L of Example (240 mg, 0.82 mmol), Pd2(dba)3 (CAS 52409-22-0, 38 mg, 0.04 mmol), XantPhos (CAS 161265-03-8, 40 mg, 0.07 mmol), and cesium carbonate (447 mg, 1.37 mmol) were added. The mixture was degassed using a nitrogen stream and stirred at 100°C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled, diluted with ethyl acetate, filtered through diatomaceous earth, concentrated under reduced pressure, and purified by silica chromatography using ethyl acetate and petroleum ether to produce the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 9.97-10.11 (m, 2H), 7.92-8.11 (m, 4H), 7.72 (d, J=8.11 Hz, 2H), 7.44 (dd, J=9.12, 2.80 Hz, 1H), 5.46 (m, 1H), 3.75-3.89 (m, 2H), 3.61 (br d, J=11.09 Hz, 1H), 3.17 (br d, J=11.80 Hz, 3H), 2.90-3.00 (m, 1H), 1.53 (d, J=7.03 Hz, 3H), 1.41 (s, 9H), 1.37 (s, 9H), 0.88 (d, J=6.32 Hz, 3H) ppm.LC / MS(ESI+):m / z676.4(M+H) + .

[0162] [Example 14H] 3-(tert-butyl)-N-((R)-1-(2-chloro-4-(6-((5-((S)-2-methylpiperazine-1-yl)pyridine-2-yl)amino)pyrimidine-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide In Example 1, 258 mg (0.38 mmol) of 1,4-dioxane was dissolved in 3 mL of 1,4-dioxane, to which hydrochloride (4N in 1,4-dioxane, 3 mL) was added dropwise. The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, dissolved in 10 mL of water, and made basic with saturated sodium bicarbonate aqueous solution to adjust the pH to 8. The mixture was extracted with dichloromethane (10 mL, 3 times), the combined organic phase was washed with brine (10 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to produce the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 10.08 (br s, 2H), 8.72 (s, 1H), 7.91-8.10 (m, 4H), 7.71 (br d, J=8.13 Hz, 2H), 7.40 (br dd, J=9.13, 2.75 Hz, 2H), 5.46 (br s, 1H), 3.64-3.80 (m, 1H), 3.01-3.15 (m, 1H), 2.79-2.98 (m, 3H), 2.62-2.77 (m, 2H), 1.53 (br d, J=6.88 Hz, 3H), 1.36 (s, 9H), 0.95 (d, J=6.38 Hz, 3H) ppm.LC / MS(ESI+):m / z576.3(M+H) + .

[0163] [Example 14I] 3-tert-butyl-N-[(1R)-1-{2-chloro-4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]phenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide To a solution of Example 14H (85 mg, 0.15 mmol) in acetonitrile (2 mL), Example 1J (102 mg, 0.30 mmol), sodium iodide (66 mg, 0.44 mmol), and N,N-diisopropylethylamine (129 μL, 0.74 mmol) were added. The mixture was stirred at 80°C for 16 hours. The mixture was cooled to ambient temperature, filtered, and the title compound was isolated by direct reverse-phase preparative HPLC (Phenomenex Luna® C18 column, 30 × 75 mm × 3 μm, mobile phase: water and 0.1% formic acid in acetonitrile). 1H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 10.34 (s, 1 H), 9.97-10.13 (m, 2 H), 8.73 (s, 1 H), 7.91-8.11 (m, 4 H), 7.72 (br d, J=8.13 Hz, 2 H), 7.47 (br d, J=8.00 Hz, 1 H), 7.20-7.33 (m, 4 H), 5.46 (quintet, J=7.10 Hz, 1 H), 3.80 - 3.95 (m, 1 H), 3.76 (t, J=6.63 Hz, 2 H), 3.16-3.26 (m, 2 H), 2.95-3.10 (m, 2 H), 2.57-2.93 (m, 8 H), 1.53 (d, J=7.00 Hz, 3 H), 1.37 (s, 9 H), 1.00 (br d, J=6.00 Hz, 3 H) ppm.MS(ESI)m / z792.2(M+H) + .

[0164] [Example 15] 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2R)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-(methoxymethyl)piperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide

[0165] [Example 15A] (R)-1-benzyl 4-tert-butyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylate To a solution of (R)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1.5 g, 6.94 mmol) in tetrahydrofuran (30 mL), a solution of sodium carbonate (2.205 g, 20.81 mmol) in water (6.00 mL) was added at 20°C. Benzyl chloroformate (1.775 g, 10.40 mmol) was added dropwise at 0°C. The reaction mixture was extracted with ethyl acetate (three times), washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using ethyl acetate in petroleum ether to produce the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 7.28-7.39 (m, 5 H), 5.09 (s, 2 H), 4.82 (br t, J=4.63 Hz, 1 H), 3.97 (br d, J=13.63 Hz, 1 H), 3.80 (br d, J=12.76 Hz, 2 H), 3.34-3.49 (m, 2 H), 2.68-3.07 (m, 4 H), 1.99 (s, 1 H), 1.40 (s, 9 H), 1.17 (t, J=7.07 Hz, 1 H) ppm.MS(ESI)m / z295.2(M-tBu+H) + .

[0166] [Example 15B] (R)-1-benzyl 4-tert-butyl 2-(methoxymethyl)piperazine-1,4-dicarboxylate Example 15A (2.0 g, 5.71 mmol) was dissolved in dichloromethane (40 mL), and the mixture was cooled to 0°C. 1,8-bis(dimethylamino)naphthalene (4.89 g, 22.83 mmol) was added to the mixture in one addition, followed by the slow addition of trimethyloxonium tetrafluoroborate (3.38 g, 22.83 mmol) over 5 minutes. The mixture was stirred at 0°C for 30 minutes, then allowed to stand, and was heated to 20°C and stirred for 1 hour. The reaction mixture was extracted with ethyl acetate (5 times). The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica column chromatography using ethyl acetate in petroleum ether to obtain the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 7.27-7.40 (m, 4 H), 5.01-5.17 (m, 2 H), 4.18 (br d, J=0.88 Hz, 1 H), 3.68-3.97 (m, 3 H), 3.32 (d, J=2.26 Hz, 2 H), 3.24 (br s, 3 H), 2.68-3.04 (m, 3 H), 1.40 (s, 9 H) ppm.

[0167] [Example 15C] tert-butyl(R)-3-(methoxymethyl)piperazine-1-carboxylate To a suspension of Pd / C (10 wt%, 0.38 g, 0.357 mmol) in ethyl acetate (26 mL), Example 15B (1.3 g, 3.57 mmol) was added. The reaction mixture was hydrogenated using a hydrogen balloon at ambient temperature for 16 hours. The mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure to produce the crude title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 3.65-3.87 (m, 2 H), 3.26 (s, 3 H), 3.20-3.22 (m, 1 H), 3.22 (d, J=6.02 Hz, 1 H), 2.83 (br d, J=11.80 Hz, 1 H), 2.59-2.77 (m, 2 H), 2.46-2.56 (m, 2 H), 2.30 (br s, 1 H), 1.40 (s, 9 H) ppm.

[0168] [Example 15D] (R)-tert-butyl 3-(methoxymethyl)-4-(6-nitropyridine-3-yl)piperazine-1-carboxylate To a mixture of dimethyl sulfoxide (16 mL) and 5-fluoro-2-nitropyridine (740 mg, 5.21 mmol), Example 15C (800 mg, 3.47 mmol) and N,N-diisopropylethylamine (1.820 mL, 10.42 mmol) were added at ambient temperature. The reaction mixture was heated to 120 °C and stirred for 12 hours. The reaction mixture was cooled, poured into water, and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica column chromatography using ethyl acetate in petroleum ether to obtain the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 8.64 (d, J=2.88 Hz, 1 H), 8.44 (d, J=8.88 Hz, 1 H), 8.22 (d, J=3.00 Hz, 1 H), 8.16 (d, J=9.26 Hz, 1 H), 8.04 (dd, J=8.94, 2.81 Hz, 1 H), 7.44 (dd, J=9.26, 3.00 Hz, 1 H), 4.34 (br s, 1 H), 3.96-4.07 (m, 1 H), 3.90 (br d, J=1.63 Hz, 1 H), 3.80 (br d, J=12.88 Hz, 1 H), 3.36 - 3.48 (m, 2 H), 3.32 (s, 1 H), 3.23 (s, 5 H), 1.42 (s, 9 H) ppm.MS(ESI)m / z353.3(M+H) + .

[0169] [Example 15E] (R)-tert-butyl4-(6-aminopyridine-3-yl)-3-(methoxymethyl)piperazine-1-carboxylate To a suspension of Pd / C (10 wt%, 362 mg, 0.341 mmol) in ethyl acetate (36 mL), Example 15D (1.2 g, 3.41 mmol) was added. The reaction mixture was hydrogenated using a hydrogen balloon at ambient temperature for 16 hours. The reaction mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure to produce the crude title compound. 1 ¹H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 7.62 (d, J=2.63 Hz, 1 H), 7.21 (dd, J=8.76, 2.50 Hz, 1 H), 6.40 (d, J=8.76 Hz, 1 H), 5.51 (br s, 2 H), 3.39-3.69 (m, 3 H), 3.01-3.18 (m, 5 H), 2.72-2.94 (m, 2 H), 1.41 (s, 9 H) ppm.

[0170] [Example 15F] tert-butyl(R)-4-(6-((6-(4-((R)-1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide)ethyl)-3-methylphenyl)pyrimidine-4-yl)amino)pyridine-3-yl)-3-(methoxymethyl)piperazine-1-carboxylate To a solution of Example 1E (300 mg, 0.75 mmol) in 1,4-dioxane (5 mL), Example 15E (363 mg, 1.13 mmol), Pd2(dba)3 (CAS 52409-22-0, 69 mg, 0.075 mmol), XantPhos (CAS 161265-03-8, 43 mg, 0.075 mmol), and cesium carbonate (489 mg, 1.50 mmol) were added. The mixture was degassed using an argon stream and stirred at 100°C for 12 hours. The reaction mixture was cooled, diluted with ethyl acetate, filtered through diatomaceous earth, concentrated under reduced pressure, and purified by silica chromatography using ethyl acetate and petroleum ether to produce the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 10.02 (s, 1 H), 9.91 (d, J=7.89 Hz, 1 H), 8.70 (s, 1 H), 8.02 (br d, J=2.85 Hz, 1 H), 7.79 - 7.87 (m, 2 H), 7.65 - 7.74 (m, 1 H), 7.60 (d, J=8.55 Hz, 1 H), 7.46 (dd, J=9.21, 2.63 Hz, 1 H), 7.25 - 7.35 (m, 1 H), 5.24 - 5.39 (m, 1 H), 3.69 - 4.00 (m, 3 H), 3.24 - 3.33 (m, 2 H), 3.20 (br s, 5 H), 2.89 - 3.10 (m, 2 H), 2.47 (s, 3 H), 1.51 (d, J=6.80 Hz, 3 H), 1.42 (s, 9 H), 1.36 (s, 9 H) ppm.LC / MS(ESI+):m / z686.5(M+H) + .

[0171] [Example 15G] 3-(tert-butyl)-N-((R)-1-(4-(6-((5-((R)-2-(methoxymethyl)piperazine-1-yl)pyridine-2-yl)amino)pyrimidine-4-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide To a solution of Example 15F (450 mg, 0.66 mmol) in 1,4-dioxane (3 mL), the hydrochloride salt (4N in dioxane, 3 mL) was added dropwise at ambient temperature. The mixture was stirred for 1 hour and concentrated under reduced pressure to produce the crude title compound as the hydrochloride salt. 1 H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 9.97 (s, 1 H), 9.91 (br d, J=8.11 Hz, 1 H), 8.69 (s, 1 H), 7.95 - 8.00 (m, 1 H), 7.80 - 7.86 (m, 2 H), 7.55 - 7.70 (m, 2 H), 7.38 - 7.43 (m, 1 H), 7.27 - 7.34 (m, 1 H), 5.27 - 5.38 (m, 1 H), 3.67 - 3.81 (m, 2 H), 3.56 (s, 6 H), 3.51 - 3.61 (m, 1 H), 3.34 (s, 3 H), 3.14 - 3.20 (m, 3 H), 3.12 - 3.20 (m, 1 H), 2.92 - 3.05 (m, 1 H), 2.90 - 3.03 (m, 1 H), 2.78 - 2.86 (m, 1 H), 2.65 - 2.74 (m, 1 H), 2.47 (s, 3 H), 1.51 (br d, J=6.80 Hz, 3 H), 1.33 - 1.39 (m, 9 H) ppm.LC / MS(ESI+):m / z586.4(M+H) + .

[0172] [Example 15H] 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2R)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-(methoxymethyl)piperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide Example 15G (130 mg, 0.22 mmol), Example 1J (115 mg, 0.33 mmol), N,N-diisopropylethylamine (194 μL, 1.11 mmol), and sodium iodide (100 mg, 0.66 mmol) were mixed in acetonitrile (5 mL). The mixture was stirred at 80°C for 16 hours. The mixture was cooled, quenched with a few drops of formic acid, and the title compound was isolated by direct reverse-phase preparative HPLC (Phenomenex Luna® C18 column, 30 × 75 mm × 3 μm, mobile phase: water and 0.1% formic acid in acetonitrile). 1H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 10.33 (s, 1 H), 9.96 (s, 1 H), 9.88 (br d, J=7.65 Hz, 1 H), 8.70 (s, 1 H), 8.14 (s, 1 H), 8.00 (br d, J=2.38 Hz, 2 H), 7.76-7.91 (m, 2 H), 7.64-7.73 (m, 1 H), 7.60 (br d, J=8.66 Hz, 1 H), 7.44 (br dd, J=8.91, 2.64 Hz, 1 H), 7.18-7.31 (m, 4 H), 5.33 (quintet, J=7.09 Hz, 1 H), 3.85-3.96 (m, 1 H), 3.76 (t, J=6.65 Hz, 2 H), 3.51-3.68 (m, 1 H), 3.29 (br s, 1 H), 3.17 (s, 3 H), 2.85-3.08 (m, 3 H), 2.73-2.82 (m, 2 H), 2.69 (br t, J=6.65 Hz, 2 H), 2.51-2.63 (m, 3 H), 2.47 (s, 3 H), 2.17-2.34 (m, 2 H), 1.51 (br d, J=6.90 Hz, 3 H), 1.36 (s, 9 H) ppm.MS(ESI)m / z802.3(M+H) + .

[0173] [Example 16] 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-(trifluoromethyl)phenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide

[0174] [Example 16A] (S,E)-N-(4-bromo-2-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide A 500 mL flask was packed with 4-bromo-2-(trifluoromethyl)benzaldehyde (10.00 g, 39.5 mmol) and dichloromethane (100 mL). To the stirred mixture, (S)-2-methylpropane-2-sulfinamide (6.23 g, 51.4 mmol) was added, followed by titanium(IV) ethoxide (18.03 g, 79.0 mmol) at ambient temperature. The mixture was stirred at 30 °C for 12 hours and quenched with ethyl acetate (50 mL) and water (50 mL). The mixture was filtered to separate the organic phase. The aqueous phase was extracted with ethyl acetate (100 mL, 3 times), and the combined organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to produce the crude title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 8.89 (d, J=1.5 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.91 (d, J=1.3 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 1.31-1.21 (m, 9H) ppm.

[0175] [Example 16B] (S)-N-((R)-1-(4-bromo-2-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide A 250 mL flask was packed with anhydrous toluene (60 mL) and Example 16A (5.40 g, 15.16 mmol). The mixture was cooled to -5°C. CH3MgBr (3.0 M in tetrahydrofuran, 10.1 mL, 30.3 mmol) was added dropwise. The mixture was then stirred at 0°C for 3 hours, and the reaction was quenched by adding saturated aqueous NH4Cl solution (120 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (30 mL, 3 times). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica column chromatography using ethyl acetate and petroleum ether to produce the title compound. 1¹H NMR (400 MHz, dimethyl sulfoxide): δ ppm 7.92 (dd, J=8.50, 1.75 Hz, 1 H), 7.81 (d, J=1.88 Hz, 1 H), 7.74 (d, J=8.50 Hz, 1 H), 5.63 (d, J=4.50 Hz, 1 H), 4.69 (quintuplet, J=5.78 Hz, 1 H), 1.44 (d, J=6.63 Hz, 3 H), 1.06 (s, 9 H) ppm. MS(ESI) m / z 372.0, 374.0 (M+H) + .

[0176] [Example 16C] (S)-N-((R)-1-(2-trifluoromethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide To a solution of Example 16B (1.00 g, 2.69 mmol) in 1,4-dioxane (20 mL), bis(pinacolate)diborone (853 mg, 3.36 mmol) and potassium acetate (527 mg, 5.37 mmol) were added at 20°C. The reaction vessel was evacuated, refilled with nitrogen three times, and then 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (197 mg, 0.27 mmol) was added. The reaction vessel was evacuated and again refilled with nitrogen three times. The reaction mixture was heated to 80°C and stirred for 16 hours. The reaction mixture was cooled and filtered through a diatomaceous earth pad. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography by elution with petroleum ether and ethyl acetate to produce the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 7.93 (br d, J=6.58 Hz, 1 H), 7.71 - 7.89 (m, 2 H), 5.62 (br d, J=3.73 Hz, 1 H), 4.66 - 4.82 (m, 1 H), 1.45 (br d, J=6.14 Hz, 3 H), 1.30 (s, 9 H), 1.06 (br d, J=2.19 Hz, 12 H) ppm.MS(ESI)m / z420.2(M+H) + .

[0177] [Example 16D] (R)-1-(2-trifluoromethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethane-1-amine To a solution of Example 16C (900 mg, 2.15 mmol) in 1,4-dioxane (5 mL), hydrochloride (4N in 1,4-dioxane, 10 mL) was added dropwise at ambient temperature. The mixture was stirred for 1 hour and then concentrated under reduced pressure to produce the crude title compound as hydrochloride. 1 ¹H NMR (400 MHz, dimethyl sulfoxide-d6): 8.94 (br s, 3 H), 8.01 - 8.15 (m, 2 H), 7.93 (s, 1 H), 4.52 (br d, J=4.75 Hz, 1 H), 1.54 (d, J=6.63 Hz, 3 H), 1.31 (s, 12 H) ppm. MS (ESI) m / z 316.2 (M+H) + .

[0178] [Example 16E] (R)-3-(tert-butyl)-N-(1-(2-trifluoromethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide Triethylamine (622 mg, 6.14 mmol) was added at 20°C to a solution of Example 16D (360 mg, 1.02 mmol) and methyl 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate (471 mg, 2.56 mmol) in ethanol (8 mL). The mixture was stirred at 60°C for 16 hours, and then concentrated under reduced pressure to remove the ethanol. The crude substance was purified by column chromatography of silica gel eluted with petroleum ether and ethyl acetate to produce the title compound. 1 ¹H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 10.04 (d, J=7.23 Hz, 1 H), 7.93 - 8.00 (m, 1 H), 7.84 - 7.92 (m, 2 H), 5.40 (quintuplet, J=6.91 Hz, 1 H), 1.49 (d, J=6.80 Hz, 3 H), 1.36 (s, 9 H), 1.30 (s, 12 H) ppm.MS(ESI)m / z468.2(M+H) + .

[0179] [Example 16F] (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidine-4-yl)-2-(trifluoromethyl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide A mixture of Example 16E (230 mg, 0.49 mmol) and 4,6-dichloropyrimidine (147 mg, 0.98 mmol) in tetrahydrofuran (10 mL) was added to potassium phosphate (209 mg, 0.98 mmol) in water (2.5 mL) and a solution of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (22 mg, 0.03 mmol). The mixture was degassed at ambient temperature using a nitrogen stream and stirred at 80°C for 2 hours under a nitrogen atmosphere. The mixture was cooled, poured into water, and extracted with ethyl acetate (three times). The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica column chromatography eluting with ethyl acetate in hexane to obtain the crude title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 10.10 (br d, J=7.23 Hz, 1 H), 9.14 (s, 1 H), 8.52 - 8.59 (m, 2 H), 8.49 (s, 1 H), 8.06 (d, J=8.11 Hz, 1 H), 5.45 (br t, J=6.91 Hz, 1 H), 1.55 (d, J=6.80 Hz, 3 H), 1.37 (d, J=1.32 Hz, 9 H) ppm.MS(ESI)m / z454.1(M+H) + .

[0180] [Example 16G] tert-butyl(S)-4-(6-((6-(4-((R)-1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide)ethyl)-3-(trifluoromethyl)phenyl)pyrimidine-4-yl)amino)pyridine-3-yl)-3-methylpiperazine-1-carboxylate To a solution of Example 16F (170 mg, 0.38 mmol) in 1,4-dioxane (4 mL), Example 1 L (138 mg, 0.45 mmol), Pd2(dba)3 (CAS 52409-22-0, 21 mg, 0.022 mmol), XantPhos (CAS 161265-03-8, 22 mg, 0.037 mmol), and cesium carbonate (244 mg, 0.75 mmol) were added. The mixture was degassed using a nitrogen stream and stirred at 100°C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled, diluted with ethyl acetate, and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by silica chromatography using ethyl acetate and petroleum ether to produce the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 10.24 (br s, 1 H), 10.10 (d, J=7.23 Hz, 1 H), 8.78 (s, 1 H), 8.34 (s, 1 H), 8.29 (br d, J=8.33 Hz, 1 H), 7.99 - 8.07 (m, 2 H), 7.67 - 7.78 (m, 1 H), 7.49 (br dd, J=8.99, 2.41 Hz, 1 H), 7.25 - 7.35 (m, 1 H), 5.45 (br t, J=7.13 Hz, 1 H), 3.77 - 3.92 (m, 2 H), 3.56 - 3.69 (m, 1 H), 3.26 - 3.37 (m, 1 H), 3.19 (br d, J=11.18 Hz, 2 H), 2.91 - 3.01 (m, 1 H), 1.56 (br d, J=6.80 Hz, 3 H), 1.42 (s, 9 H), 1.37 (s, 9 H), 0.89 (d, J=6.58 Hz, 3 H) ppm.LC / MS(ESI+):m / z710.4(M+H) + .

[0181] [Example 16H] 3-(tert-butyl)-N-((R)-1-(2-trifluoromethyl-4-(6-((5-((S)-2-methylpiperazine-1-yl)pyridine-2-yl)amino)pyrimidine-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide In Example 1, 100 mg (0.14 mmol) of the compound was dissolved in 20 mL of methanol, to which the hydrochloride salt (4N in methanol, 20 mL) was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to produce the crude title compound as the hydrochloride salt. 1H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 9.99 - 10.17 (m, 2 H), 8.75 (s, 1 H), 8.35 (s, 1 H), 8.28 (br d, J=8.25 Hz, 1 H), 7.93 - 8.18 (m, 3 H), 7.65 - 7.78 (m, 1 H), 7.41 (dd, J=9.13, 2.75 Hz, 1 H), 7.22 - 7.35 (m, 1 H), 5.45 (quintet, J=6.69 Hz, 1 H), 3.68 - 3.78 (m, 1 H), 3.18 - 3.35 (m, 1 H), 3.01 - 3.12 (m, 1 H), 2.81 - 2.98 (m, 3 H), 2.66 - 2.77 (m, 2 H), 1.55 (br d, J=6.88 Hz, 3 H), 1.37 (s, 9 H), 0.96 (d, J=6.38 Hz, 3 H) ppm.LC / MS(ESI+):m / z610.3(M+H) + .

[0182] [Example 16I] 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-(trifluoromethyl)phenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide To a solution of Example 16H (63 mg, 0.11 mmol) in acetonitrile (2 mL), Example 1J (56 mg, 0.16 mmol), sodium iodide (65 mg, 0.43 mmol), and N,N-diisopropylethylamine (56 μL, 0.32 mmol) were added. The mixture was stirred at 80°C for 16 hours. The mixture was cooled to ambient temperature, filtered, and the title compound was isolated by direct reverse-phase preparative HPLC (Waters® Xbridge C18 column, 30 × 100 mm × 10 μm, mobile phase: water and 10 mM ammonium bicarbonate in acetonitrile). 1H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 10.34 (br s, 1 H), 10.10 (s, 2 H), 8.75 (s, 1 H), 8.35 (s, 1 H), 8.28 (br d, J=8.25 Hz, 1 H), 8.10 (br s, 1 H), 8.02 (br d, J=10.38 Hz, 2 H), 7.72 (br s, 1 H), 7.39 - 7.54 (m, 1 H), 7.17 - 7.33 (m, 4 H), 5.45 (br d, J=5.88 Hz, 1 H), 3.88 (br d, J=5.13 Hz, 1 H), 3.76 (br t, J=6.57 Hz, 2 H), 3.22 (br d, J=11.88 Hz, 1 H), 2.99 (br t, J=9.38 Hz, 1 H), 2.86 (br d, J=10.76 Hz, 1 H), 2.78 (br t, J=7.32 Hz, 2 H), 2.66 - 2.73 (m, 4 H), 2.44 (br d, J=11.63 Hz, 2 H), 2.31 (br d, J=11.63 Hz, 1 H), 1.56 (br d, J=6.75 Hz, 3 H), 1.37 (s, 9 H), 0.99 (br d, J=6.25 Hz, 3H) ppm.MS(ESI)m / z826.4(M+H) + .

[0183] [Example 17] 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-fluorophenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide

[0184] [Example 17A] (S,E)-N-(4-bromo-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide A 1 L reactor was packed at ambient temperature with triisopropyl borate (243 g, 1.29 mol), 4-bromo-2-fluorobenzaldehyde (250 g, 1.23 mol), and (S)-2-methylpropane-2-sulfinamide (179 g, 1.48 mol). The mixture was stirred at 70°C for 12 hours. Water (500 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (500 mL x 3). The combined organic phase was washed with brine (1.0 L), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to produce the title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 8.82 (s, 1H), 7.81-8.92 (m, 1H), 7.30-7.47 (m, 2H), 1.26 (s, 9H) ppm.

[0185] [Example 17B] (S)-N-((R)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide A 5 L reactor was packed with anhydrous dichloromethane (3.0 L) and Example 16A (150 g, 0.49 mol). The mixture was cooled to 0°C. CH3MgBr (3.0 M in tetrahydrofuran, 245 mL, 0.73 mol) was added dropwise. The mixture was left to stand, then heated to ambient temperature and stirred for 12 hours. Then, saturated NH4Cl aqueous solution (1.0 L) was added to quench the reaction. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (1.0 L, 3 times). The combined organic layers were washed with brine (2.0 L), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to produce the crude title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 7.21-7.28 (m, 3H), 4.73-4.90 (m, 1H), 3.33 (d, J=4.03 Hz, 1H), 1.56 (d, J=6.85 Hz, 3H), 1.20 (s, 9H) ppm.

[0186] [Example 17C] (R)-1-(4-bromo-2-fluorophenyl)ethane-1-amine A 1 L reactor was filled with Example 17B (87.0 g, 0.27 mol) and methanol (870 mL). To the stirred solution at 0°C, hydrochloride (4N in methanol, 435 mL, 1.74 mol) was added. The reaction mixture was stirred at 0°C for 2 hours and concentrated under reduced pressure until dry to produce the crude title compound as hydrochloride. 1 ¹H NMR (400 MHz, dimethyl sulfoxide-d6): δ ppm 8.80 (s, 3H), 7.59-7.76 (m, 2H), 7.53 (dd, J=8.38, 1.41 Hz, 1H), 4.41-4.63 (m, 1H), 1.44-1.57 (m, 3H) ppm.

[0187] [Example 17D] tert-butyl(R)-(1-(4-bromo-2-fluorophenyl)ethyl)carbamate A 3 L reactor was filled with Example 17C (65.0 g, 0.30 mol), tetrahydrofuran (650 mL), and water (650 mL). Sodium hydroxide (35.8 g, 0.89 mol) and di-tert-butyl decarbonate (78.1 g, 0.36 mol) were added to the stirred solution at 0°C. The reaction was allowed to stand, then heated to ambient temperature and stirred for 2 hours. The mixture was diluted with water (1.0 L) and extracted with ethyl acetate (1.0 L, 3 times). The combined organic layers were washed with brine (2.0 L), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica column chromatography using ethyl acetate and petroleum to produce the title compound. 1 H NMR (400 MHz, CD3OD): δ ppm 7.18-7.39 (m, 3H), 4.88-4.95 (m, 1H), 1.28-1.49 (m, 12H) ppm.

[0188] [Example 17E] tert-butyl(R)-(1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate To a solution of Example 17D (76.0 g, 0.24 mol) in 1,4-dioxane (760 mL), bis(pinacolate)diborone (72.8 g, 0.29 mol) and potassium acetate (46.9 g, 0.48 mol) were added at 20°C. The reaction vessel was evacuated, refilled with nitrogen three times, and then 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (17.5 g, 0.02 mol) was added. The reaction vessel was evacuated and again refilled with nitrogen three times. The reaction mixture was heated to 100°C and stirred under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled and filtered through a diatomaceous earth pad. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography by elution with petroleum ether and ethyl acetate to produce the title compound. 1 H NMR (400 MHz, CDCl3): δ ppm 7.54 (d, J = 7.50 Hz, 1H), 7.45 (d, J = 11.03 Hz, 1H), 7.28 - 7.32 (m, 1H), 4.99 (s, 2H), 1.42 (s, 12H), 1.34 (s, 12H) ppm.

[0189] [Example 17F] (R)-1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethane-1-amine To a solution of Example 17E (1030 mg, 2.15 mmol) in dichloromethane (20 mL), hydrochloride (4N in 1,4-dioxane, 14 mL) was added dropwise at ambient temperature. The mixture was stirred for 3 hours and concentrated under reduced pressure to produce the crude title compound as hydrochloride. 1 ¹H NMR (400 MHz, dimethyl sulfoxide-d6): 8.68 (br s, 3H), 7.64-7.72 (m, 1H), 7.56 (d, J=7.58 Hz, 1H), 7.40 (d, J=10.64, 1H), 4.62 (br s, 1H), 1.52 (d, J=6.85 Hz, 3H), 1.31 (s, 12H) ppm. MS (ESI) m / z 249.2 (M+H) + .

[0190] [Example 17G] (R)-3-(tert-butyl)-N-(1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide To a solution of Example 17F (850 mg, 2.82 mmol) and methyl 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate (779 mg, 4.23 mmol) in 2-methyltetrahydrofuran (10 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.28 mL, 8.46 mmol) was added at ambient temperature. The mixture was stirred for 2 hours and then diluted with ethyl acetate (50 mL) and brine (20 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (20 mL). The combined organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography of silica gel eluted with hexane and ethyl acetate to produce the title compound. 1 ¹H NMR (400 MHz, dimethyl sulfoxide-d6): 9.95 (d, J=7.70 Hz, 1H), 7.49-7.63 (m, 2H), 7.39 (d, J=10.64 Hz, 1H), 5.42 (t, J=7.27 Hz, 1H), 1.56 (d, J=6.97 Hz, 3H), 1.42 (s, 9H), 1.35 (s, 12H) ppm. MS(ESI) m / z 418.2(M+H) + .

[0191] [Example 17H] (R)-3-(tert-butyl)-N-(1-(4-(6-chloropyrimidine-4-yl)-2-fluorophenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide A mixture of Example 17G (762 mg, 1.83 mmol) and 4,6-dichloropyrimidine (326 mg, 2.19 mmol) in 1,4-dioxane (7.3 mL) was added to water (2 mL) of potassium phosphate (775 mg, 3.65 mmol) and a solution of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (149 mg, 0.18 mmol). The mixture was degassed at ambient temperature using a nitrogen stream and stirred at 85°C for 20 minutes under a nitrogen atmosphere. The mixture was cooled, poured into water, and extracted with ethyl acetate (three times). The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica column chromatography eluting with ethyl acetate in hexane to obtain the crude title compound. MS(ESI)m / z404.1(M+H) + .

[0192] [Example 17I] tert-butyl(S)-4-(6-((6-(4-((R)-1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide)ethyl)-3-fluorophenyl)pyrimidine-4-yl)amino)pyridine-3-yl)-3-methylpiperazine-1-carboxylate To a solution of 1,4-dioxane (10 mL) containing 7 G (268 mg, 0.66 mmol) of Example 17, 1 L (349 mg, 1.20 mmol), racemic BINAP-Pd-G3 (CAS2151915-22-7, 66 mg, 0.066 mmol), and cesium carbonate (649 mg, 1.99 mmol) were added. The mixture was heated at 75°C for 40 minutes under a nitrogen atmosphere. The mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica chromatography using ethyl acetate and hexane to isolate the title compound. LC / MS (ESI+): m / z 660.4 (M+H) + .

[0193] [Example 17J] 3-(tert-butyl)-N-((R)-1-(2-fluoro-4-(6-((5-((S)-2-methylpiperazine-1-yl)pyridine-2-yl)amino)pyrimidine-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide To a solution of Example 17I (346 mg, 0.52 mmol) in dichloromethane (10 mL), hydrochloride (4N in 1,4-dioxane, 6.6 mL) was added. The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by silica column chromatography using dichloromethane and methanol (with 7N ammonia added to methanol) to produce the title compound. LC / MS (ESI+): m / z 560.3 (M+H) + .

[0194] [Example 17K] 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-fluorophenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide To a solution of Example 17J (80 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL), Example 1J (56 mg, 0.16 mmol), potassium iodide (119 mg, 0.72 mmol), and N,N-diisopropylethylamine (50 μL, 0.29 mmol) were added. The mixture was stirred at 80°C for 2 hours. After cooling to ambient temperature, it was filtered, and the filtrate was directly subjected to reverse-phase preparative HPLC to isolate the title compound (Phenomenex Gemini® NX C18 column, 30 × 250 mm × 5 μm, mobile phase: water and 0.1% ammonium hydroxide in acetonitrile). 1H NMR (500 MHz, dimethyl sulfoxide-d6): δ ppm 10.30 (s, 1H), 9.98 (s, 1H), 9.86 (d, J = 7.8 Hz, 1H), 8.66 (s, 1H), 8.00 (s, 1H), 7.94 (d, J = 2.9 Hz, 1H), 7.78 (dd, J = 8.1, 1.7 Hz, 1H), 7.71 (dd, J = 11.5, 1.7 Hz, 1H), 7.66 - 7.57 (m, 2H), 7.37 (dd, J = 9.3, 2.9 Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 5.34 (p, J = 7.2 Hz, 1H), 3.80 (s, 1H), 3.69 (t, J = 6.7 Hz, 2H), 3.15 (d, J = 11.3 Hz, 1H), 2.93 (dd, J = 10.6 Hz, 1H), 2.79 (d, J = 10.4 Hz, 1H), 2.71 (dd, J = 7.7, 7.7 Hz, 2H), 2.66 - 2.59 (m, 2H), 2.55 - 2.42 (m, 2H), 2.38 (d, J = 10.9 Hz, 1H), 2.31 - 2.20 (m, 2H), 1.49 (d, J = 7.0 Hz, 3H), 1.30 (s, 9H), 0.93 (d, J = 6.3 Hz, 3H) ppm.MS(ESI)m / z776.4(M+H) + .

[0195] Summary BTK screening Btk kinase activity was measured in vitro using electrophoretic mobility shift analysis (MSA). The ability of Btk to phosphorylate the fluorescent peptide substrate (FAM-GEEPLYWSFPAKKK-NH2) was assessed. The kinase reaction was assembled in a total volume of 25 μL per well in a 384-well plate. Each well was filled with the following: compound buffer (or control), enzyme buffer, and substrate buffer, as further described below.

[0196] In particular, the following were added: (1) Compound buffer or control: 5 μL of 5× compound buffer [(1× main buffer, X μM test compound of 5% dimethyl sulfoxide; 2X main buffer consisting of 200 mM HEPES, pH 7.5, 0.2% BSA and 0.02% Triton X-100)]; and (2) Enzyme buffer: 10 μL of 2.5× enzyme buffer (1× main buffer, 12.5 mM MgCl2, 2.5 mM DTT, 25 μM sodium orthovanadate, 25 μM β-glycerophosphate and 1.25 nM BTK enzyme). (Human BTK enzyme Nanosyn-293HEK, wild type, available from Nanosyn, Santa Clara, CA). The enzyme and compound were pre-incubated for 15 minutes. Furthermore, the following was added: (3) Substrate buffer: 10 μL of 2.5 × substrate buffer (1 × main buffer, 50 μM ATP and 2.5 μM peptide substrate FAM). Each plate was incubated at 25°C for 3 hours. The reaction was stopped by adding 45 μL of 1.55 × stop buffer (1 × main buffer and 31 mM EDTA) to each well. The final reaction mixture was as follows: 100 mM HEPES, pH 7.5; 0.1% BSA; 0.01% Triton X-100; 1 mM DTT; 5 mM MgCl2; 10 μM sodium orthovanadate; 10 μM β-glycerophosphate; 50 μM ATP; 1% dimethyl sulfoxide (obtained from the compound); 1 μM fluorescent peptide substrate and 0.5 nM BTK-enzyme.

[0197] The stalled reaction was analyzed using a 12-channel LABCHIP® 3000 microfluidic detector (available from Caliper Life Sciences, Waltham, MA). Enzymatic phosphorylation of the peptide altered its effective charge, enabling electrophoretic separation of the product from the substrate peptide. Since the substrate and product peptides were separated, two fluorescence peaks were observed. The change in the relative fluorescence intensity of the substrate and product peaks was a measured parameter reflecting enzyme activity. The ratio between the product and substrate was changed in the presence of the active compound. The product signal decreased, and the substrate signal increased. Capillary electrophoresis maps (RDA acquisition files) were analyzed using HTS Well Analyzer software (available from Caliper Life Sciences, Waltham, MA).

[0198] The activity in each sample was determined as the product-to-total ratio (PSR): P / (S+P) [where P is the peak height of the product peptide and S is the peak height of the substrate peptide]. For each compound, enzyme activity was measured at various concentrations (12 different concentrations of the compound, spaced apart by a 3x dilution interval). Negative control samples (0% inhibition in the absence of the active compound) and positive control samples (100% inhibition in the presence of 20 mM EDTA) were assembled in a 4-cylinder configuration and used to calculate the inhibition percentage for each active compound at each concentration. The inhibition percentage (Pinh) was determined using the following equation: Pinh = (PSR0% - PSRinh) / (PSR0% - PSR100%) * 100 [wherein PSRinh is the total product ratio in the presence of the inhibitor, PSR0% is the average total product ratio in the absence of the active compound, and PSR100% is 100% - the average total product ratio in the inhibitory control sample].

[0199] IC of active compounds 50 The values ​​were determined using XLfit® 4 software (IDBS, Boston, MA) by fitting a four-parameter S-shaped dose-response model of the inhibition curve (Pinh vs. inhibitor concentration). IC 50The value is BTK IC 50 The (nM) column is reported in Table 2.

[0200] Cereblon binding assay Cereblon binding was measured in vitro using the AlphaLISA® Human Cereblon Binding Kit (PerkinElmer, Waltham, MA) according to the manufacturer's protocol ("Alpha" refers to the amplified emission proximity homogeneity assay). In this assay, donor beads and acceptor beads are brought into proximity by ligand binding to the CRBN protein. Excitation of the donor beads stimulates the release of singlet oxygen, which triggers a cascade of energy transfer reactions to the acceptor beads, resulting in a sharp peak in light emission at 615 nm.

[0201] Specifically, nickel chelate acceptor beads (PerkinElmer AL108M) were used to capture 6×HIS-tagged CRBN protein, and streptavidin-coated donor beads (PerkinElmer 6760002) were used to capture 50 nM biotinylated ligands. Each well contained: sample or control; HIS-tagged CRBN protein; biotinylated ligand; nickel chelate acceptor beads; and streptavidin donor beads.

[0202] Antagonism Experiment: The test compound in 100% dimethyl sulfoxide was seeded onto a small amount of white, 384-well plate (PerkinElmer Proxiplate 384 plus #6008289) using a Labcyte Echo acoustic dispenser in an 11-point dose curve and a 3-fold dilution scheme. This was followed by the addition of 10 μL of an assay mixture containing a His-tagged cereblon / DDB1 complex and a 50 μM biotin-labeled ligand in buffer (buffer: 10 mM HEPES pH 7.4, 150 mM NaCl, 0.05% Tween-20, and 10 mM DTT) to a maximum dose of 10 μM (starting concentration) and a final concentration of 0.1% DMSO. The plate was incubated at room temperature for 30 minutes.

[0203] Detection: 10 μL of detection reagent was added under low-light conditions to a plate containing nickel chelate acceptor beads and streptavidin donor beads (Perkin Elmer 6760002), resulting in a final concentration of 20 μg / ml. The plate was incubated for 1 hour and read using a PerkinElmer® Envision® plate reader (680 nm excitation and 570 nM emission setting). IC of each compound was measured. 50 The K of each compound was determined by calculating the inhibition percentage from drug-free and protein-free controls. i This was calculated using the Chain-Soft Lance Formation. i From, 50 The value was determined. IC 50 The value is CRBN IC 50 The (nM) column is reported in Table 2.

[0204] Bik protein in human whole blood MSD ELISA-based assays Btk proteolysis was tested using a mesoscale discovery-ELISA system (MSD-ELISA): (1) the test compound was added to human whole blood; (2) human whole blood cells treated with the test compound were lysed; (3) the lysed cells were treated with a capture antibody and an antibody against Btk; (4) the lysed cells were treated with an anti-mouse primary antibody against Btk; and (5) the lysed cells were treated with a (tagged) anti-mouse antibody.

[0205] Specifically, approximately 80 μL of fresh human whole blood obtained from a healthy donor was transferred to each well of a 96-well V-bottom plate (Costar, catalog number 3894). Using a TECAN® D300e Digital Dispenser (Tecan), the compound was added twice in a 1:4 serial dilution [in DMSO solution (final 0.2%) starting at a maximum concentration of 3 μM (8-point assay)]. The plate was then placed in a 37°C incubator and incubated for 6 hours.

[0206] At the end of incubation, 80 μL of 2X CST lysis buffer (Cell Signaling Technology, catalog number 9803), prepared from 10× stock solution, was added to each well to dissolve the blood. The plate was then sealed with a plate sealer, and the samples were frozen overnight at -80°C.

[0207] The total amount of Btk protein remaining in blood samples after compound treatment was measured using MSD-ELISA. After thawing the frozen plates, the blood lysates were thoroughly mixed and transferred to small spot-binding MSD plates (mesoscale discovery, catalog number L45XB-3), which were then coated with the supplementing antibody, rabbit anti-human BTK (D3H5) (Cell Signaling Technology, catalog number 8547CF). Subsequently, the primary detection antibody, mouse anti-human BTK monoclonal antibody (BD Biosciences, catalog number 611117), and the secondary detection antibody, anti-mouse SULFO-TAG (mesoscale discovery, catalog number R32AC-1) were added. The assay plates were read using an MSD S600 plate reader by adding 2× MSD reading buffer (mesoscale discovery, R92TC-1). All reagent transfers, including hemolysis, were performed using a Biomed i7 liquid handler. From the dose-response curve, DC 50 The values ​​were calculated by averaging data obtained from overlapping experiments, and curve fitting was performed using nonlinear regression with GraphPad Prism. DC 50 The value is hWB BTK DC 50 (nM) is reported in Table 2. max The value represents the maximum amount of BTK degradation observed during compound treatment, compared to samples treated with DMSO alone. The dMax(%) value is reported in Table 2 in the hWB BTK dMax(%) column.

[0208] Mouse bone marrow assay Female C57BL / 6J mice (Jackson Laboratories) were used in this study. Compounds or vehicle / controls were prepared using EtOH;PEG-400;Phosal 53 MCT (10:30:60, v / v). Four mice were tested for each compound or vehicle / control. On day 1, the mice were administered a single dose of dose A. On day 2 (24 hours later), tissue (bone marrow) was collected from one hind limb per mouse.

[0209] BTK degradation in mouse bone marrow was determined using an assay based on MSD (mesoscale discovery) ELISA (enzyme-linked immunosorbent assay). The following materials and equipment were used: 10% NP40 solution (nonionic polyoxyethylene surfactant, ThermoFisher, catalog number 28324); protease inhibitor mini tablets (Roche, catalog number 05 892 970 001); PhosphoSTOP® tablets (Roche, catalog number 04 906 837 001); Pierce® BCA protein assay kit (ThermoFisher, catalog number 23225); Precellys® 2mL dissolution tube with 2.8mm beads (VWR, catalog number 10032-756); Bertin Precellys® 24 / Cryolys® cooling system; 96-well MSD streptavidin precoated plate (MSD, catalog number L15SA-1); MSD Blocker A (MSD, catalog number R93BA-4); capture antibody, biotinylated BTK mAb (BD Biosciences, catalog number 624008; custom order); primary detection antibody, BTK RpAb (rabbit polyclonal antibody, CST, catalog number 8547S, D3H5 clone); secondary detection antibody, anti-rabbit-Sulfo-Tag (MSD, catalog number R32AB-1); read buffer, 4× (MSD, catalog number R92TC-1); recombinant Btk protein (ThermoFisher, catalog number PR5442A); MSD Tris wash buffer (10×) (MSD, catalog number R61TX-1); PBS (phosphate buffered saline); deionized water (diH2O); lysis buffer [0.2% NP40 + protease inhibitor tablet (1 tablet / 10mL) + PhosphoSTOP tablet (1 tablet / 10mL) in PBS]; 3% MSD Blocker A [MSD Blocker A + 450mL diH2O + 50mL]; and 10× MSD Tris wash buffer.

[0210] procedure Sample processing for PD assays Mouse bone marrow lysate preparation A lysis buffer [(PBS + 0.2% NP40 + PI (protease inhibitor) + PhosphoSTOP)] was prepared and placed on ice until completely cooled. 300 μL of ice-cold lysis buffer was added to each Precellys® tube containing the beads and bone marrow samples. The sample tubes were transferred to a Precellys® machine and homogenized at 5000 rpm - 2 × 20 seconds. After homogenization, the sample lysates were centrifuged at 14,000 rpm for 20 minutes at 4°C.

[0211] Protein Prediction (BCA) Protein concentrations were determined using the Pierce® BCA protein assay kit according to the manufacturer's recommended protocol. Protein normalization standard solutions were prepared using 30 μg of protein per sample lysate for the assay.

[0212] Preparation of standard curve samples A 300 ng / ml standard stock solution of recombinant Btk protein was prepared in lysis buffer, and the sample was serially diluted 3-fold (10-point assay; the highest concentration was 300 ng / mL, and the lowest concentration was 0.015 ng / mL).

[0213] Performing an MSD assay Day 1 MSD plate coating: The stock solution of coating antibody (biotinylated BTK mAb) was prepared in PBS buffer at a concentration of 1 μg / mL. 50 μL of capture antibody (biotinylated BTK mAb) solution was added per well, and the plate was gently shaken at ambient temperature for 2 hours. The plate was washed three times with 1× MSD Tris wash buffer in a plate washer (300 μL per well), and the plate was blocked with 3% MSD Blocker A (150 μL per well). The plate was incubated at ambient temperature for a further 1-2 hours with gentle shaking. The plate was washed three times with 1× MSD wash buffer using a plate washer. 50 μL of bone marrow lysate (30 μg) per well was added to the plate. Serially diluted standard samples were added to the same plate with a final volume of 50 μL per well. The plate was incubated overnight at 4°C with gentle shaking.

[0214] Day 2 The plate was washed three times using a plate washer with 1x MSD wash buffer (prepared from 10x concentration buffer). 50 μL of primary detection antibody was added per well (BTK RpAb; 1:1000 dilution in 1% MSD Blocker A). The plate was incubated at ambient temperature for 2 hours with gentle shaking. The plate was washed three times using a plate washer with 1x MSD wash buffer. Anti-rabbit-SULFO-TAG secondary antibody (50 μL per well) was added, diluted 1:500 in 1% MSD Blocker A, and the plate was incubated at ambient temperature for 1-2 hours. The plate was washed three times using a plate wash with 1x MSD Tris wash buffer. MSD reading buffer (150 μL) (1x) was added, and the plate was read using an MSD machine. A standard curve was generated, and the residual BTK% in the vehicle-treated sample was calculated using the absolute BTK amount. The residual BTK% in the sample is reported in Table 2.

[0215] The assay results for Examples 1-19 are shown in Table 2 in the "Mouse Bone Marrow (%) Column".

[0216] [Table 3]

[0217] Development of tumor cells Eμ-TCL1 CLL transgenic mice (Crogen Pharmaceuticals LLC) C481S Crossbreeding with a knock-in mouse (AbbVie) to produce BTK C481S We generated Eμ-TCL1 transgenic mice that carry the mutation. These BTK C481S When leukemic spleen cells derived from Eμ-TCL1 transgenic mice (first passage cells) were intravenously transplanted into C57BL / 6 mice, CLL development occurred in the peripheral blood and spleen. When the circulating CLL load (CD5+CD19+ cells, as described below) in the recipient mice reached 90%, those spleen cells (second passage cells) containing high CLL load were cryopreserved and used for CLL efficacy testing.

[0218] Livestock The mouse tumor efficacy study was conducted at a vivarium in Southern San Francisco, California, in accordance with the AbbVie Animal Experimentation Committee and the National Institutes of Health's Guide for Care and Use of Laboratory Animals guidelines. C57BL / 6 mice were obtained from Jackson Laboratories and housed in groups of five per cage on a 14-hour light:10-hour dark schedule.

[0219] Tumor transplantation and animal therapy Second-passage Eμ-TCL1 BTK containing high CLL load C481S Splenocytes were thawed, washed, and filtered through a 70-μM strainer in cold Hanks equilibrium salt solution (HBSS). 10 × 10 in 0.2 mL of HBSS 6 Splenocytes were intravenously injected into the tail vein of 8-10 week old female C57BL / 6 mice to induce CLL.

[0220] To determine the absolute / total white blood cell count, the total blood cell count was determined for each mouse using a Genesis® animal blood analyzer (Oxford Science Inc.).

[0221] Flow cytometry Cells isolated from mouse peripheral blood mononuclear cells (PMBCs) were collected, and antigen expression was determined. PMBCs were stained with antibodies specific to mouse CD5, CD19, and CD45 (cells expressing CD5+CD19+ are frequently present in mouse B-cell leukemia, and CLL cells are considered). Cells were gated with CD45+, and then the percentage of CD5+CD19+ cells obtained from the subset was calculated. Flow cytometry was performed using a BD LSRFortessa®X-20 Cell Analyzer (BD Biosciences).

[0222] Whole blood was collected weekly via submandibular cheek bleeding after tumor transplantation. Circulating leukemia burden was calculated as absolute white blood cell count / total white blood cell count, and immunophenotype CD19. + CD5 + The value was calculated by multiplying by the percentage of white blood cells that possessed the specified characteristic.

[0223] The procedure began 9 days after vaccination, and mice were weighed and allowed to lose blood, with N=10 (mean circulating CD19). + CD5 + Participants were randomized into five groups with a CLL cell count of 1,525 / μL. Compound 1 (Example 1) was compounded at different concentrations in a vehicle containing 10% ethanol, 30% PEG-400, and 60% Phosal-50 MCT.

[0224] Two days after randomization of CLL numbers, mice were treated once daily (QD) for the next 19 days. Group 1: vehicle; Group 2: compound 1 dose 1; Group 3: compound 1 dose 2; Group 4: compound 1 dose 3; Group 5: compound 1 dose 4.

[0225] As shown in Figure 1, Compound 1 (Example 1) produced a dose-dependent BTK in C57BL / 6 mice. C481S The circulating leukemia burden in TCL1-driven CLL with mutations was controlled. The y-axis shows the number of CLL cells (CD19+CD5+) per 1 μL of mouse PMBC. Complete CLL burden control (i.e., no increase from the initial tumor burden) was achieved with compound 1 at doses 3 and 4.

[0226] All publications and patents cited herein are incorporated herein by reference in whole, as if each individual publication or patent were specifically and individually incorporated by reference.

[0227] It should be understood that the above-mentioned detailed descriptions and attached examples are merely illustrative and should not be construed as limiting the scope of this disclosure as defined by the attached claims and their equivalents.

Claims

1. Compound of formula (I): 【Chemistry 1】 [In the formula, R １ is selected from the group consisting of hydrogen, C １ to C ３ alkyl, CN, C １ to C ３ haloalkyl, halo, CH ２ OCH ３ , CH ２ OH and CH ２ CN; R ２ and R ３ These are independently selected from the group consisting of hydrogen and halos; R ４ａ and R ４ｂ is hydrogen, C １ ~C ３ Alkyl and CH ２ OCH ３ Each of the groups consisting of these is independently selected; R ５ These are hydrogen, halo, and C １ ~C ３ Selected from the group consisting of alkyl groups; Or a pharmaceutically acceptable salt thereof.

2. R ４ａ However, H is R ４ｂ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is methyl.

3. R １ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is methyl.

4. R ２ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

5. R ３ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

6. R ５ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen. 【Request Item 7】 【Chemistry 2】 A compound that is, or a pharmaceutically acceptable salt thereof. 【Request Item 8】 【Chemistry 3】 A compound that is a pharmaceutically acceptable salt of [a certain substance]. 【Request Item 9】 【Chemistry 4】 A compound that is

10. 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2R)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-{(1R)-1-[4-(6-{[5-(4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}piperazine-1-yl)pyridine-2-yl]amino}pyrimidine-4-yl)-2-methylphenyl]ethyl}-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)-3-fluorophenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2R)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)-3-fluorophenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-ethylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)-3-fluorophenyl]ethyl}-2-ethylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2R)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-ethylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-{(1R)-1-[4-(6-{[5-(4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2,2-dimethylpiperazine-1-yl)pyridine-2-yl]amino}pyrimidine-4-yl)-2-methylphenyl]ethyl}-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-3-fluoro-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-{(1R)-1-[4-(6-{[5-(4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}piperazine-1-yl)pyridine-2-yl]amino}pyrimidine-4-yl)-3-fluoro-2-methylphenyl]ethyl}-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-{(1R)-1-[4-(6-{[5-(4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}piperazine-1-yl)pyridine-2-yl]amino}pyrimidine-4-yl)-5-fluoro-2-methylphenyl]ethyl}-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-(propan-2-yl)piperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-[(1R)-1-{2-chloro-4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]phenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2R)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-(methoxymethyl)piperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-(trifluoromethyl)phenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; and A compound according to claim 1, selected from the group consisting of 3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diadinane-1-yl)phenyl]ethyl}-2-methylpiperazine-1-yl]pyridine-2-yl}amino)pyrimidine-4-yl]-2-fluorophenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide, or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising, in combination with a pharmaceutically acceptable carrier, a therapeutically effective amount of the compound according to claim 1 of formula (I), or a pharmaceutically acceptable salt thereof.

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